bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrical Disturbances in the Brain and Heart in Long QT Syndrome: A Dangerous Synergy
Authors: Auerbach David , McNitt Scott , Dirksen Robert , Moss Arthur 
Published: June 2021

Patients with genetic ion channel diseases, such as Long QT Syndrome (LQTS), experience electrical disturbances in the brain (seizures) and heart (arrhythmias) that can lead to sudden death. Mutated genes in LQTS1‐3 are expressed in the heart and brain. The objective was to determine the co‐prevalence and severity of seizures and arrhythmias in LQTS. We hypothesized: 1) LQTS mutations and QT prolongation are associated with seizures; 2) LQTS subjects with seizures have an increased risk of cardiac arrhythmias.Prevalence of seizures and arrhythmias were assessed using the Rochester LQTS Registry. LQTS analyses were limited to LQTS1‐3 subjects (LQTS+,n=965) and those with no known LQTS mutation (LQTS‐,n=936). Patients were assigned to the seizure group if they answered yes to seizures/epilepsy or were prescribed an anti‐seizure medication.LQTS+, particularly LQTS2, patients were at a 3‐4x higher total risk of seizures, compared to LQTS‐ subjects (p<0.0001), and at each 10 year mark over 40 years of follow‐up (p<0.01). There was a positive correlation of QTc to the percentage of subjects in the seizure group (R2=0.998). The percentage of LQTS genotype/phenotype positive subjects in the seizure group was 4x greater than LQTS genotype/phenotype negatives (p<0.0001). Those in the seizure group had longer QTc and a 4‐9x higher risk of cardiac arrhythmias, compared to non‐seizure group, with a higher probability of arrhythmias over time in LQTS1 & LQTS2 (p<0.001). A complex network of factors coalesces to promote neuro‐cardiac electrical disturbances.
Multiple Micronutrients And Early Learning Interventions Promote Infant Micronutrient Status And Development
Authors: Fernandeez‐Rao Sylvia , Hurley Kristen , Nair Madhavan , Balakrishna N , Tilton Nicholas , Radhakrishna V , Reinhart Greg , Harding Kimberly , Black Maureen 
Published: June 2021

BackgroundMalnutrition and lack of early learning (EL) opportunities are major causes for children not reaching their developmental potential. ObjectiveTo evaluate the impact of multiple micronutrient powder (MNP) and EL intervention on infants' micronutrient status and development. Methods497 infants (6‐12 mos) were enrolled from 26 villages in rural India and randomized using a 2X2 design to receive MNP (iron, zinc, vitamins A,B2,B12, C and folic acid ) vs. placebo (B2) and EL vs. control. The EL intervention was based on the UNICEF‐developed Care for Child Development and delivered through biweekly home visits. Baseline, post‐intervention (6 mos) and follow‐up (12 mos) evaluations included 2ml venous blood and Mullens Scales of Early Learning. Data were analyzed using 2‐way ANOVA, adjusting for baseline, with MNP X EL interactions to assess intervention synergy. ResultsNo baseline differences (66% anemic (Hb<11 g/dL), 31% inadequate iron stores (ferritin>12 µg/L), 20% stunted (HAZ<‐2), 19% underweight (WAZ<‐2). At follow‐up, the prevalence of micronutrient (MN) deficiencies was significantly lower in the MNP group. Significant interactions in motor and language performance showed that children who received either or both interventions had better scores than children who received neither.

Table 1. Percent MN Deficiencies at Follow‐Up * p &lt; .05

MNP
Placebo

Infant
%
%

Hemoglobin (&lt; 11g/dL) *
50.2
74.2

Ferritin (&lt;12 ug/L) *
32.6
81.6

Transferrin receptor (&gt; 2mg/L) *
44.1
81.7

Vitamin B12 (&lt;200p/mL) *
2.6
9.1

Zinc (&lt;65 ug/dL)
2.1
1.8

Table 2. MNP x EL Interaction at Post Intervention: Mean (SE) * p&lt;.05

MNP
Placebo

EL
Control
EL
Control

Gross Motor
50.2 (1.0)
51.8 (1.0)
51.7 (1.0)
48.7 (1.0) *

Language
38.9 (0.6)
39.3 (0.6)
40.3 (0.6)
48.1 (0.6) *

ConclusionHome MNP and EL can improve infant MN status and development.
From Lipidomics to Cellular Functions: Lipids as Modulators of Protein Activity
Authors: Brügger Britta 
Published: June 2021

Given the fact that membranes are composed of hundreds of different lipid species, it is believed that beyond their well‐established functions as structural membrane components and solvents for membrane protein, individual lipid species fulfill specific roles in cellular membranes. Lipidomics analysis of COPI‐coated vesicles and their donor Golgi membranes revealed a role of COPI vesicles in intracellular lipid sorting. While the majority of sphingomyelin species together with cholesterol were segregated from COPI vesicles, one single sphingomyelin species, namely N‐stearoyl‐sphingomyelin, was significantly enriched in the vesicular membrane. In order to elucidate the underlying molecular mechanism of sorting of this lipid species into COPI vesicles, we have established novel in vivo and in vitro chemical biology lipid tools. Capitalizing on these tools, we discovered a direct and highly specific interaction of N‐stearoyl‐sphingomyelin with the transmembrane domain of p24, a protein involved in vesicular trafficking. p24 is a type I transmembrane protein that continuously cycles within the early secretory pathway and is suggested to act in its dimeric form as coat and cargo receptor in COPI vesicle biogenesis. Our data suggest that binding of sphingomyelin to p24 facilitates formation of p24 homodimers, and thereby triggers initiation of COPI vesicle buddingThis specific protein‐lipid interaction within the hydrophobic phase of the membrane is defined by a signature within the TMD of p24 that is responsible for lipid selection. Bioinformatic analyses using a motif‐probability algorithm predict that this signature represents a conserved sphingolipid‐binding motif in mammalian membrane proteins, suggesting a widespread function of sphingolipids in modulating membrane protein activities.
Efficient Conversion of Human Fibroblasts to Functional Neurons by Sequential Inactivation of PTB/nPTB‐regulated RNA Programs
Authors: Fu Xiang‐Dong , Xue Yuanchao , Qian Hao , Hu Jing 
Published: June 2021

Cellular reprogramming can be accomplished by using a set of cell lineage‐specific transcription factors. Our recent work reveals a key RNA program regulated by the RNA binding protein PTB, which is not only necessary but also sufficient to trans‐differentiate diverse cell types into neuronal‐like cells or even functional neurons (Xue et al., Cell 152:82‐96, 2013). In this RNA program, PTB down‐regulation allows the neuronal‐specific microRNA miR124 to more efficiently target its substrates, including multiple components of the REST complex responsible for repressing a large array of neuronal‐specific transcription factors in non‐neuronal cells. Down‐regulated REST also further depresses miR124, thus creating a sustainable signal for reprogrammed cells to maintain the neuronal identity.One application of this new neuronal induction protocol is to convert patient fibroblasts into neurons for mechanistic studies of neurodegenerative diseases. Interesting, unlikely mouse cells, human fibroblasts can only be converted to neuronal‐like cells with complex neuronal morphology but without functional neuronal properties, suggesting the existence of another gatekeeper(s) that uniquely operates for neuronal maturation in human cells. We now demonstrate that this gatekeeper consists of the PTB paralog called nPTB and a specific transcription factor Brn2, which together forms another feedback loop critical for neuronal maturation. Either overexpression of Brn2 or down‐regulation of nPTB in PTB down‐regulated cells induces mature neuronal marks and a full spectrum of neuronal activities. These data demonstrate a sequential control mechanism for neuronal induction and maturation in human cells.
Knockout of Histidine Decarboxylase (HDC) Reduces Hepatic Fibrosis in Bile Duct Ligated (BDL) Mice
Authors: Francis Heather , Hargrove Laura 
Published: June 2021

BackgroundHistamine (HA) is formed by the conversion of histidine by histidine decarboxylase (HDC). Cholangiocytes (i) express HDC; (ii) secrete HA; and (iii) proliferate after HA treatment. In cholestatic rodents, there is enhanced biliary hyperplasia and fibrosis.Aimto demonstrate that knockdown of HDC inhibits hepatic fibrosis.MethodsHDC‐/‐ mice along with matching wild‐type (WT) were subjected to sham or bile duct ligation (BDL). Immunohistochemistry was performed for evaluating (i) bile duct mass by CK‐19 and (iii) collagen content by Masson's Trichrome. We measured: (i) serum histamine levels; and (ii) lobular damage, necrosis, inflammation and fibrosis (Sirius Red staining) in liver sections. In cholangiocytes, we studied the expression of a‐SMA, collagen 1, fibronectin and matrix metalloproteinases (MMPs) by qPCR. HA levels were assessed by EIA in serum and cholangiocyte supernatants. In vitro, cholangiocyte cultures were stably transfected with shRNA‐HDC to knockdown HDC expression. After transfection we evaluated: a‐SMA, collagen 1, fibronectin and MMPs by qPCR.ResultsIn BDL HDC‐/‐ mice, there was decreased collagen content, necrosis, inflammation and fibrotic reaction compared to BDL WT mice.imageHA levels were decreased in BDL HDC‐/‐. In BDL HDC‐/‐ cholangiocytes, there was a reduction of a‐SMA, collagen 1, fibronectin and MMP expression compared to BDL WT. In vitro, knockdown of HDC decreased a‐SMA, collagen 1, fibronectin and MMP expression.ConclusionLoss of HDC decreases BDL‐induced hepatic fibrosis. Our data suggests that HDC is a key regulator of the fibrotic reaction seen during cholangiopathies and may be a potential target for treatment.
Impact of Aging on Aortic Wave Reflection during Lower Body Negative Pressure
Authors: Schneider Aaron , Barnes Jill , Joyner Michael , Casey Darren 
Published: June 2021

Evidence suggests that increased sympathetic tone but no change of blood pressure (BP) via lower body negative pressure (LBNP) reduces indices of aortic wave reflection in young adults. The aim of this study was to examine whether aging affects central artery hemodynamics and indices of wave reflection during LBNP. In 12 young (27 ± 2 years, 5F/7M) and 10 older (70 ± 2 years 5F/5M) subjects, noninvasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms via applanation tonometry before and during 10 minutes of LBNP (‐20mmHg). Aortic BP and indices of aortic wave reflection (i.e. Augmentation index; AIx) were calculated from the generated aortic pressure waveform. Aortic systolic BP decreased during LBNP in the young (110 ± 3 vs. 106 ± 3 mmHg, P<0.05), but not the older adults (139 ± 3 vs. 136 ± 3 mmHg, P=0.15). Aortic diastolic BP did not change in either group (P=0.56). Since heart rate (HR) changed in the young (P<0.05) but not in the older adults (P=0.33) during LBNP, we used the AIx normalized to a HR of 75bpm as an index of wave reflection. AIx@75bpm decreased in young adults (‐6 ± 3 vs. ‐13 ± 3%, P<0.001), whereas no change was observed in older adults (26 ± 3 vs. 25 ± 3%, P=0.39). Our data suggest that reductions in aortic systolic blood pressure and wave reflection during lower body negative pressure are attenuated in older compared to young adults.Funded by NIH HL‐105467
Computational Analysis of Cellular Environment During Neural Progenitor Cell Differentiation
Authors: Mahadevan Arun , Robinson Jacob , Qutub Amina 
Published: June 2021

ObjectiveThe objective of this study is to quantify the influence of multi‐cellular environment in Neural Progenitor Cell (NPC) differentiation using time‐lapse phase contrast microscopy.MethodsDifferentiating human NPCs were tracked over 14 days using time‐lapse phase contrast microscopy.
imageAn intensity‐gradient thresholding method was used to extract cell locations and morphological features such as neurite length. A graph theory‐based approach was then employed to quantify cellular neighborhood, with vertices defined as cell centroids and spatial proximity between cells used to define edges.
imageGlobal network properties such as characteristic path length and global clustering coefficient were evaluated at each time point to quantify the spatial topology of differentiating cells. Parallel assays in patch‐clamp electrophysiology were performed to compare functional maturation with network properties.ResultsOur image‐processing algorithm rapidly and robustly extracts relevant cell morphological features and locations. Time‐lapse image sequence analysis showed that cultures at different stages of electrical maturation (assayed through patch clamp electrophysiology) exhibit unique network topology.ConclusionWe have developed a method to analyze NPC differentiation based on time‐lapse microscopy, which can be used to non‐invasively investigate the role of multi‐cellular neighborhood at different stages of NPC differentiation.SupportThis work is supported in part by NSF CAREER Award 1150645 and an NSF IGERT Training Grant.
EXPLORING THE CORRELATION BETWEEN INTRINSIC FLUORESCENCE AND PROTEIN AGGREGATION
Authors: Bennett Christopher , Alibeik Sara , Valverde Paloma 
Published: June 2021

Progressive nerve and brain cell damage associated with Alzheimer's disease, has been attributed to the build‐up of aggregated proteins. Detection of amyloid aggregation, through the measuring their intrinsic fluorescence, could be a valuable approach for early detection of the disease.The purpose of our study was to teach the correlation between intrinsic fluorescence and protein aggregation within the visible range in an interdisciplinary undergraduate summer research course. Students used purified green fluorescent protein (GFP, Biorad), unpurified enhanced green fluorescent protein (EGFP, Edvotek) and liquid silk fibroin protein (SFP, Silktap) as model proteins. We focused our experimentation on sonication conditions that led to gelation of SFP due to β‐sheet formation. Using single model proteins and combined protein solutions, samples were sonicated and fluorescence was measured at 405 and 500nm wavelengths. UV light was also used to compare the green fluorescence emitted by the GFP and EGFP samples.Our results showed an increase in fluorescence of single model protein solutions post‐sonication when compared with the pre‐sonication protein solutions. When EGFP and SFP solutions were combined and sonicated together, we observed a decrease in fluorescence. Similar results were obtained when purified GFP and SFP solutions were combined and sonicated.In future experiments, students are planning to design a minimally invasive device able to detect early stages of amyloid aggregation in the brain as a senior project for an undergraduate biomedical engineering major.
Using Generalizability Analysis to Establish Guidelines for Designing Horizontally Integrated Anatomy Assessments
Authors: Byram Jessica , McAteer James , Seifert Mark , Wilson Adam 
Published: June 2021

Background & PurposeIn the context of planning assessments for a combined gross anatomy/histology course, this study used generalizability analysis to estimate the number of gross anatomy and histology items that would be needed on a series of examinations to reliably assess discipline‐specific knowledge.MethodsScores of first‐year medical students (n=145) who sat for 3 gross anatomy and histology written and practical examinations were analyzed. A generalizability study (G‐study) estimated the reliability of the written and practical examination scores, and a decision study (D‐study) estimated the optimum assessment parameters for reaching a minimum reliability of 0.8.ResultsEstimated G coefficients for calculating reliability were 蠅0.782 for the gross anatomy examinations and 蠅0.659 for the histology examinations. Assuming that a series of 4 separate examinations would be ideal for assessing a breadth of content in a combined gross anatomy/histology course, the D‐study estimated that a minimum of 35 and 40 items for a gross anatomy written and practical examination, respectively, would be needed to reach a reliability of 0.8 for measuring gross anatomy knowledge alone. Furthermore, each of the 4 examinations would require an additional 40 written and 45 practical items to reliability assess one's knowledge of histology.ConclusionThis study helps to establish basic parameters for designing horizontally integrated anatomy assessments. Future studies will investigate how incorporating ‘truly integrated items' (that require knowledge of histology and gross anatomy to answer a single question) may affect the reliability of such assessments.
The Impact of Ultrasound Education in Medical Gross Anatomy on Student Experience During Clinical Rotations
Authors: Zoll Kyle , Arseneaux Mattie , Atieh Tahani , Beatty Derek , Kondrashova Tatyana , Kondrashov Peter 
Published: June 2021

ObjectiveTo show the effect of ultrasound education on clinical rotations, we surveyed students at the conclusion of their third year and evaluated their perception of: (1) how ultrasound training in gross anatomy impacted their clinical thinking; (2) how often they were able to use ultrasound; (3) the obstacles that prevented them from using ultrasound; and (4) the specialties in which students were able to use ultrasound most.MethodsOsteopathic medical students received ultrasound training as part of their anatomy course during the first two years of their education. At the conclusion of their first year of clinical rotations, 85 students were surveyed about the impact that ultrasound training had on their clinical thinking, and if they were able to use their skills.ResultsThe students thought that ultrasound training had a significant effect on their clinical decision making during their first year of rotations (P<.05). Students were able to use their ultrasound skills during clinical rotations (P<.05). Many students experienced at least one obstacle preventing them from using ultrasound. The most common cause was lack of permission (P<.05). They also listed shortage of equipment and lack of confidence as other obstacles. Ultrasound was most commonly used during obstetrics/gynecology rotations (P<.05).ConclusionUltrasound training had a strong impact on clinical rotations and aided in student decision‐making ability. Ultrasound was used in a variety of specialties throughout clinical rotations. Despite encountering obstacles, the current study supports the inclusion of ultrasound into medical school curriculum as it improves clinical thinking and skills during clinical rotations.
The Long‐Term Impact of Water and Sanitation on Childhood Cognition
Authors: Wulan Nisaa' , Smith Emily , Prado Elizabeth , Apriatni Mandri , Muadz Husni , Shankar Anuraj 
Published: June 2021

Unsafe water and poor sanitation may negatively affect brain development, however few studies have examined the long‐term impact on children's cognitive function.Our objective was to assess the relationship between household access to safe water and toilet facilities during the prenatal period with childhood cognition 9‐12 years later.The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), conducted in 2001‐2004 In Indonesia, compared the health effects of a prenatal multiple micronutrient supplement to an iron and folic acid supplement. At baseline, information collected included water supply, sanitation, and maternal education. We assessed cognition in 3687 children of SUMMIT participants at 9‐12 years of age. Children of mothers who had access to safe toilet facilities during pregnancy had higher scores in Digit Span Forward (95%CI 0.008‐0.17, P<0.03), Information (95%CI 0.08‐0.2, P<0.001), Block Design (95%CI 0.01‐0.1, P<0.02), and Word List Memory (95%CI 0.006‐0.17, P<0.03) tests after adjusting for cluster randomization, data collector, maternal education, socio‐economic status and home environment score. Children of mothers with access to safe water during pregnancy had higher Word List Memory scores (95%CI 0.01‐0.19, P<0.02).The finding that safe water and toilet facilities were associated with child cognition even after adjustment for socio‐economic status and maternal education suggests that interventions to improve water and sanitation in early life may have long‐term benefits on child cognitive abilities.
Members of the CCN Family of Matricellular Proteins are Required for the Formation and Maintenance of Multiple Skeletal Tissues
Authors: Lyons Karen 
Published: June 2021

The roles of members of the CCN (Cyr61/CTGF/Nov) family of matricellular proteins have been best characterized in the context of fibrosis. It is clear that CCNs also have roles in normal tissues, but these are less well characterized. Moreover, CCN1 has anti‐fibrotic properties, whereas CCN2 is profibrotic, indicating that these CCNs have unique functions in fibrosis. Multiple CCN family members are expressed in skeletal tissues, including bone and tendon. The objective of this study was to examine whether various CCN family members are required in these tissues, and whether or not they may have divergent functions during development, as is the case in fibrotic conditions. We therefore generated mice lacking CCN1 (Cyr61) or CCN2 (CTGF) in osteoblasts using osteoblast‐specific Cre drivers, and in tendon using Scx‐Cre. Mice lacking CCN1 or CCN2 in osteoblasts exhibited an osteopenic phenotype, suggesting that CCN1 and CCN2 have some overlapping functions in osteoblasts. Studies are ongoing to define the impact of CCN1 and CCN2 on osteoblast survival, proliferation, and differentiation. Moreover, these studies revealed a unique role for CCN1 in a subset of tendons in the mouse. In the absence of CCN1, tendon fibroblasts acquire a fibrotic phenotype. Thus, the antifibrotic properties of CCN1 that have been demonstrated in the context of pathological conditions are required for the normal formation of organized extracellular matrix in the tendon. Our results thus indicate that CCN1 and CCN2 have both overlapping and opposing functions, depending on the cell type. The mechanisms leading to these differential activities of CCN1 and CCN2 are under investigation.These studies were supported by NIH AR052686 and the Jonsson Comprehensive Cancer Center, UCLA (KML)
The Zinc Transporting Network is a Central Component of Dysregulation in Breast Cancer
Authors: Chandler Paige , Kochupurakkal Bose , Lopez Veronica , Alam Samina , Soybel David , Kelleher Shannon 
Published: June 2021

Breast cancer is classified into 3 major molecular subtypes (Luminal, HER2 and Basal), which differ in prognosis and therapeutic options. Numerous reports find that zinc (Zn) hyperaccumulates in breast tumors; however, the mechanisms responsible for Zn accumulation and the functional consequences of zinc accumulation are not understood. We tested the hypothesis that mechanisms responsible for Zn accumulation are subtype‐specific and that distinct patterns of sub‐cellular Zn distribution reflect the malignant phenotype of the cancer.Microarray gene expression revealed a subtype‐dependent pattern of Zn transporter expression in human breast tumors and cancer cell lines. Breast cancer cells accumulated significantly more Zn (p<0.05) than nonmalignant cells. Protein profiling of all 24 Zn transporters revealed that T47D luminal cells (LC) had greater expression of vesicular Zn importers and more vesicularized Zn pools, while MDA‐MB‐231 basal cells (BC) overexpressed the cytoplasmic Zn binding protein metallothionein. A primary difference was that LCs overexpressed the key Zn transporter ZnT2 and hyperaccumulated 2.5‐fold more Zn than BCs which did not express ZnT2. ZnT2 overexpression in MDA‐MB‐231 cells accumulated Zn in vesicles, altered morphology, arrested cells in G1 of the cell cycle and reduced invasion by ~80%.Zn accumulation in breast tumors is due to subtype‐specific alterations in the Zn transporting network. This suggests that these alterations may underlie differences in the malignant phenotype observed in certain breast cancer subtypes.