bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin‐(1–7) Prevents cardiovascular changes induced by hyperthyroidism
Authors: Senger Nathalia , Melo Marcos Barrouin , Santos Maria José Campagnole , Santos Robson Augusto , Barreto‐Chaves Maria Luiza Morais
Published: November 2023

High levels of thyroid hormone (TH) are commonly associated with cardiac hypertrophy and with a hyperdynamic heart condition. We previously demonstrated that cardiac hypertrophy induced by TH is mediated by Renin‐Angiotensin System (RAS) activation. In present study we tested the hypothesis that elevated circulating Angiotensin‐(1–7) levels attenuate the cardiovascular changes induced by TH. Wild Sprague‐Dawley (SD) or transgenic rats (TG) that constitutively overexpress an Angiotensin‐(1–7)‐producing fusion protein (TGR‐L3292) received daily injections (i.p.) of triiodothyronine (T3) (7μg/100g of body weight/day) for 14 days in order to develop hyperthyroidism. Cardiac hypertrophy was characterized and echocardiography experiments were performed to evaluate cardiac function parameters. The animals were handled according to National Institute of Health guidelines (NIH) – guide for the care and use of laboratory animals. Hyperthyroid wild‐type rats (SD‐T3) presented a significant increase in the cardiac mass, which was undetectable in the transgenic rats treated with T3 (TG‐T3). The administration of A779 (5μg/Kg/h), an antagonist of Angiotensin‐(1–7) receptor (Mas receptor), prevented the anti‐hypertrophic effect of Angiotensin‐(1–7) observed in TG‐T3. Echocardiography parameters showed that TG‐T3 rats exhibited a mitigation of the cardiac hyperdynamic condition observed in SD‐T3 rats, improving the following parameters: ejection fraction (EF%), fractional shortening (FS%), E/A ratio and heart rate. On the other hand, the treatment with A779 inhibited or attenuated the cardioprotective actions of Angiotensin‐(1–7) observed in TG‐T3. Collectively, these findings improve understanding of the cardiac hypertrophy observed in hyperthyroidism and may provide groundwork for the development of a new pharmacological strategy to the cardiac hyperdynamic condition observed in this disease.

Support or Funding Information

Foundation for the Support of Research in the State of São Paulo; [FAPESP #2013/16348‐6] and CNPq [National Council of Technological and Scientific Development].
Mitronic tsmiR miR6855 biosynthesis regulation by oxidative stress in the basal‐like breast cancer cells
Authors: Ellison Marshall , Misra Smita , Chaudhuri Gautam
Published: November 2023

Radiation and chemotherapeutic agents eradicate tumors by inducing irreparable DNA damage. However, cancer cells often develop resistance to therapy by manipulating the DNA repair machinery. Conversely, a dividing cell constantly exposed to environmental and endogenous DNA damaging agents can transform into a tumor due to incorrect repair. Therefore the expression level of DNA repair proteins is critical both for cancer therapy and tumorigenesis. Our preliminary studies implied a unique mechanism involving an miRNA miR‐6855‐3p that promotes the biosynthesis of the transcriptional regulator protein SPRDX5 which enhances the expression of the tumor suppressor protein BRCA2 leading to the genotoxin and radiation‐resistance of aggressive SLUG‐high basal‐like breast cancer (BLBC) cells. The miRNA miR‐6855‐3p thus acts as a tumor suppressor miRNA (tsmiR). Interestingly, the gene for the miRNA miR‐6855‐3p is mitronic and is nested within the intron#13 of the USP20 gene which is a deubiquitinase. Thus, the transcription of miR‐6855‐3p gene is regulated through the USP20 gene promoter. We present evidence here that USP20 and miR‐6855 gene transcriptions are up regulated by oxidative stress. Tert‐butylhydroperoxide was used for oxidative stress. Under the oxidative stress conditions tested, NRF2 level and the levels of several NRF2‐regulated proteins are increased, indicating activation of NRF2 in the stressed BLBC cells. Under the stress conditions the levels of USP20 and miR‐6855‐3p are increased significantly. Knockdown of NRF2 prevented stress‐induced elevation of USP20 and miR‐6855‐3p RNA level in the BLBC cells indicating the involvement of NRF2 in this process. The binding of NRF2 to the USP20 gene promoter and its function were characterized by ChIP analysis, site‐directed mutagenesis and using the promoter‐luciferase reporter constructs. We conclude that the biosynthesis of the tsmiR miR‐6855‐3p in the BLBC cells is regulated by oxidative stress and involves NRF2. Since oxidative stress is a hallmark in the etiology and progression of metastatic breast cancer, understanding the redox regulation of a tsmiR that positively influences BRCA2 gene expression in the BLBC cells could be clinically significant.

Support or Funding Information

Supported in part by DOD‐CDMRP IDEA Expansion Grant# BC103645 and NIH/NCI grant 1R21CA181920‐01 to GC and 1U54RR026140 to SM.
Mechanical Stretch on Endothelial Cells Promotes Monocyte Differentiation into Immunogenic Dendritic Cells
Authors: Loperena Roxana , Gomez Jose A , Engel Noah , Harrison David G
Published: November 2023

Hypertension is a leading cause of mortality in Western society, attributed in part to the oxidative injury and inflammation. We have shown that dendritic cells (DCs) from hypertensive mice accumulate isolevuglandins (IsoLGs) that adduct to proteins and promote T cell activation. In hypertension, the endothelium is activated to produce reactive oxygen species and to express adhesion molecules and chemokines that attract inflammatory cells. Human monocytes that traverse the endothelium differentiate into monocyte‐derived DCs upon exposure to pro‐inflammatory state. We hypothesized that human endothelial cells exposed to mechanical stretch will promote conversion of human monocytes into activated DCs. We co‐cultured human aortic endothelial cells (HAECs) with monocytes from normotensive human donors and exposed the HAEC monolayer to either normal cyclical stretch (5%) or hypertensive cyclical stretch (10%) using the Flexcell® Tension System for 48 hours. We found that co‐culture of monocytes with HAECs exposed to 10% mechanical stretch have a marked increase in pro‐inflammatory cytokines such as IL‐6, I‐23A and IL‐1β compared to 5% stretch. HAECs exposed to 10% stretch promoted monocytes in culture to differentiate into DCs, as evidenced by the surface expression of CD209, CD83 and the co‐stimulatory marker CD86. These monocytes also had an accumulation of IsoLG‐adducted proteins compared to controls (69.73 ± 5.802 vs 10.79 ± 1.854 respectively, p = 0.0001) as evidenced by intracellular staining and flow cytometry. In addition, these monocytes in culture with endothelial cells exposed to 10% stretch expressed the phosphorylated form of STAT3 (pSTAT3) and this was prevented when cell cultures were treated with STAT3 inhibitor, stattic. Monocytes co‐cultured with 10% stretched HAECs induced a 1,500‐fold increase in CD4+ T cell proliferation and a 1,300‐fold increase in CD8+ T cells proliferation as monitored by CFSE compared to 5% stretch controls. Conversely, monocytes‐HAEC cultures exposed to 10% stretch and treated with STAT3 inhibitor prevented both CD4+ and CD8+ T cell proliferation. Monocytes were plated inside a transwell dish that only allows the exchange of small molecules while the endothelial cells were stretched to either 5% or 10%. We found that monocytes expressed DC markers, pSTAT3, and accumulated IsoLG‐peptides without direct contact with endothelial cells exposed to hypertensive mechanical stretch. These data show that endothelial cells exposed to mechanical stretch cross‐talk with monocytes to promote differentiation into DCs that are immunogenic potentially via the STAT3 pathway and that this is not cell contact‐driven. These findings give insight into a new mechanism of lymphocyte activation in the vascular endothelium during hypertension.

Support or Funding Information

Ruth L. Kirschstein National Research Service Award (NRSA) Diversity F31HL132526
Acute Exercise Rescues Cortex BDNF Signaling In High Fat Fed Male Mice
Authors: Baranowski Bradley , Peppler Willem T , MacPherson Rebecca EK
Published: November 2023

High fat diet induced obesity and insulin resistance have been directly implicated in the neuropathology of Alzheimer's disease. It is thought that high fat diets induce a reduction in neuronal plasticity through a reduction in the neurotrophin, brain‐derived neurotrophic factor (BDNF). Previous work has demonstrated that acute exercise can reverse high fat diet induced alterations in cortices from obese mice, however the underlying mechanisms remain unknown. The purpose of this study was to determine the effects of a single bout of exercise on BDNF content and signaling in the prefrontal cortex from obese insulin resistant mice. Male C57BL/6 mice were fed a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7 weeks. The HFD increased body mass and glucose intolerance (p<0.05). HFD mice underwent an acute bout of exercise (treadmill running: 15m/min, 5% incline, 120min) followed by a recovery period of 2 hours, after which point the prefrontal cortex was collected. Prefrontal cortex from HFD mice demonstrated lower BDNF protein content and phosphorylation of the BDNF receptor (TrkB) and downstream effector cAMP response element‐binding protein (CREB), as well as PGC‐1alpha and ER‐alpha protein content (p<0.05). Two hours following the acute exercise bout there was no change in BDNF protein content or mRNA expression. Further, there was no effect of exercise on the gene expression of PGC‐1alpha or ER‐alpha. However, TrkB and CREB phosphorylation, as well as PGC‐1alpha and ER‐alpha protein content were recovered (p<0.05). Our findings demonstrate for the first time that an acute bout of exercise can increase BDNF signaling in the prefrontal cortex of obese male mice.

Support or Funding Information

Rebecca EK MacPherson was supported by an Alzheimer's Society post‐doctoral fellowship as well as a research grant from the Alzheimer Society Foundation of Brant, Haldimand Norfolk, Hamilton and Halton.
Molecular Mechanism of Insulin Resistance in Offspring of Obese Fathers
Authors: Liu Xinhao , Consitt Leslie , Nowak Felicia , Slyvka Yuriy
Published: November 2023

Parental diet and increased BMI are correlated with abnormal metabolic profile of offspring. Male offspring of high fat diet‐fed obese father have increased mesenteric adipose tissue (MAT) at 12 months and show increased systemic insulin resistance (IR) when compared to that of lean father. Hypothesis of our study is IR develops in offspring due to abnormal adipokine production under epigenetic regulation in adipose tissue, decreasing glucose uptake in muscle contributing to systemic IR. Our present goals are 1) to investigate the synthesis and trafficking of GLUT4 in muscle, the largest organ using glucose; and 2) to investigate the differential gene expression pattern focusing on adipokines and intracellular signaling molecules and differentially methylated sites in MAT in IR offspring. To achieve our objectives, male C57B/6 mice were placed on either LFD (10%) (Gr1) or HFD (45%) (Gr2) for 12 weeks, and then mated with females who had been on LFD. Offspring were maintained on regular chow. Glucose Insulin resistance Index was calculated based on blood insulin and glucose level at 30 mins of Glucose Tolerance Test. Gastrocnemius muscles and MAT were obtained from male offspring at 12 months. Total cell homogenates, subcellular plasma membrane, and GSV fractions were analyzed for GLUT‐4 by Western blot. Results showed increased Insulin resistance Index (IRI), a measure of insulin sensitivity, in 12 months in male offspring in Gr2 when compared with Gr1. Expression of total Glut‐4, 46kd band, shows no difference between Gr1 and Gr2. We developed a subcellular fractionation protocol to measure GLUT‐4 in the plasma membrane and Glucose Storage Vesicles (GSV) to investigate Glut‐4 trafficking which can affect GLUT‐4 function independent of a change in total GLUT‐4. Additional studies will include microarray analysis and methylation specific PCR of MAT. Identification of the underlying epigenetic mechanism of the change in insulin sensitivity will allow us to develop the diagnostic, therapeutic, and preventative strategies against obesity and diabetes in the offspring of obese parents.
Quantification of Sulfide in the Human Cutaneous Microcirculation Bioassay: Methylene Blue Assay Versus an Amperometric Sensor
Authors: Shank Sean , Alexander Lacy , Castro Rita
Published: November 2023

Impaired microvascular function, characterized by attenuated nitricoxide (NO)‐mediated endothelium‐dependent dilation, is one of the earliestmanifestations of cardiovascular disease, and occurs prior to dysfunction inconduit arteries and veins. In addition to NO, hydrogen sulfide (H2S)is an important signaling molecule involved in the regulation of vascular tone throughits direct effects on vascular endothelial and smooth muscle cells, andindirect effects by interacting with the NO‐synthase signaling pathway. Atphysiologic pH, H2S is easily lost by dissipation into theatmosphere, making it difficult to reliably quantify in biological samples. Thepurpose of this experiment was to compare methods for quantifying H2Sconcentration in our in vivo bioassayexamining H2S‐dependent mechanisms in the human cutaneousmicrovasculature. We compared a sulfide‐sensitive amperometric sensor to amethylene blue assay to measure sulfide concentration in dialysate obtained fromintradermal microdialysis probes. We hypothesized that the methylene blue assaywould be more accurate than the amperometric sensor in quantifying H2Sconcentration because the former uses zinc acetate, which traps the H2Sin solution, preventing dissipation to the atmosphere. To test this we perfusedtwo different concentrations of Na2S (20 and 60 mM), a H2Sdonor, through four intradermal microdialysis fibers placed into the ventralforearm. Dialysate from the probes was collected in either phosphate‐bufferedsaline or in zinc acetate (1%) solution for immediate H2Squantification. The ratio between the sulfide content pre‐to‐post dialysis was quantified in one set of samples using the amperometric probe and in a second set of samples by methylene blue assay. Using the methylene blue assay, the sulfide ratios were 0.94 ± 0.06 and 0.91 ± 0.18 for 20 and 60 mM Na2S, respectively. Using the amperometric sensor, the ratios were 0.69 ± 0.16 and 0.74 ± 0.14 for 20 and 60 mM Na2S, respectively. We concluded thatthe methylene blue assay is a more accurate method to quantify H2Sconcentration in dialysate from intradermal microdialysis fibers. Therefore, amethylene blue assay may be a better method to quantify H2S concentration in microdialysis dialysate samples.

Support or Funding Information

NIH HL093238 (LMA)
INTERMITTENT SPONTANEOUS BREATHING PREVENTS MECHANICAL VENTILATION‐INDUCED DIAPHRAGM ATROPHY AND DYSFUNCTION
Authors: Ichinoseki‐Sekine Noriko , Yoshihara Toshinori , Tsuzuki Takamasa , Morton Aaron , Hinkley Matthew J , Powers Scott K , Naito Hisashi
Published: November 2023

Mechanical ventilation (MV) is used to provide adequate pulmonary ventilation for patients in respiratory failure. Although MV is often a life‐saving intervention, prolonged MV results in the rapid development of diaphragm atrophy and contractile dysfunction (collectively known as ventilator‐induced diaphragm dysfunction (VIDD)). Importantly, VIDD contributes to difficulty in weaning patients from MV, which is in turn associated with increased mortality and morbidity. Therefore, developing a strategy to protect the diaphragm against VIDD is important. Although studies have investigated the impact of prolonged MV on VIDD, limited data exist regarding the impact of intermittent spontaneous breathing during MV on protection against VIDD. Therefore, we investigated the effects of intermittent spontaneous breathing on VIDD. Adult male Wistar rats (n = ~10/group) were randomly assigned to one of three groups: 1) anesthetized control (CON) with no MV; 2) controlled MV (CMV) for 12 hours; and 3) intermittent spontaneous breathing during MV (1‐min spontaneous breathing phase per hour (IMV). In the IMV group, voluntary diaphragm activation occurred 89.2 ± 6.8 times during each minute of spontaneous breathing. As expected, CMV resulted in significant diaphragm atrophy and contractile dysfunction (P < 0.05) along with activation of caspase‐3 and phosphorylation of signal transducer/transcriptional activator‐3 (STAT3) in the diaphragm. In contrast, intermittent breathing prevented MV‐induced activation of caspase‐3 and phosphorylation of STAT3. Importantly, animals in the IMV group were protected against VIDD. These findings reveal that as little as 1‐min/hour of spontaneous breathing during MV is protective against VIDD, in part, by prevention of MV‐induced activation of caspase‐3 and STAT3 in the diaphragm.

Support or Funding Information

This work was supported by JSPS KAKENHI Grant Number 26350820 and 15KK0131 and NIH R01, R01AR064189
A Possible Role of Skeletal Muscle‐Derived Adiponectin in the Regulation of Skeletal Muscle Mass
Authors: Goto Katsumasa , Ito Rika , Higa Masaki , Yokoyama Shingo , Sugiura Takao , Miyata Hirofumi , Ohira Yoshinobu , Yoshioka Toshitada
Published: November 2023

Aging‐associated severe skeletal muscle atrophy, so‐called sarcopenia, is considered as a risk factor for falls in older adults. Recent cohort studies shows high circulating adiponectin levels predict decreased muscle strength among older adults. Adiponectin, one of adipokines, is exclusively synthesized in adipocytes, is secreted into circulation, binds to adiponectin receptors (AdRs), especially AdR1, and exhibits insulin‐sensitizing effects to stimulate the utilization of glucose and lipids in skeletal muscle cells. We hypothesize that high adiponectin levels may have atrophic effects on skeletal muscle cells. Therefore, this study investigated aging‐associated changes in adiponectin expression in skeletal muscle and effects of high adiponectin levels on myogenic differentiation. All procedures for animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health (Bethesda, MD, USA) and were approved by the Animal Use Committee of Toyohashi SOZO University. Aging‐associated up‐regulation of adiponectin in fast extensor digitorum longus muscle was observed. Agonist for AdRs, AdipoRon, suppressed myogenic differentiation of C2C12 cells in a dose‐dependent manner. Knockdown of AdR1 in C2C12 myoblasts induced by small interfering RNA (siRNA), partially depressed the AdipoRon‐induced suppression of C2C12 differentiation. Aging‐associated up‐regulation of adiponectin in skeletal muscle may induced muscle atrophy in especially fast skeletal muscle.

Support or Funding Information

This study was supported, in part, by Grants‐in‐Aid for challenging Exploratory Research (26560372), and Grants‐in‐Aid for Scientific Research (C, 26350818) from the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, the Naito Foundation, Graduate School of Health Sciences, Toyohashi SOZO University, Descente Sports Foundation, and All Japan Coffee Association. No COI.
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 Information

This 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 Information

NIH and AHA
3D Virtual Anatomic Models of Ventricle and Brainstem from Computed Tomography Arteriograms
Authors: Palmer Sam A. , Smith Andrew D , Lynch James C , Cui Dongmei
Published: November 2023

The use of 3D models to understand complex human anatomic structures has received more and more attention as technology improves. The ventricles of the brain are comprised of a communicating network of cavities, which include two lateral ventricles, a third ventricle within the diencephalon, and a fourth ventricle within the brainstem. Using computed tomography arteriogram (CTA) images of the head, anatomic structures of the brain were manually segmented using surface rendering display of the CTA images Image segmentation was facilitated by use of a Wacom pen and tablet. Amira software version 5.6 was used to develop the 3D models of the ventricles and brain stem. The axial, sagittal, and coronal images of the brain were used in tandem to provide a holistic view for segmentation. The 3D virtual models of the ventricles and brainstem can then be presented stereoscopically to show spatial relationships between the ventricle cavity space and the brainstem with a stereoscopic view via polarized 3D glasses. These structures can be rotated through 360 degrees in all axes, and can be zoomed in and zoomed out. 3D models like these help students understand the complex spatial relationships between the ventricles and brainstem that are otherwise difficult to visualize in traditional, 2D textbook images.
Blood Pressure and Cerebral Blood Flow Following Concussion: Implications for Diagnosis
Authors: Knox Allan , Falvo Michael , Favre Michelle , Serrador Jorge
Published: November 2023

Purpose

The 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.

Methods

We 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.

Results

Mean 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).

Conclusion

Changes 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

Introduction

The 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.

Objectives

To 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.

Methods

A 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.

Results

The 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.

Conclusion

The 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 Information

Supported 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
Arginine vasopressin acts directly upon human placental trophoblasts to elicit calcium responses
Authors: Deng Guorui , Perschbacher Katherine J , Carrillo‐Saenz Leslie , Warwick Charles A , Scroggins Sabrina M , Devor Eric J , Santillan Donna A , Usachev Yuriy M , Gibson‐Corley Katherine N , Santillan Mark K , Grobe Justin L
Published: November 2023

Previously we demonstrated that preeclampsia, a hypertensive disorder of pregnancy, is associated with elevated secretion of arginine vasopressin (AVP) as early as the sixth week of gestation. In addition, chronic low‐dose infusion of AVP into pregnant wildtype C57BL/6J is sufficient to initiate all of the cardinal phenotypes of preeclampsia including gestational‐dependent de novo hypertension, renal glomerular endotheliosis, placental hypoxia and intrauterine growth restriction. We hypothesize that AVP acts directly upon placental trophoblasts to cause placental dysfunction, and that this mechanism contributes to placental dysfunction during preeclampsia. First, we performed in silico re‐analyses of a published microarray dataset (GSE75010). In this dataset (n=77 controls, n=80 preeclampsia), all five types of AVP receptors were abundantly expressed at the mRNA level in placental tissue. Interestingly, placentas from human pregnancies complicated by preeclampsia exhibited increases in expression of the AVPR1A (p=0.03) and OXTR (p<0.01) receptors, but no significant changes in the other AVP‐sensitive receptors including AVPR1B (p=0.14), AVPR2 (p=0.98), or CUL5 (p=0.09). Second, we confirmed that all five receptor subtypes are expressed at the mRNA level in cultured immortalized human first‐trimester trophoblasts (HTR8/SVneo cells). Third, we examined second‐messenger signaling mechanisms, focusing on intracellular Ca2+ release, as the Gαq‐calcium pathway is commonly activated by AVPR1A, AVPR1B, and OXTR. Increases in intracellular Ca2+ concentration ([Ca2+]i) with graded doses of AVP were examined in HTR8/SVneo cells pre‐loaded with the fluorescent Ca2+‐sensitive indicator FURA‐2. AVP evoked [Ca2+]i responses of increasing amplitude at 10, 100 and 1000 nM. Fourth, we examined AVPR1A receptor‐dependence of these [Ca2+]i responses. Pre‐treatment of the HTR8/SVneo cells with the AVPR1A‐selective antagonist relcovaptan (1 uM) abolished [Ca2+]i responses to AVP (100 nM), and subsequent washout of the antagonist restored responsiveness. These findings lead us to conclude that human placental trophoblasts express AVP receptors which functionally couple to Gαq‐calcium signaling. Together, the findings that (i) AVP secretion is elevated during preeclampsia, (ii) AVP is sufficient to initiate preeclampsia phenotypes in mice, (iii) AVPR1A appears to be increased in placenta from preeclamptic pregnancies, and (iv) AVPR1A activation functionally couples to Ca2+ signaling in trophoblasts supports the overall concept that AVP‐AVPR1A‐Ca2+ signaling in the trophoblast may contribute to placental dysfunctions in preeclampsia.
Measurement of body fluid distribution with posture change using segmental bioelectrical impedance analysis
Authors: Nishimura Naoki , Sugimoto Naotoshi , Ohnishi Norikazu , Matsumoto Takaaki , Masuo Yoshihisa , Iwase Satoshi
Published: November 2023

Bioelectrical Impedance Analysis (BIA) is adopted as a simple method to measure the body composition including the body fluid volume, muscle volume, and body fat volume in human. Using segmental BIA, we investigated time‐course changes in the body fluid distribution in various body segments with posture change and during −6° head‐down bed rest, regarded as simulated space flight. The body fluid distribution was measured in 9 body segments during the following periods: (1) 15‐minute supine position, (2) 15‐minute standing position, and (3) 60‐minute −6° head‐down bed rest. The body fluid volumes in the forearms and lower limbs gradually increased with posture change from supine to a standing position, but those in the upper arms slightly decreased. In addition, the body fluid volume in the trunk retained a steady state during standing. However, it decreased gradually in one subject and he could not complete the 15‐minute standing position. The body fluid volumes in the arms, abdomen, and lower limbs gradually decreased during the 60‐minute −6° head‐down bed rest, and the decrease was greater in the arms than in the abdomen and lower limbs. In contrast, the body fluid volume in the trunk tended to gradually increase during the −6° head‐down bed rest. It was suggested that segmental BIA provides more information on the indices of orthostatic intolerance.
Management of positive peritoneal cytology gastric cancer patients
Authors: Lianos Georgios D. , Bali Christina D. , Schizas Dimitrios , Mitsis Michail , Galli Federica , Rausei Stefano
Published: November 2023

Prognosis of patients with stage IV gastric cancer remains up to date dramatically poor. A subgroup of these patients has only positive peritoneal cytology in the peritoneal lavage and represents a target issue of the recent ongoing research. The administration of neoadjuvant chemotherapy, either systemic or intraperitoneal or hyperthermic intraoperative peritoneal chemotherapy, with a variety of combinations of drugs has assisted some of these patients to become peritoneal cytology negative, with a significant implication in their prognosis. Staging laparoscopy is widely used to detect occult peritoneal disease and has, therefore, reduced the number of unnecessary laparotomies. However, recent reports point out a low sensitivity of staging laparoscopy and cytological exam in detecting viable cancer cells and focus on the need of more accurate methods of examining the peritoneal fluid by immunohistochemistry or molecular assays. This review focuses on the latest scientific evidence regarding the optimal management of positive peritoneal cytology gastric cancer patients.
Evolutionary dynamics in Irano-Anatolian and Caucasus biodiversity hotspots: Evolutionary radiation and its drivers inGypsophila(Caryophyllaceae)
Authors: Madhani Hossein , Rabeler Richard K. , Heubl Guenther , Stacy Elizabeth , Madhani Navid , Zarre Shahin
Published: November 2023

● Diversification rates vary through time, with bursts of rapid diversification underscoring species richness across the Tree of Life. Yet the abiotic and biotic factors that correlate with periods of rapid diversification are not well known. ● We explored the diversification dynamics ofGypsophila(Caryophylleae: Caryophyllaceae), a large and diverse genus with a high degree of endemism in the Irano-Anatolian and Caucasus biodiversity hotspots. We tested the hypothesis of young and recent diversification of biodiversity in these two hotspots and investigated the biotic and abiotic, and paleoenvironmental cofactors of diversification within the Caryophylleae tribe, with a special focus onGypsophila. ● Our analysis identified multiple shifts in the diversification rate within Caryophylleae, including a newly identified shift inGypsophila, which began approximately 3 million years ago and was triggered by both paleoenvironmental factors and morphological novelties. These novelties were enabled by explosive diversification of woodiness and perenniality and were facilitated through the high adaptability ofGypsophilato gypsum soil and the harsh environments of alpine habitats. ● These findings reveal the highly dynamic evolutionary history of both the Caryophylleae clade andGypsophila, consistent with the extensive historical fluctuations in the geology and climate of the Irano-Anatolian and Caucasus biodiversity hotspots. This study significantly improves our understanding of the dynamics of evolution in the Irano-Anatolian and Caucasus biodiversity hotspots and highlights the impact of environmental changes and morphological innovations on diversification rates.
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

During 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

Mammalian 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

Tactile 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.