bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic and Transcriptomic Effects of Mediator Kinase Inhibition on the Interferon Response in Down Syndrome
Authors: Cozzolino Kira A. , Jones Taylor , Ajit Deepa , Dowell Robin , Taatjes Dylan 
Published: May 2022

Down syndrome, also known as Trisomy 21, is a condition in humans resulting from full or partial triplication of chromosome 21. Affected individuals present with a constellation of symptoms that includes an increased risk of autoimmune disorders. Cells of patients with Down syndrome exhibit chronic, hyperactivated interferon (IFN) signaling, due in part to the presence of several interferon receptors on chromosome 21. Partial knockout of these receptors has been shown to increase cellular viability, indicating that treatments targeting the IFN response may ameliorate the comorbidities associated with Down syndrome.Among the regulators of the IFN response are the Mediator‐associated kinases, CDK8 and CDK19. Studies using inhibitors such as cortistatin A, which targets the enzymatic activity of both kinases, have demonstrated improved outcomes in autoimmune disease models. However, the specific mechanisms and contributions of CDK8 vs. CDK19 remain unclear. In mouse and human cells, we and others have shown that the transcriptional response to IFN is different when CDK8/19 are inhibited as opposed to when CDK19 specifically is degraded, suggesting that each kinase regulates distinct sets of IFN‐responsive genes through divergent mechanisms. While it seems likely that CDK8 acts through phosphorylation of proteins such as the transcription factor STAT1, CDK19 may instead serve as a physical scaffold.To begin to examine whether inhibition of the Mediator kinases is a viable strategy to treat Down syndrome‐associated comorbidities, I assessed the metabolic effects of CDK8/19 inhibition in patient‐derived lymphoblastoid cell lines from a pair of age‐ and sex‐matched siblings, one with Down syndrome (T21) and one without (D21). Metabolomic analysis demonstrated a severely blunted response to IFNγ treatment in T21 cells as compared to D21 cells, and revealed genotype‐specific changes in energy, nucleotide, and fatty acid metabolism. Interestingly, a subset of metabolites that were decreased or elevated in T21 cells treated with IFNγ alone showed no significant changes in cells also treated with cortistatin A, suggesting that Mediator kinase inhibition may reduce the responsiveness of T21 cells to IFNγ.Ongoing RNA‐seq experiments are assessing the transcriptional response to IFN in D21 and T21 cells following CDK8/19 inhibition, with a focus on potential splicing defects and altered gene expression programs in T21. In sum, these experiments will address the under‐explored question of how T21 alters metabolic and transcriptional responses to IFNγ and how these responses are controlled by the Mediator kinases. This work will also shed light on the therapeutic potential of Mediator kinase inhibitors, as a means to dampen hyper‐activated IFN signaling in Down syndrome.
Loss of eNOS in Endothelial Cells Promotes Proliferation
Authors: Bu Shuhan , Nguyen Hien C. , Nikfarjam Sepideh , Michels David C. , Rasheed Berk , Ramesh Sauraish , Patel Darshil , Patel Margi , Singh Shweta , Frisbee Jefferson , Singh Krishna 
Published: May 2022

BackgroundEndothelial cells help maintain vascular homeostasis mainly by balancing interplay between vasorelaxation and vasoconstriction via regulating availability of Nitric Oxide (NO). Endothelial nitric oxide synthase (eNOS) is one of three NOS isoforms that catalyses the synthesis of NO to regulate endothelial function. To date, however, eNOS’s role in endothelial cell proliferation, remains unclear.Methods and ResultsTo gain a better understanding about eNOS and cell proliferation, we genetically inhibited eNOS viasilencing by transfecting cultured human umbilical vein endothelial cells with sieNOS or scrambled control. Successful eNOS silencing was confirmed at transcript and protein levels, and then endothelial cell proliferation was evaluated. Surprisingly, loss of eNOS significantly induced endothelial cell proliferation, concomitant with significant downregulation of both cell cycle inhibitor p21 and cell proliferation antigen Ki‐67. To confirm the specificity of eNOS silencer, we used another sieNOS molecule, which also showed the similar results as endothelial proliferation was significantly induced in eNOS‐silenced endothelial cells. Later, to demonstrate that the induced endothelial cell proliferation is due to eNOS inhibition, we pharmacologically inhibited eNOS by treating endothelial cells with L‐NAME. Contrastingly, L‐NAME‐treatment significantly inhibited endothelial cell proliferation in a dose‐dependent manner.ConclusionOur findings, for the first time, indicate that eNOS regulate endothelial function by directly controlling endothelial cell proliferation. Observed inhibition of endothelial cell proliferation by L‐NAME, may be due to its non‐specific effects. The findings also indicate that eNOS and L‐NAME might employ different pathways regulating endothelial cell proliferation warranting further investigation.
A Non‐Invasive Method to Estimate Pulmonary Oxygen Transfer Rate
Authors: Shukla Pooja Rajesh , Limberg Jacqueline K. , Jacob Dain W. , Tan Jinglu 
Published: May 2022

ObjectiveIneffective transfer of oxygen from the atmospheric air to the circulation is associated with low cardiorespiratory fitness and increased disease risk. Unfortunately, measuring the efficiency of gas exchange requires invasive and expensive procedures. We first sought to develop a parameter (Do) that reflects the capacity to move oxygen from air to the arterial circulation using non‐invasive methods. We then tested the utility of Do to detect changes in pulmonary oxygen transfer rate under differing conditions of oxygen supply and demand. Last, we compared Do with the Oxygen Deficit (OD) method, a non‐invasive way to estimate gas‐exchange impairment.MethodsHeart rate (ECG), tidal volume (pneumotachometer), respiratory rate (pneumobelt), and oxygen saturation (finger pulse oximeter) were measured in 25 young healthy adult participants (13 males, 12 females; 25 ± 4 years of age). Participants completed 4 trials: 1) Resting normoxia, 2) Steady‐state hypoxia (80% SpO2, SSH), 3) Cold pressor test (CPT, to increase oxygen demand), and 4) SSH + CPT. Do was derived by engineering analysis considering the biophysics of the 3 major process essential for effective oxygen transfer (i.e., ventilation, alveolar gas exchange, hemoglobin binding). Do was estimated for each condition and results were compared with the OD method.ResultsDoincreased during SSH (5.13±1.07×10‐2L/min/kPa) and CPT (2.91±1.03 ×10‐2L/min/kPa) when compared to resting normoxia (2.24±0.66×10‐2 L/min/kPa, p<0.05). Dowas further increased during SSH+CPT (5.71±1.52×10‐2L/min/kPa) when compared to SSH alone (p<0.05). Applicability of the OD method was limited to SpO2<95%; thus OD could only be calculated in 40% of participants (n=10). OD was lower during SSH (2.18±0.63 kPa) and CPT (2.48±1.56 kPa) versus normoxia (3.15±1.3 kPa, p<0.05). In contrast, OD increased during SSH+CPT (2.42±0.59 kPa) when compared to SSH alone (p<0.05).ConclusionApplication of the novel parameter, Donot only showed the ability to respond to changes in supply and demand of oxygen but exhibited advantages over a conventional measure (OD). Specifically, Do showed consistent effect of CPT under normoxic and hypoxic conditions, whereas: 1) OD could only be determined in 40% of study participants, and 2) OD exhibited a paradoxical increase during SSH+CPT, despite a decrease during SSH and/or CPT alone. Future studies seek to test the utility of Do in cardiopulmonary patients.
Exploring the Combined Effect of High‐Fat High‐Sugar Diets and Volumetric Muscle Injury on Skeletal Muscle Metabolic and Contractile Function in Mice
Authors: Heo Jun‐Won , Schifino Albi , McFaline‐Figueroa Jennifer , Greising Sarah , Call Jarrod 
Published: May 2022

INTRODUCTIONVolumetric muscle loss (VML) injuries due to trauma or surgery cannot fully recover muscle mass and function, resulting in long‐term disability. Western diets, i.e., high‐fat, high‐sugar (HFHS) diets, promote metabolic stress and are associated with impaired skeletal muscle contractile function. The objective of this study was to investigate the extent to which a HFHS diet affected the pathophysiology following a VML injury as diet and disability may influence the effectiveness of rehabilitation. To determine the combined effects of HFHS diet and VML injury on skeletal muscle, metabolic and muscle contractile function was assessed. We hypothesized that a HFHS diet would worsen skeletal muscle metabolic and contractile function after VML injury.METHODSMale C57BL/6 mice (N=23) were randomly divided into four groups: Normal Chow (NC), High‐Fat High‐Sugar (HFHS), Volumetric Muscle Loss (VML), Volumetric Muscle Loss plus High‐Fat High‐Sugar (VML+HFHS). At age 12 weeks, VML animals underwent unilateral VML surgery to the ankle plantarflexors (gastrocnemius, plantaris, soleus muscles). HFHS groups received 60% high‐fat diet and 11% high‐fructose corn syrup for 8 weeks ad libitum. Oxygen respiration and electron conductance of mitochondria within permeabilized gastrocnemius muscle fibers and peak‐isometric torque of the ankle plantarflexors were measured to assess skeletal muscle metabolic and contractile function, respectively. Data were analyzed using a two‐way ANOVA to detect significant interactions between diet and injury, or in the absence of a significant interaction, the main effects of diet or injury.RESULTSIndependent of injury, mice on HFHS diet had 51% greater body mass compared to mice on NC (p<0.001). Additionally, mice on HFHS diet had less endurance capacity on a treadmill test compared to NC, independent of injury (77% less distance covered, p<0.001). Peak‐isometric torque was 6% less in HFHS mice, independent of injury (p=0.011) and peak‐isometric torque was 20% less in VML‐injured mice, independent of diet (p<0.01). There was a significant interaction between diet and injury for permeabilized muscle fiber oxygen respiration (p=0.016) where NC mice had greater oxygen respiration compared to HFHS, VML, and VML+HFMS mice. Electron conductance was 32% less in mice on HFHS diet, independent of injury (p<0.001) and 20% less in VML‐injured mice, independent of diet (p<0.001).CONCLUSIONThe current study indicates that both HFHS diet and VML injury have detrimental consequences on skeletal muscle contractile and metabolic function. Ongoing and future research is needed to determine the extent to which HFHS diets influence skeletal muscle plasticity and if diet impacts the effectiveness of rehabilitation strategies for VML‐injured skeletal muscle.
Anatomical Study of the Innervation of the Tibialis Anterior Muscle and its Correlation with Miofascial Trigger Points: Preliminary Results
Authors: Akamatsu Flávia E. , de Alencar Cesar R. , Hojaij Flávio , Andrade Mauro , Jacomo Alfredo L. 
Published: May 2022

BackgroundMyofascial syndrome is a common cause of chronic musculoskeletal pain. It is associated with movement restriction and is characterized by myofascial pain syndrome (MPS). Myofascial trigger points (MTPs) represent tender areas of the muscle where painful symptoms are elicited whenever stimulated. Although pathophysiology of MTPs is unclear, some authors report that they coincide with motor plates at the innervation zone (IZ). Trigger points of the tibialis anterior muscle are located at the anterior third of the muscle.ObjectiveOur study aimed to describe the innervation of the tibialis anterior muscle and relate it to clinically described MTPs.MethodsTibial anterior muscles from five cadavers were dissected from their origins to observe the exact point where the deep fibular nerve penetrates the muscle belly. The entry points were mapped using a Cartesian graph. Statistical analysis was performed with Poisson marginal distribution and identity linkage function followed by Bonferroni multiple comparisons. Significance was set in p <0.05.ResultsAreas I and II had most of the deep fibular nerve branches, with a mean of 5 sites (42%) and 4 sites (33%) respectively. Area 3 and 4 had a mean of 2 (17%) and one (8%) respectively.ConclusionIn accordance with the clinical literature, the branches of the deep fibular nerve in the tibialis anterior muscle seem to correspond to the described areas of the MTPs. Anatomical correlations between MTPs may be a useful tool for a better understanding of the physiopathology of these disorders and may provide a rational basis for their treatment.
Anatomical Study of the Innervation of the Fibularis Longus (FL) Muscle and its Correlation with Miofascial Trigger Points: Preliminary Results
Authors: Park Lucas Y. , Akamatsu Flávia E. , Hojaij Flávio , Andrade Mauro , Jacomo Alfredo L. 
Published: May 2022

BackgroundMyofascial syndrome is a common cause of chronic musculoskeletal pain and results in dysfunction of the affected muscles. It is characterized by myofascial trigger points (MTPs) which are clinically identified by palpation of a muscle or fascial taut band. Previous publications have found MTPs to coincide with neuromuscular junctions at the innervation zone (IZ). The fibularis longus syndrome is one of the most frequent myofascial syndrome of the lower limbs and occurs due to a wide variety of etiologies, most commonly, overuse and ankle sprain. Referred pain and tenderness caused by the trigger points of the FL muscle are located above, behind and below the lateral malleolus and may extend along the lateral aspect of the foot and leg.ObjectiveOur study aimed to correlate the innervation of the FL muscle to clinically described MTPs.MethodsFL muscles from five cadavers were dissected to observe the exact point where nerve fibers penetrated the muscle belly. As muscle size varies among individuals, we describe the relative entry point of the nerve into the muscle by defining four different areas in the muscle belly: two superior (I, II) and two inferior (III and IV). Statistical analysis of anatomical data was obtained by Poisson distribution and logarithm link function followed by Bonferroni multiple comparisons.ResultsWe found a mean of 12 branches of the superficial fibular nerve to the FL muscle. All of them were located into the areas I (67%) and II (33%). No branches were observed in areas III and IV. Our findings corresponded to previously described MTPs.ConclusionAnatomical correlation between MTPs may be a useful tool for a better understanding of the physiopathology of these disorders and may provide a rational basis for their treatment.
What does the Historical Record Say about the Chances of Surviving an Escape from a Disabled Submarine?
Authors: Fothergill David M. , Whybourn Leslie A. 
Published: May 2022

IntroductionDespite US Navy and international Disabled Submarine (DISSUB) rescue capabilities, escape remains an important means of DISSUB crew survival as the crew may be forced to conduct an escape before rescue assets arrive on site due to adverse conditions onboard or operational or engineering constraints that may render rescue impossible. The main aims of the current study were to conduct an analysis of historical DISSUB records to describe the likely biomedical evolution of crew survivability following the disabling of a submarine in shallow waters, in order to develop a casualty estimate and define the main risks to escapee survival.MethodsFrom unclassified historical and scientific publications, we collated and categorized international DISSUB events in which escape was effected or attempted by any part of the crew, dating from the earliest documented DISSUB escape in 1851 until September 2019. Both non‐combat and combat sinkings were included. We also reviewed at‐sea submarine escape trial experience and medical incidents from US Navy pressurized submarine escape training records to estimate air embolism and extra‐alveolar air casualties and fatalities during escape training. Our analysis identified the casualty risk for DISSUB survivors for the following three phases: (1) survival in the submarine before escape, (2) survival during the escape ascent, and (3) survival on the surface.Results & ConclusionsUsing historical data from a total of 437 attempted DISSUB escapes that included 37 accidental and combat submarine sinkings, the following observations were made:

The largest number of casualties occurred during the onboard survival phase due to atmospheric toxicity.
72% of the submariners who attempted an escape survived the escape.
Escapes have been successful from a DISSUB as deep as 240 feet sea water (fsw) and experimentally during at sea submarine escape trials from depths down to 600 fsw.
All historical escapes were effected within the current 72‐hour time to first rescue timeframe, with the majority occurring within 4 hours of DISSUB onset.
The majority of escapees who survived were recovered from the water within 60 min.
Early rescue surface response mobilization and detailed crew knowledge of escape equipment, procedures, and the physiological phenomena encountered under increased and changing pressures are essential to enhance escapee survivability.
US Navy submarine escape training records indicated very low risk (<0.5%) of pulmonary over inflation syndrome or arterial gas embolism and no fatalities during the past 11 years of pressurized escape training.
BPA and BPS increase oxidative stress inducing a decrease in physical fitness and dyslipidemia in young adults
Authors: dos Santos Julia M. , Jones Jessica N. , Sine Tyler , Senador Daniela , Metcalf Amanda A. , Haney Andrea C. 
Published: May 2022

ObjectivesBisphenol‐A and ‐S (BPA and BPS, respectively) exposure occurs primarily due to leaching of these chemicals from the packaging of industrialized food. BPA and BPS intake is indicative of unhealthy lifestyle choices. Levels of BPA and BPS in human specimens have been closely associated with dyslipidemia and insulin resistance. Physical exercise has been shown to attenuate insulin resistance and the development of type 2 diabetes (T2D). The aim of this study was to investigate the relationship between lipid profiles, levels of BPA, BPS, oxidative stress, and their influence on glucose uptake induced by insulin and aerobic exercise.MethodsHealthy young adults (age 23.5±2 years old) participated in 2 separate testing days. In both days, subject’s blood glucose (BG) was measured before 50g of maltodextrin consumption and following 30‐, 60‐, and 75‐minutes. On the “Exercise” testing day, subjects ran for 30‐minutes, while on the “Rest” day, they remained seated. Urinary BPA, BPS, and oxidative stress (OS), lipid profile, as well as body fat were also assessed. Distance ran was used to assess physical fitness.ResultsThe exercise condition produced a decrease in BG during the 30‐60‐minute protocol interval when compared to the resting day. The decrease of BG in the resting and exercise days were correlated with body fat (r=0.5 and 0.51, respectively). Levels of BPA and OS were negatively associated with decreased physical fitness (r=‐0.45 and ‐0.5, respectively), while BPS and OS were associated with increased triglycerides (TG) levels (r=0.5 for both). Levels of OS were positively associated with levels of BPA and BPS (r=0.62 and 0.82), respectively.DiscussionConcentration of BPA and BPS in urine may not directly affect glucose transport in healthy young adults. BPA and BPS might induce increase in OS and further TG affecting physical fitness and potentially mediating changes linked to the development of T2D.
A structurally preserved allosteric site in the MIF superfamily affects enzymatic activity and CD74 activation in D‐dopachrome tautomerase
Authors: Chen Emily , Shah Dilip , Bhandari Vineet , Lisi George P. 
Published: May 2022

The human macrophage migration inhibitory factor (MIF) superfamily consists of MIF and D‐dopachrome tautomerase (also called MIF‐2). Both MIF proteins have critical innate and adaptive immunomodulatory functions in regulating differentiation, expression of pro‐inflammatory cytokines, and activation and recruitment of immune cells. They are broadly and constitutively expressed, but elevated levels of MIF family proteins are upregulated in various inflammatory diseases such as asthma, acute respiratory distress syndrome (ARDS) and arthritis, and antibody neutralization of MIF decreased inflammatory symptoms in murine models. While their potential as drug targets has led to the creation of a few commercial inhibitors of MIF, the efficacy of targeting MIF proteins as a therapeutic is currently obstructed by a lack of molecular level detail about their structures and dynamics and how those properties impact disease‐state activity.Previously, we reported a dynamic relay connecting the MIF catalytic site to an allosteric site at its solvent channel. The MIF homolog DDT (MIF‐2) has low sequence identity with MIF (35%) though they overlap in multiple functions, including activation of the CD74 receptor, and share a nearly identical tertiary structure. This prompted the question of whether this dynamic regulatory network is conserved within the superfamily. We identify a comparable allosteric network in MIF‐2, connecting the catalytic site to CD74‐activating residues, showing with solution nuclear magnetic resonance (NMR) spectroscopy that dynamic communication is preserved in MIF‐2 despite differences in primary sequence. Disruption of the allosteric relay by mutagenesis also attenuates MIF‐2 enzymatic activity in vitro and biological CD74 signaling in vivo, highlighting amino acids in this pathway as trigger residues for potential functional control of the protein.