bluuebunny/crossref_metadata_2025_split huggingface dataset:
Employing Spherical Harmonics in Assessing the 3D Shape Variation and Evolutionary Potential of Human Sphenoidal Sinuses
Authors: Ryan Katharine G. J. , Auerbach Benjamin , Sylvester Adam , Butaric Lauren 
Published: May 2022

The evolutionary potential and shape variation of the human sphenoidal sinus are unknown. Moreover, a consensus about the function or evolutionary forces that influence variation of paranasal sinuses among humans remains unestablished. One initial approach to address this lies in determining the covariance of sinus shape with surrounding morphology. The sphenoidal sinus is centrally located within the basicranium at the intersection of the three cranial fossae, and is adjacent to the synchondroses where primary cranial base angulation occurs. The angulation of the cranial base and its relative orientation with the face is a distinctive, derived trait in Homo sapiens and is important to our understanding of the evolution of our species. Yet, the shape of the sphenoidal sinus is highly variable and cannot be quantified with traditional landmarking methods. Originally developed in gravitational physics, spherical harmonics has been successfully leveraged in biological morphological studies to quantify and assess 3D shape variation of complex structures. This research will use spherical harmonics to for the first time quantify the 3D shape of the sphenoidal sinuses and assess their covariation with the sphenoid body. By demonstrating the utility of spherical harmonics for human morphometric research, we are opening up new ways for investigating biological and evolutionary questions of human anatomical features that to date have been difficult to evaluate.Here we preliminarily analyze the covariance of sphenoid sinus and basicranial shape. The sphenoidal sinuses of 120 human crania were segmented (Avizo) from CT scans. We quantified the three‐dimensional shape variation of sphenoidal sinuses using spherical harmonic analyses (SHARM, Matlab), producing coefficients comparable to traditional landmarks placed virtually on the basicranial surface. Landmarks were chosen that capture the general shape of the sphenoid body. Two‐Block Partial Least Squares (2B‐PLS) analyses revealed no significant covariation (p=0.59) between the shape of the sphenoidal sinus and its surrounding bony architecture. This indicates the establishment of sinus shape occurring independently of the surrounding bone. This is contrary to previous research, which has suggested that paranasal sinuses opportunistically pneumatize within the available space of their respective cranial bones. Future research will need to investigate this relationship further with additional sets of landmarks representing different developmental regions and functional matrices that interface with the sphenoid body. This research is also foundational to investigate to what extent mutual constraint among these traits may exist in the ability to respond to natural selection, i.e. evolvability.
Evaluation of Loaded Breathing on Inspiratory Intercostal Muscle Activation During High Frequency Spinal Cord Stimulation to Restore Breathing in Spinal Cord Injury – Animal Model
Authors: Kowalski Krzysztof E. , DiMarco Anthony F. 
Published: May 2022

BackgroundHigh Frequency Spinal Cord Stimulation (HF‐SCS) is a unique method of inspiratory muscle activation and has the potential to restore breathing in ventilator dependent tetraplegic subjects. However, these subjects are 3‐4 times more likely to have sleep disordered breathing (SDB) and have a higher incidence of obstructive airways disease than individuals in the general population, resulting in an increased inspiratory load.ObjectiveTo examine the effects of increased inspiratory load (airway occlusion) on inspiratory intercostal muscle activation during HF‐SCS.MethodsIn 3 spinalized (C2 level) anesthetized dogs, recording electrodes were positioned in the parasternal (PA) and external (EI) intercostal muscles (2nd and 3rd interspaces respectively) to record multiunit (integrated) and single motor units (SMU) EMG activities. During HF‐SCS at functional residual capacity (FRC), respiratory muscle activity was assessed before and after single and multi‐breath airway occlusion.ResultsDuring HF‐SCS, tracheal occlusion resulted in augmentation of peak multi‐unit integrated EI, but little change in PA EMG activity. During the occluded breath, EI activity increased to 148 ± 3% of that observed during control breaths (p<0.01) whereas PA activity was little changed (105 ± 5%; NS). EI instantaneous SMU peak firing frequency (PFF) was also greater during the occluded breath (15.7 ± 1.6Hz vs. 11.3 ± 0.3Hz; p<0.05). whereas there was only a small increase in PA PFF (10.8 ± 0.6Hz vs. 10.0 ± 0.6Hz; NS).SummaryHF‐SCS during airway occlusion results in significant increases in activation of the EI but not PA muscles.ConclusionHF‐SCS applied to support ventilation in high tetraplegics with airway obstruction may elicit compensatory increases in EI muscle activation. These results support the concept that spinal reflex effects remain functional during HF‐SCS. The EI have a much higher density of muscle spindles compared to the PA muscles, which may mediate the differential activation of these muscles.
IRBIT as a Regulator of Bicarbonate Transport in the Small Intestine
Authors: Sarthi Jessica B. , van Unen Vincent , Chan Joshua E. , Abazari Shayda , Trumbull Annie , Guh‐Siesel Alexander , Kuo Calvin J. , Sellers Zachary M. 
Published: May 2022

BackgroundSmall intestinal bicarbonate transport, is critical for epithelial protection, digestion, and absorption. Membrane trafficking and/or recycling of transporters is a critical means to modulate their function, however, the cellular mechanisms that drive these processes in the duodenum remain unclear. The inositol 1,4,5‐trisphosphate (IP3) receptor binding protein released with IP3 (IRBIT) is an intracellular protein that has been shown to regulate localization of bicarbonate transporters outside of the intestine, yet its role in regulating duodenal bicarbonate secretion is unknown.AimTo examine duodenal expression and function of IRBIT in regulating bicarbonate transport.MethodsDuodenal endoscopic biopsies from subjects without gross or histological evidence of disease were used directly or cultured using traditional apical‐in or flipped apical‐out enteroids. mRNA expression was evaluated using qPCR and re‐analysis of a duodenal sc‐RNAseq dataset. Protein expression and localization was determined by Western blot and confocal immunofluorescence, respectively. In vivo bicarbonate secretion was measured in anesthetized mice by duodenal perfusion and back‐titration.ResultsIRBIT is highly expressed in human duodenal biopsies, with protein densitometric analysis showing ≥3.5‐fold higher expression than Calu‐3 airway submucosal gland cells or HEK293 kidney‐derived cells (n=1 each). Analysis of duodenal sc‐RNAseq data (1,625 cells) showed ACHYL1 in crypts and villi. Immunofluorescence staining of human duodenal biopsies (n=3) showed IRBIT staining along the crypt‐villus axis, primarily localizing in E‐cadherin positive epithelial cells, but also present in the lamina propria. In patient‐derived duodenal enteroids, IRBIT was expressed in both crypt‐like (undifferentiated) and villus‐like (differentiated) enteroids (n=3 each), with greater IRBIT mRNA and protein expression in the latter, a pattern similar to SLC26A3 and SLC26A6 chloride/bicarbonate exchangers (n=3 each). In sc‐RNAseq analysis, AHCYL1 and SLC26A3 were co‐expressed in 38% of all villus cells, compared to only 5% co‐expressing AHCYL1 and SLC26A6. CFTR‐independent duodenal bicarbonate secretion stimulated by linaclotide (10‐7 M) was significantly inhibited by phospholipase C inhibition (U7312, 10‐6 M; 91±11%, n=3), which we showed disrupts IRBIT membrane localization, or SLC26A3 inhibition (DRAinh‐A250, 10‐5 M; 68±8%, n=10). Linaclotide stimulation of apical‐out enteroids increased both IRBIT (n=3) and SLC26A3 (n=12) membrane trafficking.Summary and ConclusionsIRBIT is highly expressed in the duodenum and appears to functionally interact with SLC26A3. IRBIT may be an attractive target to modulate small intestinal pH in diseases like cystic fibrosis, where impaired bicarbonate secretion contributes to intestinal disease and malnutrition.
Do We Have a New Psoriasis Drug?
Authors: Šola Marija , Skroza Nevena , Mangino Giorgio , Škrtić Anita , Seiwerth Sven , Sikirić Predrag 
Published: May 2022

Pentadekapeptide BPC 157 was used in numerous laboratory rat animal models with proven cytoprotective and organ protective properties. In different wound therapy (incisional/excisional wound, deep burns, diabetic ulcer, alkali burns) fast and complete tissue restitution was achieved. BPC 157 was found to rapidly stimulate the expression of various genes involved in the healing process of the skin and mucosal lesions in these models. Psoriasis is a chronic, relapsing, immune‐mediated skin disease pathogenically driven by proinflammatory cytokines of which: TNF‐alpha, IL‐12, IL‐17, IL‐23 play a key role. Since BPC 157 has shown a significant anti‐inflammatory effect in several studies, the aim of this study is to show that it has the same role in the regression of inflammatory skin lesions such as those in psoriasis. An experimental model of psoriasis in laboratory animals is easily feasible, using 5% imiquimod topically.MATERIALS AND METHODS The experiment is done on male Wistar Albino rats. Animals are divided into groups of 6. „Psoriasis‐like” lesions are induced in all animals applying 5% imiquimod cream topically on shaved skin on their backs for 7 consecutive days. On the 7th day, 3 hours after applying imiquimod cream treatment starts usage BPC 157 in cream (conc. 1μg/g neutral cream) or only neutral cream (Belobaza) in control groups. Animals are treated and observed daily, video documentation was made. Animals are treated until the sacrifice day according to schedule. The severity of skin lesions is measured clinically using a modified version of Psoriasis Area Severity Index‐PASI score. Modified PASI includes scoring the following lesion features: erythema, infiltration, desquamation on scale 1‐4; maximum modified PASI value is 12. Two way ANOVA and Bonferroni post hoc test were used for statistical analysis. Data represented as mean SD for N=6/group.RESULTS Animals treated using BPC 157 conc.1μg/g in a cream had significantly lower values of PASI score when compared to control group. Faster resolution of imiquimod induced „psoriasis‐like” lesions was achieved using BPC 157 when compared to control group.CONCLUSION BPC 157 is well‐known peptide used in various experimental models without any side effects of it's use, with proven effects on the NO‐system, and excellent results in wound healing. Psoriasis is a rather common immune‐mediated skin disease driven by proinflammatory cytokines. TNF‐alpha, IL‐12, IL‐17, IL‐23 play a key role in the pathogenesis of psoriasis. It is undisputably that the use of BPC 157 topically successfully neutralizes the effects of imiquimod and induces regression of „psoriasis‐like“ lesions, the question that needs to be answered yet is whether BPC 157 has an impact on one of the above‐mentioned cytokines. It is yet to be explored which mechanism is the key to it´s beneficial effects in treating „psoriasis‐like“ lesions in experimental models.
Investigating the Anticancer Activity of Novel Norethindrone Derivatives in PC3 Prostate Cancer Cells
Authors: Hollenbacher Courtney A. , Harris Katelyn A. , Reid Nicholas A. , Schneider Ryan A. , Dudley Richard W. 
Published: May 2022

It is estimated that over 248,000 new cases of prostate cancer will be diagnosed this calendar year (2021) representing upwards of 20% of newly diagnosed cancer cases in men.1,2 Despite these numbers, prostate cancer‐related deaths have significantly declined over the period of time from 1993 to 2016, yet prostate cancer was expected to be responsible for almost 10% of cancer‐related deaths in 2018.1 Metastasis and cancer cell resistance results in treatment failure and progressive disease, and this remains a significant concern in the care of men with prostate cancer.To address the significant need for novel agents in the treatment of resistant prostate cancer, we designed and synthesized a small library of norethindrone (NE) derivatives with varying substituents attached to the 17‐position (Compounds A‐D) with the hopes of identifying androgen receptor antagonists. Click chemistry was utilized to facilitate the formation of a triazole linking NE to alkyl and aryl substituents. The corresponding azides were synthesized in situ from alkyl bromides or aryl bromides in a one‐pot microwave‐assisted reaction in an Anton Parr Monowave‐50 reactor at 150℃ for 20 minutes.Here we present initial data of our small library of NE derivatives which were screened for anticancer activity using the XTT cell viability assay in PC3 prostate cancer cells. Two of the compounds (A and D) failed to induce an anticancer response. Compound B demonstrated weak anticancer activity with an IC50 of greater than 100 µM, whereas Compound C demonstrated low micromolar activity with an IC50 of 19 µM. Further studies are ongoing to determine the mechanism(s) by which Compound C elicits its anticancer activity in the metastatic‐derived PC3 prostate cancer cells. Additionally, these results will assist with further rational design using NE as a scaffold in an attempt to increase the potency against PC3 and other prostate cancer cell lines.1. American Cancer Society. Cancer Facts & Figures 2021. Atlanta: American Cancer Society; 20212. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7‐34. doi: 10.3322/caac.21551. Epub 2019 Jan 8. PMID: 30620402.
Student Approach to Learning and Visuospatial Ability as Independent Predictors of Academic Performance in Human Anatomy
Authors: Wang Catherine , McWatt Sean 
Published: May 2022

Several indices have been investigated for their accuracy as predictive metrics of students’ performance in anatomy courses. Both student approaches to learning (SAL) and visuospatial ability (VA) have been shown to be predictive of learning outcome achievement. However, far less anatomy‐specific evidence exists for SAL than for VA, and their respective predictive strength has yet to be examined.The present study investigated the relationship between SAL and VA as predictive metrics for student academic performance, as measured by laboratory‐based assessments. In addition, the predictive strength of each metric was evaluated to determine which of the two was most effective at quantitatively assessing anatomy learning environments. It was hypothesized that the variation in grades could be partially explained by both SAL and VA, and that the latter would have a stronger relationship to performance.Undergraduate students enrolled in an anatomy course at McGill University were surveyed for this study (total n = 138; 76.8% female; average years of age = 19.46, SD = ±1.04). Students were from kinesiology (58.0%), physical therapy (19.6%), occupational therapy (19.6 %), and other (2.9%) programs. In addition to collecting demographic data, the survey included the Revised 2‐factor Study Process Questionnaire to collect SAL on deep and surface scales, and the Mental Rotations Test to quantify VA.A multiple linear regression model was used to assess deep and surface approach to learning scores and VA as covariates that influence grades, while controlling for age, sex, and program of study [F(6,131) = 7.741, P < 0.001, adjusted R2 = 0.228]. Data analyses revealed that both VA (β = 0.802, SEM = 0.284; P = 0.006) and deep approach scores (β = 0.776, SEM = 0.246; P = 0.002) had significant positive correlations with grades; however, surface approach scores (β = ‐0.399, SEM = 0.280; P = 0.157) were not significantly correlated at P ≤ 0.05. Based on the coefficients, a one‐point increase on the deep approach scale was slightly more beneficial than the same point‐increase on the Mental Rotations Test; however, the advantage was minimal (+0.026%).These findings assert that SAL and VA can independently predict performance on laboratory‐based assessments in human anatomy – with VA representing a personal presage factor, and SAL representing a process factor. A deeper understanding of these metrics allows for better quantitative assessment of success when implementing curricular changes intended to improve anatomy learning environments. Therefore, both metrics should be used for a more comprehensive approach to evaluating educational interventions in anatomy.
Nitric oxide synthase inhibitor is an effective therapy for ischemia‐reperfusion injury in mice
Authors: Wisen William P. , Evans Wesley R. , Sure Venkata N. , Sperling Jared A. , Sakamuri Siva S. , Mostany Ricardo , Katakam Prasad V. 
Published: May 2022

BackgroundInhibition of nitric oxide synthase (NOS) has been shown to paradoxically protect against ischemic brain injury by an unknown mechanism. Recently, we found that NOS inhibitor, N (gamma)‐nitro‐L‐arginine methyl ester (L‐NAME), protects primary cultures of endothelial cells and neurons against oxygen‐glucose deprivation‐reoxygenation injury by preventing NOS uncoupling. Thus, the objective of the present study was to demonstrate the effectiveness of locally administered L‐NAME against ischemia‐reperfusion (I‐R) injury.MethodsTransient focal cerebral ischemia in male mice (C57Bl/6, 2‐4 months) was achieved by filament method of MCAO with a 60 min occlusion. We employed a novel approach to inject L‐NAME (1 mg/Kg dosages at a rate of 60 ug/minute) locally into the ischemic zone by threading a catheter up the middle cerebral artery. This was timed to the onset of reperfusion by rapidly followng the removal of the occlusion with the silicon suture. Following 24‐hour reperfusion, infarct size was determined by 2,3,5‐Triphenyltetrazolium chloride (TTC) staining and neurological function was assessed by employing a standard neurological score (0‐4 range) and Rotarod performance test.ResultsAdmnistration of FITC Dextran 40K and fluorescence microscopy of the brain slices 1 hour post‐ischemia confirmed the effective delivery of injected L‐NAME into the ischemic tissue. Localized injection of L‐NAME was protective against I‐R injury and promoted significant recovery of neurological and motor function (Figure).ConclusionLocal NOS inhibition could serve as an adjuvant for reperfusion therapies of ischemic stroke.
TNK1 is a ubiquitin‐sensing kinase that can be targeted to block tumor growth
Authors: Andersen Joshua L. , Chan Tsz‐Yin , Egbert Christina M. , Lopez‐Palacios Tania , Maxson Julia E. , Tyner Jeffrey W. , Warner Steven L. 
Published: May 2022

Thirty‐eight negative kinase‐1 (TNK1) is an understudied non‐receptor tyrosine kinase with no established function or mechanism of regulation. We recently identified TNK1 as the primary kinase driver of cell survival in subsets of patient blood cancer samples1. We discovered that one unusual feature of TNK1 is a functional ubiquitin‐association (UBA) domain that binds with high affinity to multiple poly‐ubiquitin linkages. Our recent 1.5 angstrom crystal structure of the TNK1 UBA shows an atypical five‐helix UBA domain with two predicted ubiquitin‐binding interfaces. We found that TNK1 relies on its UBA domain to home to phase‐separated poly‐ubiquitylated protein condensates and becomes fully active at these sites. To our knowledge, this feature of TNK1—a bona‐fide ubiquitin‐association domain that promotes kinase activation—makes TNK1 unique across the human kinome. Our data also suggest that 14‐3‐3 interacts with a MARK‐mediated phosphorylation at S502 of TNK1 to sequester the kinase away from ubiquitin and inhibit kinase activation. Thus, TNK1 toggles between poly‐ubiquitin bound (active) and 14‐3‐3‐bound (inactive) states. Our preliminary data suggest that the interaction with poly‐ubiquitin at condensates tethers TNK1 to substrates, facilitating its phosphorylation of substrates involved in the lysosomal degradation of condensates. Furthermore, we found that patient mutations that truncate the 14‐3‐3 binding site and UBA domain convert TNK1 into a cancer driver with an altered substrate profile, skewed toward pro‐growth substrates like STAT3. Finally, we show that mutant TNK1‐driven tumors can be targeted in vivo with a novel anti‐TNK1 small molecule. Thus, together our data suggest that TNK1 acts as a ubiquitin sensor and is a candidate for targeted therapy.1. Chan TY and Egbert CM et al., (2021) TNK1 is a ubiquitin‐binding and 14‐3‐3‐regulated kinase that can be targeted to block tumor growth. Nature Communications(in press)
Resistance profile of bacteria to antibiotics in city laboratories
Authors: CHEMSI Hicham , Haitam Abdelaziz , Hilali Farida , Sekhsokh Yassine 
Published: May 2022

IntroductionBacteria are the causative agents most frequently described in infections. Therefore, antibiotic resistance is a real public health problem. Thus, bacterial infections are becoming one of the major threats to public health in the world. The objective of this study is to evaluate the frequency of isolation of bacteria and to study the sensitivity of bacteria isolated in different biological samples at the level of city laboratories in the entire population (women, men and children).Patients and methodsThis is a prospective descriptive study carried out in city medical analysis laboratories. The inclusion criteria were all positive samples from the examinations performed: urinary examination, vaginal swab, urethral swab, pus, sputum, semen. The exclusion criteria concerned patients with negative examinations and other microorganisms (viruses, mycoses and parasites). Data collection was carried out using an information sheet. An antibiogram is carried out to study the resistance of bacteria. Data processing was carried out and statistically analyzed at a risk of 5%.ResultsOut of a total of 8,594 samples identified, 2,465 strains isolated were responsible for bacterial infections with a prevalence of 28.7%. A clear predominance was noted in the female sex with 1710 (69%) versus 755 (31%) in the male. The F / M sex ratio was 2.2. The most affected of the patients were those over 60 years of age with an enrollment of 832 (33.7%). 1954 strains were Gram negative bacilli or a frequency of 79.3%, 462 strains were Gram positive coccis or a frequency of 18.7% and 49 strains were Gram negative coccis or a frequency of 2%. The distribution of isolates according to the type of sample revealed a predominance of urine samples with a frequency of 1703 (69%), followed by vaginal samples with a frequency of 276 (11.2%), urethral samples with a frequency of 166 (6.8%), sputum with a frequency of 154 (6.2%) and others. The bacteriological profile was largely dominated by Escherichia coli 1410 (57.2%), Klebsiella pneumoniae 355 (14.4%), Staphylococcus sp 294 (12%), Enterococcus sp 109 (4.4%), Streptococcus sp85 (3,4%). For Enterobacteriaceae, the lowest sensitivities in out‐of‐hospital settings were recorded with Amoxicillin followed respectively by Ticarcillin, Cefalotin, and Amoxicillin‐clavulanic acid. High sensitivities have been observed for Imipenem, Colistin, Furan, and Aminoglycosides.ConclusionAt the end of the study, the results showed an increase in the resistance of bacteria. This rise could be linked to selection pressure due to the overuse of antibiotics. Regular monitoring is essential to define effective and appropriate therapeutic strategies, limiting the emergence and dissemination of very resistant strains.