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Diabetes has reached worldwide epidemic proportions, and threatens to be a significant economic burden to both patients and healthcare systems, and an important driver of cardiovascular mortality and morbidity. Improvement in lifestyle interventions (which includes increase in physical activity via exercise) can reduce diabetes and cardiovascular disease mortality and morbidity. Encouraging a population to increase physical activity and exercise is not a simple feat particularly in individuals with co-morbidities (obesity, heart disease, stroke, peripheral vascular disease, and those with cognitive and physical limitations). Translation of the physiological benefits of exercise within that vulnerable population would be an important step for improving physical activity goals and a stopgap measure to exercise. In large part many of the beneficial effects of exercise are due to the introduction of pulsatile shear stress (PSS) to the vascular endothelium. PSS is a well-known stimulus for endothelial homeostasis, and induction of a myriad of pathways which include vasoreactivity, paracrine/endocrine function, fibrinolysis, inflammation, barrier function, and vessel growth and formation. The endothelial cell mediates the balance between vasoconstriction and relaxation via the major vasodilator endothelial derived nitric oxide (eNO). eNO is critical for vasorelaxation, increasing blood flow, and an important signaling molecule that downregulates the inflammatory cascade. A salient feature of diabetes, is endothelial dysfunction which is characterized by a reduction of the bioavailability of vasodilators, particularly nitric oxide (NO). Cellular derangements in diabetes are also related to dysregulation in Ca 2+ handling with increased intracellular Ca 2+ overload, and oxidative stress. PSS increases eNO bioavailability, reduces inflammatory phenotype, decreases intracellular Ca 2+ overload, and increases antioxidant capacity. This narrative review and perspective will outline four methods to non-invasively increase PSS; Exercise (the prototype for increasing PSS), Enhanced External Counterpulsation (EECP), Whole Body Vibration (WBV), Passive Simulated Jogging and its predicate device Whole Body Periodic Acceleration, and will discuss current knowledge on their use in diabetes., Competing Interests: MS and JA draw no salary from Sackner Wellness Products LLC a company which has a patent on a passive jogging device. MS owns 80% and JA 20% of the domestic and foreign patents. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Adams, Uryash, Lopez and Sackner.)

The assembly and activation of the spliceosome rely upon the phosphorylation of an essential family of splicing factors known as the serine-arginine (SR) proteins. Although it has been demonstrated recently that two enzyme families, the SR protein kinases (SRPKs) and the Cdc2-like kinases (CLKs), can function as a complex to efficiently phosphorylate these SR proteins in the nucleus, the molecular features involved in such a connection are unknown. In this study, we identified a group of conserved residues in the large lobe of SRPK1 that interact with the N terminus of CLK1 stabilizing the SRPK1-CLK1 complex. Mutations in this motif not only disrupt formation of the kinase-kinase complex but also impair SRPK1-dependent release of the phospho-SR protein from CLK1. The binding motif potently up-regulates CLK1-specific phosphorylation sites, enhances SR protein diffusion from nuclear speckles, and impacts the alternative splicing of several target genes. These results indicate that CLK1 binds a conserved, electronegative surface on SRPK1, thereby controlling SR protein phosphorylation levels for enhanced subnuclear trafficking and alternative splicing regulation., (© 2020 Federation of European Biochemical Societies.)

There has not been any means to inhibit replication of the SARS-CoV-2 virus responsible for the rapid, deadly spread of the COVID-19 pandemic and an effective, safe, tested across diverse populations vaccine still requires extensive investigation. This review deals with the repurpose of a wellness technology initially fabricated for combating physical inactivity by increasing muscular activity. Its action increases pulsatile shear stress (PSS) to the endothelium such that the bioavailability of nitric oxide (NO) and other mediators are increased throughout the body. In vitro evidence indicates that NO inhibits SARS-CoV-2 virus replication but there are no publications of NO delivery to the virus in vivo. It will be shown that increased PSS has potential in vivo to exert anti-viral properties of NO as well as to benefit endothelial manifestations of COVID-19 thereby serving as a safe and effective backstop., (© 2020 The Author(s).)

Advance care planning (ACP) is a cornerstone of self-determination for the type of care provided at the end of life. Despite many national efforts to improve American adults' engagement in ACP, statistics indicate low engagement. Low engagement, especially among racial and ethnic minority populations, immigrants, people with lower socioeconomic status, young adults, rural residents, or non-English speakers, is common. Advance care planning engagement among Muslims living in the United States has been minimally studied. The purpose of this study was to explore Muslims' engagement in ACP. A cross-sectional descriptive design was used. Participants were recruited from Islamic organizations through convenience and snowball sampling. Engagement in ACP was measured by the Advance Care Planning Engagement Survey. A sample of 148 Muslims (18-79 years of age) participated in the study. The average engagement scores ranged from 1.97 to 2.09, with about two-thirds in the precontemplation stage. Significant differences in engagement scores were found according to health condition and end of life experiences. Results suggest a need for further collaborative efforts by health care providers, policymakers, and researchers to mitigate the disparities in ACP engagement in the American Muslim community.

Background: Sedentary time poses a risk to health. Substituting physical activity for inactivity is obvious but this requires a behavior change. Interventions advocated to decrease uninterrupted physical inactivity (defined as Metabolic Equivalent of Task (METS) less than 1.5) are important. One such intervention is accomplished with the Gentle Jogger (GJ), a low risk motorized wellness device which produces effortless, rapid motion of the lower extremities simulating locomotion or fidgeting. GJ produces health benefits in type 2 diabetes, heart disease, and high blood pressure. The purpose of this trial was to ascertain whether GJ increases METS above 1.5 to explain its effectiveness despite sedentary behavior or whether tapping is responsible., Methods: A randomized single-arm trial was conducted. Subjects were randomized to begin the study in either the supine or seated postures and on the same day crossed over with the starting posture reversed. Oxygen consumption was measured at rest and during GJ., Results: Twenty-six subjects were studied (15 women and 11 men) with a mean age of 44 ± 15 years and BMI 27.9 ± 5.0, 19 were overweight or obese, and 7 had normal BMI. GJ increased oxygen consumption and METS 15% in the seated posture and 13% in the supine posture. No individual receiving GJ achieved METS exceeding 1.5., Conclusions: In a moderately obese population, GJ in seated or supine posture did not exceed 1.5 METS. The values are comparable to those reported for sit-stand interventions and cannot explain the health benefits of GJ., Trial Registration: ClinicalTrials.gov, NCT03602365 . Registered on July 26, 2018.

Soil anthropogenic contaminants can limit enzymatic nutrient mineralization, either by direct regulation or via impacts on the microbial community, thus affecting plant growth in agricultural and non-agricultural soils. The impact on phosphatase activity of mixing two contaminated, post-industrial rail yard soils was investigated; one was vegetated and had high phosphatase function, the other was barren and had low enzymatic function. The two soils had different abiotic properties, including contaminant load, vegetation cover, soil aggregate size distribution, and phosphatase potential. An experimental gradient was established between the two soils to systematically vary the abiotic properties and microbial community composition of the two soils, creating a gradient of novel ecosystems. The time dependence of extracellular phosphatase activity, soil moisture, and organic matter content was assessed along this gradient in the presence and absence of plants. Initially, mixtures with higher percentages of functional, vegetated soil had higher phosphatase activities. Phosphatase activity remained unchanged through time (65 days) in all soil mixtures in unplanted pots, but it increased in planted pots. For example, in the presence of plants, phosphatase activity increased from 0.6 ± 0.1 to 2.4 ± 0.3 μmol•h -1 •g dry soil -1 from day one to day 65 in the 1:1 functional:barren soil mixture. The presence of plants also promoted moisture retention. Inoculation of poorly functioning soil with 10% of the functional soil with its microbial community did not, over 65 days, revitalize the poorly functioning soil. The findings showed that abiotic limitations to enzymatic activity in barren brownfield soils could be mitigated by establishing primary production but not by the addition of enzymatically active microbial communities alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The medical evaluation of a child who may have been sexually abused can be a challenge for physicians who are unfamiliar with the wide variation in normal genital anatomy in prepubertal girls. Signs of injury are rarely found, unless the child is examined within 72 hours of the event. This article will provide some history about how guidelines for medical care of these children have been developed, and list some of the findings that are normal or normal variants, caused by other conditions, or due to trauma or infection.

Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes via distinct mechanotransduction pathways. In breast cancer, increased ECM stiffness promotes epithelial-to-mesenchymal transition (EMT), cell invasion, and metastasis. Here, we identify a mechanosensitive EPHA2/LYN protein complex regulating EMT and metastasis in response to increasing ECM stiffness during tumor progression. High ECM stiffness leads to ligand-independent phosphorylation of ephrin receptor EPHA2, which recruits and activates the LYN kinase. LYN phosphorylates the EMT transcription factor TWIST1 to release TWIST1 from its cytoplasmic anchor G3BP2 to enter the nucleus, thus triggering EMT and invasion. Genetic and pharmacological inhibition of this pathway prevents breast tumor invasion and metastasis in vivo. In human breast cancer samples, activation of this pathway correlates with collagen fiber alignment, a marker of increasing ECM stiffness. Our findings reveal an EPHA2/LYN/TWIST1 mechanotransduction pathway that responds to mechanical signals from the tumor microenvironment to drive EMT, invasion, and metastasis., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuronal intracellular Ca 2+ homeostasis is critical to the normal physiological functions of neurons and neuronal Ca 2+ dyshomeostasis has been associated with the age-related decline of cognitive functions. Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca 2+ levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca 2+ homeostasis in cortical ( in vivo) and hippocampal ( in vitro) neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice. We found a progressive age-related elevation of intracellular resting calcium ([Ca 2+ ] r ) in cortical ( in vivo ) and hippocampal ( in vitro ) neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. In vitro , removal of extracellular Ca 2+ or treatment with SAR7334 or dantrolene reduced [Ca 2+ ] r in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. In vivo , both middle-aged and aged mice showed cognitive deficits compared to young mice, which improved after dantrolene treatment. These findings support the hypothesis that intracellular Ca 2+ dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases., (Copyright © 2020 Uryash, Flores, Adams, Allen and Lopez.)

Information about a patient's state is critical for hospitals to provide timely care and treatment. Prior work on improving the information flow from emergency medical services (EMS) to hospitals demonstrated the potential of using automated algorithms to detect clinical procedures. However, prior work has not made effective use of video sources that might be available during patient care. In this paper we explore the use convolutional neural networks (CNNs) on raw video data to determine how well video data alone can automatically identify clinical procedures. We apply multiple deep learning models to this problem, with significant variation in results. Our findings indicate performance improvements compared to prior work, but also indicate a need for more training data to reach clinically deployable levels of success.

Background: High rates of missed appointments for routine HIV care are associated with unsuppressed viremia, increasing morbidity., Local Problem: The Clinic no-show rate ranged between 30% and 35%, and only 69% of patients were considered retained in care within a 24-month time frame., Methods: The Woodward Risk Prediction Tool was completed on all patients to stratify patient risk for missing the next appointment., Interventions: All patients were offered text message along with standard phone message appointment reminders, and patients who missed appointments were called within 24 hours to reschedule. Medium-risk patients received a previsit planning call to remove barriers to appointment attendance, and high-risk patients received a home visit from the peer navigator., Results: The project resulted in a 3.8% reduction rate in the overall no-show rate in the first 5 months of implementation. Using risk stratification and targeted interventions allowed valuable resources to be allocated where they were needed.

The paternal genome undergoes a massive exchange of histone with protamine for compaction into sperm during spermiogenesis. Upon fertilization, this process is potently reversed, which is essential for parental genome reprogramming and subsequent activation; however, it remains poorly understood how this fundamental process is initiated and regulated. Here, we report that the previously characterized splicing kinase SRPK1 initiates this life-beginning event by catalyzing site-specific phosphorylation of protamine, thereby triggering protamine-to-histone exchange in the fertilized oocyte. Interestingly, protamine undergoes a DNA-dependent phase transition to gel-like condensates and SRPK1-mediated phosphorylation likely helps open up such structures to enhance protamine dismissal by nucleoplasmin (NPM2) and enable the recruitment of HIRA for H3.3 deposition. Remarkably, genome-wide assay for transposase-accessible chromatin sequencing (ATAC-seq) analysis reveals that selective chromatin accessibility in both sperm and MII oocytes is largely erased in early pronuclei in a protamine phosphorylation-dependent manner, suggesting that SRPK1-catalyzed phosphorylation initiates a highly synchronized reorganization program in both parental genomes., Competing Interests: Declaration of Interests The authors declare no competing financial interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical documentation in the pre-hospital setting is challenged by limited resources and fast-paced, high-acuity. Military and civilian medics are responsible for performing procedures and treatments to stabilize the patient, while transporting the injured to a trauma facility. Upon arrival, medics typically give a verbal report from memory or informal source of documentation such as a glove or piece of tape. The development of an automated documentation system would increase the accuracy and amount of information that is relayed to the receiving physicians. This paper discusses the 12-week deployment of an Automated Sensing Clinical Documentation (ASCD) system among the Nashville Fire Department EMS paramedics. The paper examines the data collection methods, operational challenges, and perceptions surrounding real-life deployment of the system. Our preliminary results suggest that the ASCD system is feasible for use in the pre-hospital setting, and it revealed several barriers and their solutions., (©2019 AMIA - All rights reserved.)

Duchenne muscular dystrophy (DMD) is an irreversible muscle disease characterized by a progressive loss of muscle function, decreased ambulation, and ultimately death as a result of cardiac or respiratory failure. DMD is caused by the lack of dystrophin, a protein that is important for membrane stability and signaling in excitable cells. Although vascular smooth muscle cells (VSMCs) dysfunction occurs in many pathological conditions, little is known about vascular smooth muscle function in DMD. We have previously shown that striated muscle cells, as well as neurons isolated from dystrophic (mdx) mice have higher intracellular Ca 2+ ([Ca 2+ ] i ) and Na + ([Na + ] i ) concentrations and decreased cell viability in comparison with wild type (Wt). Experiments were carried out in isolated VSMCs from mdx (a murine model of DMD) and congenic C57BL/10SnJ Wt mice. We found elevated [Ca 2+ ] i and [Na + ] i in VSMCs from mdx mice compared to Wt. Exposure to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC3 and TRPC6 channel activator, induced a greater elevation of [Ca 2+ ] i and [Na + ] i in mdx than Wt VSMCs. The OAG induced increases in [Ca 2+ ] i could be abolished by either removal of extracellular Ca 2+ or by SAR7334, a blocker of TRPC3 and TRPC 6 channels in both genotypes. Mdx and Wt VSMCs were susceptible to muscle cell stretch-induced elevations of [Ca 2+ ] i and [Na + ] i which was completely inhibited by GsMTx-4, a mechanosensitive ion channel inhibitor. Western blots showed a significant upregulation of TRPC1 -3, -6 proteins in mdx VSMCs compare to age-matched Wt. The lack of dystrophin in mdx VSMCs produced a profound alteration of [Ca 2+ ] i and [Na + ] i homeostasis that appears to be mediated by TRPC channels. Moreover, we have been able to demonstrate pharmacologically that the enhanced stretch-induced elevation of intracellular [Ca 2+ ] and concomitant cell damage in mdx VSMCs also appears to be mediated through TRPC1, -3 and -6 channel activation., (Copyright © 2020 Lopez, Uryash, Faury, Estève and Adams.)

Background: The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus-1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years., Methods: HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO)., Results: Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P < .001, P = .036, and P < .001, respectively) and age when SVS was achieved (P = .002, P = .038, and P < .001, respectively) and inversely with the proportion of life spent on effective cART (P < .001, P = .01, and P < .001, respectively) and proportion of life spent with SVS (P < .001, P = .079, and P < .001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P = .037) or later (rho = 0.87; P < .001). S/COs correlated with HIV-1 DNA (P = .003), but less so with inducible cell-free HIV-1 RNA (P = .09)., Conclusions: The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Nonsteroidal anti-inflammatory medications (NSAIDs) are one of the most commonly used analgesics in the world. NSAIDs decrease prostaglandin synthesis through cyclooxygenase inhibition (COX-1 or COX-2). The effects of NSAIDs on survival and outcomes from global ischemia reperfusion events and specifically from cardiac arrest (CA) remain controversial. We hypothesized that NSAIDs prior to global whole-body ischemia reperfusion (I/R) injury impairs survival and outcomes. We explored this hypothesis in our swine model of Cardiac Arrest (CA) which involves global I/R with pretreatment using a predominantly COX-1 inhibitor (Indomethacin [COX-1/min COX-2 Inh], a COX-2 Inhibitor [COX-2-Inh, (Celecoxib)] or placebo control. We determined the effects of each inhibitor on a) survival, b) myocardial injury biomarker (Troponin 1), and c) Autonomic Nervous System (ANS) injury marker (heart rate variability [HRV]) up to 3 h after resuscitation. There were no survivals in COX-1/min COX-2-Inh pretreated animals and, 87% survived in both COX-2 Inhibited and control animals. COX-2 Inh pretreated animals had an 1800 fold increase of Troponin 1 compared to baseline whereas control animals had a 90 fold increase (p < 0.001). These results along with literature review of focal I/R in animal models with COX-2 overexpression, human studies of CA, and post myocardial infarction treatment with NSAIDs, support the hypothesis that NSAIDs prior to an I/R event impairs survival and outcomes. Specifically, predominantly COX-1 inhibition impairs survival, and COX-2 inhibition induces myocardial damage, autonomic nervous system dysfunction, and increases the risk for all-cause mortality and morbidity in humans post-MI which has significant implications for the nearly 10% of the population who are taking NSAIDs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Physical inactivity is a high-risk factor for type 2 diabetes. Increased physical activity improves indices of glycemic control. Continuous glucose monitoring (CGM) allows the investigation of glycemic control during activities of daily living. A pilot study was undertaken to determine the effects of the portable Gentle Jogger (passive simulated jogging device (JD)) that decreases physical inactivity by effortlessly producing body movements on glycemic indices of healthy and type 2 diabetes subjects using CGM during activities of daily living., Methods: A single-arm, nonblinded study was carried out in 22 volunteers (11 type 2 diabetics and 11 healthy subjects), using continuous glucose monitoring (CGM) for 14 days. On day 4, subjects were provided with JD and instructed to use it a minimum of 3 times per day for 30 min for 7 days. CGM data was analyzed at baseline (BL) and during 2, 3, 4, 5, 6, and 7 days of JD (JD 2, 3, 4, 5, 6, 7) and 1-2-day post JD (Post JD1 and 2) and the following 24 hr indices computed mean glucose (mGLu), SUM of all glucose values, % coefficient of variation (%CV), area under the 24-hour curve (AUC), time spent above range (TAR, glucose 180-250 mg/dl), and time in range (TIR)., Results: In healthy subjects, there were significantly lower values of mGlu and SUM compared to BL for all days of JD usage. In type 2 diabetics, mGlu, SUM, and AUC were significantly lower compared to BL, for all days of JD usage and Post JD1. TAR was significantly lower and TIR significantly improved during JD, in type 2 diabetics without change in %CV., Conclusion: Gentle Jogger is a portable, passive movement technology that reduces physical inactivity while improving 24 hr glycemic control. It can be self-administered as a standalone device or as an adjunct to diabetic medications. This trial is registered with NCT03550105., Competing Interests: JAA performs research for Sackner Wellness Products LLC and is a US copatent holder for Gentle Jogger®, the passive simulated jogging device. VB is a part time study coordinator and employee of Sackner Wellness Products LLC. JRL is a research scientist consultant with Sackner Wellness Products LLC. MAS is the president of Sackner Wellness Products LLC and is a US copatent holder for Gentle Jogger®, the passive simulated jogging device., (Copyright © 2020 Jose A. Adams et al.)

Integrins are transmembrane multi-conformation receptors that mediate interactions with the extracellular matrix. In cancer, integrins influence metastasis, proliferation, and survival. Collagen-binding integrin-α11/β1, a marker of aggressive tumors that is involved in stroma-tumor crosstalk, may be an attractive target for anti-cancer therapeutic antibodies. We performed selections with phage-displayed synthetic antibody libraries for binding to either purified integrin-α11/β1 or in situ on live cells. The in-situ strategy yielded many diverse antibodies, and strikingly, most of these antibodies did not recognize purified integrin-α11/β1. Conversely, none of the antibodies selected for binding to purified integrin-α11/β1 were able to efficiently recognize native cell-surface antigen. Most importantly, only the in-situ selection yielded functional antibodies that were able to compete with collagen-I for binding to cell-surface integrin-α11/β1, and thus inhibited cell adhesion. In-depth characterization of a subset of in situ -derived clones as full-length immunoglobulins revealed high affinity cellular binding and inhibitory activities in the single-digit nanomolar range. Moreover, the antibodies showed high selectivity for integrin-α11/β1 with minimal cross-reactivity for close homologs. Taken together, our findings highlight the advantages of in-situ selections for generation of anti-integrin antibodies optimized for recognition and inhibition of native cell-surface proteins, and our work establishes general methods that could be extended to many other membrane proteins.

Identifying inorganic and organic soil contaminants in urban brownfields can give insights into the adverse effects of industrial activities on soil function, ecological health, and environmental quality. Liberty State Park in Jersey City (N.J., USA) once supported a major rail yard that had dock facilities for both cargo and passenger service; a portion remains closed to the public, and a forest developed and spread in this area. The objectives of this study were to: 1) characterize the organic and inorganic compounds in Liberty State Park soils and compare the findings to an uncontaminated reference site (Hutcheson Memorial Forest); and 2) identify differences between the barren low-functioning areas and the forested high-functioning areas of the brownfield. Soil samples were solvent-extracted, fractionated, and analyzed by gas chromatography-mass spectrometry and subjected to loss-on-ignition, pyrolysis-gas chromatography-mass spectrometry, inductively-coupled-plasma mass spectrometry, and optical microscopy analyses. Compared to soil from the reference site, the forested soils in Liberty State Park contained elevated percentages of organic matter (30-45%) and more contaminants, such as fossil-fuel-derived hydrocarbons and coal particles. Microscopy revealed bituminous and anthracite coal, coke, tar/pitch, and ash particles. Barren and low-functioning site 25R had a similar organic contaminant profile but contained a higher metal load than other Liberty State Park sites and also lacked higher plant indicators. These can obscure the signatures of contaminants, and data from adjacent barren and vegetated sites are valuable references for soils studies. A deeper understanding of the chemistry, biochemistry, and ecology of barren soils can be leveraged to prevent land degradation and to restore dysfunctional and phytotoxic soils., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The purpose of this investigation was to ascertain whether nitric oxide (NO) released into the circulation by a noninvasive technology called whole body periodic acceleration (WBPA) could increase mucociliary clearance (MCC). It was based on observations by others that nitric oxide donor drugs increase ciliary beat frequency of nasal epithelium without increasing mucociliary clearance. Tracheal mucous velocity (TMV), a reflection of MCC, was measured in sheep after 1-hour treatment of WBPA and repeated after pretreatment with the NO synthase inhibitor, L-NAME to demonstrated action of NO. Aerosolized human neutrophil elastase (HNE) was administered to sheep to suppress TMV as might occur in cystic fibrosis and other inflammatory lung diseases. WBPA increased TMV to a peak of 136% of baseline 1h after intervention, an effect blocked by L-NAME. HNE reduced TMV to 55% of baseline but slowing was reversed by WBPA, protection lost in the presence of L-NAME. NO released into the circulation from eNOS by WBPA can acutely access airway epithelium for improving MCC slowed in cystic fibrosis and other inflammatory lung diseases as a means of enhancing host defense against pathogens., Competing Interests: The following authors JRS and WMA have declared that no competing interests exist. JAA owns minimal number of stocks in Noninvasive Monitoring Systems (NIMS), a company which manufactures a platform similar to the one described in this study, and co-patent USPATENT 9,622,933 – April 18, 2017; Passive Simulated Jogging Device (Gentle Jogger). MAS is president of Sackner Wellness Products, a company which manufactures a wellness device called Gentle Jogger referenced in the manuscript, and co-patent owner of the above mentioned patent. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

This review deals with opioid addiction, chronic pain, and an innovative, noninvasive technology with simultaneous, beneficial applications for both conditions. This technology, called passive simulated jogging device (GENTLE JOGGER, JD) targets addiction and pain by increasing endothelial nitric oxide (NO) bioavailability. It can be self-administered while sitting or lying without resorting to multitasking thereby allowing watching television or operating a computer while effortless, physical activity is produced from motorized foot pedals repetitively striking a bumper at 175-190 times per minute which adds small pulses to the circulation. This action increases shear stress (friction) to vascular endothelium that stimulates endothelial nitric oxide synthase (eNOS) to increase NO that decreases oxidative stress and inflammation, and, slows accelerated vascular ageing associated with opioids. Since the 1970s, clonidine, lofexidine, and dexmedetomidine have been used offlabel to suppress opioid withdrawal symptoms precipitated by excessive release of norepinephrine. These pharmacotherapy aids to withdrawal and tapering opioid dosagadrenoceptor agonists that act through eNOS to inhibit norepinephrine. Increasing NO as with JD and/ or in conjunction with opioid agonists should help stabilization, tapering, withdrawal, and relapses stages of addiction. Nitric oxide as increased with JD technology is antinociceptive as demonstrated in chronic and subacute pain states, viz., fibromyalgia, osteoarthritis, peripheral arterial disease, delayed onset of muscle soreness (DOMS), and sickle cell disease. Jogging device decreases elevated blood pressure that is produced with physical inactivity, a risk to opioid use disorder (OUD). Thus, JD provides holistic, cost-effective approach to opioid addiction as well as chronic and subacute pain., Competing Interests: Sponsored Review

The ubiquity of urban brownfields presents not only a challenge for environmental managers but also an opportunity to study the functional aspects of degraded ecosystems that are in close contact with human habitation. In this study, we investigate the soil microbial community response to heavy metal contamination at Liberty State Park (LSP), an urban brownfield in Jersey City, NJ, USA. Heavy metal contamination of the soils at LSP is heterogeneous, varying widely across site and among metals. We collected soils along a previously mapped gradient of metal contamination at LSP and sampled soil from a local and uncontaminated reference site (Hutcheson Memorial Forest (HMF)) for comparison. For all soils, we measured soil heavy metal concentrations, soil organic carbon content, bacterial density, and extracellular phosphatase activity as a proxy of ecosystem functioning. Additionally, we analyzed the microbial community composition using high-throughput sequencing. Data show that some sites within LSP have significantly higher phosphatase activity compared to HMF, indicating that some heavily contaminated LSP soils are highly functional. We also found that soil organic carbon and bacterial density have a significant and positive relationship with phosphatase activity. The microbial community analyses showed that the bacterial communities were sensitive to heavy metals and that the composition was significantly affected in particular by copper, zinc, and lead. The fungal communities, however, did not vary significantly with heavy metals. Our results shed important light on the composition and functioning of urban brownfield soils. A deeper understanding of these unique ecosystems is required for successful remediation, restoration and urban sustainability., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Understanding a patient's state is critical to providing optimal care. However, information loss occurs during patient hand-offs (e.g., emergency services (EMS) transferring patient care to a receiving hospital), which hinders care quality. Augmenting the information flow from an EMS vehicle to a receiving hospital may reduce information loss and improve patient outcomes. Such augmentation requires a noninvasive system that can automatically recognize clinical procedures being performed and send near real-time information to a receiving hospital. An automatic clinical procedure detection system that uses wearable sensors, video, and machine-learning to recognize clinical procedures within a controlled environment is presented. The system demonstrated how contextual information and a majority vote method can substantially improve procedure recognition accuracy. Future work concerning computer vision techniques and deep learning are discussed.

Serine-arginine (SR) proteins are essential splicing factors that promote numerous steps associated with mRNA processing and whose biological function is tightly regulated through multi-site phosphorylation. In the nucleus, the cdc2-like kinases (CLKs) phosphorylate SR proteins on their intrinsically disordered Arg-Ser (RS) domains, mobilizing them from storage speckles to the splicing machinery. The CLKs have disordered N termini that bind tightly to RS domains, enhancing SR protein phosphorylation. The N termini also promote nuclear localization of CLKs, but their transport mechanism is presently unknown. To explore cytoplasmic-nuclear transitions, several classical nuclear localization sequences in the N terminus of the CLK1 isoform were identified, but their mutation had no effect on subcellular localization. Rather, we found that CLK1 amplifies its presence in the nucleus by forming a stable complex with the SR protein substrate and appropriating its NLS for transport. These findings indicate that, along with their well-established roles in mRNA splicing, SR proteins use disordered protein-protein interactions to carry their kinase regulator from the cytoplasm to the nucleus., (© 2019 George et al.)

Objectives: To describe what is known about the national prevalence of intimate partner violence (IPV) against women in the Americas across countries and over time, including the geographic coverage, quality, and comparability of national data., Methods: This was a systematic review and reanalysis of national, population-based IPV estimates from 1998 - 2017 in the Americas. Estimates were reanalyzed for comparability or extracted from reports, including IPV prevalence by type (physical; sexual; physical and/or sexual), timeframe (ever; past year), and perpetrator (any partner in life; current/most recent partner). In countries with 3+ rounds of data, Cochran-Armitage and Pearson chi-square tests were used to assess whether changes over time were significant ( P < 0.05)., Results: Eligible surveys were found in 24 countries. Women reported ever having experienced physical and/or sexual IPV at rates that ranged from 14% - 17% of women in Brazil, Panama, and Uruguay to over one-half (58.5%) in Bolivia. Past-year prevalence of physical and/or sexual IPV ranged from 1.1% in Canada to 27.1% in Bolivia. Preliminary evidence suggests a possible decline in reported prevalence of certain types of IPV in eight countries; however, some changes were small, some indicators did not change significantly, and a significant increase was found in the reported prevalence of past-year physical IPV in the Dominican Republic., Conclusions: IPV against women remains a public health and human rights problem across the Americas; however, the evidence base has gaps, suggesting a need for more comparable, high quality evidence for mobilizing and monitoring violence prevention and response., Competing Interests: Conflict of interests: None declared.

This study determines the impact of change in aeration in sinonasal cavities on the robustness of passive-scattering proton therapy plans in patients with sinonasal and nasopharyngeal malignancies. Fourteen patients, each with one planning CT and one CT acquired during radiotherapy were studied. Repeat and planning CTs were rigidly aligned and contours were transferred using deformable registration. The amount of air, tumor, and fluid within the cavity containing the tumor were measured on both CTs. The original plans were recalculated on the repeat CT. Dosimetric changes were measured for the targets and critical structures. Median decrease in gross tumor volume (GTV) was 19.8% and correlated with the time of rescan. The median change in air content was 7.1% and correlated with the tumor shrinkage. The median of the mean dose D mean change was +0.4% for GTV and +0.3% for clinical target volume. Median change in the maximum dose D max of the critical structures were as follows: optic chiasm +0.66%, left optic nerve +0.12%, right optic nerve +0.38%, brainstem +0.6%. The dose to the GTV decreased by more than 5% in 1 case, and the dose to critical structure(s) increased by more than 5% in three cases. These four patients had sinonasal cancers and were treated with anterior proton fields that directly transversed through the involved sinus cavities. The change in dose in the replanning was strongly correlated with the change in aeration (P = 0.02). We found that the change in aeration in the vicinity of the target and the arrangement of proton beams affected the robustness of proton plan., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era., Methods and Materials: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method., Results: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95% confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity., Conclusions: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Whole community microbial inoculation can improve soil function in contaminated environments. Here we conducted a case study to investigate whether biotic factors (inoculum) or abiotic factors (soil base) have more impact on the extracellular enzymatic activities in a whole community microbial inoculation. To this end, we cross-inoculated microbial communities between two heavy metal-contaminated soils, with high and low extracellular enzyme activities, respectively. We measured extracellular phosphatase activity, a proxy for soil function, after self- and cross-inoculation of microbial communities into sterilized soils, and all activities were normalized to non-inoculated controls. We found that inoculation increased phosphatase activity in the soils. For soils treated with different inocula, we found significant differences in the microbial community compositions but no significant differences in the extracellular phosphatase activities normalized to their respective sterilized, non-inoculated controls (4.7 ± 1.8 and 3.3 ± 0.5 for soils inoculated with microbial communities from 146 to 43, respectively). On the other hand, normalized phosphatase activities between the two soil bases were significantly different (4.1 ± 0.12 and 1.9 ± 0.12 for soil bases 146 and 43, respectively) regardless of the source of the inoculum that did not vary between soil bases. The results indicate that the abiotic properties of the soils were a significant predictor for phosphatase activity but not for the end-point composition of the microbial community. The findings suggest that targeted microbial inocula from metal contaminated soils can increase phosphatase activity, and likely soil functioning in general, but the degree to which this happens depends on the abiotic environment, in this case, metal contamination., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sepsis is a life threatening condition which produces multi-organ dysfunction with profound circulatory and cellular derangements. Administration of E.Coli endotoxin (LPS) produces systemic inflammatory effects of sepsis including disruption of endothelial barrier, and if severe enough death. Whole body periodic acceleration (pGz) is the headward-footward motion of the body. pGz has been shown to induce pulsatile shear stress to the endothelium, thereby releasing vascular and cardio protective mediators. The purpose of this study was to determine whether or not pGz performed as a pre-treatment or post-treatment strategy improves survival in a lethal murine endotoxin model.This study was designed as a prospective randomized controlled study in mice. pGz was performed in mice as pre-treatment (pGz-LPS, 3 days prior to LPS), post-treatment (LPS- pGz, 30 min after LPS) strategies or Control (LPS-CONT), in a lethal murine model of endotoxemia. Endotoxemia was induced with intraperitoneal injection of E.Coli LPS (40mg/kg). In a separate group of mice, a nonspecific nitric oxide synthase inhibitor (L-NAME) was provided in their drinking water and pGz-LPS and LPS-pGz performed to determine the effect of nitric oxide (NO) inhibition on survival. In another subset of mice, micro vascular leakage was determined. Behavioral scoring around the clock was performed in all mice at 30 min intervals after LPS administration, until 48 hrs. survival or death. LPS induced 100% mortality in LPS-CONT animals by 30 hrs. In contrast, survival to 48 hrs. occurred in 60% of pGz-LPS and 80% of LPS-pGz. L-NAME abolished the survival effects of pGz. Microvascular leakage was markedly reduced in both pre and post pGz treated animals and was associated with increased tyrosine kinase endothelial-enriched tunica interna endothelial cell kinase 2 (TIE2) receptor and its phosphorylation (p-TIE2). In a murine model of lethal endotoxemia, pGz performed as a pre or post treatment strategy significantly improved survival, and markedly reduced microvascular leakage. The effect was modulated, in part, by NO since a non-selective inhibitor of NO abolished the pGz survival effect., Competing Interests: The following authors AU, JRL have declared that no competing interests exist. JAA owns minimal number of stocks in Noninvasive Monitoring Systems (NIMS), a company which manufactures a platform similar to the one described in this study. MAS is president of Sackner Wellness Products, a company which manufactures a wellness device called Gentle Jogger (a passive jogging device (JD)) referenced in the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: To determine whether an innovative, motorized, wellness device that effortlessly produces physical activity (JD) can mitigate the hypertensive effects of prolonged sitting or lying down., Methods: Twenty-two normotensive and hypertensive adults of both genders gave informed consent to participate in a randomized controlled crossover study of a passive simulated jogging device (JD) in both supine and seated postures. Each study participant was monitored with a continuous non-invasive arterial pressure monitoring device (CNAP) over 60 min. The initial 10 min served as baseline for each posture. The subjects were randomized to begin with either JD or SHAM control for 30 min, and monitoring was continued for an additional 10 min in one posture; three days later posture and order of JD or SHAM were changed., Results: In both seated and supine postures, SHAM was associated with a significant rise in blood pressure (BP) which was observed within 5-10 min; it continued to rise or remain elevated for over a 40-min observation period. In contrast, JD produced a significant decrease in both systolic and diastolic blood pressure in both postures. During recovery in seated posture JD decreased systolic and diastolic BP by - 8.1 and - 7.6 mmHg, respectively. In supine posture, a similar decrease in BP occurred., Conclusions: There is rapid onset of increase in systolic and diastolic BP with physical inactivity in both supine and seated postures. Administration of JD significantly decreased BP in both postures. Further studies are needed to assess long-term effectiveness.

Chronic Hepatitis C (CHC) is the most common blood-borne infection in the U. S. Patients with CHC undergoing treatment face many challenges including adherence to medications and management of symptoms; health care practitioners are well positioned to facilitate patients' ability to address these challenges. We used the Adaptive Leadership for Chronic Illness Framework to investigate the difficulties inherent in affecting behavior change in patients undergoing treatment. We enrolled 11 patient participants and 10 provider participants. We used data from the first clinical encounter between patients and providers during which treatment was discussed. We found examples of adaptive leadership and categorized these behaviors into three themes: support for medication, coping with family/ home life, and strategizing to manage employment. We also saw examples of what we termed missed opportunities for adaptive leadership. This study illustrates the contributions of adaptive leadership behaviors by healthcare providers and the potential risk to patients in their absence.

When child sexual abuse is suspected, it is important for medical professionals to understand normal as well as abnormal features of the external genital and anal tissues in children. Physicians and other healthcare professionals who rarely perform a detailed examination of these areas may mistakenly interpret normal findings, or findings caused by conditions unrelated to abuse, as signs of injury due to sexual abuse. For this reason, it is important for all medical professionals to have a basic understanding of the appearance of the genital and anal tissues in children. Examples of normal and abnormal genital and anal findings are provided via annotated images. This review presents a research-based summary of how medical findings in children should be interpreted with respect to possible sexual abuse. Resources for obtaining expert review of medical findings are described., Competing Interests: Disclosures & Declaration of Conflicts of Interest: The author, reviewers, editors, and publication staff do not report any relevant conflicts of interest

We reviewed the available literature on measuring human performance to evaluate human-system interfaces (HSIs), focused on high-fidelity simulations of industrial process control systems, to identify best practices and future directions for research and operations. We searched the available literature and then conducted in-depth review, structured coding, and analysis of 49 articles, which described 42 studies. Human performance measures were classified across six dimensions: task performance, workload, situation awareness, teamwork/collaboration, plant performance, and other cognitive performance indicators. Many studies measured performance in more than one dimension, but few studies addressed more than three dimensions. Only a few measures demonstrated acceptable levels of reliability, validity, and sensitivity in the reviewed studies in this research domain. More research is required to assess the measurement qualities of the commonly used measures. The results can provide guidance to direct future research and practice for human performance measurement in process control HSI design and deployment., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We have previously shown that inadequate dystrophin in cortical neurons in mdx mice is associated with age-dependent dyshomeostasis of resting intracellular Ca 2+ ([Ca 2+ ] i ) and Na + ([Na + ] i ), elevated reactive oxygen species (ROS) production, increase in neuronal damage and cognitive deficit. In this study, we assessed the potential therapeutic properties of the whole body periodic acceleration (pGz) to ameliorate the pathology observed in cortical neurons from the mdx mouse. pGz adds small pulses to the circulation, thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of nitric oxide (NO). We found [Ca 2+ ] i and [Na + ] i overload along with reactive oxygen species (ROS) overproduction in mdx neurons and cognitive dysfunction. mdx neurons showed increased activity of superoxide dismutase, glutathione peroxidase, malondialdehyde, and calpain as well as decreased cell viability. mdx neurons were more susceptible to hypoxia-reoxygenation injury than WT. pGz ameliorated the [Ca 2+ ] i , and [Na + ] i elevation and ROS overproduction and further increased the activities of superoxide dismutase, glutathione peroxidase and reduced the malondialdehyde and calpains. pGz diminished cell damage and elevated [Ca 2+ ] i during hypoxia-reoxygenation and improved cognitive function in mdx mice. Moreover, pGz upregulated the expression of utrophin, dystroglycan-β and CAPON, constitutive nitric oxide synthases, prosaposin, brain-derived neurotrophic, and glial cell line-derived neurotrophic factors. The present study demonstrated that pGz is an effective therapeutic approach to improve mdx neurons function, including cognitive functions.

Splicing generates many mRNA strands from a single precursor mRNA, expanding the proteome and enhancing intracellular diversity. Both initial assembly and activation of the spliceosome require an essential family of splicing factors called serine-arginine (SR) proteins. Protein phosphatase 1 (PP1) regulates the SR proteins by controlling phosphorylation of a C-terminal arginine-serine-rich (RS) domain. These modifications are vital for the subcellular localization and mRNA splicing function of the SR protein. Although PP1 has been shown to dephosphorylate the prototype SR protein splicing factor 1 (SRSF1), the molecular nature of this interaction is not understood. Here, using NMR spectroscopy, we identified two electrostatic residues in helix α2 and a hydrophobic residue in helix α1 in the RNA recognition motif 1 (RRM1) of SRSF1 that constitute a binding surface for PP1. Substitution of these residues dissociated SRSF1 from PP1 and enhanced phosphatase activity, reducing phosphorylation in the RS domain. These effects lead to shifts in alternative splicing patterns that parallel increases in SRSF1 diffusion from speckles to the nucleoplasm brought on by regiospecific decreases in RS domain phosphorylation. Overall, these findings establish a molecular and biological connection between PP1-targeted amino acids in an RRM with the phosphorylation state and mRNA-processing function of an SR protein., (© 2018 Aubol et al.)

Background: Heart rate variability (HRV) reflects neural balance between sympathetic and parasympathetic autonomic nervous systems (ANS). Reduced HRV occurs in several chronic diseases and physical inactivity. External addition of pulses to the circulation restores HRV. A new method to add pulses to the circulation can be accomplished with a passive simulated jogging device (JD). We hypothesized that application of JD might increase HRV in seated and supine postures in a heterogeneous group of volunteer subjects., Methods: Twenty ambulatory persons (age range 31-88) were recruited. The physical activity intervention (JD) moved the feet in a repetitive and alternating manner; upward movement of the pedal is followed by a downward movement of the forefoot tapping against a semirigid bumper to simulate tapping of feet against the ground during jogging. Each subject underwent four, 30 min sessions in seated and supine postures with the active JD and same with Sham. HRV was assessed at baseline (BL), and Recovery (REC) from analysis of an electrocardiogram. Time domain variables were computed, namely, standard deviation of all normal RR intervals (SDNN) and square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD). Frequency domain measures were determined using a standard Fast Fourier spectral analysis, as well as parameters of Poincaré plots., Results: Thirty minutes of JD significantly increased time domain measures and Poincaré parameters of HRV in both seated and supine postures. Frequency domain parameters showed no change. The effects of JD on HRV measures were not affected by age, gender, or posture., Conclusion: The passive simulated jogging device increased HRV in both seated and supine postures. This intervention that provided effortless physical activity is a novel method to harness the beneficial effects of increasing HRV.

Patient safety may be at risk when details are omitted during anesthesia handoff. The Written Handoff Anesthesia Tool (WHAT), designed by the author, was implemented to improve the quality of anesthesia handoffs in the operating room and postanesthesia care unit (PACU). The author used the Anesthesia Handoff Communication survey to evaluate Certified Registered Nurse Anesthetist (CRNA) and PACU registered nurse (RN) satisfaction with anesthesia handoff and the Targeted Solutions Tool to identify the adequacy, contributing factors, and specific patient data omitted by senders of anesthesia handoff before and after implementation of the WHAT. Adequacy of the handoff process significantly improved for CRNAto-PACU RN (P < .0001) and CRNA-to-CRNA (P < .0001) handoffs. After implementation of the WHAT, satisfaction with anesthesia handoff significantly improved for CRNAs (P < .001) and PACU RNs (P = .001). Factors contributing to inadequate handoffs and omitted patient details were identified and significantly improved for CRNA-to-PACU RN and CRNA-to-CRNA handoffs, respectfully: ineffective method (P < .001; P < .001), baseline vital signs (P = .009; P = .014), and preoperative neurologic status (P = .012; P = .004). Implementation of the WHAT led to evidence-based changes in practice, standardization, and improved anesthesia handoff communication., Competing Interests: The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article., (Copyright© by the American Association of Nurse Anesthetists.)

A bis(cyclam)-capped cholesterol lipid designed to bind C-X-C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C-X-C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 μM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.

Selecting amino acids to design novel protein-protein interactions that facilitate catalysis is a daunting challenge. We propose that a computational coevolutionary landscape based on sequence analysis alone offers a major advantage over expensive, time-consuming brute-force approaches currently employed. Our coevolutionary landscape allows prediction of single amino acid substitutions that produce functional interactions between non-cognate, interspecies signaling partners. In addition, it can also predict mutations that maintain segregation of signaling pathways across species. Specifically, predictions of phosphotransfer activity between the Escherichia coli histidine kinase EnvZ to the non-cognate receiver Spo0F from Bacillus subtilis were compiled. Twelve mutations designed to enhance, suppress, or have a neutral effect on kinase phosphotransfer activity to a non-cognate partner were selected. We experimentally tested the ability of the kinase to relay phosphate to the respective designed Spo0F receiver proteins against the theoretical predictions. Our key finding is that the coevolutionary landscape theory, with limited structural data, can significantly reduce the search-space for successful prediction of single amino acid substitutions that modulate phosphotransfer between the two-component His-Asp relay partners in a predicted fashion. This combined approach offers significant improvements over large-scale mutations studies currently used for protein engineering and design., Competing Interests: The authors have declared that no competing interests exist.

Most sexually abused children will not have signs of genital or anal injury, especially when examined nonacutely. A recent study reported that only 2.2% (26 of 1160) of sexually abused girls examined nonacutely had diagnostic physical findings, whereas among those examined acutely, the prevalence of injuries was 21.4% (73 of 340). It is important for health care professionals who examine children who might have been sexually abused to be able to recognize and interpret any physical signs or laboratory results that might be found. In this review we summarize new data and recommendations concerning documentation of medical examinations, testing for sexually transmitted infections, interpretation of lesions caused by human papillomavirus and herpes simplex virus in children, and interpretation of physical examination findings. Updates to a table listing an approach to the interpretation of medical findings is presented, and reasons for changes are discussed., (Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

The splicing of mRNA is dependent on serine-arginine (SR) proteins that are mobilized from membrane-free, nuclear speckles to the nucleoplasm by the Cdc2-like kinases (CLKs). This movement is critical for SR protein-dependent assembly of the macromolecular spliceosome. Although CLK1 facilitates such trafficking through the phosphorylation of serine-proline dipeptides in the prototype SR protein SRSF1, an unrelated enzyme known as SR protein kinase 1 (SRPK1) performs the same function but does not efficiently modify these dipeptides in SRSF1. We now show that the ability of SRPK1 to mobilize SRSF1 from speckles to the nucleoplasm is dependent on active CLK1. Diffusion from speckles is promoted by the formation of an SRPK1-CLK1 complex that facilitates dissociation of SRSF1 from CLK1 and enhances the phosphorylation of several serine-proline dipeptides in this SR protein. Down-regulation of either kinase blocks EGF-stimulated mobilization of nuclear SRSF1. These findings establish a signaling pathway that connects SRPKs to SR protein activation through the associated CLK family of kinases., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

We hypothesized that pGz has cardio and neuroprotective effects due to upregulation of pathways which include eNOS, anti-apoptotic, and anti-inflammatory pathways. We analyze protein expression of these pathways in the brain of neonatal piglets, as well as report on the myocardial function after Deep Hypothermic Circulatory Arrest (DHCA) and pGz preconditioning. Animal data affirms both a cardio and neuroprotective role for pGz. These findings suggest that pGz can be a simple, non-invasive cardio and neuroprotective strategy preconditioning strategy in children requiring surgical intervention., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder characterized by skeletal muscle wasting, cardiomyopathy, as well as cognitive impairment. Lack of dystrophin in striated muscle produces dyshomeostasis of resting intracellular Ca 2+ ([Ca 2+ ] i ), Na + ([Na + ] i ), and oxidative stress. Here, we test the hypothesis that similar to striated muscle cells, an absence of dystrophin in neurons from mdx mice (a mouse model for DMD) is also associated with dysfunction of [Ca 2+ ] i homeostasis and oxidative stress. [Ca 2+ ] i and [Na + ] i in pyramidal cortical and hippocampal neurons from 3 and 6 months mdx mice were elevated compared to WT in an age-dependent manner. Removal of extracellular Ca 2+ reduced [Ca 2+ ] i in both WT and mdx neurons, but the decrease was greater and age-dependent in the latter. GsMTx-4 (a blocker of stretch-activated cation channels) significantly decreased [Ca 2+ ] i and [Na + ] i in an age-dependent manner in all mdx neurons. Blockade of ryanodine receptors (RyR) or inositol triphosphate receptors (IP3R) reduced [Ca 2+ ] i in mdx. Mdx neurons showed elevated and age-dependent reactive oxygen species (ROS) production and an increase in neuronal damage. In addition, mdx mice showed a spatial learning deficit compared to WT. GsMTx-4 intraperitoneal injection reduced neural [Ca 2+ ] i and improved learning deficit in mdx mice. In summary, mdx neurons show an age-dependent dysregulation in [Ca 2+ ] i and [Na + ] i which is mediated by plasmalemmal cation influx and by intracellular Ca 2+ release through the RyR and IP3R. Also, mdx neurons have elevated ROS production and more extensive cell damage. Finally, a reduction of [Ca 2+ ] i improved cognitive function in mdx mice.

Maxillary hypoplasia (MH) is a rare cause of respiratory dysfunction in infants and may occur in association with genetic abnormalities or as an isolated condition. It is included in the differential diagnosis of congenital nasal obstruction. This paper seeks to report a case series of infants with MH, discuss methods for its diagnosis, and compare computed tomography (CT) measurements of nasal cavities of infants with MH and without craniomaxillofacial abnormalities. The therapeutic approach in each patient is also described. All infants with MH admitted to a tertiary hospital between 2012 and 2015 were included. Baseline nasal endoscopy was performed at bedside. The width of the infants' nasal cavities was measured by a radiologist with experience in CT scanning of facial bones. Control patients were infants of matched sex and similar age who underwent head CT scanning for various reasons. Overall, 8 infants with MH and 8 controls were assessed. All nasal cavity dimensions of infants with MH were significantly smaller than those of control subjects. The authors conclude that the diagnosis of MH should be considered in infants with nasal obstruction and nasal cavity narrowing at nasal endoscopy.

Background: The A3669G single nucleotide polymorphism (SNP) of the glucocorticoid receptor (GR) gene NR3C1 is associated with altered tissue sensitivity to glucocorticoids (GCs). GCs modulate the food reward circuitry and are implicated in increased intake of palatable foods, which can lead to the metabolic syndrome and obesity. We hypothesized that presence of the G variant of the A3669G SNP would affect preferences for palatable foods and alter metabolic, behavioural, and neural outcomes., Methods: One hundred thirty-one adolescents were genotyped for the A3669G polymorphism, underwent anthropometric assessment and nutritional evaluations, and completed behavioural measures. A subsample of 74 subjects was followed for 5 years and performed a brain functional magnetic resonance imaging (fMRI) paradigm to verify brain activity in response to food cues., Results: Sugar and total energy consumption were lower in A3669G G allele variant carriers. On follow-up, this group also had reduced serum insulin concentrations, increased insulin sensitivity, and lower anxiety scores. Because of our unbalanced sample sizes (31/37 participants non-G allele carriers/total), our imaging data analysis failed to find whole brain-corrected significant results in between-group t-tests., Conclusion: These results highlight that a genetic variation in the GR gene is associated, at the cellular level, with significant reduction in GC sensitivity, which, at cognitive and behavioural levels, translates to altered food intake and emotional stress response. This genetic variant might play a major role in decreasing risk for metabolic and psychiatric diseases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although phosphorylation directs serine-arginine (SR) proteins from nuclear storage speckles to the nucleoplasm for splicing function, dephosphorylation paradoxically induces similar movement, raising the question of how such chemical modifications are balanced in these essential splicing factors. In this new study, we investigated the interaction of protein phosphatase 1 (PP1) with the SR protein splicing factor (SRSF1) to understand the foundation of these opposing effects in the nucleus. We found that RNA recognition motif 1 (RRM1) in SRSF1 binds PP1 and represses its catalytic function through an allosteric mechanism. Disruption of RRM1-PP1 interactions reduces the phosphorylation status of the RS domain in vitro and in cells, redirecting SRSF1 in the nucleus. The data imply that an allosteric SR protein-phosphatase platform balances phosphorylation levels in a "goldilocks" region for the proper subnuclear storage of an SR protein splicing factor., (Copyright © 2017 Elsevier Ltd. All rights reserved.)