bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible Respiratory Modulation of Sympathetic Activity in Rats After Sino‐aortic Denervation
Authors: Amorim Mateus R , Bonagamba Leni G. H. , Souza George M. P. R. , Moraes Davi J. A. , Machado Benedito H. 
Published: November 2023

It is well known that several days after sino‐aortic denervation (SAD) rats present normal levels of sympathetic activity and mean arterial pressure (MAP). However, the mechanisms involved in the modulation of the sympathetic activity after SAD remain unclear. Here we hypothesized that the respiratory network may contribute to the modulation of the pre‐sympathetic neurons preventing sustained increase in MAP in SAD rats. To study this mechanism we recorded the activities of phrenic, thoracic sympathetic (tSNA) and cervical vagus nerves (cVN) in male juvenile Wistar rats in the working heart‐brainstem preparation, at high or low respiratory drive induced by hypercapnia or hypocapnia, respectively (SAD, n = 26 and Sham, n = 33). The duration of inspiration significantly increased in SAD rats (1.46 ± 0.05 vs 1.14 ± 0.07 s, P < 0.001). It was also observed that SAD increases cVN inspiratory activity (25 ± 1 vs 32 ± 2%, P < 0.05) and decreases in its post‐inspiratory component (76 ± 1 vs 68 ± 2%, P < 0.05), suggesting an increased upper airway resistance during inspiration in SAD rats. Regarding the baseline tSNA, no changes were observed in the baseline tSNA in all phases of the respiratory cycle in SAD rats, which presented significant reduction in the Traube‐Hering waves magnitude (2.57 ± 0.04 vs 1.19 ± 0.20 mmHg, P = 0.0048). In order to reveal the influence of the respiratory network on the modulation of sympathetic activity rats were exposed to hypercapnia (from 5 to 10 % of CO2) or hypocapnia (from 5 to 3 and 1 % of CO2). High respiratory drive induced by hypercapnia increases tSNA in all phases of respiration in Sham rats (n=13), but in SAD rats (n=14) a significant increase in tSNA was observed only during inspiration (43 ± 3% vs 55 ± 3%, P < 0.01). On the other hand, hypocapnia reduced the respiratory drive and induced sympatho‐inhibition in the SAD (n=8) and in Sham rats (n=10). The data show that in spite of longer inspiratory activity, the baseline sympathetic activity is normal in SAD rats. Whether or not the longer inspiratory activity is driving the sympathetic activity in SAD rats is still matter for further investigation.Support or Funding InformationFAPESP, CAPES and CNPq
Neural circuit mechanism for hypothalamic neuropeptide Y‐induced inhibition of brown adipose tissue thermogenesis
Authors: Nakamura Yoshiko , Yanagawa Yuchio , Morrison Shaun F , Nakamura Kazuhiro 
Published: November 2023

Hunger stimulates neuropeptide Y (NPY)‐containing neurons in the arcuate nucleus of the hypothalamus, which then release NPY from their nerve endings in the paraventricular hypothalamic nucleus (PVH) to inhibit metabolic activities including brown adipose tissue (BAT) thermogenesis. However, the neural circuit mechanism by which the NPY‐triggered signaling from the PVH inhibits BAT thermogenesis remains unknown. We found that NPY injection into the PVH in rats inhibits BAT thermogenesis through GABAergic inhibitory inputs to BAT‐controlling sympathetic premotor neurons in the rostral medullary raphe (rMR). Our anterograde and retrograde tract tracing revealed that GABAergic neurons in the intermediate and parvicellular reticular nuclei (IRt/PCRt) of the medulla oblongata directly project to sympathetic premotor neurons in the rMR. In vivo stimulation of neurons in the IRt/PCRt with a nanoinjection of bicuculline, a GABAA receptor antagonist, strongly inhibited either skin cooling‐evoked or pyrogen‐evoked BAT thermogenesis. Furthermore, inactivation of IRt/PCRt neurons with bilateral nanoinjections of muscimol, a GABAA receptor agonist, reversed the inhibition of BAT thermogenesis by hypothalamic NPY. These data indicate that the hunger‐driven hypothalamic NPY signaling inhibits BAT thermogenesis through the GABAergic innervation from IRt/PCRt neurons to sympathetic premotor neurons in the rMR.Support or Funding InformationFunding Program for Next Generation World‐Leading Researchers from the Japan Society for the Promotion of Science (LS070 to K.N.); Grants‐in‐Aids for Scientific Research from the MEXT of Japan (15H05932, 26118508 and 26713009 to K.N., 26290002 and 15H01415 to Y.Y., and 26860159 to Y.N.); Grant‐in‐Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the MEXT of Japan (to Y.Y.); NIH grant (R01NS40987 to S.F.M.); Takeda Science Foundation (to K.N. and Y.Y.); Nakajima Foundation (to K.N.); Brain Science Foundation (to K.N.); Kowa Life Science Foundation (to K.N.).
Cerebrovascular Reactivity Is Reduced in Postmenopausal Women with a History of Hypertensive Pregnancy Disorders
Authors: Harvey Ronee E , Johnson Maja C , Johnson Christopher P , Joyner Michael J , Miller Virginia M , Barnes Jill N 
Published: November 2023

Women who have experienced hypertensive pregnancy disorders (HPD) are at an increased risk for developing cardiovascular disease later in life, including fatal and non‐fatal stroke. Cerebrovascular reactivity is related to stroke in individuals with carotid artery disease, and it is possible that this measure may be altered in women with a history of HPD prior to overt cerebrovascular disease. It is unknown if cerebrovascular reactivity is altered in postmenopausal women decades after experiencing a hypertensive pregnancy. Therefore, the goal of this study was to determine if cerebral blood flow velocity and cerebrovascular reactivity are altered in women with a history of HPD in comparison to women with no history of HPD. We studied a cohort of postmenopausal women approximately 35 years after they experienced an HPD (n=27, age at testing: 58±1) and a group of age‐ and parity‐matched women with no history of HPD (n=30, age at testing: 59±1). We measured middle cerebral artery velocity (MCAv, via transcranial Doppler), continuous blood pressure (finger photoplethysmography), and end‐tidal CO2 (nasal cannula) in these women at baseline (room air) and during stepped hypercapnia at 2, 4, and 6% inhaled CO2 for 3 minutes at each condition. Women with a history of HPD had a higher body mass index than women without a history of HPD (29±1 vs. 26±1 kg/m2, respectively; p<0.05). At baseline and during 6% CO2, MCAv was lower in women with a history of HPD (baseline: 60±4 vs. 71±3 cm/s, respectively; 6% CO2: 82±6 vs. 99±5 cm/s, respectively; p<0.05 for both conditions) compared to women without a history of HPD. Cerebrovascular reactivity, the slope defining the association between MCAv and end‐tidal CO2 across the entire breathing trial, was also lower in women with a history of HPD (2.0±0.2 vs. 2.7±0.2 cm/s/mmHg, respectively; p<0.05). Body mass index was not correlated with MCAv or cerebrovascular reactivity in either group (p>0.05). In conclusion, resting MCAv and cerebrovascular reactivity to CO2 is lower in women with a history of HPD in comparison with women who have never experienced HPD. Our findings suggest that HPD may have long‐term effects on cerebrovascular regulation in women who have suffered from these conditions.Support or Funding InformationNIH HL083947, NIA 1P50AG044170‐01, and CTSA UL1TR000135
Stimulation of beta adrenergic receptor type‐3 (β3‐AR) in the kidney triggers antidiuresis: physiological implications and possible therapeutic target to treat NDI
Authors: Procino Giuseppe , Carmosino Monica , Milano Serena , Dal Monte Massimo , Schena Giorgia , Mastrodonato Maria , Torretta Silvia , Gerbino Andrea , Bagnoli Paola , Svelto Maria 
Published: November 2023

BackgroundBeta‐adrenergic receptors β1‐AR and β2‐AR regulate important renal functions. However, the presence, localization and possible physiological role of β3‐AR in the kidney is still debated.MethodsImmunolocalization of β3‐AR was performed in mouse kidney. Live mouse kidney slices were treated with the β3‐AR selective agonist BRL37344, in the presence or in the absence of the PKA inhibitor H89 or β3‐AR antagonists.To unmask the possible antidiuretic effect of β3‐AR stimulation, we tested the urine concentrating ability of β3‐AR KO mice and injected BRL37344 in wt and vasopressin V2 receptor (V2R) KO mice.Resultsβ3‐AR is expressed at the basolateral membrane of most of the vasopressin‐sensitive nephron segments: thick ascending limb (TAL), distal convolute tubule (DCT) and the cortical/outer medullary collecting duct (CD).Interestingly, in live kidney slices, BRL37344 elicited a vasopressin‐like effect on cAMP production, AQP2 apical expression and KNCC2 phosphorylation/activity. These effects were prevented by β3‐AR antagonists or H89. β3‐AR KO mice showed reduced AQP2 plasma membrane expression, increased diuresis, reduced urine osmolality and increased urine excretion of Na, K and Cl compared to control mice. Moreover, in both wt and V2R‐KO mice, BRL37344 increased Na, K, Cl and water reabsorption and promoted a significant antidiuretic effect.ConclusionsTaken together, these findings are of great physiological importance as they uncover an antidiuretic effect of β3‐AR stimulation in the kidney and suggest that β3‐AR agonists might be useful to bypass V2R inactivating mutations.Support or Funding InformationTelethon foundation grants n. GGP15083 and n. GGP12040
Anatomical substract of the masseter muscle myofascial trigger points
Authors: Akamatsu Flávia , Gaubeur Matheus Acquesta , Itezerote Ana Maria , Saleh Samir , Hojaij Flávio , Figueredo Mauro , Jacomo Alfredo 
Published: November 2023

Myofascial pain syndrome (MPS) is a common cause of chronic musculoskeletal pain and is characterized by myofascial trigger points (MTP), limited range of motion in joints, referred pain and local twitch response during mechanical stimulation of MTP. MTP are clinically identified by palpation of a taut band of muscle or fascia. Physiopathology of MPS remains unclear and it has been suggested that MTP occur when a nociceptor and a muscular motor endplate coincide. Eight different MTP are clinically described for the masseter muscle, but anatomical correlation is still lacking. Masseter muscles from ten cadavers were carefully dissected from their origins in order to observe the exact point where nerve fibers penetrated the muscle belly.As muscle size varies among individuals, we calculated the relative entry point of the nerve into the muscle by defining six different areas in the muscle belly: three superior (I, II and III) and three inferior (IV, V and VI), beginning at the posterior margin of the muscle. Areas II (36.6%), I (22.2%) and V (16.6%) concentrated the masseteric nerve entry points and statistical analyzis using Chi square fit quality test showed a significant higher in these areas (p <0.001). These locations correspond to the clinically described MTP. Anatomical correlation of the MTP may be useful for a better understanding of the physiopathology of these disorders and provide basis for their treatment.
The ISW1, CHD1 and RSC Remodelers Combine to Organize Chromatin in Yeast
Authors: Ocampo Josefina , Chereji Razvan V , Eriksson Peter R , Clark David J 
Published: November 2023

In yeast, most genes have a nucleosome‐depleted region (NDR) at the promoter and an array of regularly spaced nucleosomes that is phased relative to the transcription start site (TSS). We addressed the roles of four remodeling machines (ISW1, ISW2, CHD1 and RSC) in specifying this chromatin organization. We sequenced nucleosomes from isogenic strains with the essential RSC8gene linked to a GAL promoter and isw1Δ, isw2Δ or chd1Δ mutations in all combinations. Globally, RSC depletion results in a shift of the array into the NDR, isw1Δ shows reduced spacing and both isw1Δ and chd1Δ show weakened phasing, whereas isw2Δ has no effect. Generally, chromatin organization in the multiple mutants is the sum of the effects observed in the single mutants, indicating that these remodelers are not redundant but have distinct functions. Our data suggest that RSC determines the location of the first (+1) nucleosome relative to the TSS, which is then used as a reference nucleosome by the spacing enzymes, ISW1 and CHD1, to build nucleosomal arrays on genes. Our current focus is on the interactions between RSC and the nucleosome spacing enzymes, and their roles in transcription.Support or Funding InformationThis research was supported by the Intramural Research Program of the NIH (NICHD).
Roles of the Histone Chaperone FACT in Drosophila Gene Regulation and Chromatin Architecture
Authors: Tettey Theophilus , Story Benjamin , Glaser Robert L , Blanchette Marco , Conaway Joan W , Conaway Ronald C 
Published: November 2023

The highly conserved histone chaperone FACT (Facilitates Chromatin Transcription) is thought to contribute to the disassembly and reassembly of nucleosomes in the wake of RNA polymerase II passage through chromatin. In yeast, mutation of FACT subunits leads to decreased nucleosome occupancy at the promoters and transcribed regions of genes. In addition, genetic experiments suggest that yeast FACT plays a critical role in restricting initiation of transcription to normal promoters, ensuring that only appropriate mRNAs are synthesized. However, FACT's roles in chromatin biology and transcriptional regulation in higher eukaryotes are not well understood. Using Drosophila S2 cells as a model, we observe that depletion of the FACT complex results in aberrant transcriptional regulation. Surprisingly, we observe in genome‐wide experiments that FACT depletion has little effect on total nucleosome occupancy or position, but dramatically alters the distribution of various histone modifications, including histone 3 lysine 4 trimethylation (H3K4me3), histone 2A variant (H2Av) and histone 3 lysine 36 trimethylation (H3K36me3), in the promoters and transcribed regions of genes. Our results thus far provide valuable insight into roles of FACT in transcriptional regulation and chromatin dynamics in higher eukaryotes.Support or Funding InformationStowers Institute for Medical Research
Impact of Microbicide Formulation on Glycosylation and Innate Immunity in Cervicovaginal Fluid
Authors: Koppolu Sujeethraj , Wang Linlin , Dezzutti Charlene S , Isaacs Charles E , Moncla Bernard , Hillier Sharon L , Rohan Lisa Cencia , Mahal Lara K 
Published: November 2023

Glycosylation is a key component in the establishment of healthy symbiotic bacterial colonization patterns and is involved in the maintenance of mucosal barriers to infection, regulating both adaptive and innate immunity. Changes in glycosylation state have powerful effects on the stabilization and activation of antibodies and can alter the microbicidal effects of immune molecules. Thus glycome is both a marker and modulator of innate immunity. We recently showed a strong correlation between glycosylation status in the cervicovaginal (CVL) fluid and microbiome status, using lectin microarray analysis. Here, we report on the impact of thin film versus hydrogel placebos, for vaginal delivery of drugs, on the glycosylation status and innate antiviral immunity of CVL fluids. CVL samples from 52 women were studied for glycosylation status using lectin microarray analysis and their impact on the infectivity of herpes simplex virus 1 & 2 (collectively HSV) and HIV‐1 using Plaque and TZM‐bl assays respectively. In our studies, we identified lower levels of high‐mannose, as indicated by the high‐mannose binding lectins griffithsin (GRFT) and scytovirin (SVN) that correlated with lower anti‐HIV‐1 (SVN, p = 0.02; n= 90; t‐test) and anti‐HSV activities (GRFT, p=0.001; n= 139; t‐test). We also found that the drug delivery mode has a significant impact on the glycan composition of the CVL, which in turn may affect innate immunity. Gel use had a greater impact on the glycome with a significant loss of high‐mannose signature (GRFT, p = 0.008; SVN, p = 0.01; n= 53; paired t‐test). GRFT immobilized on agarose beads were used to isolate GRFT‐binding glycoproteins in the CVL and a proteomic analysis on those samples identified a number of protease inhibitors that were previously associated with reduced susceptibility to HIV infection. Collectively, our data suggests that high‐mannose in the CVL is a marker for anti‐viral activity and that thin films do not impact the innate anti‐viral immunity in the CVL.Support or Funding InformationThis work was funded by the National Institutes of Health, Grant # U191AI082639.
LEPTIN LEVELS ATTENUATED BY COCONUT WATER IN HIGH‐FAT AND HIGH‐FRUCTOSE DIET FED ANIMAL MODELS
Authors: Imaga Ngozi A , Obafemi Adepoju , Onadeko Oluwadamilola , Okafor Uzoma A 
Published: November 2023

Coconut water is the liquid endosperm of coconut fruitrich in important nutrients such as vitamins, phytohormones, amino acids andphytochemicals. Tender coconut water, the fluid present in young green coconuts and mature coconut water, the clear liquid present in the older brown coconut have been shown to significantly reduce hyperlipidemia in cholesterol fed rats. Leptin is a 16 KDa peptide hormone that is the product of ob gene in adipose tissues. Leptin level in circulation is directly related to adipose tissue mass. The effect of tender and mature coconut water on the leptin level of high‐fat and high‐fructose diet fed rats was investigated in this study. 55 rats were separated into 11 experimental groups of which 4 groups each had high‐fat and high‐fructose feeding respectively with and without coconut water treatment. The rats were fed for 8 weeks followed by 4 weeks of treatment with tender coconut water, mature coconut water and atorvastatin as reference standard. Leptin level was significantly reduced(p<0.01) by tender and mature coconut water in a manner that was comparable to atorvastatin in both high‐fat and high‐fructose diet fed rats. Leptin lowering in the high‐fat fed rats was similar in both mature and tender coconut water, but the lowering effect was more in the mature coconut water (MCW) than in the tender coconut water (TCW) in the high‐fructose fed rats. Tender and mature coconut water thus, have a lowering effect on leptin level in circulation. This lowering effect might be due to the reduction of adipose tissue mass by the metabolic action of tender and mature coconut water or the interplay of their phytochemical and proximate constituents in a synergistic fashion or the contribution of all the factors.Support or Funding Informationna
Finding Inhibitors for The Type II Phosphatidylinositol 4‐kinase Alpha Enzyme
Authors: SENGUPTA NIVEDITA , JOVIC MARKO , BARNAEVA ELENA , Baumlova Adriana , Southall Noel , Hu Xin , Marugan Juan , Ferrer Marc , Boura Evzen , Balla Tamas 
Published: November 2023

Type II phosphatidylinositol 4‐kinases (PI4K2A and 2B) are two of four lipid kinases that synthesize phosphatidylinositol 4‐phosphate (PI4P) in vertebrates. PI4K2A and PI4K2B are highly homologous only differing in their NH2 termini. PI4K2A is tightly membrane bound via palmitoylation and is the most active PI4K associated with various cellular membranes. It has been shown to play important roles in trafficking of several cargoes from the plasma membrane to the sorting endosomes and beyond. The enzyme is localized to endosomes and the trans‐Golgi network (TGN) where it was shown to recruit various clathrin adaptor proteins. Given its central function in vesicular trafficking, and possibly controlling viral replication and assembly, development of PI4K2A‐specific inhibitors would greatly facilitate research in understanding the role of the protein in controlling all of these processes. Few compounds have been described to inhibit these enzymes and they lack selectivity and access to intracellular compartments. The aim of this study was to identify potent and specific small molecule inhibitors for this enzyme.A high throughput inhibitor screen was performed with ~350,000 compounds from the molecular library repository using a bacterially expressed human PI42A enzyme. Based on primary screen results and counter‐screens with PI4KB (a type III PI4K that belongs to a different class of proteins) 14 inhibitors were short listed for further studies. The kinase activity of the human PI4K2A is strongly dependent on a cysteine‐rich sequence that is palmitoylated in the vertebrate enzyme providing stronger membrane association. Hence, all 14 inhibitors were re‐tested using expressed enzymes isolated from COS‐7 cells or using assays that tested the activity of the enzyme in situ. We found a strong correlation between the potency of inhibitors between the enzymes isolated from COS‐7 cell or expressed in bacteria. In situ kinase assays were then performed in the presence of type III PI4K inhibitors in permeabilized cells showing two inhibitors that reduced PI4P and PIP2 phosphorylation, thus confirming the effect of these inhibitors on the intracellular PI42A activity. Lastly, confocal microscopy revealed that these two inhibitors reduced the Golgi and endosomal pool of PI4P. Further studies are in progress to improve the selectivity and potency of these lead compounds.
Selective inhibitors epigenetically modify and eradicate tumor‐initiating stem‐like cells through downregulating microRNA 22‐mediated TET induction and apoptosis
Authors: Machida Keigo , Chen Chia‐Lin NONE , Kumar Dinesh Babu Uthaya , Swaminathan Suresh , French Samuel W , Panyam Jayanth 
Published: November 2023

A critical barrier to improved cancer therapy is the recurrence of drug‐resistant tumors expanded from tumor‐initiating stem‐like cells (TICs). Discovery of a drug that specifically targets the TIC population is critical for effective treatment. We first performed drug screening on TICs for the identification of cell‐type specific drugs and found that all‐trans retinoic acid (ATRA) specifically inhibited cell viability. Additionally, transduction of human TICs with a lentivirus Nanog‐GFP reporter was used to perform high‐throughput screening for Nanog‐inhibitory drugs. HDAC inhibitor (SAHA), among several candidates, suppressed Nanog expression. Three high‐throughput screenings identified the best combination of repurposed FDA‐approved drugs (ATRA and SAHA). Moreover, combination of RA with SAHA synergistically reduced Nanog expression and inhibited the self‐renewal abilities of TICs resulting in apoptosis in vitro and in vivo. Genome‐wide transcriptome analysis by using of RNA‐seq showed that combined treatment reduced microRNA‐22, which induced phosphatase and tensin homolog (PTEN) and ten‐eleven translocation (TET). PTEN‐mediated FOXO activation promotes BIM‐mediated apoptosis. TET induction demethylates p53‐binding sites within the Nanog promoter proximal region. The drug combination epigenetically altered DNA methylation of Nanog promoter leading to inactivation of Nanog in TICs. Taken together, ATRA and SAHA may serve as a novel strategy for HCC treatment.Support or Funding InformationThis project was supported by NIH research grants R01AA018857, P50AA011999 (Southern California Research Center for ALPD and Cirrhosis, pilot project, program, animal core, morphology core), Lee‐Summer‐Project funding, P30DK048522 (USC Research Center for Liver Diseases, pilot project program), Non‐Parenchymal Liver Cell Core (R24AA012885) and UO‐021898. This research was also supported by a Research Scholar Grant (RSG‐12‐177‐01‐MPC); pilot funding from American Cancer Society (IRG‐58‐007‐48); The Cell and Tissue Imaging Core ‐ USC Research Center for Liver Diseases (P30 DK048522).