bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of M2 and M3 Muscarinic Receptors Across Medullary Respiratory Nuclei
Authors: Burgraff Nicholas , Neumueller Suzanne , Langer Thomas , Bukowy John , Talwar Sawan , Hodges Matthew , Forster Hubert
Published: November 2023

The M2 and M3 muscarinic receptors in mammals have been shown to be expressed in the brainstem, but there are differences in expression among respiratory nuclei. We previously found in goats that the nonspecific muscarinic receptor antagonist atropine, when dialyzed into rostral pontine respiratory nuclei depressed breathing, whereas atropine dialyzed into the pre‐Bötzinger (preBötz) region increased breathing. Since M2 receptors are thought to decrease breathing, whereas M3 receptors are thought to increase breathing, we hypothesized the stimulation of breathing by atropine dialysis into the medullary nuclei could be because only M2 receptors are expressed in the medulla of goats. Accordingly, we currently investigated the distribution of M2 and M3 receptors in medullary respiratory nuclei. We used immunohistochemistry to quantify the relative distribution of the M2 and M3 muscarinic receptors across respiratory nuclei of the goat medulla. We found that both M2 and M3 receptors were expressed in the pre‐Bötzinger region, hypoglossal nucleus, dorsal motor nucleus of the vagus, nucleus ambiguous, and nucleus tractus solitarius. These data lay the foundation to characterize the expression of the M2 and M3 muscarinic receptors across the goat medullary respiratory nuclei, which is critical for understanding their function in the neural control of breathing.

Support or Funding Information

Supported by NIH Grant HL‐112996, HL‐007852, and the Department of Veterans Affairs
BOSTON CHILDREN'S MUSEUM: A WONDERLAND FOR PHYSIOLOGY
Authors: Gwosdow Andrea , Daniels Alissa
Published: November 2023

PhUn (Physiology Understanding) Days at Boston Children's Museum are a collaboration between a physiologist and the science program at the museum. The goal is to have fun and teach children (ages 0 to 12 years) and their grown‐ups physiology while visiting the museum. We plan a variety of activities around the museum that are both located in stations and take advantage of exhibits already in the museum. All activities are explained by student volunteers from area colleges. When children enter the museum, they are welcomed to PhUn Day and told the location of activities. A fun activity, the lungometer, is located close to the museum entrance. Station activities include an anatomy puzzle called Insides Out; Digestion, which provides an inside look at digestion in your gastrointestinal tract; You're the Doctor, which provides children the opportunity to explore medical equipment in a non‐scary non‐threatening environment; Bend It explores joints and all of the places in the body that bends; Making Snot focuses on the different components of mucous, and why it's important to your health; Blood Vessel Volume enables children to learn what happens when your heart pumps blood through the blood vessels, as well as what happens when blood vessels are clogged; a heart dissection is nearby for those interested. Keep the Heat is a comparative physiology activity that explains how different animals maintain their body temperature. An activity in an existing exhibit has children check their pulse before and after trying one of the many activities in KidPower, an exhibit that focuses on helping families live active, healthy lifestyles together. Another, the light table, has x‐rays for visitors to see different parts of the body and explore x‐rays of animals as well as people. Nearby are bones from different animals and related puzzles for children to play with. Through these activities, physiology is experienced by 800 to 2500 museum visitors over 2 days—Friday evening and Saturday. This is a great way to teach the community about their body, health and physiology and engage students and faculty in science outreach. It is always an exciting time for everyone!
Teaching the themes: PhUn Week student‐led stations
Authors: Crecelius Anne R
Published: November 2023

Physiology Understanding (PhUn) Week is an outreach program that encourages connections between scientists and their local schools. Students (n=25) enrolled in an undergraduate Human Physiology course served as visiting scientist teachers for four 7th grade science classes at a non‐traditional charter school (82 participants). University students designed a brief lesson plan that related to one of the four themes of physiology: 1) Structure and function are closely related; 2) living organisms need energy; 3) Information flow coordinates body functions; and 4) homeostasis maintains internal stability. Each lesson also included a physiology‐related career. Seventh grade participants rotated through the 4 stations for ~10 minutes each. A 6 question assessment was administered to 7th graders pre‐ and post‐visit addressing the definition of physiology (open‐ended), each of the 4 themes (true or false), and careers in physiology (open‐ended). Post‐visit, students’ average percent correct responses on the themes increased ~16% (pre vs post: 58% vs 74%) and the majority of students demonstrated partial or complete knowledge of the definition of physiology and related careers (63% and 59%, respectively). These results suggest brief, theme‐focused stations can be an effective PhUn Week teaching activity for partnering undergraduates and middle‐school students.

Support or Funding Information

None.
Interactions with Volunteers at a Day of Hands‐on Physiology Demonstrations Increases Interest in Scientific Careers in a Native American Indian Population of Middle and High School Students
Authors: Schiller Alicia M , Becker Bryan , Zucker Irving , Godfrey Maurice
Published: November 2023

Purpose

To provide middle and high school students from Nebraska and South Dakota Native American reservations with an interactive and physiology based educational experience and exposure to scientific careers.

Methods

We partnered with several schools representing middle and high school students from various Native American Indian tribes of Nebraska and South Dakota. Approximately 300 children were bussed in for a day of physiology‐based activities presented by graduate students and faculty. The “Physiology Day” experience included 9 booths focusing on multiple physiological systems. Students spent approximately 25 minutes at the different booths, and each highlighted a different physiological system. Students completed an assessment designed to determine their baseline knowledge and exposure to science as a career prior to engaging in the educational activities. A second assessment was completed following the day of activities to evaluate the effectiveness of the activities to change students’ perceptions and knowledge of physiology.

Results

Before beginning activities, only 17% of students reported “knowing” a scientist, and this number more than doubled to 44% after interacting with graduate/medical students throughout the event. When students were asked if they “knew anyone that was a healthcare provider” the response pre and post tests were similar (73% vs 76%, respectively). Students were also asked how interested they were in becoming a scientist. At the beginning of the day, almost one quarter (23%) of students indicated that they “did not know” if they were interested in becoming a scientist, which decreased by approximately half (12%) at the end of the day. The proportion of students that indicated that were “very interested” in becoming a scientist increased by 8%. By way of control, students were asked about their interest in health‐related careers by evaluating their interest in working in a hospital or clinic. There was only a 3% decrease in students answering “did not know” to this question in the pre and post‐tests and a 1% decline in students answering “very interested”. Before the activities 64% of students indicated that they believed science to be “very useful”, which increased to 72% of responders following the day of activities.

In conclusion, students participating in our physiology‐themed outreach event were able to interact with volunteers at a level sufficient to increase their awareness of individuals that are scientists. Our event also promoted an increased interest in considering a career in science and increased students’ perceptions of the usefulness of science.

Support or Funding Information

SEPA (RR032178) (OD011071)
Borderline high blood pressure in people with Miltenberger GP.Mur phenotype is associated with elevated band 3 expression on the erythrocyte membrane
Authors: Hsu Kate , Lin Hui‐Ju , Yao Chin‐Che , Cheng Han‐Chih , Kuo Mei‐Shin
Published: November 2023

The erythrocyte surface antigen GP.Mur (also known as Miltenberger subtype III, or Mi.III) is one of the most clinically important red blood cell (RBC) antigens in the field of transfusion in Southeast Asia. GP.Mur is a hybrid membrane protein based on the structure of glycophorin B, inserted with a piece of glycophorin A. The incidence of GP.Mur is rare in Caucasians and northern Asians, but between 2 – 6% among Southeast Asians. We previously showed that GP.Mur+ RBCs express 10% or more band 3 (Cl−/HCO3− exchanger) on the erythrocyte surface. GP.Mur promotes structural and functional expressions of band 3. Our most recent human study uncovered that GP.Mur+ healthy people bear larger capacities of HCO3−/CO2 respiration. Unexpectedly, GP.Mur+ subjects also have slightly higher blood pressure than the control subjects.

Objective

In this study, we further explored whether borderline hypertension in these healthy GP.Mur+ subjects could be associated with their unusual expression of GP.Mur‐band 3 complexes on the erythrocyte membrane. We quantitated band 3 levels in RBC ghosts, and combined these biochemical data with physiologic measurements from the previous human study.

Results

The two parameters—blood pressure and band 3 expression, were both higher in GP.Mur+ people, and there were no differences between GP.Mur+/+ and GP.Mur+/−. However, there was a direct correlation between pulse pressure and the concentration of band 3 in GP.Mur+/+ subjects, which was not observed in GP.Mur+/− or the control subjects. By comparison, physiologic HCO3−/CO2 respiration was also slightly faster in GP.Mur+/+ than in GP.Mur+/− subjects.

Conclusion

From these findings, elevated blood pressure and expedited CO2 respiration are likely both resulted from GP.Mur‐assisted higher band 3 expression on the RBC membrane. Further, the biochemical and physiologic differences between GP.Mur+/+ and GP.Mur+/− could be due to their variations in the structural organizations of band 3 complexes on the red cell membrane.

Support or Funding Information

Supported by MOST 103‐2320‐B‐195‐001‐MY3 from Taiwan Ministry of Science & Technology
Higher anxiety is associated with elevated inflammation independent of obesity in humans
Authors: Holwerda Seth , Fiedorowicz Jess , Kalil Graziela , Persons Jane , Stroud Amy M. , Ajibewa Tiwaloluwa , Dubishar Kaitlyn , Moser David , Abboud Francois M. , Pierce Gary L.
Published: November 2023

Obesity and anxiety states are both associated with elevated cardiovascular disease (CVD) risk. Anxiety and obesity are also linked with an increased pro‐inflammatory phenotype; however, the extent to which anxiety is associated with inflammation independent of obesity remains unclear. We hypothesized that anxiety would be independently associated with elevated inflammation in two cross‐sectional samples, one with obesity [body mass index (BMI) ≥ 30 kg/m2] and one with higher anxiety. In cross‐sectional samples of individuals with obesity and at least one CVD risk factor (n=100; 58 ± 8 yrs; BMI: 37 ± 6 kg/m2) or with moderate‐to‐high anxiety (n=38; 36 ± 1 yrs; BMI: 28 ± 1 kg/m2), subjects had assessments of anxiety using the Beck Anxiety Inventory (BAI) and serum highly sensitive C‐reactive protein (CRP) as a generalized marker of inflammation. BMI was significantly correlated with CRP in both groups (obesity: rho=0.42, p<0.001; moderate‐to‐high anxiety: rho=0.46, p=0.004), and BAI scores were also significantly correlated with CRP similarly in both groups (obesity: rho=0.28, p=0.005; moderate‐to‐high anxiety: rho=0.33, p=0.04). In multivariate models in the obesity cohort, the relation between BAI and CRP remained significant (p=0.038), independent of BMI (p=0.02), age and sex. In multivariate models in the moderate‐to‐high anxiety cohort, BAI was only marginally associated with CRP (p=0.10), adjusting for age, sex, and BMI (p=0.007). State‐trait Anxiety Inventory (STAI) scores in the moderate‐to‐high anxiety group demonstrated a marginal association with CRP for trait (chronic) anxiety (rho=0.30, p=0.07) but not state (acute) anxiety (rho=0.23, p=0.16). These preliminary findings suggest that higher anxiety levels are associated with elevated inflammation in persons with obesity beyond that attributable to higher BMI, and that trait anxiety may be more relevant to a pro‐inflammatory state than state anxiety. Further study is warranted to assess whether elevated inflammation in persons with anxiety and obesity represents a potential therapeutic target to mitigate the attendant increased CVD risk.

Support or Funding Information

NIH T32 HL07121, AHA13SDG143400012, NIH P01 HL014388, NIH CTSA U54TR001356.
Decrease in Erythrocyte Deformability Promotes the Cell Accumulation near the Vessel Wall in Small Arterioles
Authors: NAMGUNG BUMSEOK , JU MEONGKEUN , NG YAN CHENG , KIM SANGHO
Published: November 2023

This study demonstrated that the deformability‐impaired red blood cells (RBCs) preferentially accumulate near the vessel walls in arterioles in vivo. Chemically hardened RBCs (hRBCs) with fluorescent labeling from the donor rat were infused into the recipient rat circulatory system while maintaining the total blood volume. Fluorescent imaging analysis was performed to quantify the radial (R) distribution of the labeled hRBCs in small arterioles (~76 μm of diameter). In vivo experimental results showed that majority of the hRBCs (65%) were accumulated near the vessel wall (0.7R–0.9R). This near‐wall accumulation of hRBCs partly contributed to the decrease in the mean cell‐free layer width, and significantly increased the variation of cell‐free layer width (P < 0.05). Dynamic particle simulation by modeling individual RBCs was in agreement with the in vivo experiments by predicting that the hRBCs exhibit relatively weakened tank‐treading motion as compared with normal RBCs. Consequently, this leads to an attenuation in the inward migration of the cells toward the flow center. Our findings conclusively proposed that the preferential near‐wall accumulation of hRBCs in vivo could be attributed by the attenuated dispersion of hRBCs with reduced tank‐treading motion once they entered into the near‐wall zone. In addition, frequent sudden changes of lateral displacement of hRBCs while passing through multiple bifurcations partly contributed to their near‐wall accumulation despite the relatively shorter cell travel distance in vivo.

Support or Funding Information

This work was supported by National Medical Research Council (NMRC)/Cooperative Basic Research Grant (CBRG) No./0078/2014
Post‐treatment with Ma‐Huang‐Tang ameliorates cold‐warm‐cycles induced rat lung injury
Authors: Han Jing‐Yan , Xiao Meng‐Meng , Pan Chun‐Shui , Liu Yu‐Ying , Ma Li‐Qian , Yan Li , Wang Chuan‐She , Fan Jing‐Yu
Published: November 2023

Frequent and drastic ambient temperature variation may cause respiratory diseases such as common cold and pneumonia, the mechanism for which is not fully understood, however, due to lack of appropriate animal model. Ma‐Huang‐Tang (MHT), a traditional Chinese medicine formula, is widely used in China for treatment of respiratory diseases including common cold, upper respiratory tract infection, among others. The present study aimed to investigate the effect of MHT treatment on temperature alternation‐induced rat lung injury and explore the underlying mechanisms. Male Sprague‐Dawley rats (180–200 g) were exposed to a cold environment (−15 °C) for 1 h and then shifted to a warm environment (25 °C) for 30 min. This cold and warm alteration cycled 4 times to imitate ambient temperature variation. Rats were administrated with MHT (1.87 g/kg) or saline by gavage 6 h after cold‐warm‐cycles. Lung injury was assessed 6h and 24h after cold‐warm‐cycles, respectively. Cold‐warm‐cycles induced pulmonary microcirculatory disorders including leukocyte adhesion and infiltration, lung perivascular edema, decrease in the expression of tight junction proteins, increase in the expression and activation of Caveolin‐1, Src and NF‐κB activation, NADPH oxidase subunits p47phox, p40phox and p67phox membrane translocation and inflammatory cytokines production. All the alterations were significantly ameliorated by post‐treatment with MHT. This study showed that rat subjected to cold‐warm‐cycles may be used as an animal model to investigate ambient temperature variation induced lung injury, and suggested MHT as a potential strategy to combat lung injury induced by temperature variation.
Remote Control of Intracerebral Arteriole Diameter by Capillary TRPV4 and TRPV3 Channels
Authors: Dabertrand Fabrice , Harraz Osama F , Longden Thomas A , Brayden Joseph E , Nelson Mark T
Published: November 2023

Brain parenchymal arterioles (PAs) terminate to from a dense network of hundreds of miles of capillaries, which are in close apposition to all neurons. Capillary endothelial cells (cECs) are therefore ideally positioned to detect and respond to local neuronal activity. Using a novel intact ex vivo preparation of pressurized PAs and capillaries from mouse, we revealed that application of the postulated neurovascular coupling agent prostaglandin E2 (PGE2‐1μM) onto capillaries triggered an upstream arteriolar vasodilation (38.6%). We then investigated the hypothesis that activation of EP1 receptors (Gq protein‐coupled PGE2 receptor) in the cECs initiates a retrograde Ca2+ signal mediated by transient receptor potential vanilloid (TRPV) cation channels. Selective capillary stimulation with TRPV4 (GSK1016790A‐1 μM) or TRPV3 (Carvacrol‐10 μM) agonists induced upstream PAs dilation (37.9% and 26.2% respectively). Patch clamp electrophysiology performed on acutely isolated cECs from mouse brain confirmed the presence of both TRP channels (TRPV4: 160.3±26.2 pA/pF at +100 mV; and TRPV3: 14.9±1.7 pA/pF at +100 mV). The TRPV4 antagonist HC‐067047 (1 μM) abolished GSK1016790A‐induced currents and upstream arteriolar dilation, while carvacrol‐induced responses were absent in TRPV3 knock out animals, further supporting the role played by both channels in the capillary to arteriole signaling. Finally, using an adeno‐associated virus approach, we transfected cECs with fluorescent Ca2+ indicator protein GCaMP6f and recorded TRPV4 and TRPV3 channel‐dependent propagating Ca2+ signals within cECs of the aforementioned pressurized ex vivo preparation. We have previously shown that activation of cEC KIR2.1 channels by external K+ initiates a propagated, regenerative hyperpolarization causing upstream arteriolar dilation, which promotes rapid hyperaemia at the site of the K+ increase. Here we present data supporting the presence of a Ca2+ signaling route, acting in parallel with the electrical pathway, that communicates activation of capillary TRPV4 and TRPV3 channels to dilate upstream PAs. In this model, capillary GqPCR activation would reinforce and sustain electrical signals by providing an additional level of spatial and temporal control over cerebral blood flow.

Support or Funding Information

Supported by the NIH (R01HL121706, PO1HL‐095488, R37‐DK‐053832; MTN), the Totman Medical Research Trust (MTN), the Fondation Leducq (MTN), the AHA (14POST20480144; TAL), and the United Leukodystrophy Foundation (FD).
Microfluidics‐based side view flow chamber reveals tether‐to‐sling transition in rolling neutrophils
Authors: Marki Alex , Gutierrez Edgar , Zbigniew Mikulski , Groisman Alex , Ley Klaus
Published: November 2023

Neutrophils rolling at high shear stress (above 6 dyn/cm2) form tethers in the rear and slings in front. Here, we developed a novel photo‐lithographically fabricated, PDMS‐based side‐view flow chamber to dynamically visualize tether and sling formation. Fluorescently membrane‐labeled mouse neutrophils rolled on P‐selectin substrate at 10 dyn/cm2. Most rolling cells formed 5 tethers that were 2–30 μm long. Breaking of a single tether caused a reproducible forward microjump of the cell, showing that the tether was load‐bearing. About 15% of all tether‐breaking events resulted in slings. The tether‐to‐sling transition was fast (<100 ms) with no visible material extending above the rolling cell, suggesting a very low bending modulus of the tether. The sling extended downstream in front of the rolling cell at a downward angle of 6°, without touching the flow chamber for 3.19±0.78(SEM) sec. These new observations explain how slings form from tethers and provide unexpected insight into their biomechanical properties.

Support or Funding Information

This project was supported by the P01 HL078784 grant of Klaus Ley.
The Membrane Lipid Composition Regulates The Activity of Talin
Authors: Ye Xin , McLean Mark A , Sligar Stephen G
Published: November 2023

Integrins plays a central role in the dynamics of cell‐cell and cell to extra‐cellular matrix interactions and signaling. A key step in the activation of integrin receptors is the binding of the cytoplasmic domain of integrin subunits by talin. This interaction leads to separation of the integrin transmembrane domains and significant conformational changes in the extracellular domains, resulting in a dramatic increase in integrin's affinity for ligands. Talin is a 470 kDa adapter protein that consists of a N‐terminal head domain (THD) and a C‐terminal rod domain. THD is homologous to to the domain found in band 4.1/ezrin/radixin/moesin family of proteins (FERM domain) with uncanonical linear arrangement of F0–F3 domains. A second mechanism in the regulation of integrin activation is directly related to the fact that full‐length talin adopts an auto‐inhibited conformation. In the cytosol, the rod domain binds THD, preventing talin interactions with the membrane surface and the integrin cytoplasmic domain. The membrane bilayer also plays a critical role in the talin ‐integrin interaction, where anionic lipids are required for proper interaction, yet a detailed picture of the interplay between talin and the membrane has remained elusive. We describe a new fluorescence based assay for probing talin – membrane interactions with Nanodisc bilayers of controlled composition. We show that recruitment of THD to the membrane surface is governed by the absolute charge. Measurement of the donor‐acceptor distances reveals that anionic lipids promote a conformational change in the THD favoring a direct interaction of the F3 domain with the phospholipid bilayer. The magnitude of this conformational change is regulated by the identity of the phospholipid headgroup with phosphatidylinositides (e.g. PI4P and PIP2) promoting the largest conformational motions. In addition, the binding of THD to bilayers containing PIP2 is insensitive to the presence of the inhibitory segments of the talin rod domain, while the association of THD to other tested anionic lipid bilayers are strongly inhibited by purified talin rod domains. Furthermore, we have mapped the activation to the interaction of PIP2 with the F2–F3 domain of the THD. Thus, we show that PIP2 plays a central role in the converting talin to a conformation optimized for interactions with integrin cytoplasmic tails and regulation of the auto‐inhibited form of talin, which are essential for integrin inside‐out activation.

Support or Funding Information

Supported by NIH grant GM101048.
Neuroanatomy Education: Evaluating Methods Of Delivery On Student Opinions And Academic Performance
Authors: Bergen Hugo , Longo Alison , Peeler Jason
Published: November 2023

INTRODUCTION

Medical schools have traditionally used a dissection‐based approach for educating students in neuroanatomy. There is a trend towards increased use of prosected specimens, models, and 3‐D imaging materials as learning resources. It is not known which method constitutes the most effective way to teach students a basic understanding of human neuroanatomy. The purpose of this study was to examine whether the method of educational delivery influences student perceptions about learning anatomy, as well as performance on a practical exam.

METHODS

Undergraduate students from the same medical school were compared. One cohort was taught using a method that involved some dissection of brain specimens while the the second cohort was taught using a method of delivery that employed more prosected specimens. Contact hours for both groups were similar. A standardized educational survey was used to collect information regarding student perceptions and evaluate 6 different methods of delivery. This data was compared against student performance on neuroanatomy practical exams.

Seventy students (dissection=40, prosection=30) completed the survey. Survey results revealed that teaching that used clinical cases was the most effective approach for relating anatomical structure to function, while the use of medical imaging was the most effective approach for instilling anatomical knowledge. When comparing the performance of students on the lab practical exam, the dissection group outperformed the prosection group (mean=83% vs 72%). The dissection group also outperformed the prosection group on exam questions that were given to both groups (mean=80% vs 76%).

CONCLUSIONS

Data suggest that student perceptions and academic performance are influenced by the method of delivery, and that medical imaging and case based scenarios enhance the learning environment. The results will be used to guide the selection of delivery method in future neuroanatomy curriculum.

Support or Funding Information

Funding provided by the Teaching and Learning Enhancement Fund of the University of Manitoba.
THE STIM1 REGULATORS SARAF IN CA2+ SIGNALING IN VIVO
Authors: Son Aran , Ahuja Malini , Muallem Shmuel
Published: November 2023

Store‐Operated Ca2+ influx(SOCs) is mediated by the pore forming channel Orai1, which is activated and regulated by the ER Ca2+ sensor STIM1. In turn, the function of STIM1 is regulated by the SOC‐Associated Regulatory Factor SARAF. SARAF is an ER protein that interacts with STIM1 to mediate the slow Ca2+ dependent inactivation (SCDI) of Orai1 to inhibit SOC and prevent pathological Ca2+ overload. How SARAF functions in vivo is unknown. In the present work, we developed and partially characterized SARAF deficient (SARAF−/−)mice and investigated the role of SARAF in Ca2+ signaling inpancreatic and salivary gland acinar cells. At 8 weeks of age, the body weight of SARAF−/− mice is about 20% lower and the mice show significant cardiac hypertrophy and increased receptor stimulated fluid and electrolyte secretion by the salivary glands. SARAF−/− pancreatic and salivary glands acini have higher resting free cytosolic Ca2+ ([Ca2+]i) levels, increased SOC‐mediated Ca2+ influx and higher agonist‐evoked Ca2+ oscillation frequency. As a consequence, the SARAF−/− cells have higher resting and receptor‐mediated mitochondrial Ca2+ load. The interaction between STIM1 and SARAF in vitro and in vivo is regulated by stimulus intensity. Physiological stimulus intensity increased interaction of SARAF with STIM1, which remains stable for the duration of cell stimulation. At pathological high stimulus intensity interaction of SARAF with STIM1 is transient, accounting for the sustained activation of Ca2+ influx and cell toxicity. These findings suggest that SARAF plays a critical role as a regulator of SOC‐mediated Ca2+ influx in vivo and aberrant SARAF function maybe associated with Ca2+ overload and associated cytotoxicity.

Support or Funding Information

National Institutes of Health, National Institute for Dental and Craniofacial Research
The Potential of Anatomy Ontology in Anatomy Education
Authors: Barger J. Bradley
Published: November 2023

Anatomy students frequently use a superficial study strategy when learning anatomy content. Superficial studying is characterized by a reliance on memorization, and a lack of connections between topics. One way to help students form connections and a deeper understanding of anatomy is to explicitly demonstrate the interconnectedness of anatomy topics. This explicit demonstration is rarely used in lectures, or if it is demonstrated, students fail to understand the utility of making mental connections. The Foundational Model of Anatomy is an anatomy ontology which makes explicit the relatedness of anatomical entities. The original purpose of the FMA was to create a computational tool for bioinformatics work, but I believe it has educational significance, and can help students to build a more connected and useful mental framework of anatomy. In the constructivist theory of education, a student must build their own mental framework to make sense of a complicated topic, but many students lack the tools to do this when presented with the seemingly endless content in an introductory anatomy course. Using the FMA as an organizing principle for anatomy content, students may feel less overwhelmed, and will have a starting point for building their own mental frameworks for anatomy content. This presentation will introduce the philosophical concept of ontology, and discuss the background of the FMA. A review of the literature involving the FMA will be included, and pedagogical implications will be discussed.

Support or Funding Information

None to disclose.
Signalling hypoxia by protein hydroxylation: Transcriptional architecture of the HIF response
Authors: Ratcliffe Peter J.
Published: November 2023

Animal use a set of 2‐oxoglutarate dependent dioxygenases to signal cellular oxygen levels to the transcription factor, HIF, via the post‐translational hydroxylation of specific prolyl and asparaginyl residues. These hydroxylations promote the inactivation and proteolytic destruction of HIF and hence regulate a broad range of cellular and systemic responses to hypoxia. The involvement of this system in a many medically important physiological responses presents both an opportunity and challenge, particularly in defining how the system operates to generate co‐ordinated physiological responses, and in understanding how it might be manipulated therapeutically in specific medical conditions. Advances in the understanding of the pan‐genomic architecture of the HIF transcriptional response, will be described together with the implications of activating such extensive pathways in cancer, and mechanisms that modulate the oncogenic output of HIF pathway activation.
On‐Target Efficacy of a HIF2α Antagonist in Preclinical Kidney Cancer Models
Authors: Kaelin William
Published: November 2023

Biallelic inactivation of the VHL tumor suppressor gene is the signature “truncal” event in clear cell renal cell carcinoma, which is the most common form of kidney cancer. The VHL gene product, pVHL, is the substrate recognition subunit of a Cullin‐dependent ubiquitin ligase that targets the alpha subunits of the HIF transcription factor for destruction when oxygen is available. Pathological accumulation of HIF, and especially HIF2, plays an important role in the progression and maintenance of pVHL‐defective clear cell renal cell carcinomas in preclinical models. Peloton Therapeutics, based on the pioneering work of Drs. Rick Bruick and Kevin Gardner, has developed small molecules that bind to HIF2α and disrupt its interaction with its heterodimeric partner ARNT. We showed that one such tool compound, PT2399, which is closely related to the Peloton lead compound PT2385, inhibits HIF2‐dependent transcription, soft agar growth, and pVHL‐defective tumor formation. These effects are reversible with a PT2399‐resistant version of HIF2α, strongly arguing that they are “on‐target”. pVHL‐defective renal carcinoma cell lines display surprising heterogeneity with respect to HIF2α dependence and PT2399 sensitivity, however, arguing that predictive biomarkers will be needed to optimize the use of HIF2α antagonists in the clinic.
Illegal Substance Abuse among Adolescents with Depressive Symptoms
Authors: Garn Hannah Elizabeth , Kim Hyun
Published: November 2023

Depression is one of the most prevalent mental disorders, while risky behaviors, such as smoking, alcohol consumption and illicit drug use also remain an issue among adolescents. Early smoking has shown a positive association with drug and alcohol consumption as well as increased risk for developing depression, although depressive behavior has not been linked to subsequent smoking of tobacco. This study further examines depression as a positive indicator for smoking, alcohol consumption, and illicit drug use, such as marijuana, cocaine, and heroin, in order to identify health risks in youth. The data come from the National Health and Nutrition Examination Survey (NHANES) from 2011–2012 and 2013–2014, and the study is comprised of adolescents aged 12–17 years (n=3,761). Depressive symptoms are analyzed using the Patient Health Questionnaire (PHQ‐9) which assesses frequency of depressive symptoms. The scoring scheme ranges from 0 to 27, indicating the severity of depressive symptoms. The study uses the structural equation modeling (SEM) to investigate whether depression is likely to provide an incentive for smoking, alcohol consumption, and illicit drug use. Depressive symptoms are positively associated with risky behaviors among adolescents, and additionally, higher PHQ‐9 scores indicate an increased likelihood of engaging in risky behaviors. These results may aide health and educational professionals in identifying youth at risk for smoking, alcohol consumption and illicit drug use. By diagnosing adolescents with depression, interventions to reduce risky behavior in “at risk” youth may be implemented in order to decrease illegal substance abuse.
Dexmedetomidine and propofol differentially alter human immune cell metabolism
Authors: Schilling Jan M , Singaram Vinod , Dhanani Mehul , Habib Andy M , Bui Jack D , Patel Hemal H , Meier Angela
Published: November 2023

Introduction

Prolonged treatment with sedatives such as dexmedetomidine or propofol is common in the critically ill patient, yet their differential impact on immune cell metabolism, specifically, on mitochondrial function, remains to be elucidated. Here we hypothesize that propofol and dexmedetomidine differentially impact human immune cell mitochondrial function.

Material and Methods

Blood was drawn from healthy male and female human donors and peripheral blood mononuclear cells (PBMCs) were isolated and treated with dexmedetomidine and propofol at concentrations achieved in human plasma. Intralipid was used as the control for propofol. Metabolic function (mitochondrial stress and glycolysis) was assessed using the Seahorse XF analyzer.

Results

Cells treated with dexmedetomidine showed decreased maximal respiration, reserve capacity, increased non‐mitochondrial respiration, and overall decreased mitochondrial health as determined by an overall decreased respiratory control ratio (RCR) compared to buffer control in a dose dependent manner. Propofol decreased basal respiration, ATP‐linked respiration, reserve capacity, and non‐mitochondrial respiration dose dependently when compared to intralipid control. Glycolysis assay revealed that propofol treated cells had an increased glycolytic rate with glucose treatment compared to intralipid control and this rate could not be further increased upon addition of Oligomycin A, suggesting a potential glycolytic compensation.

Conclusion

Human immune cell mitochondrial function is significantly and differentially altered by commonly used clinical sedatives. The phenomenon of “immune cell paralysis” has been shown to be associated with increased mortality in septic patients that are commonly treated with sedatives. Mitochondrial function has been tied to immune cell fate and our finding may therefore pose a relevant consideration when treating patients in the intensive care unit.

Support or Funding Information

Angela Meier is supported by the Mentored Research Award of the International Anesthesia Research Society. Furthermore this research was supported by funds from the UCSD Department of Anesthesiology.
Correlation between beta‐arrestin1 and prolactin levels in women with depression during premenstrual dysphoric disorder
Authors: Smith Keisha , Archibong Anthony E , Ansah Twum A , Nayyar Tultul
Published: November 2023

OBJECTIVE

Measurements of beta‐arrestin1 in women with premenstrual dysphoric disorder (PMDD) may potentially serve for biochemical diagnostic purposes and might be useful as evidence‐based support for questionnaires. A reduction in beta‐arrestin1 protein in peripheral blood mononuclear leukocytes (PBMC) and associated increased levels of plasma testosterone were demonstrated previously, during depression in women with PMDD. Hyperprolactinemia in patients with mood disorders are well evident. The present study extended our previous work by examining whether disturbances in the prolactin level distinguish in women with PMDD from premenstrual syndrome (PMS). PMDD is a severe form of PMS and as such have been suggested that women with PMDD have greater risk for future depression during pregnancy, post‐partum period and perimenopause.

DESIGN METHODS

Study participants (n=25) were non‐pregnant women between 18–42 years of age with the symptoms of PMS/PMDD, but not taking any antidepressants and at the luteal phase of menstruation. The protein levels of beta‐arrestin1 in the PBMC were determined by ELISA and the prolactin levels in plasma were measured by radioimmuno assay. The participants were evaluated with Neuropsychiatric Interview (DSMIV‐TR). The severity of depression were determined by the Hamilton Depression Rating Scale scores (HRSD).

RESULTS

Reduction in beta arrestin1 protein levels in mononuclear leukocytes with the increased levels of plasma prolactin concentrations were significantly correlated in women with depression (PMDD) as compared to PMS women.

CONCLUSION

These findings support that reduction in beta‐arrestin1 protein in PBMC are significantly correlated with increased levels of plasma prolactin concentrations during depression in women with PMDD.

Support or Funding Information

Clinical Research Education and Career Development in Minority R25RR17577 (NCRR/NIMHD) and U54 MD007593 (NIMHD) and U54 RR026140 (NCRR) at NIH.
Effect Of (−)‐Epicatechin On Muscle Atrophy After Spinal Cord Injury In Rat
Authors: Gonzalez‐Ruiz Cristian , Gutierrez‐Salmean Gabriela , Rubio‐Gayosso Ivan , Salgado‐Ceballos Hermelinda , Mondragon‐Lozano Rodrigo , Morales‐Guadarrama Axayacatl , Fabela Omar , Saldaña‐Rodriguez Paula , Najera Nayelli , Villarreal Francisco , Ceballos Guillermo
Published: November 2023

Spinal Cord Injury (SCI) is a condition that produces a partial or total loss of physiological functions below the lesion. SCI typically leads to severe muscle atrophy, which limits the recovery from SCI. With muscle atrophy, the muscle fiber size diameter is reduced as cell mass decreases through increased protein turnover/degradation, loss of organelles and cytoplasm. Muscle atrophy after SCI can produce a diversity of system stressors, including neural inactivity, elevated glucocorticoid levels and notable metabolic imbalances. Treatment of such sequelae is limited. In the recent past, we have demonstrated that treatment with the flavanol (−)‐epicatechin (Epi) can trigger multiple positive effects in skeletal muscle including a decrease in the expression of myostatin and increased expression of follistatin, markers of regeneration and multiple mitochondrial proteins suggesting the activation of skeletal muscle repair and/or growth. To determinate the effect of (−)‐epicatechin on muscle atrophy after SCI in rats. Adult female Long Evans rats (250–300 g body weight) were anesthetized with ketamine and xylazine and a laminectomy was performed at T9 vertebra level, followed by spinal cord transection. After recovery from surgery, rats were randomly divided into 2 groups, 1) control group (water) and, 2) (−)‐epicatechin treated (1 mg/kg/day by oral gavage) and evaluated at 7, 30 and 60 days after lesion. Anthropometric measurements of gastrocnemius and soleus sections were performed in hindlimbs with a Vernier caliper and using conventional magnetic resonance spectroscopy. Basso, Beattie and Bresnahan (BBB) functional (locomotor) assessments were performed at 1, 7, 14, 28 days and scoring was evaluated using a circular open field. MRI evidences a 25% less decrease in crosssectional area in hindlimb muscles of Epi treated rats vs. controls. Likewise treated animals demonstrate higher BBB scores. In conclusion, Epi decreases muscle loss after SCI and appears to promote functional recovery in rats

Support or Funding Information

NIH grants # K98717, DK92154 to FV and IPN grants # 20161576 and 2016118 and CONACyT grant # 253769
Rodent Model of Diffuse Acute and Chronic Gastritis with Translational Relevance
Authors: Csekő Kata , Deng Xiaoming , Pécsi Dániel , Hegedűs Ivett , Perkecz Anikó , Szabó Imre , Helyes Zsuzsanna , Szabó Sándor
Published: November 2023

Objective

Stress & anti‐inflammatory drugs induce focal superficial erosions or ulcers, however, there has been no animal model of diffuse gastritis. Sulfhydryl (SH) groups offer gastroprotection, therefore we postulated that drinking water containing SH alkylators may cause diffuse lesions in rats by depleting glutathione (GSH). Transient Receptor Potential Vanilloid 1 (TRPV1) & Ankyrin 1 (TRPA1) ion channels play role in inflammation, but their functions in gastritis have not been investigated. After demonstrating decreased TRPV1 expression in human chronic gastritis biopsies of, we wanted to optimalize and characterize a translational animal model to gain insight into the molecular mechanisms of gastritis.

Aims

1) Test the gastritis‐inducing effect of the SH alkylator iodoacetamide (IA); 2)observe potential strain differences in the inflammatory reactions; 3)investigate TRPV1/A1 expression alterations in comparison with human samples.

Methods

We administered 0.05% & 0.2% IA to the drinking water of Wistar & CFY male rats (8–12‐week‐old) for 7 & 14days. Body weight & water consumption were recorded daily. Macroscopic lesions were scored by the extent of hyperemia, erosions/ulcers & sections were taken for histological assessment. TRPV1/A1 mRNA expressions were determined by qPCR.

Results

IA intake resulted in concentration‐dependent weight loss & reduced water consumption. Diffuse hyperemia & erosions were observed macroscopically after 7 days in all IA‐exposed rats & in 14 days ulcers were induced by both concentrations. Microscopically submucosal edema was observeable followed by leukocytic & lymphocytic infiltration. Susequently, superficial, often hemorrhagic mucosal erosions were seen after 7 days, followed by ulcers in 14 days. In CFY rats, TRPV1 & TRPA1 mRNA expressions were significantly lower in the antrum, similarly to human biopsies. In Wistar rats TRPV1 expression did not change, but a markedTRPA1 increase was seen in both time intervals.

Conclusions

1) IA ingestion for 7 & 14 days caused diffuse acute & chronic gastritis, associated with hemorrhagic erosions & ulcers. 2) Ion channel expression showed a strain difference; TRPA1 mRNA level increased in Wistar rats with both IA‐concentrations & at both time intervals. 3) Since TRPV1/A1 expression in CFY rats was similar to the human gastritis, this strain has translational value to investigate the pathophysiological role of these channels in chronic gastritis.

Support or Funding Information

University funds and grant from Hungary Academy of Science.
Multipronged Therapeutic Effects of Chinese Herbal Medicine Sini San in the Treatment of Depressive Disorder
Authors: Wang Yong , Bai Yiqin , Nugent Colleen A. , Zhu Lixin , Wang Tian , Zhu Ruixin , Wang Wei
Published: November 2023

Background

The traditional Chinese medicine (TCM) Sini San has been known to be effective in depressive disorder treatment. Clinical studies and preclinical researches in human and animal models have confirmed the effects of Sini San on depressive disorder. However, the molecular mechanism of how Sini San affecting depressive disorder is still unclear. This study aimed to reveal the therapeutic mechanism of Sini San in depression by global transcriptomics analysis, and to understand the traditional Chinese medical theory “homogeny of liver and brain” for Sini San from the molecular level.

Methods

We performed systematical analysis on RNA expression profiles in hippocampus, hypothalamus and hepatic tissue with a depression Sprague‐Dawley (SD) rats model induced by chronic unpredictable mild stress (CUMS). We compared the depression model group (N=20) with naive rats as controls (N=20) and with the depression model with Sini San treatment group (N=20) respectively. Bioinformatics methods including differential expression analysis, gene enrichment and expression correlation analysis were conducted.

Results

We found that the expression of 77, 724, 173 genes were influenced by Sini San treatment in depression individuals in hippocampus, hypothalamus and hepatic tissue respectively. Function of these differentially expressed genes (DEGs) covered depression‐associated genes and was consistent with established depression pathology. Among these DEGs, expression of 496 genes were reversed by Sini San, which made the expression profiles of Sini San treatment groups more similar to healthy controls than to depression model groups. Specifically, a multi‐target mechanism involving immune response and steroid synthesis was proposed to explain how Sini San exerts positive influence on depressive disorder. Hub genes like Ciita, Lcp2 and Dusp2 in immunity, and Hmgcr and Cyp1a2 in steroid metabolism exhibited significant response to Sini San treatment. Moreover, to explore the TCM theory which holds that liver in Chinese Medicine includes both anatomical liver and brain, the correlation between brain and liver in depressive disorder treated by in Sini San was investigated. Lcp2 and Cyp1a2 are highly correlated genes in brain and liver, and therefore also identified as the most important components of the therapeutic mechanism of Sini San.

Conclusion

The results of the study for the first time provide a systematic molecular insight into the therapeutic mechanism of Sini San in alleviating depressive disorder.

Support or Funding Information

This work was financially supported, in part, by the Grants from the National Natural Science Foundation of China (No. 81302908, 81530100, 81473456, 81503379 and 81470191), Beijing Natural Science Foundation (No.7142099), Fok Ying Tung Education Foundation (No. 151044), and excellent young scientist foundation of BUCM (No.2016‐JYB‐XJ003, 2015‐JYB‐QNJSZX001 and 2015‐JYB‐XYQ001).