bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological changes, gene expression and prognosis in papillary thyroid carcinoma
Authors: Bai Yanhua , Nakamura Misa , Li Yaqiong , Liu Zhiyan , Ozaki Takashi , Mori Ichiro , Yashihiro Ito , Miyauchi Akira , Kakudo Kennichi
Published: June 2021

Loss of cellular polarity/cohesiveness (LPC) and periostin expression are involved in the epithelial‐mesenchymal transition in the epithelial malignancies. Their roles in papillary thyroid carcinoma (PTC) were studied. There was a significant correlation between LPC in the invasive front and the up‐regulation of periostin in the tumors. Both of them were significantly correlated with extrathyroid invasion (ex) and pT. In addition, LPC in the invasive front was correlated with a significant poor disease‐free survival(DFS) in 181 cases of PTC. The presence of psammoma body was correlated with a significant poor DFS, but not stromal calcification and bone formation. The up‐regulation of BMP‐1 was in association with psammoma body.
Genetic Modulation of Cardiac Functional Aging
Authors: Bodmer Rolf
Published: June 2021

New methods for analysis of cardiac function in Drosophila have allowed us to study the genetic control of heart function as it deteriorates with age. We found that pacing‐induced cardiac arrest or fibrillation (a form of 'heart failure') is increased with age. In addition, the regularity of the myogenic heart in aging flies is perturbed, resulting in elevated incidence of arrhythmias. We also examined the roles of potassium channels in fly heart function and and found, for example, that compromised KCNQ K‐channel function also aggravates the age‐dependent decline in heart performance. In part responsible for the cardiac functional decline is a reduced expression of these K‐channels with age. Modulation of insulin/TOR signaling pathways is well known to affect overall aging in many organisms. Interestingly, manipulation of insulin/TOR‐signaling autonomous within the myocardium dramatically alters the age‐dependent decline in cardiac performance. In genetic interaction and epistasis experiments, we have identified the TOR target, 4E‐BP, the Drosophila eif4e‐Binding Protein, as a critical effector down‐stream of insulin/TOR signaling for maintaining robust heart function with age. The fly heart is thus emerging as a promising genetic model for studying the age‐dependent decline in organ function.
Central Arterial Aging: Humans to Molecules
Authors: Wang Mingyi , Lakatta Edward G
Published: June 2021

Aging is a major risk factor for cardiovascular diseases, i.e., atherosclerosis and hypertension. The cellular and molecular mechanisms of age‐associated arterial restructuring, however, are not fully understood. Our series of studies have shown that levels of angiotensin II (Ang II) protein, its precursor, angiotensinogen and the receptor AT1, as well as its downstream signaling products monocyte chemoatractant protein‐1 (MCP‐1), matrix metalloproteinase type II (MMP‐2), calapain‐1, and transforming growth factor beta‐1 (TGF‐β1 are markedly increased in vivo within the aortic walls and in vitro in early passage primary vascular smooth muscle cells (VSMC) in rats, nonhuman primates, and humans. Exposure of Ang II to young rat VSMC (8 mo) increases levels of MCP‐1, MMP‐2, calpain‐1, and TGF‐β1 activation in a dose‐and time‐dependent manner, up to those of untreated old cells (30 mo). These effects are substantially reduced by a blockade of AT1 signaling. Furthermore, we also found that MMP‐2 activation is central to the Ang II/MCP‐1/TGF‐β1 signaling cascade during aging. Chronic administration of Ang II (50‐200 ng/kg/min) to young rats, via an osmotic minipump, converts the structural and molecular profile of MMP‐2, MCP‐1, calpain‐1, and TGF‐β1 activation, collagen deposition, and intimal medial thickening towards that of untreated old animals. Collectively, these findings indicate that increased Ang II signaling plays a causal role in arterial aging.
Role of the RGS (regulator of G protein signaling) domain of Axin in vertebrate axis formation
Authors: Schneider Patricia , Slusarski Diane , Houston Douglas
Published: June 2021

The Wnt signaling network has major roles in developmental processes, human diseases and stem cell biology. A protein complex that includes Axin, APC and GSK3 tightly regulates this signaling. Axin, a key player in this complex, contains four critical domains: a β‐catenin binding domain, a GSK binding domain, an RGS domain and a DIX domain. Our study focuses on the role of the Axin‐RGS domain. Typically, RGS domains contain a conserved asparagine (Asn), critical for the ability to bind heterotrimeric G‐proteins. Interestingly, we find that the Axin‐RGS domain encodes a glutamine (Gln) at the equivalent position, suggesting a novel function for Axin‐RGS. We tested whether the Axin‐RGS domain functions in the context of Wnt signaling. We generated point mutations that converts the original Gln to Asn, predicted to increase affinity for Gα, and that converts Gln to Ala, predicted to abolish binding activity. We tested for the ability of the mutant forms to rescue Axin function in masterblind (mbl) zebrafish mutant embryos and in antisense morpholino knockdown of Axin in zebrafish and frog (Xenopus laevis). We found that the mutant constructs showed a differential ability to restore normal development in fish and frog embryos. These results suggest that the Axin‐RGS domain may be playing a role in regulating zygotic Wnt signaling.

Grant Funding Source

Roy J. Carver Charitable Trust
Sleep deprivation and stress: an inseparable pair
Authors: Suchecki Deborah
Published: June 2021

Prolonged sleep deprivation (SD) represents a stressful event for it activates the neuroendocrine stress response, as reflected by increased plasma levels of adrenaline, adrenocorticotropic hormone (ACTH) and corticosterone. However, the extent to which SD activates the hypothalamic‐pituitary‐adrenal (HPA) axis can be modulated by environmental factors. Using two versions of the platform method ‐ individual or group SD for 96h, we observed that group support reduces anxiety‐like behavior of animals in the elevated plus maze and, consequently, the stimulation of the HPA axis in response to this test. In a second study, we tested the influence of palatable solutions to reduce SD‐stimulated HPA axis activity. Although SD continued to result in high adrenocorticotropic hormone (ACTH) and corticosterone (CORT) plasma levels, animals provided with saccharin or sucrose (palatable) solutions exhibited lower hormone levels than those provided with water. Despite the fact that sleep‐deprived rats consumed a large amount of sucrose solution, they still consumed more chow than their control counterparts and lost just as much weight as the water‐provided sleep‐deprived group, indicating augmented energy expenditure. We pursued the mechanisms that could contribute to such an intense metabolic change and found that insulin levels were greatly reduced after SD and remained low after 96h of sleep recovery, whereas CORT levels were elevated at the end of SD and remained so after sleep recovery. Interestingly, the loss of body weight was due to loss of fat mass, but not to protein in the carcass. Finally, we looked at the feeding pattern and immunoreactivity (ir) of CRH and orexin in the hypothalamus of sleep‐deprived rats. The results showed that sleep‐deprived rats ate more during the daytime than control rats, ACTH and CORT levels were higher than in control rats throughout the entire period of SD and that both CRH and orexin‐ir were increased. The loss of body weight appeared to be related to elevated CORT levels, insofar as chronic administration of metyrapone (a CORT synthesis inhibitor) prevented this phenomenon. In conclusion, this set of data suggests that SD activates the HPA axis in its entirety, despite the modulatory influence of environmental factors. In addition, increased orexin‐ir appears to be involved with both stress and feeding responses induced by SD.

Financial support provided by grants from Fundação de Amparo àPesquisa do Estado de São Paulo (FAPESP ‐ CEPID 98/14303‐3) and from Associação Fundo de Incentivo àPsicofarmacologia (AFIP).
Generation of Morphological Diversity by Pleiotropy in Blind Cavefish
Authors: Jeffery William R.
Published: June 2021

The evolution of eye degeneration and related morphological traits is studied in the teleost Astyanax mexicanus, a single species with eyed (surface fish) and eyeless (cavefish) forms. In addition to eye and pigment regression, cavefish exhibit increased numbers of taste buds and other feeding structures. A candidate gene survey showed that about 150 key eye regulatory and structural genes are expressed normally in cavefish. However, a small number of these genes show subtle changes in their embryonic expression patterns. The midline signaling gene Sonic hedgehog (Shh) and its downstream target genes are expanded in cavefish embryos. Shh overexpression in surface fish embryos resulted in a blind cavefish phenocopy. We have also shown that Shh expression is sufficient and necessary for increasing taste bud development in cavefish. The results support a developmental trade‐off in which adapative and regressive characters evolve in concert based on the pleiotropic effects of Shh.
Aging, Exercise Training, and eNOS Uncoupling
Authors: Muller‐Delp Judy M
Published: June 2021

We sought to determine the effects of age and exercise training on coupling of endothelial nitric oxide synthase (eNOS) and flow‐mediated dilation in skeletal muscle arterioles. Young (4 mos) and old (22 mos) rats underwent exercise training or remained sedentary for 10 weeks. Flow‐induced increases in NO and O2− were assessed in arterioles from soleus muscle. Levels of the co‐factor, tetrahydrobiopterin (BH4) were also determined. Flow‐induced increases in NO were reduced in arterioles from old rats as compared to those from old rats. L‐NAME eliminated flow‐induced increases in NO. Flow increased O2−, which was inhibited by L‐NAME, in arterioles from old but not young rats. Exercise training augmented flow‐induced increases in NO in arterioles from old but not young rats. Exercise training increased flow‐induced O2− production (which was inhbiited by L‐NAME) in arterioles from young but not old rats. Arteriolar BH4 levels were reduced with age, and restored by exercise training. Thus, reduced BH4 and uncoupling of eNOS contributes to the age‐induced reduction of NO signaling in skeletal muscle arterioles. In arterioles from old rats, exercise training restores BH4 and increases flow‐induced production of NO, whereas, in arterioles from young rats, eNOS‐derived production of O2− is increased by exercise training.
Chromatin assembly factors and the challenges of DNA replication and repair
Authors: Almouzni Geneviève
Published: June 2021

Inheritance and maintenance of the DNA sequence and its organization into chromatin are central for eukaryotic life. To orchestrate DNA‐replication and ‐repair processes in the context of chromatin is a challenge.

Factors have been isolated from cell extracts that stimulate early steps in chromatin assembly in vitro. One such factor, chromatin assembly factor‐1 (CAF‐1), facilitates nucleosome formation coupled to DNA synthesis. It is thought to participate in a marking system at the crossroads of DNA replication and repair to monitor genome integrity and to define particular epigenetic states. We have now identified a chromatin assembly pathway independent of DNA synthesis involving the HIRA protein. Notably, CAF‐1 is part of the histone H3 complex, H3.1 complex (replicative form) and HIRA of the H3.3 complex (replacement form) (Tagami et al, 2004, Nakatani et al, 2004). In addition, another histone chaperone, Asf1, has to be integrated in a network of interactions leading to nucleosome deposition. A major goal in our laboratory is now to better integrate the function of these factors in vivo during development and also in connection with replication, repair and control of histone pools.

We will discuss our recent findings on this topics and the interrelationships with other assembly factors.
Molecular structure of amyloid and prion fibrils
Authors: Tycko Robert
Published: June 2021

At the end of the 20th century, we knew that amyloid fibrils contain β‐sheets with a "cross‐β" orientation relative to the fibril's long axis, but nearly all other aspects of the molecular structures of amyloid fibrils were uncertain. By now, we have a much clearer picture of amyloid structures, largely due to solid state nuclear magnetic resonance (NMR) measurements that are capable of providing detailed constraints on secondary, tertiary, and quaternary structure within noncrystalline biopolymers. I will describe recent results from solid state NMR for fibrils formed by the Aβ peptide associated with Alzheimer's disease, the amylin peptide associated with type 2 diabetes, and yeast prion proteins (collaboration with Dr. Reed Wickner of the NIH). In particular, we have shown that the Aβ peptide can form a variety of fibrils with distinct molecular structures, and we have characterized two of the Aβ fibrils in detail, revealing the molecular basis for amyloid polymorphism. We have developed an experimentally‐based molecular model for amylin fibrils that is strikingly similar to molecular models for Aβ fibrils, despite significant differences in amino acid sequence and composition. We have demonstrated that in‐register parallel β‐sheets are nearly universal in amyloid fibrils, including those formed by yeast prion proteins. These results provide insight into the nature of the interactions that drive amyloid formation and that account for the nearly generic propensity of polypeptides to form amyloid fibrils. Finally, I will describe attempts to determine the molecular structures of Aβ fibrils that develop within the brain in Alzheimer's disease (collaboration with Dr. Stephen C. Meredith, University of Chicago).
The Trials and Tribulations of Attaining Tenure for Minority Scientists
Authors: Haro Luis S.
Published: June 2021

We will inject vitality into your thinking and actions to prepare you for the array of obstacles you will face in achieving tenure and promotion. The unique challenges faced by underrepresented minorities in academic science will be addressed by discussing my personal experiences and challenges in the tenure and promotion process. Steps that can be taken to successfully challenge negative tenure/promotion decisions will be addressed. We don't have all the answers but we can provide a guide and overview to successfully achieve all that you are expected to do as a faculty member. You will need to figure out the institution's requirements for demonstrating the quality of your research and scholarly activity and also procure funds for carrying out those endeavors. As an academician you must carry out your role as an educator teaching and mentoring an array of students from undergraduates to postdoctoral fellows and teach organized classes in both your area of expertise and in your departmental discipline. You must be a service provider to your department, college and university as well as to your profession and the community. Ascertaining the unique requirements for tenure and promotion at your institution is paramount and documentation of your achievements is essential. Lastly, proper allocations of time are required to focus your academic capabilities to create an outstanding individual academic portfolio.
The ESCRT Complexes: from Lysosome Biogenesis to Viral Budding
Authors: Hurley James H
Published: June 2021

The ESCRT machinery consists of five complexes conserved from yeast through humans, ESCRT 0‐III and VPS4‐VTA1, and the ALIX protein. These complexes carry out a conserved membrane scission reaction in HIV‐1 budding, the biogenesis of multivesicular bodies, and the membrane abscission step in cytokinesis. I first address how ESCRT complexes assemble on membranes. With respect to cytokinesis, ESCRT‐I and ALIX are recruited to the midbody, the site of the membrane abscission step in the final separation of daughter cells, by interactions between GPPXY motifs and a non‐canonical coiled‐coil in CEP55. The ESCRT complexes and spastin coordinate membrane abscission with the cleavage of microtubules in the central spindle. ESCRT‐I and ALIX are targeted to the site of HIV‐1 budding by direct interactions with PTAP and YPXL motifs, respectively, in HIV‐1 Gag p6. In MVB biogenesis, HIV‐1 budding, and cytokinesis, ESCRT‐I and ALIX either directly or indirectly, recruit ESCRT‐III. ESCRT‐III is thought to be responsible for the membrane scission. A model for the recruitment and action of the ESCRTs and ALIX to their sites of action in HIV‐1 budding, cytokinesis, and MVB biogenesis has been formulated.
The Role of Lipin Proteins in Lipid Storage and Metabolism
Authors: Reue Karen
Published: June 2021

The three members of the lipin protein family (lipin‐1, lipin‐2 and lipin‐3) are Mg2+dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin‐1 has also been shown to act as a transcriptional coactivator to modulate gene expression in response to fasting in the liver. Each of the lipin genes exhibits a distinct tissue expression pattern suggesting unique physiological functions. Lipin‐1 is prominently expressed in adipose tissue and muscle, and mutations in the lipin‐1 gene cause lipodystrophy in the mouse and myoglobinuria in humans. In contrast, lipin‐2 is most prominently expressed in tissues such as liver, kidney, brain, and lung. Mutations in human lipin‐2 cause Majeed syndrome, an inflammatory disorder characterized by osteomyelitis, anemia, and cutaneous inflammation, but the mechanism underlying this phenotype is not understood. To address questions concerning the roles of each lipin family member in normal physiology and disease we have developed mutant mouse models for each of the lipin family members. Characterization of their phenotypes demonstrates unique, but interacting, roles for the lipin proteins in lipid storage and metabolism.
Suppression of Angiopoietin‐2 using in vivo siRNA following hemorrhagic shock ameliorates acute lung injury in murine shock/sepsis model
Authors: Lomas‐Neira Joanne , Venet Fabienne , Chung Chun‐Shiang , Ayala Alfred
Published: June 2021

Pulmonary endothelial cell (EC) dysfunction with increased vascular permeability and edema represents a major component in the pathogenesis of acute lung injury (ALI). Angiopoietins (Ang)‐1 & 2 are endothelial growth factors that, under normal physiological conditions, mediate blood vessel formation and remodeling. They share similar affinity for a tyrosine kinase receptor, Tie2, expressed on endothelial cells. Ang‐1/Tie2 binding has been shown to promote vessel integrity and stimulate pro‐survival/anti‐inflammatory down stream signaling; alternatively, Ang‐2, released from storage granules of activated ECs, has been reported to play a role in destabilizing vessels. However, their role in indirect ALI is unclear. Here we report that Ang‐2 is significantly elevated in our shock/sepsis model of ALI in mice. To the extent that this rise in Ang‐2 expression/release plays a role in development of ALI, we observed that not only could Ang‐2 expression be significantly reduced in the lungs and plasma of shocked/septic mice post treated in vivo with Ang‐2 siRNA, but also that this reduction was associated with decreased histological evidence of tissue injury and inflammatory cytokines. These findings illustrate the contribution of Ang‐2 expression, not only to the development of indirect ALI, but represent a potential therapeutic target in its treatment. (Funded by NIH‐HL73525)
Multi‐modal CNS pharmacology teaching in an integrated curriculum for sophomore medical students
Authors: Arai Amy C. , Caspary Donald M. , Faingold Carl L.
Published: June 2021

The Pharmacology Department at SIUSM has developed a multi‐modal approach for teaching CNS pharmacology in our Neuromuscular and Behavior Unit. Important concepts of drug action are introduced at first in clinical cases and then by building extensively upon the students' prior basic science knowledge. The students are also exposed to pharmacology in differing contexts and modes, which allows them to develop a deeper understanding of therapeutic principles and appreciate how pharmacological intervention relates to disease processes. The students learn pharmacology first in a clinical case setting through electronic problem‐based learning modules (ePBLM). This self‐directed learning is done in small groups led by a facilitator who is supplied with complete sets of 2nd year learning objectives and resources for all disciplines. Following the closing of a case in the small group, the learning issues are reviewed in a multi‐disciplinary case wrap‐up large group session that integrates lectures by content experts (clinicians, pathologists and pharmacologists). Pharmacology learning objectives containing hyperlinks to related articles and information on the latest drug evaluations are made available through a Blackboard web‐based interface, along with self‐assessment questions and assignments. Active discussions between students and faculty are moderated on‐line through Blackboard. Testing of the material involves clinically‐based performance evaluations and vignette‐based multiple choice questions. Both components must be successfully mastered for the student to receive a satisfactory evaluation on this material.
Interactive computer‐based exercises enhance preclinical medical education
Authors: Reilly Frank , Allen Edwin , Walls Richard
Published: June 2021

We investigated the effects of interactive instructional techniques in a Web‐based peripheral nervous system component of a first‐year medical school human anatomy course. Existing data from 9 years of instruction involving 856 students and 240 exam questions were used to evaluate 5 interactive learning objects developed in Flash MX or Authorware, i.e., patient case studies, review games, simulated interactive patients, flashcards, and quizzes. Data analysis included one‐way analyses of variance and Tukey post‐hoc tests. Exam item analysis scores were found to be significantly higher (p <0.05) for students receiving the instructional treatment incorporating the Web‐based interactive learning objects. Questionnaires using a five‐point Likert scale were analyzed to determine student opinion ratings of the interactive learning objects. Students reported favorably on the benefit level of all learning objects. They rated the advantages of simulated interactive patients significantly higher (p <0.05) than all other interactive learning objects. This study suggests that Web‐based interactive instructional techniques improve student exam performance. Students indicated a strong acceptance of simulated interactive patient learning objects. (Supported in part by the Neurobiology and Anatomy Department, West Virginia University School of Medicine, account#:491030050, fund#:12305495.)
Engaging pharmacy and other health profession students in K‐12 science education
Authors: Blankenship Jim , Wilson Judi
Published: June 2021

Our objective is to stimulate interest in science in K‐12 grade classrooms by involving pharmacy students. Health profession students are well‐trained in science, can support K‐12 science teachers and be role models for students. In 2007, we began a course with 34 second year pharmacy students assigned to work with teachers in 17 local 2nd and 5th grade classrooms. Prior to their assignment, students attended three training sessions on K‐12 education and curricula. Teachers also attended a session to learn program guidelines and meet pharmacy students. Pharmacy students led science activities in assigned classrooms once a week for the remainder of the semester. Evaluations showed improvement in attitudes toward science among participating elementary students and increased interest and confidence in participation in K‐12 science education among pharmacy students. In 2008‐09, we are repeating our course at Pacific with 40 new students, and pharmacy school faculty at the University of Arizona and Washington State University are conducting parallel classes at their schools. To facilitate training for these courses, we have developed a website. Evaluations will be used to determine the effectiveness of the program. The long‐term goal of this project is to stimulate involvement of practicing pharmacists in science education in their local K‐12th grade schools. (Supported by NIH grant # 2‐R25‐RR012319‐004A2)
Wnt7a is up‐regulated in mice with heritable misexpression of Six2 associated with frontonasal dysplasia
Authors: Hynd T.J. , Fong Keith S. K. , Fogelgren Ben , Kuroyama Mari , Lozanoff Scott
Published: June 2021

Wnts are secreted glycoproteins involved in an array of developmental processes. In facial morphogenesis, Wnts appear to mediate development of the midface and fusion of the upper lip. We have previously described the Br mutant mouse displaying heritable frontonasal dysplasia (FND). Linkage analysis mapped the Br mutation near the homeobox transcription factor Six2, normally expressed in the facial mesenchyme during embryonic development. The purpose of this study is to determine possible upstream and downstream events of Six2, notably in the Wnt signaling pathway, leading to FND. Frontal nasal prominences (FNP) of E11.5 embryos were dissected and RNA extracted via Qiagen's RNeasy Mini Kit. Total RNA was reverse transcribed using Bio‐Rad's iScript cDNA Synthesis Kit. qRT‐PCR reactions were performed with SYBR Green Supermix and novel primers for Six2 and SABiosciences RT² Profiler PCR Array for Wnt signaling pathway molecules. The MyiQ iCycler thermocycler and single color real‐time PCR detection system (Bio‐Rad) were also used. Results suggest Six2 is expressed in a haploinsufficient pattern in the FNP. Additional data indicates Wnt7a expression is up‐regulated three‐fold in the Br/Br mutant. These data suggest Six2 may down‐regulate Wnt7a in the face and in the absence of suppression, Wnt7a may prevent further differentiation of midfacial structures resulting in FND. Further work will be necessary to determine specific downstream targets of Six2. Supported by R0‐1 DK064752 (SL).

Grant Funding Source

NIH
Penetration of Fluorescent Nanospheres through the Canine Zona Pellucida
Authors: Lunn Matthew O. , Wright Shirley J.
Published: June 2021

Mammalian oocytes are surrounded by an extracellular glycoprotein matrix called the zona pellucida (ZP). Sperm bind and penetrate the ZP to fertilize the oocyte. ZP structure and composition varies depending on the species. Surprisingly little is known about the ultrastructure of the ZP in companion animals. Our previous studies have shown the canine ZP is porous. The objective of this study was to determine whether the canine ZP prevents nanospheres the size of canine viruses from penetrating the ZP. Oocytes (n = 184) were isolated from ovaries from 21 dogs aged 6 months to 9 years. Oocytes were exposed to fluorescent nanospheres (24, 100, 210 nm), and confocal microscopy was used to determine how far the nanospheres penetrated the ZP. The 210 nm nanospheres penetrated the entire width of the ZP in only 24.6% of the oocytes (n = 57), whereas the 100 nm and the 24 nm nanospheres penetrated the ZP more often, 41.5% (n = 53 oocytes) and 86.3% (n = 74 oocytes), respectively. In some oocytes, most of the ZP was resistant to penetration, however, the nanospheres penetrated the ZP in discrete patches reminiscent of the path of transzonal processes of cumulus cells. Since the ZP inconsistently blocks nanospheres, in vitro fertilization is not a means to consistently produce viable, virus‐free offspring from infected dogs and endangered canids.

Grant Funding Source

AKC Canine Health Foundation
Shunt revisions effect on frontal occipital horn ratio‐an anatomic study
Authors: Osuagwu Ferdnand Chisom , Lazareff Jorge
Published: June 2021

Background

Ventricular volume estimates can be challenging if dealing with multiple imaging modalities. Frontal and occipital horn ratio has been described as a simple linear measurement that correlates well with ventricular volume estimates. Multiple shunt revisions have been associated with potential changes in ventricular volumes.

We aimed our study at determining the association between multiple shunt revisions with distal slit valve and evaluated the effect on the frontal‐occipital horn ratio (FOR).

Materials and Methods

We compared the frontal and occipital horn ratio in 16 children with one or more ventriculoperitoneal shunts insertion with distal slit valves.

Results

The mean frontal‐occipital horn ratio in all groups was 0.55±0.04.

The mean frontal‐occipital horn ratio for the patients shunted once (n=2) was 0.48±0.02, the patients shunted twice (n=3) was 0.56±0.03, the patients shunted thrice (n=5) was 0.55±0.04, the patients shunted four times (n=5) had a value of 0.56±0.02 while the patient who was shunted five times (n=1) had an FOR value of 0.57.

Conclusion

The frontal and occipital horn ratio did not exhibit much change if two or more shunt revisions are conducted.

Grant Funding Source

None
Sexual dimorphism asymmetry of central sulcus
Authors: Sun Bo , Ge Haitao , Tang Yuchun , Fan Lingzhong , Lin Xiangtao , Yu Taifei , Xu Junhai , Liu Shuwei
Published: June 2021

The central sulcus (CS), which is located between the primary motor and primary somatic sensory cortexes, is an important structure and landmark of the brain. In this study, we investigated the sexual dimorphism asymmetry of CS morphology. With three‐dimensional magnetic resonance images of 40 right‐handed volunteers (male 20 and female 20, aged 20‐30 year old), we retrospectively measured the length, depth and width of the CS (LCS, DCS and WCS) by using a ROI (region of interest) method combining automated sulcus reconstruction and recognition. Group differences of the both genders and the bilateral hemispheres were statistically tested. The average LCS was significantly larger in males (93.28 ± 3.91 mm) than females in the left hemisphere (87.41 ± 6.19 mm) (P < 0.05), while the average WCS was significantly larger in females (2.72 ± 0.71 mm) than males (2.38 ± 0.46 mm) in the right hemisphere (P < 0.01). In males, the average LCS and WCS were significantly larger in the left hemisphere (93.28 ± 3.91 mm, 2.85 ± 0.71 mm) than in the right hemisphere (84.59 ± 5.11 mm, 2.38 ± 0.46 mm) (P < 0.05). No significant CS morphology asymmetry was found in females. The results demonstrate that there was a much more significant CS morphologic asymmetry in males than females.
Right aortic arch, aberrant left subclavian artery and ruptured breast implants presenting with thoracic outlet syndrome (TOS) and migraine: MRI, MRA, MRV
Authors: Saxton Ernestina H. , Collins James D. , Ahn Samuel S. , Gelabert Hugh , Carnes Alfred
Published: June 2021

A right aortic arch arises from interruption of the aortic arch between the left common carotid and the left subclavian arteries. The aorta descends on the right. The left aberrant subclavian artery courses posterior to the trachea and esophagus. Bilateral MRI/MRA/MRV displays congenital vascular abnormalities that alter fascial planes and result in costoclavicular compression of bicuspid valves within lymphatics and draining veins of the neck and supraclavicular fossae and the subclavian and axillary arteries with binding nerve roots (JNMA 1999; 91:333‐41). Patients with TOS complain of upper extremity pain, numbness, tingling and edema; facial, back and lower extremity pain; visual blurring and "floaters"; syncope, and headache. Monitored multiplanar images with abduction external rotation and 2D Time of Flight MRA/MRV without contrast were acquired on a 1.5 Tesla GE Signa LX unit, 44 cm field of view, 521 x 256 matrix and saline water bags to enhance signal to noise ratio. Two patients with TOS were selected who also presented with severe hoarseness and dysphagia. Both cases displayed a right aortic arch and left aberrant subclavian artery displacing the esophagus, trachea and aorta anteriorly, compressing the posterior margin of the esophagus (hoarseness and dysphagia). In one patient rupture of a breast implant caused fibrosis and scarring of the pectoralis muscles, contributing to her symptoms.
Student performance on embryology exam questions is equivalent for students instructed by a live versus a video lecture format
Authors: Beale Elmus G. , Tarwater Patrick M. , Lee Vaughan H.
Published: June 2021

Embryology is taught by lectures integrated into the anatomy course at TTUHSC School of Medicine. This year the individual who taught embryology moved to a new medical school in El Paso. As a means of dealing with this departure, all twelve lectures were videotaped digitally and placed online via WebCT. Thus the same person delivered the same lectures live in 2007 (to 149 students) and by online videos in 2008 (to 150 students). The same learning objectives and embryology questions on three exams were used both years. This allowed us to directly compare student performance. There was no significant difference in overall class performance on 29 embryology questions asked (P ≥ 0.625). This suggests that the method of lecture delivery neither helped nor hindered learning. Students also completed a survey to assess their opinions about live versus video lectures. They rated the two forms of delivery equally on a five‐point Likert scale and reported that live lectures have the advantage of allowing questions whereas online lectures could be paused and replayed. The experience suggests that scripted video lectures may be developed into valuable adjuncts to traditional methods.
The Use of Team Process Framework to Improve Small Group Learning
Authors: Khalil Mohammed K , Johnson Tristan E , Spector J. Michael , Payer Andrew F
Published: June 2021

Working in teams is an important aspect of clinical practice and medical education. Medical educators have embraced instructional strategies that use multiple learners to facilitate learning. However, the learning benefits of these strategies should be substantiated by additional inquiries in the area of team cognition and team processes. There are limited efforts to evaluate the efficacy of learning processes associated with learning teams. This presentation provides theoretical background for team learning processes that influence team and individual learning. It also outlines the development of shared understanding or shared mental models, and how they impact students' performance. Team process behaviors, such as team communication and team coordination, mediate the process of developing shared mental models, which in turn affect learning outcomes. Understanding the role of shared mental models in small group learning improves the efficacy of small group learning.

Grant Funding Source

N/A
Identification and characterization of a novel p300 HAT inhibitor
Authors: Bowers Erin Michele , Yan Gai , Mukherjee Chandrani , Wang Ling , Larocca Cecilia , Meyers David J. , Orry Andrew , Alani Rhoda M. , Cole Philip A.
Published: June 2021

p300 is a histone acetyltransferase (HAT) with important roles in chromatin remodeling and transcriptional coactivation. Along with its homolog CBP, p300 is involved in many cellular functions, including cell cycle regulation and differentiation, and has been implicated in many diseases, including heart disease, diabetes, HIV, neurodegenerative disorders, and several forms of cancer. Despite its importance, few inhibitors of p300's HAT activity have been found to date. A recent X‐ray crystal structure of p300 HAT in complex with the bisubstrate analog Lys‐CoA served as a template for computational docking analysis. We utilized virtual ligand screening (VLS) to identify novel inhibitors of the p300 HAT domain. After an iterative screening process of the VLS hits using spectrophotometric and radioactive assays, a new p300 HAT inhibitor was identified. This compound was found to be a potent competitive inhibitor of p300 vs. acetyl‐CoA and noncompetitive vs. peptide substrate, consistent with prediction. Furthermore, this small molecule p300 HAT inhibitor demonstrated high selectivity versus other acetyltransferases tested. Preliminary analysis with this compound supports its ability to block p300/CBP HAT activity in cell culture. Ongoing studies are directed at characterizing the structural basis of inhibition and the range of cellular actions of this compound and related analogs. Funding: NIH, FAMRI.
ALC1: A Chromatin Remodeling Enzyme Activated by Poly(ADP‐Ribose) Polymerase (PARP) and NAD
Authors: Gottschalk Aaron J. , Swanson Selene K. , Washburn Michael P. , Florens Laurence , Conaway Joan W. , Conaway Ronald C.
Published: June 2021

ALC1 (Amplified in Liver Cancer 1) is a member of the SNF2 ATPase superfamily and is an oncogene implicated in the pathogenesis of hepatocellular carcinoma. Mass spec analyses suggest that unlike many SNF2 superfamily members, ALC1 does not reside in a multi‐subunit complex, but instead interacts transiently with proteins, including high‐mobility group proteins, histones, PARP1 and PARP2, that are known to be involved in chromatin biology. ALC1 contains a carboxy‐terminal macrodomain that is necessary and sufficient for binding to poly(ADP‐ribose). Free ALC1 has little or no ATPase or chromatin remodeling activity in vitro; however, these activities are strongly activated by PARP1 and the PARP1 substrate NAD. ATPase and chromatin remodeling activities require an intact macrodomain capable of binding poly(ADP‐ribose). ALC1 binds nucleosomes with substantially greater affinity in the presence of PARP1 and NAD, suggesting the poly(ADP‐ribosyl)ation of PARP1 and/or histones may serve as a novel method of targeted chromatin remodeling.
Temporal Control of Histone H4 methylation in SV40 minichromosomes during lytic infection
Authors: Milavetz Barry I , Gefroh Amanda , Hamling Megan , Balakrishnan Lata
Published: June 2021

Acetylation and methylation of histones are known to play critical roles in many biological processes. We have previously shown that in the coding region of a transcribing SV40 minichromosome, histone hyperacetylation is a dynamic process regulated by the interplay of p300, a histone acetyltransferase and a histone deacetylase, co migrating along with the transcription complex. Our current studies are focused on histone H4 methylation in SV40 minichromosomes. Histone H4 is known to undergo mono, di, or tri methylation of lysine 20 (H4K20me1, H4K20me2, and H4K20me3 respectively) with differing biological effects. Using various chromatin immunoprecipitation procedures we have determined that minichromosomes containing H4K20me1 were present throughout an SV40 infection, and minichromosomes containing H4K20me3 were present only during the first hours of infection. Minichromosomes containing H4K20me2 were not present in infected cells. Combining ChIP analysis with tritiated thymidine pulse radiolabeling of chromatin we observed direct evidence for conservation of histone methylation in daughter minichromosomes following replication. In contrast to our results with histone hyperacetylation in SV40 minichromosomes, methylation of H4K20 appears to define a small conserved stable subclass of minichromosomes with the potential to participate in various biological functions.
Identifying determinants of chromosomal domains as defined by time of replication
Authors: Keaton Mignon A , Malhotra Ankit , Dutta Anindya
Published: June 2021

The genome is organized into functional domains in which gene expression, chromatin modifications, and DNA replication is coordinately regulated. The time at which a genomic locus replicates during S phase appears to be dependent on subnuclear positioning and chromatin conformation. Recently, our lab generated a high resolution replication timing profile for 30 Mb of the human genome (1%) as part of the ENCODE consortium. Using a computational approach, we have identified regions of rapid transition in replication timing that coincide with changes in chromatin modifications. We hypothesize that these regions contain genomic elements, such as nuclear matrix attachment regions and binding sites for insulator proteins, that that are responsible for the organization of chromatin into functional domains. To test this hypothesis, we are mapping matrix attachment sites in HeLa cells and utilizing enhancer‐blocking insulator assays to identify potential boundary elements in these regions. These results will yield a better understanding of how replication domains are organized and insight to the mechanisms that regulate chromatin domain structure. This work is supported by NIH R01 CA089406 to A.D.
Identifying the potential gene targets of microRNAs involved in the metastasis of prostate cancer to bone
Authors: Kasmari Allison Jane , Zhang Chu , Farach‐Carson Mary C.
Published: June 2021

Preferential metastasis of human prostate cancer cells to bone marrow contributes to disease mortality and morbidity. MicroRNAs (miRNAs) are endogenous ~22nt RNAs that play important regulatory roles in animals and plants by binding to specific messenger RNA (mRNA) targets to either block their translation or trigger their degradation. Accumulating evidence indicates that miRNAs are involved in human cancer. Here we used the human prostate cancer cell line, LNCaP, and its derivative bone metastatic subline, C4‐2B, as a model system to study the roles of miRNAs in prostate cancer progression. We sequenced more than two million small RNAs from LNCaP and C4‐2B cell lines using a 454 library. Known miRNAs and new small candidate miRNAs with expression differences between these two cell lines were selected for analysis. Various bioinformatics tools and gene databases were used to identify potential targets for both novel and known microRNAs. Prostate cancer gene expression microarray data were used to further narrow the prospective target genes for known microRNAs. Biobase (http://bkl.biobase.de/cgi‐bin/bkl/idb/1.0/searchengine/start.cgi) software was used to place these gene targets in relevant cellular pathways. Ongoing studies seek to explore the potential targets of miRNAs involved in these pathways. These data provide us with important information about how miRNAs are involved in prostate cancer including identification of new pathways for modulation of gene expression during progression to bone. Understanding the targets and functions of these miRNAs will translate into new means to inhibit prostate cancer metastasis and growth in bone. (Supported by NCI P01 CA098912 and University of Delaware Science and Engineering Scholars Cancer and Genetics Fellowship.)
Identifying Novel Cell Cycle Regulators in Budding Yeast
Authors: Stephenson Tesia , Fearon Paula , Cohen‐Fix Orna
Published: June 2021

The spindle assembly checkpoint allows for the bipolar attachment of microtubules to sister chromatids. Apq12p, an endoplasmic reticulum protein, is implicated in the spindle checkpoint based on its genetic interactions with known spindle checkpoint components. Previous studies show Apq12p has a synthetic lethal interaction with Bub3p (binds to kinetochores not attached to microtubules), suggesting an additional role for Apq12p in the spindle assembly checkpoint. The aim of this study was to determine the role of Apq12p in the spindle checkpoint pathway. A plasmid‐based multi‐copy suppressor screen was used to identify genes that when over expressed would suppress the lethality of apq12 Δ bub3 Δ. To determine which gene on the plasmid was rescuing the apq12 Δ bub3 Δ synthetic lethality, an in vitro transposition reaction was used during which a transposable element was randomly inserted into the plasmid. The mutagenized plasmids unable to suppress were sequenced to identify the gene disrupted by the transposon. Results show that high copy of ALY2, TAX4, IML2SKT5, YEL1, YBL059C‐A, YBL059W, and SHP1 suppress the lethality of apq12 Δ bub3 Δ. These results suggest these genes could be involved in regulating chromosome segregation. The suppressor screen will be repeated until saturation and verification experiments conducted. This investigation was sponsored by an NIDDK intramural grant to Orna Cohen‐Fix.
The effects of tributyltin on the transcription regulator AP‐1
Authors: Person Rachel Joy , Whalen Margaret M
Published: June 2021

Tributyltin (TBT) is a widespread environmental contaminant and there is significant exposure of humans to TBT. Measurable levels of TBT have been found in human blood samples. It appears to increase the risk of cancer and viral infections in exposed individuals. Natural Killer (NK) cells are lymphocytes that are capable of killing tumor cells, virally infected cells and antibody coated cells. NK cells are our primary immune defense against viruses and cancer cells. In past studies, we demonstrated that exposure to TBT produced a decrease in the tumor‐cell killing function of human NK cells. Previous studies also showed that exposure of NK cells to TBT activated mitogen activated protein kinases (MAPKs), p44/42 and p38. MAPKs are known to be critical regulators of the tumor‐destroying function of NK cells, in part, by their capacity to alter the function of the transcription regulator AP‐1. The current study addresses the effect of TBT exposure on the phosphorylation state and overall levels of the AP‐1 components, Fos and jun. Such studies are necessary to determine if the alterations in MAPK activity induced by TBT are potentially altering the function of these transcription regulators. NK cells were exposed to TBT and the levels and/or phosphorylation states of Fos and jun were determined using western blotting. The results showed that there was an increase in the phosphorylation (activation) of jun within 10 min of exposure to TBT. There was also an increase in the overall level of fos within 1 hour exposure to the compound. The results indicated that there were alterations of the components of AP‐1, which would result in increased functional capacity. Altered AP‐1 function could in part explain changes in the expression of several NK proteins that have previously been observed.
Investigation of the Interaction between RFX5 and CREB: Implications for the Regulation of MHC II Gene Expression
Authors: Awe Olufolakemi Olaiya , Garvie Colin
Published: June 2021

Major Histocompatibilty Class II (MHC II) molecules play a major role in the proper functioning of our immune system. MHC II molecules are responsible for the presentation of antigenic peptides from foreign bodies to the receptors of CD4+ T lymphocytes which in turn initiate an immune system response. MHC II gene expression is dependent upon the assembly of a multi‐protein complex. Mutations or deletions in specific proteins of this multi‐protein complex lead to a severe immunodeficiency disorder. The RFX complex is a key DNA binding component of this multi‐ protein complex. In the RFX complex there are three proteins: RFX5, RFXAP, and RFXB. The ability of the RFX complex to bind DNA is proposed to be stabilized by an interaction between RFX5 and CREB another protein that binds to the MHC II promoter adjacent to the RFX complex. The interaction between CREB and RFX5 is proposed to be mediated by the bZIP domain of CREB. Little is currently known about the regions of RFX5 that are required to interact with the bZIP domain of CREB. Full length CREB was inserted into a bacterial expression vector, and the protein was successfully expressed in E. coli bacterial cells. This therefore places us in a position to analyze the interaction between CREB and RFX5 using chemical cross linking, size exclusion chromatography, and static light scattering techniques, in order to determine the minimal regions of RFX5 required interacting with CREB.