bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Hippo Signaling Pathway on Muscle Wasting in ApcMin/+ Mice: A Pilot Study
Authors: Gooden Janesha L , Lim Benjamin W , Sato Shuichi 
Published: November 2023

Cancer cachexia is a wasting syndrome associated with cancer and characterized by progressive weight loss due to excessive loss of skeletal muscle. More than one‐half of all cancer patients is likely to suffer from this syndrome in our country. Despite its high prevalence and importance, cancer cachexia has been overlooked in the clinical settings and the mechanism by which the condition develops needs to be further investigated. The Hippo signaling pathway is found to be involved in determining cell growth and organ size including skeletal muscle in mammals and altered activation of this signaling has been reported in response to external stimuli such as functional overload and denervation. However, to the best of our knowledge, no study has been conducted to examine the role of this signaling during the development of cancer cachexia. The purpose of this study was to determine if Hippo signaling pathway plays a role in cancer cachexia. Age‐matched C57BL6 and ApcMin/+ (Min) mice were used in this study. The body weights of these mice were recorded weekly and muscle weights were determined at the time of sacrifice. The loss of body weight was calculated as a ratio between the peak body weight during the experiment period and the body weight at the time of sacrifice. For western blotting, isolated quadriceps was homogenized by T‐PER tissue protein extraction reagent and protein concentration was determined by Bradford assay. The equal amount of total protein was loaded on 10% acrylamide gel for SDS‐PAGE and transferred to PVDF membrane. Each membrane was blocked with 3% milk in TBST for 45 minutes, followed by primary antibody incubation overnight at 4 °C. After 45 minutes incubation with secondary antibody, the membrane was exposed to ECL for 5 minutes to visualize the bands. The intensity of bands was quantified by Image‐J. The body weights of Min mice began to be lower than control mice at the age of 18 weeks. The average loss of body weight was 13.2 ± 0.7 % in Min mice at the time of sacrifice. Likewise, quadriceps weights were smaller by 39% in cachectic mice compared to healthy control mice. The levels of total MST1 expression in Min mice was elevated compared to that in control mice; however, no difference was observed in the levels of phosphorylated and total YAP protein between two groups. These data indicate not YAP but MST1 may be involved in the progression of muscle wasting due to cancer in mice and inhibition of MST1 may be a potential target to treat cancer cachexia.Support or Funding InformationThis study was supposed by Summer Research Award at the University of Louisiana at Lafayette (SS).
Deletion of brain‐specific isoform of renin (renin‐b) increases resting metabolic rate by stimulating brown adipose tissue sympathetic nerve activity
Authors: Nakagawa Pablo , Gomez Javier , Shinohara Keisuke , Morgan Donald A , Weidemann Benjamin J. , Grobe Justin L , Rahmouni Kamal , Sigmund Curt D 
Published: November 2023

Activation of the brain renin‐angiotensin system (RAS) stimulates energy expenditure through increasing sympathetic nerve activity (SNA). In the brain, the renin gene is transcribed from an alternative promoter‐first exon resulting in a product that lacks the signal peptide and a third of the prosegment. This product, termed renin‐b, is highly brain specific and likely remains intracellular. Deletion of renin‐b induces central RAS activation and hypertension, indicating that renin‐b is a negative regulator of the brain RAS. We hypothesize that genetic deletion of renin‐b interferes with the control of metabolism and energy expenditure by inducing brown adipose tissue (BAT) SNA and enhanced insulin sensitivity. We generated a mouse model carrying a selective loss of renin‐b (Renin‐bNull) while preserving the classical renin isoform expressed in the kidney (renin‐a). Resting metabolic rate was assessed by respirometry. Basal BAT SNA was evaluated using direct multifiber recording of SNA subserving BAT. Fasted mice were subjected to glucose tolerance test (GTT) and insulin tolerance test (ITT). Renin‐bNull mice exhibited increased resting metabolic rate in comparison to their control littermates (0.156 ± 0.005 kcal/h in Renin‐bNull vs. 0.145 ± 0.003 kcal/h in control littermates, p<0.015, mean ± SEM). Under basal conditions, Renin‐bNull mice do not show differences in body weight, food consumption, and physical activity. However, weight gain was attenuated in male but not female Renin‐bNull in response to high fat diet (36.8 ± 1.2 in male Renin‐bNull vs. 41.9 ± 1.4 in male control, p<0.03). The analysis of the area under the curve (AUC) in GTT revealed mild but significant glucose intolerance in Renin‐bNull in comparison to control (152.5 ± 20.9 in Renin‐bNull vs. 93.0 ± 14.3 in control, p<0.03). However, there were no significant differences in the AUC in the ITT between Renin‐bNull and the control (174.3 ± 12.8 in Renin‐bNull vs. 207.0 ± 12.8 in control, p=0.077). Deletion of renin‐b induced an increase in SNA in BAT (40.8 ± 3.1 in Renin‐bNull vs. 27.2 ± 3.1 in control, p<0.003) and this was associated with an increase in uncoupled protein 1 (UCP1) protein expression in BAT (2.1 ± 0.5 fold increase in Renin‐bNull vs. control, p<0.05). These data suggest that renin‐b is involved in maintaining energy homeostasis likely by preventing central RAS activation. The activation of BAT SNA and the subsequent UCP1 overexpression are likely to be mechanistically involved in the increased energy expenditure observed in Renin‐bNull mice. Downregulation of renin‐b and the consequent brain RAS activation may be an important pathophysiological mechanism involved not only in the development of neurogenic hypertension, but also in obesity and other metabolic diseases.Support or Funding InformationNIH and AHA
Blood Pressure and Cerebral Blood Flow Following Concussion: Implications for Diagnosis
Authors: Knox Allan , Falvo Michael , Favre Michelle , Serrador Jorge 
Published: November 2023

PurposeThe increasing prevalence of Mild Traumatic Brian Injury (mTBI) has reached epidemic levels, accounting for 75% of all reported head injuries. No anatomical changes have been observed following mTBI, although data regarding more sensitive measures following mTBI are deficient. The objective of this work was to determine if any changes in blood pressure (BP), cerebral blood flow (CBF) or cerebral autoregulation following mTBI could be could be used in the diagnosis of concussion, and to establish if previous mTBI history has any influence.MethodsWe assessed BP, CBF, and cerebral autoregulation in rugby players immediately following mTBI (n=41) and compared with a control group (n=75) of players who completed a rugby match with no reports of mTBI. History of mTBI was self‐reported.ResultsMean arterial pressure was higher following mTBI compared to controls. (Ctrl 74±11vs 83±12 mmHg, P<0.001). Common carotid blood flow was similar between groups (Ctrl 1144±413 vs mTBI 1287±427 mL/min, P=NS) however, internal carotid artery (ICA) blood flow was reduced in the mTBI group (Ctrl 477±175 vs mTBI 317±140 mL/min, P=0.002). End tidal CO2 was lower following mTBI than controls (Ctrl 38.9±6.0 vs mTBI 36.5±3.9 mmHg, P=0.013). History of mTBI had no influence on any of these measure (P>0.05 for all). Internal Carotid CVR was also greater in those with a concussion (Ctrl 0.20±0.15 vs mTBI 0.36±0.27, P=0.007) that was affected by concussion history (P=0.022). Players experiencing a first‐time concussion had higher CVR values than those with a history of concussion (0.45±0.31 vs 0.26±0.12, P=0.028).ConclusionChanges in BP and CBF are associated with mTBI which may help in the diagnosis of concussion. Players experiencing a concussion for the first time demonstrated greater cerebral vasoconstriction in the internal carotid artery. Further research is necessary to determine the role of cerebral hypoperfusion in concussions.
A Mathematical Model for the Population Dynamics of Intestinal Microbiota: Obese Versus Healthy Gastrointestinal Tract
Authors: Giron Felipe , Pizano Alejandro , Calvachi Paola , Cordovez Juan Manuel 
Published: November 2023

IntroductionThe term microbiota refers to a community of microorganisms that are located in a certain space that have a symbiotic relationship with the host cells, in this specific case the human gastrointestinal tract. This interaction provides support to the gastrointestinal tract in different functional aspects such as trophic functions, protection (immune system) and metabolism. Related to human nutrition, it has been evidenced that intestinal microbiota plays an important role in synthesis, metabolism, and other functions associated to the nutrients and micronutrients that can lead to healthy or obese patients.ObjectivesTo understand and model the population dynamics of the intestinal microbiota using a mathematical model, and to use the model to compare lean versus obese subjects.MethodsA mathematical model was design based on the gastrointestinal division in three compartments (1. Mouth to Stomach, 2. Small bowel and 3. Colon) and two major phyla of microorganisms (Firmicutes and Bacteroidetes) according to its anatomical, physiological characteristics and in terms of its relative abundance of microbiota. The model included the subject's diet and activity level as inputs. Parameters for the model were obtained from a literature review. The model was implemented in Matlab and the equations were solved to steady state. Population sizes of the two microorganisms, for lean and obese subjects, were recorded.ResultsThe model predicted a Firmicutes to Bacteriodetes ratio close to 1:1 in lean subjects for all compartments. The ratio increased to 4:1 or higher in obese subjects. These results are in agreement with several reports obtained from the literature. In addition, the model showed an interesting shift in the ratio in compartment three for obese subjects: under some circumstances increased to 7:1. The ratio is extremely sensitive to diet and exercise.ConclusionThe simple mathematical model was helpful in understanding the distribution and dynamics of intestinal microbiota. The model can be used to predict the population dynamics under different diets, giving the possibility to estimate the efficacy of surgical intervention. The model can also shed some light on how to prevent the progression from overweight to obese just by changing the diet.
Hypoxia and Endothelin‐1 Decrease Expression of the Extracellular Matrix Protein, Cartilage Oligomeric Matrix Protein, a Potential Modulator of Iron Metabolism in Pulmonary Arteries
Authors: Yu Hang , Wolin Michael S 
Published: November 2023

Recent studies have reported low iron levels in patients with idiopathic pulmonary arterial hypertension, and there is evidence for an iron deficiency being an important risk factor for pulmonary hypertension. The extracellular matrix (ECM) plays an important role in the development of PH. In the present study, expression of cartilage oligomeric matrix protein (COMP), a newly found protein in ECM, is significantly (P<0.05) decreased in lungs of mice with hypoxia‐induced PH (10% oxygen for 21 days) and in organoid cultured bovine pulmonary arteries (BPA), but not in bovine coronary arteries, under hypoxia or treated with endothelin‐1 (ET‐1, 10nM for 24hrs). Some potential relationships between COMP and iron metabolism proteins elicited by the hypoxia and ET‐1 conditions potentially associated with PH development were studied in organoid cultured BPA by changes in the expression (Western analysis) of proteins such as ferritin, transferrin receptor 1 (TfR1), ferroportin (Fpn), hepcidin, mitoferrin, ISCU1/2, ferrochelatase (FECH), frataxin and soluble guanylate cyclase (sGC), and the influence on cGMP signaling detected by its control of VASP phosphorylation (VASP‐P). Changes in the expression of the levels of SOD2 and NOX4 were also evaluated because these ROS metabolism proteins are also altered by PH. Organoid culture of BPA with ET‐1 did not cause significant changes in the expression of frataxin, hepcidin, TFR1, ISCU1/2, FECH, sGC and Fpn. ET‐1 downregulated the protein levels of ferritin, mitoferrin, SOD2, COMP, and VASP‐P (VASP‐P/VASP ratio); ET‐1 upregulated the protein levels of NOX4. Under the environment of 3% oxygen for 24 hours, the expression of COMP decreased, but there were no obvious changes of most iron metabolism proteins in bovine PAs. Supplementing COMP (40ug/ml) into the culture media under hypoxia, increased the levels of FECH, ISCU1/2 and the VASP‐P/VASP ratio, and TFR1 levels were decreased. When treated with or without ET‐1, COMP increased the expression of SOD2 and decreased NOX4. These data suggest that COMP could normally have a protective role against PH development due to improving cGMP signaling, attenuating pathophysiological changes in ROS metabolism and by modulating aspects pulmonary arterial iron homeostasis, and these protective actions could be lost as a result of hypoxia and/or ET‐1 promoting a relatively rapid depletion of COMP.Support or Funding InformationSupported by NIH Grants HL115124 & HL12979, and the Natural Science Foundation of the P. R. China (31400989); the Natural Science (C2015069) and Postdoctoral Science (LBH‐Q15087) Foundation of Heilongjiang Province
epDevAtlas: Mapping GABAergic cells and microglia in postnatal mouse brains
Authors: Liwang Josephine K. , Kronman Fae A. , Minteer Jennifer A. , Wu Yuan-Ting , Vanselow Daniel J. , Ben-Simon Yoav , Taormina Michael , Parmaksiz Deniz , Way Sharon W. , Zeng Hongkui , Tasic Bosiljka , Ng Lydia , Kim Yongsoo 
Published: November 2023

AbstractDuring development, brain regions follow encoded growth trajectories. Compared to classical brain growth charts, high-definition growth charts could quantify regional volumetric growth and constituent cell types, improving our understanding of typical and pathological brain development. Here, we create high-resolution 3D atlases of the early postnatal mouse brain, using Allen CCFv3 anatomical labels, at postnatal days (P) 4, 6, 8, 10, 12, and 14, and determine the volumetric growth of different brain regions. We utilize 11 different cell type-specific transgenic animals to validate and refine anatomical labels. Moreover, we reveal region-specific density changes in γ-aminobutyric acid-producing (GABAergic), cortical layer-specific cell types, and microglia as key players in shaping early postnatal brain development. We find contrasting changes in GABAergic neuronal densities between cortical and striatal areas, stabilizing at P12. Moreover, somatostatin-expressing cortical interneurons undergo regionally distinct density reductions, while vasoactive intestinal peptide-expressing interneurons show no significant changes. Remarkably, microglia transition from high density in white matter tracks to gray matter at P10, and show selective density increases in sensory processing areas that correlate with the emergence of individual sensory modalities. Lastly, we create an open-access web-visualization (https://kimlab.io/brain-map/epDevAtlas) for cell-type growth charts and developmental atlases for all postnatal time points.
Development of selective pyrido[2,3-d]pyrimidin-7(8H)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors
Authors: Rak Marcel , Menge Amelie , Tesch Roberta , Berger Lena M. , Balourdas Dimitrios-Ilias , Shevchenko Ekaterina , Krämer Andreas , Elson Lewis , Berger Benedict-Tilman , Abdi Ismahan , Wahl Laurenz M. , Poso Antti , Kaiser Astrid , Hanke Thomas , Kronenberger Thales , Joerger Andreas C. , Müller Susanne , Knapp Stefan 
Published: November 2023

ABSTRACTMammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part due to the lack of potent and selective MST3/4 inhibitors. Here, we re-evaluated literature compounds, and used structure-guided design to optimize the p21-activated kinase (PAK) inhibitor G-5555 (8) to selectively target MST3/4. These efforts resulted in the development of MR24 (24) and MR30 (27) with good kinome-wide selectivity, high potency for MST3/4, and selectivity towards the closely related MST1/2. In combination with the MST1/2 inhibitor PF-06447475 (2) the two MST3/4 inhibitors can be used to elucidate the multiple roles of MST kinases in cells. We found that MST3/4-selective inhibition caused a cell cycle arrest in the G1 phase, while MST1/2 inhibition resulted in accumulation of cells in the G2/M phase. These data point to distinct functions of these closely related kinases, which can now be addressed with subfamily-selective chemical tool compounds.
Specific Fabric Properties Elicit Human Neuro and Electrophysiological Responses
Authors: Balasubramanian Mahendran , Periyaswamy Thamizhisai 
Published: November 2023

AbstractTactile perception of fabrics is a complex process challenging to parse and understand. Most studies examined fabric tactile perception through subjective means. Alternatively, neural and electrodermal signals can be used to examine fabric properties that elicit responses via tactile stimulation. Among the fabric properties, some may generate strong responses while others produce weaker responses. Here, we have shown that by studying the electroencephalography signal from the scalp areas corresponding to the sensory cortex, and the galvanic skin responses that occurred during active tactile sensation of varied fabrics, the influence of individual fabric properties can be determined. Eight subjective properties, from twenty female subjects, and seventeen objective properties, measured using Kawabata Evaluation System, were independently correlated to the biosignals. We have shown that properties related to thickness and volume were the most influential, followed by surface frictional properties. Fuzziness and linearity of compression were the least influencing properties affecting the biosignals.
Dynamic protein phosphorylation inStreptococcus pyogenesduring growth, stationary phase and starvation
Authors: Mikkat Stefan , Kreutzer Michael , Patenge Nadja 
Published: November 2023

AbstractBackgroundPhosphorylation of proteins at serine, threonine, and tyrosine residues plays an important role in physiological processes of bacteria such as cell cycle, metabolism, virulence, dormancy, sporulation, and stationary phase functions.Streptococcus pyogenespossesses a single known transmembrane serine/threonine kinase belonging to the class of penicillin-binding protein and serine/threonine-associated (PASTA) kinases. To gain initial insights into the targets and dynamics of protein phosphorylation inS. pyogenesserotype M49 strain 591, we performed a proteomics and phosphoproteomics workflow using cultures from different growth conditions, stationary phase and starvation.ResultsThe quantitative analysis of dynamic phosphorylation, which included a subset of 463 out of 815 identified phosphorylation sites, revealed two main types of phosphorylation events, distinguished by the growth phase in which they predominantly occur and their preference for either threonine or serine. A small group of phosphorylation events occurred almost exclusively at threonine residues of proteins related to the cell cycle and was enhanced in growing cells. Many of these phosphorylation sites are highly conserved targets of PASTA kinases in streptococci. The majority of phosphorylation events occurred during stationary phase or starvation, preferentially at serine residues. These phosphorylations may be important for regulatory processes in stationary phase or for persister cell formation, but their function and the kinases responsible for their formation need to be elucidated in further analyses. Moreover, our data indicate that the vast majority of proteins can be phosphorylated, but identification of their phosphopeptides depends on the sensitivity of the proteomic methods used.ConclusionsPASTA kinase-dependent cell cycle regulation processes found in related bacteria are conserved inS. pyogenes, but account for only a small part of all phosphorylation events. Most phosphorylation events take place during stationary growth phase and starvation. This phenomenon has also been described for some other bacteria and may therefore be a general feature of bacterial protein phosphorylation.
Transcranial electric stimulation modulates firing rate at clinically relevant intensities
Authors: Farahani Forouzan , Khadka Niranjan , Parra Lucas C. , Bikson Marom , Vöröslakos Mihály 
Published: November 2023

AbstractNotwithstanding advances with low-intensity transcranial electrical stimulation (TES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. We used Neuropixels 2.0 probe with 384 channels in an in-vivo rat model of TES to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 µA of applied skull currents). We demonstrate that electric fields below 0.5 V/m acutely modulate firing rate in 5% of neurons recorded in the hippocampus. At these intensities, average firing rate effects increased monotonically with electric field intensity at a rate of 7 % per V/m. For the majority of excitatory neurons, firing increased for cathodal stimulation and diminished for anodal stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. Our results indicate that responses to TES at clinically relevant intensities are driven by a fraction of high-responder excitatory neurons, with polarity-specific effects. We conclude that transcranial electric stimulation is an effective neuromodulator at clinically realistic intensities.
An Efficient Computational Method to Create Positive NIPT Samples with Autosomal Trisomy
Authors: Nguyen Tinh H. , Nguyen Huynh V. , Pham Minh D. , Le Vinh S. 
Published: November 2023

AbstractNoninvasive prenatal test (NIPT) has been widely used for screening trisomy on chromosomes 13 (T13), 18 (T18), and 21 (T21). However, the false negative rate of NIPT algorithms has not been thoroughly evaluated due to the lack of positive samples. In this study, we present an efficient computational approach to create positive samples with autosomal trisomy from negative samples. We applied the approach to establish a low coverage dataset of 1440 positive samples with T13, T18, and T21 aberrations for both mosaic and non-mosaic conditions. We examined the performance of WisecondorX and its improvement, called VINIPT, on both negative and positive datasets. Experiments showed that WisecondorX and VINIPT with a z-score threshold of 3.3 were able to detect all non-mosaic samples with T13, T18, and T21 aberrations (i.e., the sensitivity of 100%). Using a lower z-score threshold of 2.58 when analyzing mosaic samples, both WisecondorX and VINIPT have the overall sensitivity of 99.7% on detecting T13, T18, and T21 aberrations from mosaic samples. WisecondorX has the specificity of 98.5% for the non-mosaic analysis, but a considerably lower specificity of 95% for the mosaic analysis. VINIPT has a much better specificity than WisecondorX, i.e., 99.9% for the non-mosaic analysis, and 98.2% for the mosaic analysis. The results suggest that VINIPT can play as a powerful NIPT tool for the low coverage data.