Haematuria clinic--a preliminary audit and considerations for a one-stop assessment centre.
To audit and study the practicality of an integrated Haematuria Clinic as a one-stop assessment centre for the investigations of patients presenting with haematuria. A weekly clinic was organised to facilitate consultation, intravenous urogram and flexible cystoscopy for patients with haematuria. A protocol was set up and data on symptoms, types of haematuria, results of the investigations and outcomes were collected. About half of all the patients seen in this clinic were found to harbour urological lesions; of which urolithiasis (20.4%) and urological malignancies (14.2%) were the most common lesions identified. Transitional cell carcinoma of the bladder was the most common malignancy diagnosed (8%). Significantly, 2 of 9 (22.2%) bladder cancers were found on cystoscopy and missed on the cystogram phase of the intravenous urogram. Ten urological lesions would have been missed if cystoscopies were not performed. Conversely, in 14 patients, cystoscopy could be avoided because their intravenous urograms identified lesions sufficiently to allow for definitive treatment. The need and types of investigation for patients with haematuria are evolving. We recommend intravenous urogram and flexible cystoscopy as the standard investigations and caution against ignoring microscopic haematuria. These assessments can be organised into an integrated clinic improving deliverance of clinical care; which may result in better patient compliance for investigations and earlier detection and treatment of urological lesions presenting as haematuria.


Prescribing drugs for Alzheimer's disease in primary care: managing cognitive symptoms.
There are currently no interventions that cure or even alter the progressive course of dementia. In the UK, donepezil, galantamine and rivastigmine are licensed for symptomatic treatment of mild to moderate Alzheimer's disease, and memantine is licensed for use in moderate to severe Alzheimer's disease.1-4 These drugs improve cognitive function by a modest amount compared with placebo.5 Although the National Institute for Health and Care Excellence (NICE) stipulates that such treatment should be initiated by a specialist, in many parts of the UK responsibility for continued prescription of these drugs is being transferred to primary care. Here we review the evidence for drugs prescribed for cognitive symptoms in Alzheimer's disease and highlight key issues for those who are prescribing them.


Barriers to Healthcare: Non-English Speaking and Elderly Patients More Likely to Have Retained Ureteral Stents.
To identify factors for retained ureteral stents in our institution of patients receiving de novo ureteral stents. Ureteral stent placement, a commonly performed urologic procedure, is a temporary measure and requires timely removal. Retained ureteral stents may result in significant morbidities and need for additional procedures. We queried for all de novo ureteral stents indicated for calculi at our institution between July 2019-June 2021. Retained ureteral stents were defined as stents that remained indwelling for a period greater than 90days. Patients with metallic stents, stents on strings, pediatric patients, and planned therapy outside 90days were excluded. Patient demographic information including gender, race, age, insurance status, non-English speaking status as well as clinical data including location of presentation and indication were collected. Characteristics of patients with retained stents were compared to those without. Four hundred fifty-seven de novo stent patients meeting study criteria were identified, of which 61 (13%) patients had retained stents. The median duration of retention was 24days +/- 32days (IQR). Patients with retained stents were older than those with stents removed within 90days (62.1 vs 57.2years, P = .03). Retained stents were more common among non-English-speaking patients (13% vs 5%, P = .012). Stent retention was found to be associated with non-English speaking status and older age. Healthcare barriers in language and age may lead to increased morbidity due to stent retention.


Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050.
New strategies targeting Plasmodium falciparum gametocytes, the sexual-stage parasites that are responsible for malaria transmission, are needed to eradicate this disease. Most commonly used antimalarials are ineffective against P. falciparum gametocytes, allowing patients to continue to be infectious for over a week after asexual parasite clearance. A recent screen for gametocytocidal compounds demonstrated that the carboxylic polyether ionophore maduramicin is active at low nanomolar concentrations against P. falciparum sexual stages. In this study, we showed that maduramicin has an EC50 (effective concentration that inhibits the signal by 50%) of 14.8 nM against late-stage gametocytes and significantly blocks in vivo transmission in a mouse model of malaria transmission. In contrast to other reported gametocytocidal agents, maduramicin acts rapidly in vitro, eliminating gametocytes and asexual schizonts in less than 12 h without affecting uninfected red blood cells (RBCs). Ring stage parasites are cleared by 24 h. Within an hour of drug treatment, 40% of the normally crescent-shaped gametocytes round up and become spherical. The number of round gametocytes increases to >60% by 2 h, even before a change in membrane potential as monitored by MitoProbe DiIC1 (5) is detectable. Maduramicin is not preferentially taken up by gametocyte-infected RBCs compared to uninfected RBCs, suggesting that gametocytes are more sensitive to alterations in cation concentration than RBCs. Moreover, the addition of 15.6 nM maduramicin enhanced the gametocytocidal activity of the pyrazoleamide PA21A050, which is a promising new antimalarial candidate associated with an increase in intracellular Na(+) concentration that is proposed to be due to inhibition of PfATP4, a putative Na(+) pump. These results underscore the importance of cation homeostasis in sexual as well as asexual intraerythrocytic-stage P. falciparum parasites and the potential of targeting this pathway for drug development.


Learning and stabilization of winner-take-all dynamics through interacting excitatory and inhibitory plasticity.
Winner-Take-All (WTA) networks are recurrently connected populations of excitatory and inhibitory neurons that represent promising candidate microcircuits for implementing cortical computation. WTAs can perform powerful computations, ranging from signal-restoration to state-dependent processing. However, such networks require fine-tuned connectivity parameters to keep the network dynamics within stable operating regimes. In this article, we show how such stability can emerge autonomously through an interaction of biologically plausible plasticity mechanisms that operate simultaneously on all excitatory and inhibitory synapses of the network. A weight-dependent plasticity rule is derived from the triplet spike-timing dependent plasticity model, and its stabilization properties in the mean-field case are analyzed using contraction theory. Our main result provides simple constraints on the plasticity rule parameters, rather than on the weights themselves, which guarantee stable WTA behavior. The plastic network we present is able to adapt to changing input conditions, and to dynamically adjust its gain, therefore exhibiting self-stabilization mechanisms that are crucial for maintaining stable operation in large networks of interconnected subunits. We show how distributed neural assemblies can adjust their parameters for stable WTA function autonomously while respecting anatomical constraints on neural wiring.


Utility of quantitative MRI metrics for assessment of stage and grade of urothelial carcinoma of the bladder: preliminary results.
The purpose of this study was to assess associations between quantitative MRI metrics and pathologic indicators of aggressiveness of urothelial carcinoma of the bladder. In this retrospective biinstitutional study, 37 patients (28 men and nine women; mean age, 73 ± 12 years) who underwent pelvic MRI including diffusion-weighted imaging (b values 0, 400, and 800 s/mm(2)) and T2-weighted imaging before transurethral resection or cystectomy for urothelial carcinoma of the bladder were identified. Tumor diameter (measured on T2-weighted imaging), normalized T2 signal intensity (to muscle; hereafter labeled normalized T2) and apparent diffusion coefficient (ADC) were measured for all tumors. Mann-Whitney test and receiver operating characteristic analyses were used to identify associations between these metrics and histopathologic tumor stage and grade. Thirty-seven tumors were assessed (mean size, 35 ± 23 mm; range 8-88 mm). At histopathologic analysis, 16 of 37 (43%) tumors were stage T2 or greater and 21 of 37 (57%) were stage T1 or lower, whereas 34 of 37 (92%) were high grade and three of 37 (8%) were low grade. High-stage (≥ T2) tumors showed greater tumor diameter, lower normalized T2, and lower ADC (p = 0.005-0.032) than low-stage (≤ T1) tumors. Tumor diameter and ADC were significant independent predictors of stage (p ≤ 0.043), with their combination giving an area-under the-curve (AUC) of 0.804. High-grade tumors showed significantly lower ADC (p = 0.023) but no significant difference in tumor diameter or normalized T2 (p = 0.201-0.559). AUC for differentiating low- and high-grade tumors was higher for ADC (0.902) than for tumor diameter (0.603) or normalized T2 (0.725). A combination of size and quantitative MRI metrics can potentially be used as markers of stage and grade of bladder cancer.


Absolute calibration of a streaked optical pyrometer at nanosecond time scale with a luminescent concentrator.
The Streaked Optical Pyrometer (SOP) is a visible diagnostic widely used to study the warm dense matter regime at high energy laser facilities, gas guns, or ion accelerators. It is usually coupled with a Velocity Interferometer System for Any Reflector (VISAR) diagnostic for simultaneous shock wave velocity, reflectivity, and temperature measurements to study the Equation of State (EOS) of materials. While VISAR is a well-mastered technology that provides velocity measurements with low relative uncertainties (close to percent), SOP diagnostics still suffer from high imprecision. In this article, we present a new calibration method in order to obtain absolute temperature measurements with reduced uncertainties. This approach is based on a novel light source: a Ce:YAG luminescent concentrator pumped by LEDs. This device produces enough optical power for calibration at the nanosecond sweep duration of the streak camera. As a demonstration, it has first been installed at the LULI facility and tested on quartz samples shocked at temperatures above 4000 K.


Nonmetastatic gestational trophoblastic disease.
Nonmetastatic gestational trophoblastic disease encompasses a variety of related neoplasms of the human placenta. With the advent of effective chemotherapy, nearly all of these patients can be cured using a variety of regimens with acceptable toxicity. Hysterectomy is useful in selected patients to decrease the amount of chemotherapy required to produce remission and to salvage patients who have failed initial chemotherapy. The majority of patients can retain child-bearing capacity and often have normal pregnancies after therapy.


Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus.
Nutrient intake stimulates the secretion of the gastrointestinal incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert glucose-dependent insulinotropic effects and assist pancreatic insulin and glucagon in maintaining glucose homeostasis. GLP-1 also suppresses glucose-dependent glucagon secretion, slows gastric emptying, increases satiety, and reduces food intake. An impaired incretin system, characterized by decreased responsiveness to GIP and markedly reduced GLP-1 concentration, occurs in individuals with type 2 diabetes mellitus (T2DM). The administration of GLP-1 improves glycemic control, but GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide, a DPP-4-resistant exendin-4 GLP-1 receptor agonist, exhibits the glucoregulatory actions of GLP-1 and reduces body weight in patients with T2DM. It may possess cardiometabolic actions with the potential to improve the cardiovascular risk profile of patients with T2DM. DPP-4 inhibitors such as sitagliptin and saxagliptin increase endogenous GLP-1 concentration and demonstrate incretin-associated glucoregulatory actions in patients with T2DM. DPP-4 inhibitors are weight neutral. A growing understanding of the roles of incretin hormones in T2DM may further clarify the application of incretin-based treatment strategies.


Is skin biopsy a predictor of transition to symptomatic HIV neuropathy? A longitudinal study.
To investigate whether serially assessed epidermal nerve fiber (ENF) density and quantitative sensory thresholds (QSTs) are associated with the clinical transition from HIV infection with no neuropathy or asymptomatic neuropathy to symptomatic distal sensory neuropathy (SDSP). Identifying predictors of transition to SDSP would enable identification of subjects at enhanced risk for development of HIV-SDSP and facilitate intervention studies with the ultimate goal of disease prevention. Asymptomatic signs of sensory dysfunction in the feet have been shown to be weakly predictive of SDSP; however, bedside evaluation of small sensory fibers is limited. Abnormality of these fibers may play an important role in the genesis of SDSP. Fifty-eight HIV-infected subjects underwent serial clinical, virologic, immunologic, skin biopsy, and QST assessments. Cox proportional hazards modeling was used to examine the associations of serial ENF density and QST assessments with the risk of development of SDSP among the subset of 26 subjects who had asymptomatic or no neuropathy at study entry. Median follow-up was 2.9 years (range 6 months to 4.5 years) during which 19 of 26 subjects transitioned to SDSP. Using a model where ENF density and QST measures from the study visit before potential transition were examined, a lower leg ENF density, a higher cooling threshold, and a higher heat pain threshold for minimal pain (HP 0.5) were associated with a greater risk of SDSP in univariate analyses. In multiple regression analyses, leg ENF density but not QST measures were significantly associated with SDSP. A leg ENF density of 10 fibers/mm or less conferred a 14-fold greater risk of SDSP than a leg ENF density greater than 10 fibers/mm. Measures of small sensory fibers (leg epidermal nerve fiber density, cooling and heat pain thresholds) seem to be associated with transition to symptomatic HIV-associated distal sensory neuropathy 6 to 12 months later.


COVID-19 booster prioritization in the West Bank: a survey experiment among Bedouins, refugees, and the majority group.
Our main aim is to understand to what extent Bedouins, internally displaced Palestinians (refugees) and majority-group members (non-refugees, non-Bedouins, settled) in the West Bank prioritize COVID-19 booster shots for their own group over other groups. We conducted a survey experiment (face-to-face) among 678 Palestinians living in the West Bank. Participants randomly received a description of an older man (Bedouin, refugee, settled) and were asked to indicate to what extent this person should be prioritized for the booster shot. Respondents belonging to a minority saw the profile of an in-group member or a majority-group member, whereas majority-group members would see the profile of an in-group or one out-group member (Bedouin, Palestinian refugee). We found slightly higher in-group preferences for Palestinian refugees when it came to vaccination, whereas majority-group members were less inclined to support a prioritization of Palestinian refugees but equally prioritized their group and Bedouins. For Bedouins, we did not find strong in-group preferences. Our study reveals the salience of group boundaries during the COVID-19 pandemic with potentially adverse effects on the health care of minorities.


Muscle-driven simulations and experimental data of cycling.
Muscle-driven simulations have provided valuable insights in studies of walking and running, but a set of freely available simulations and corresponding experimental data for cycling do not exist. The aim of this work was to develop a set of muscle-driven simulations of cycling and to validate them by comparison with experimental data. We used direct collocation to generate simulations of 16 participants cycling over a range of powers (40-216 W) and cadences (75-99 RPM) using two optimization objectives: a baseline objective that minimized muscle effort and a second objective that additionally minimized tibiofemoral joint forces. We tested the accuracy of the simulations by comparing the timing of active muscle forces in our baseline simulation to timing in experimental electromyography data. Adding a term in the objective function to minimize tibiofemoral forces preserved cycling power and kinematics, improved similarity between active muscle force timing and experimental electromyography, and decreased tibiofemoral joint reaction forces, which better matched previously reported in vivo measurements. The musculoskeletal models, muscle-driven simulations, simulation software, and experimental data are freely shared at https://simtk.org/projects/cycling_sim for others to reproduce these results and build upon this research.


Improving the Way that We Conceptualise Adverse Childhood Experiences - A Commentary on Sisitsky et al. (2023).
Research on adverse childhood experiences (ACEs) has traditionally relied on cumulative ACE scores, which prevents understanding about the effects of distinct adversities and their mechanistic pathways. Dimensional and person-centred approaches have been proposed as alternative methods to conceptualise ACEs, which address limitations of the cumulative ACE score. In this issue, Sisitsky et al. (Research on Child and Adolescent Psychopathology, 2023) apply these approaches to identify dimensions of ACEs and profiles of children with distinct patterns of early exposure, in a large, racially diverse cohort from the US. The authors also examine the longitudinal associations between profiles of early adversity in early childhood with later mental health and telomere length. In this commentary, we discuss key findings from the study and recommend future avenues for improving the conceptualisation of ACEs.


Molecular pathways: turning proteasomal protein degradation into a unique treatment approach.
Cancer treatment regimens have evolved from single cytotoxic substances affecting all proliferative tissues toward antibodies and kinase inhibitors targeting tumor-specific pathways. Treatment efficacy and cancer survival have improved overall, and side effects have become less frequent. The ubiquitin-proteasome system-mediated proteasomal protein degradation is the most critical pathway to regulate the quantity of signal proteins involved in carcinogenesis and tumor progression. These processes are, as well as protein recycling, highly regulated and offer targets for biomarker and drug development. Unspecific proteasome inhibitors such as bortezomib and carfilzomib have shown clinical efficacy and are approved for clinical use. Inhibitors of more substrate-specific enzymes of degradation processes are being developed and are now in early clinical trials. The novel compounds focus on the degradation of key regulatory proteins such as p53, p27(Kip1), and ß-catenin, and inhibitors specific for growth factor receptor kinase turnover are in preclinical testing.


Medical treatment of malignancy-associated hypercalcemia.
Malignancy-associated hypercalcemia (MAH) is the commonest cause of hypercalcemia in hospitalized patients. Its incidence is 15 cases per 100,000 person-year. Such complication develops in almost 10% of patients with advanced cancer representing, ultimately, the most frequent cause of death in several patients with cancer. Parathyroid hormone related protein (PTHrP), which has strong homology to parathyroid hormone, is the commonest hormonal mediator of MAH. Overall, about 80% of patients with MAH have increased PTHrP serum levels. Bisphosphonates are synthetic analogues of pyrophosphate, and represent the principal support of treatment. Several bisphosphonates have shown to decrease serum calcium levels by inhibiting PTH-dependent osteoclast activation. They are potent and effective inhibitors of osteoclast-mediated bone resorption, and have shown antiangiogenic properties in some experimental models. At present, pamidronate, zoledronate and ibandronate should be considered the drugs of choice in the treatment of MAH. Old agents such as mithramycin, calcitonine, and gallium nitrate have practically been abandoned due to their limited activity and huge side effects, especially for the kidney. A new experimental approach to MAH involves the blockade of receptor activator of nuclear factor-kappa B ligand, usually abbreviated as RANKL. RANKL is a key element in the differentiation, function, and survival of osteoclasts, which plays an essential role in removing Ca(++) from the bone in response to PTH stimulation. This review provides information about the actual medical treatment of MAH.


Tweaking agonist efficacy at N-methyl-D-aspartate receptors by site-directed mutagenesis.
The structural basis for partial agonism at N-methyl-D-aspartate (NMDA) receptors is currently unresolved. We have characterized several partial agonists at the NR1/NR2B receptor and investigated the mechanisms underlying their reduced efficacy by introducing mutations in the glutamate binding site. Key residues were selected for mutation based on ligand-protein docking studies using a homology model of NR2B-S1S2 built from the X-ray structure of NR1-S1S2 in complex with glycine. Wild-type and mutant forms of NR2B were coexpressed with NR1 in Xenopus laevis oocytes and characterized by two-electrode voltage-clamp electrophysiology. By combining mutagenesis of residues His486 or Val686 with activation by differently substituted partial agonists, we introduce varying degrees of steric clash between the ligand and the two binding domains S1 and S2. In cases where ligand-protein docking predicts increased steric clashes between agonists and the residues forming the S1-S2 interface, the agonists clearly show decreased relative efficacy. Furthermore, we demonstrate that the mutation S690A affects both potency and efficacy in an agonist-specific manner. The results indicate that essential residues in the ligand binding pocket of NR2B may adopt different conformations depending on the agonist bound. Together, these data indicate that agonist efficacy at the NR2B subunit can be controlled by the extent of steric clashes between the agonist and the ligand binding domains and by ligand-dependent arrangements of residues within the binding pocket.


[Long-term clinical evaluation of different types of resin-bonded fixed partial denture to replace lost anterior teeth].
Objective: To evaluate the clinical survival rates and influence factors of different types of resin-bonded fixed partial dentures (RBFPD) used in anterior missing teeth restoration. Methods: Ninety-three RBFPD were delivered to 92 patients [92 patients,43 males and 49 females, average age (46.1±12.8) years] who visited Peking University School and Hospital of Stomatology from January 2006 to December 2021 for restoration of 1 or 2 anterior missing teeth. Altogether 32 cases of glass fiber reinforced RBFPD, 39 cases of glass-based ceramic RBFPD and 22 cases of porcelain-fused-to-metal RBFPD were retrospectively analyzed. The complete survival rate, functional survival rate, patients' satisfaction and color matching of the restorations were recorded and evaluated every year since the replacement with RBFPD. The Kaplan-Meier survival curve method was used for survival analysis, and the Log-rank analysis was used to compare the effect of the number of missing teeth, position (maxillary or mandibular), cantilever or non-cantilever and gender on the survival rate of the restorations. Results: The overall survival time for the 93 RBFPD was 13.7 years (95%CI: 12.3-15.1 years). There was a decreasing trend in complete survival and functional survival for all three material RBFPD from year to year, but complete and functional survival rates exceeded 90% at year 5 and exceeded 80% at year 10. The complete survival rate of the glass-ceramic RBFPD was higher than the other two during the follow-up period, with a complete survival rate of 90% (35/39) at year 15. The porcelain-fused-to-metal RBFPD had a higher functional survival rate in years 1-8, but the complete and functional survival rates showed a substantial decrease after year 9. The single-factor Log-rank analysis showed that the functional survival rate of porcelain-fused-to-metal RBFPD was significantly higher than that of glass fiber reinforced RBFPD (χ²=7.33, P=0.007), and the complete survival rate of RBFPD with 1 missing tooth restored was significantly higher than that of RBFPD with 2 missing teeth restored (χ²=3.23, P=0.072). The differences in survival rates between different restoration positions (maxillary and mandibular), cantilever or non-cantilever, and gender factors were not statistically significant (χ²=2.26, P=0.133; χ²=0.68, P=0.411; χ²=1.07, P=0.300). Conclusions: For the restoration of individual missing anterior teeth, both porcelain-fused-to-metal RBFPD and glass-based ceramic RBFPD achieve a high long-term clinical success rate, with glass-based ceramic RBFPD being more able to ensure long-term restorative and esthetic results.


[Insulin combinations: improving the treatment of juvenile diabetes].
In order to establish some general insulin therapy norms, a study was performed on a group of 77 young diabetics (average age 11.7) over the course of a 14 day stay at a summer camp. The children were placed on an appropriate diabetic diet and received twice daily insulin injections. 83.1% of the group (N = 64) ended up using a mixture of Regular and NPH insulin while the other 16.9% used only NPH insulin. Daily, two-thirds of the total dosage was given before breakfast (63.4 +/- 9.6%) and the other one-third (36.6 +/- 9.6%) was given before dinner. The proportion of mixed insulins were the following: before breakfast 10.3 +/- 6.6% Regular, 89.7 +/- 6.6% NPH; before dinner 12.5 +/- 7.3% Regular, 87.5 +/- 7.3% NPH, 14.9% of the blood glucose tests showed hypoglycemia. The majority of these results were after some physical activity (37.8% before breakfast, 20.7% before dinner) and a few (18.3%) become so at night. Thus, this work reflects the importance of proportion and regularity of insulin use, as well as the need for bedtime blood glucose levels in children with diabetes.


Metabolomic Analysis of the Ameliorative Effect of Enhanced Proline Metabolism on Hypoxia-Induced Injury in Cardiomyocytes.
Coronary heart disease is currently the leading cause of death in humans. Its poor prognosis and high mortality are associated with myocardial ischemia, which leads to metabolic disorder-related cardiomyocyte apoptosis and reactive oxygen species (ROS) production. Previous cardiovascular metabolomics studies in humans and mice have shown that proline metabolism is severely altered after cardiomyocyte hypoxia. Proline dehydrogenase (PRODH) is located on the inner mitochondrial membrane and is an enzyme that catalyzes the first step of proline catabolism, which plays an important role in improving the cellular redox state. In vitro oxygen-glucose deprivation can mimic in vivo myocardial ischemic injury. This study is aimed at investigating whether enhancing proline metabolism by overexpressing PRODH can ameliorate hypoxia-induced injury in cardiomyocytes and to reveal the related altered metabolites and mechanistic pathway via untargeted metabolomics analysis. First, through public database analysis and RT-qPCR and western blot analyses in a cardiomyocyte hypoxia model, we found that the expression of the proline-degrading enzyme PRODH was downregulated after myocardial infarction and hypoxia exposure. Second, LDH assays, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), DHE staining, flow cytometric apoptosis analysis with DCFH and Annexin V-FITC/PI, and western blot analysis were used to assess the injury level in cardiomyocytes. Enhanced proline metabolism induced by PRODH overexpression reduced the levels of reactive oxidative stress and apoptosis, whereas PRODH knockdown had the opposite effects. Third, untargeted metabolomics analysis revealed that the protective effect was associated with significant changes in metabolism linked to sphingolipid signaling pathways, unsaturated fatty acid biosynthesis, phosphocreatine, glutathione disulfide, aminoacyl-tRNA biosynthesis, and ABC transporters. Our study demonstrated a protective effect of enhanced proline metabolism in cardiomyocytes under hypoxia, providing a novel strategy for exploring new treatments for coronary heart disease.


Global resource potential of seasonal pumped hydropower storage for energy and water storage.
Seasonal mismatches between electricity supply and demand is increasing due to expanded use of wind, solar and hydropower resources, which in turn raises the interest on low-cost seasonal energy storage options. Seasonal pumped hydropower storage (SPHS) can provide long-term energy storage at a relatively low-cost and co-benefits in the form of freshwater storage capacity. We present the first estimate of the global assessment of SPHS potential, using a novel plant-siting methodology based on high-resolution topographical and hydrological data. Here we show that SPHS costs vary from 0.007 to 0.2 US$ m-1 of water stored, 1.8 to 50 US$ MWh-1 of energy stored and 370 to 600 US$ kW-1 of installed power generation. This potential is unevenly distributed with mountainous regions demonstrating significantly more potential. The estimated world energy storage capacity below a cost of 50 US$ MWh-1 is 17.3 PWh, approximately 79% of the world electricity consumption in 2017.


Mesenchymal stromal cells induced regulatory B cells are enriched in extracellular matrix genes and IL-10 independent modulators.
Regulatory B cells (Breg) are essential players in tolerance and immune homeostasis. However, lack of specific Breg markers limit their potential in clinical settings. Mesenchymal stromal cells (MSC) modulate B cell responses and are described to induce Breg in vitro. The aim of this work was to characterize MSC induced Breg (iBreg) and identify specific Breg biomarkers by RNAseq. After 7-day coculture with adipose tissue-derived MSC, B cells were enriched in transitional B cell populations, with increased expression and secretion of IL-10 and no TNFα. In addition, iBreg showed potential to modulate T cell proliferation at 2 to 1 cell ratios and their phenotype remained stable for 72h. RNAseq analysis of sorted IL-10 positive and negative iBreg populations identified over 1500 differentially expressed genes (DEG) among both populations. Analysis of biological processes of DEG highlighted an enrichment of immune regulation and extracellular matrix genes in IL-10- iBreg populations, while IL-10+ iBreg DEG were mostly associated with cell activation. This was supported by T cells modulation assays performed in the presence of anti-IL-10 neutralizing antibodies showing the non-essential role of IL-10 in the immunomodulatory capacity of iBregs on T cells. However, based on RNAseq results we explored the role of TGF-β and found out that it plays a major role on iBreg induction and iBreg immunomodulatory properties. Therefore, we report that MSC induce B cell populations characterized by the generation of extracellular matrix and immune modulation independently of IL-10.


Disposal of alpha-ketoisocaproate: roles of liver, gut, and kidneys.
The alpha-keto analogues of the branched-chain amino acids, and particularly that of leucine, alpha-ketoisocaproate (KIC), have been found to reduce urea synthesis and as a result have been proposed for the treatment of uremia and portal systemic encephalopathy. Because little is known about the fate of these keto acids in the intact animal, we examined the disposal of a KIC load in five conscious overnight-fasted dogs with catheters previously implanted in an artery, and in the portal, hepatic, and renal veins. During the absorptive period (54 +/- 9 min; range, 20-75 min), 62 +/- 5% of the administered load (6,358 +/- 662 mumol) of the keto acid was absorbed as KIC and 23 +/- 3% was transaminated across the gut and entered as leucine. The hepatic uptake of KIC was equivalent to 35 +/- 5% (2.316 +/- 419 mumol) of the administered load, and of that, one-third was transaminated to leucine and two-thirds were converted to ketone bodies. The splanchnic output of KIC amounted to 1,732 +/- 256 mumol of 27 +/- 2% of the administered load, half of which was transaminated across the kidneys to leucine. As a result, the amount of KIC reaching the extrahepatic extrarenal tissues as KIC carbon amounted to 15% of the load administered. We conclude that the majority of an intragastrically administered KIC load reaches the (extrarenal) peripheral tissues in the form of leucine or ketone bodies. The study also underscores the importance of the "gut," the kidneys, and the liver in metabolism of the absorbed KIC load.


Dipeptidyl peptidase IV expression in rat jejunal crypt-villus axis is controlled at mRNA level.
The expression of dipeptidyl peptidase IV (DPP IV), an intestinal brush-border hydrolase, has been studied in the rat jejunum crypt-villus axis. DPP IV enzyme activity is lower in crypt cells than in villus cells. Indirect immunofluorescence studies, using a polyclonal antibody raised against purified DPP IV, show a gradient of immunoreactivity from the crypts to the villi that was quantified using confocal laser scanning microscopy. Accordingly, Western blot analysis demonstrates that the steady-state amount of DPP IV is much lower in crypt cells than in villus cells. Northern blot analysis was performed using our cDNA probe for human DPP IV that presents more than 94% homology with rat DPP IV cDNA. Results clearly show that there is approximately seven times less DPP IV mRNA in crypt cells than in villus cells. We conclude that the differentiation-dependent expression of DPP IV in rat jejunum is primarily controlled at the mRNA level.


Differentiation of embryonic stem cells to a neural fate: a route to re-building the nervous system?
The many and varied proposed applications of cell replacement therapies in the treatment of human disease states, particularly those arising from cell loss or dysfunction, have been discussed widely in both the scientific and popular press. Although an attractive concept, cell therapies require the development of a readily available source of donor cells suitable for transplantation. Embryonic stem (ES) cells, with proven ability to differentiate to all cell populations of the embryo and adult in vitro, provide a potential source of therapeutic cells. The differentiation capability of mouse ES cells in vitro has been studied extensively over the last 20 years and the formation of neural precursors and neural cell lineages from mouse ES cells is well established. Cell populations highly enriched/homogenous in neural precursors have been achieved using a variety of chemical or biological inducing agents coupled with selective growth conditions. Preliminary reports suggest that similar neural enrichment is seen when these methodologies are applied to primate and human ES cells. ES cell-derived neural precursors have been analyzed in vitro and in vivo and found to be functionally normal and, after introduction into rodent models of human neurodegenerative diseases, capable of effecting measurable disease recovery. We review progress in the formation of neural precursors from mouse ES cells, particularly the recent reports of directed differentiation of ES in response to biological inductive factors, and assess the transfer of these approaches to human ES cells.


Biofilm activity on corrosion of API 5L X65 steel weld bead.
This work aimed to identify microbial colonization and biocorrosion in welded seam areas of API 5 L X65 carbon steel, since microorganisms are ubiquitous and there is a lack of information on their biological and electrochemical interactions with these structures. In the present study, polished and unpolished welded coupons prepared by shielded metal arc welding were assayed to identify the effect of surface roughness and local changes in the metal microstructure on microbial colonization. Experiments were performed in glass cell vessels with fresh and sterile seawater to establish the presence or absence of microorganisms. For comparison, nonwelded coupons were simultaneously tested as a control. On the 15th day, both polished and unpolished welded coupons and the nonwelded coupons immersed in fresh seawater showed microbial colonization, though the corrosion products were more abundant for the welded coupons. Nevertheless, unpolished welded coupons showed a higher predominance of pitting around the beads than polished coupons. These results suggest that filler material creates conditions more favorable for biofilm development, thus intensifying the localized corrosion on the welds. It can be concluded that adhesion and subsequent biocorrosion are directly influenced by surface roughness, whereas microstructural modifications due to welding interfere little with microbial adhesion, regardless of the greater pit depths compared to those of nonwelded coupons. Additionally, although open circuit potential measurements indicated that metal surfaces are protected when coated with biofilms, pitting corrosion was more pronounced in welded coupons immersed in fresh seawater than in those immersed in seawater without microorganisms. Therefore, the use of open circuit analysis alone is not recommended for biocorrosion monitoring of welded coupons.


Entry distribution, fission barrier, and formation mechanism of 254102No
The entry distribution in angular momentum and excitation energy for the formation of 254No has been measured after the 208Pb(48Ca,2n) reaction at 215 and 219 MeV. This nucleus is populated up to spin 22Planck's over 2pi and excitation energy greater, similar6 MeV above the yrast line, with the half-maximum points of the energy distributions at approximately 5 MeV for spins between 12Planck's over 2pi and 22Planck's over 2pi. This suggests that the fission barrier is greater, similar5 MeV and that the shell-correction energy persists to high spin.


An Atypical Case of Lymphocytic Panhypophysitis in a Pregnant Woman.
We describe a case of lymphocytic panhypophysitis (LPH) in a 30-year-old woman presenting with throbbing headaches and vision changes during her third trimester. LPH is the rarest subclassification of lymphocytic hypophysitis; it is typically found in males and has not previously been associated with pregnancy. Anterior and posterior pituitary deficits together with headaches should raise a high degree of suspicion regarding the possibility of LPH. The atypical magnetic resonance imaging finding of a heterogeneous pituitary mass additionally raised concern about pituitary apoplexy. Tissue from a transsphenoidal biopsy permitted diagnosis of lymphocytic hypophysitis. There was infiltration of the pituitary gland by small B and T lymphocytes. Resolution of the visual symptoms occurred after the biopsy and treatment with intravenous steroids.


Ethosuximide for Essential Tremor: An Open-Label Trial.
T-type calcium channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in ET. Ethosuximide reduces T-type calcium currents and can suppress tremor in two animal models of ET. We explored the effects of ethosuximide in subjects with ET in an open-label trial using both clinical scales and accelerometric recordings measures. We initially planned to conduct the trial with 15 patients, but due to lack of efficacy and a high incidence of adverse effects, the trial was stopped after seven patients had participated. Seven patients diagnosed with ET were included in the study. The ethosuximide dose was 500 mg daily (BID). The main outcome measures were: 1) tremor clinical rating scale (TCRS) score, 2) accelerometric recordings, and 3) self-reported disability scale score. Five patients completed the study, and two dropped out due to adverse effects. There were no significant changes in clinical scores in motor task performance (TCRS 1+2), daily living activities (TCRS 3), or in the patients' subjective assessment (TCRS 4) and global appraisal. There were no differences observed for accelerometry data or disability scale scores. Anxiety, nervousness, headache, and dizziness were reported by two patients while on ethosuximide, causing them to stop the trial. No patient preferred to continue ethosuximide treatment. The results of our exploratory study suggest that ethosuximide is not an effective treatment for ET.


Lumican as a novel potential clinical indicator for acute aortic dissection: A comparative study, based on multi-slice computed tomography angiography.
The aim of the present study was to investigate the association between serum lumican levels and acute aortic dissection (AAD) severity. A total of 82 patients with chest or back pain and 30 healthy volunteers were recruited. Among the patients, there were 70 cases of AAD and 12 cases of intramural hematoma (IMH). AAD severity was determined using multi-slice computed tomography angiography (MSCTA). Serum was collected from the patients upon admission, and lumican levels were detected using an enzyme-linked immunosorbent assay. In addition, correlation analyses were conducted between lumican levels and AAD severity by designing a 'SCORE X, RANGE Y' system to measure the number of affected vital arteries and vertical range of false lumen, based on the MSCTA. Lumican levels differed significantly among the AAD patients (2.32±4.29 ng/ml), IMH patients (0.72±0.32 ng/ml) and healthy volunteers (0.85±0.53 ng/ml; P=0.003). In the AAD patients presenting within 12-72 h of symptom onset, the Spearman's rho correlation coefficient between lumican and SCORE or RANGE was 0.373 (P=0.046) and 0.468 (P=0.010), respectively. The present results suggest that lumican may be a potential marker for aiding the diagnosis and screening for AAD, and may be used to predict the severity of AAD.


Low cigarette smoking prevalence in peri-urban Peru: results from a population-based study of tobacco use by self-report and urine cotinine.
A recent study found lower self-reported prevalence of tobacco smoking in a peri-urban area of Lima, Peru than previously reported in urban samples. These regions encompass substantial proportions of Peru's population - ones at greater risk of disease due to reduced healthcare access - but have been less often studied. We validate low smoking prevalence with urine cotinine and characterize chronic disease and lung function outcomes between non-, occasional, and daily smokers. Data are from the CRONICAS Cohort Study, a population-based longitudinal study in four low-resource Peruvian settings, which began in 2010. Of a baseline cohort of 2978 adults, we prospectively followed 2583 (87%) to determine prevalence of chronic illness. In a baseline sub-sample of 382 participants, median adjusted cotinine was 0.0 mcg/mg (IQR 0-0) for both self-reported non-smokers and occasional smokers compared to 172.3 mcg/mg (IQR 0-709.2) for daily smokers. Creatinine-adjusted cotinine validated daily smoking prevalence of 4.7% at a cutoff of 100 mcg/mg. Kappa statistic for daily smoking and creatinine- adjusted cotinine ≥100 mcg/mg was 0.65 (95% CI 0.47, 0.83), indicating substantial agreement. At baseline, we found 3.3% daily and 8.9% occasional smoking by self-report for the full cohort. Follow-up indicated little difference in chronic disease prevalence between groups. Daily smokers trended toward having a greater decline in FVC (-1%; 95% CI -2.9, 0.8) and FEV1 (-1.3%; 95% CI -3.2, 0.6) over 40 months when compared to non-smokers, whereas the decline in lung function for occasional smokers was similar compared to non-smokers (-0.2% FVC; 95% CI -1.5, 1.0) and (0% FEV1; 95% CI -1.3, 1.3). Our data places Peru within a previously-described pattern of smoking found in much of Latin America, favoring occasional over daily smoking and low cigarette consumption. We determine that there are not significant differences between smoking groups concerning chronic disease outcomes. We favor distinguishing between daily and occasional smokers in order to accurately characterize these low-use populations.


Effect of atrial contraction frequency on atrial natriuretic peptide secretion.
Paroxysms of atrial tachycardia are oftentimes associated with polyuria. The plasma levels of the potent diuretic hormone, atrial natriuretic peptide (ANP), are elevated during episodes of atrial tachycardia, suggesting that ANP may play a role in mediating the diuresis. The mechanism of enhanced ANP secretion associated with atrial tachycardia is not known. We examined the effect of altering the pacing frequency of isolated left rat atria on ANP secretion. Atria were suspended between an electrode and hook connected to a force transducer and superfused with medium 199. The ANP content of the superfusate was measured by radioimmunoassay. Increasing the frequency of pacing from 2 to 4 Hz resulted in a 46 +/- 5% (means +/- SE, n = 9) rise in immunoreactive ANP secretion above base line (P less than 0.01). Lowering the frequency from 4 to 2 Hz lowered immunoreactive ANP secretion by 36 +/- 3% (n = 6) relative to base line (P less than 0.02). Incremental increases in the pacing frequency from 2 to 8 Hz resulted in a continual rise in immunoreactive ANP with a peak increase of 191 +/- 6% of base line (n = 8) at 8 Hz. To examine the possibility that release of norepinephrine or acetylcholine from endogenous nerves mediated this effect, the atria were superfused with the combination of 0.1 microM propranolol, 1.0 microM phentolamine, and 10 microM atropine. The concentrations of the antagonists were 125-fold or higher than the dissociation constant for binding to receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Preclinical efficacy of humanized, non-FcγR-binding anti-CD3 antibodies in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for ∼20% of ALL cases. Intensive chemotherapy regimens result in cure rates >85% in children and <50% in adults, warranting a search of novel therapeutic strategies. Although immune-based therapies have tremendously improved the treatment of B-ALL and other B-cell malignancies, they are not yet available for T-ALL. We report here that humanized, non-Fcγ receptor (FcγR)-binding monoclonal antibodies (mAbs) to CD3 have antileukemic properties in xenograft (PDX) models of CD3+ T-ALL, resulting in prolonged host survival. We also report that these antibodies cooperate with chemotherapy to enhance antileukemic effects and host survival. Because these antibodies show only minor, manageable adverse effects in humans, they offer a new therapeutic option for the treatment of T-ALL. Our results also show that the antileukemic properties of anti-CD3 mAbs are largely independent of FcγR-mediated pathways in T-ALL PDXs.


Agricultural lung diseases.
Agriculture is considered one of the most hazardous occupations. Organic dusts and toxic gases constitute some of the most common and potentially disabling occupational and environmental hazards. The changing patterns of agriculture have paradoxically contributed to both improved working conditions and increased exposure to respiratory hazards. Animal confinement operations with increasing animal density, particularly swine confinement, have contributed significantly to increased intensity and duration of exposure to indoor air toxins. Ongoing research has implicated bacterial endotoxins, fungal spores, and the inherent toxicity of grain dusts as causes of upper and lower airway inflammation and as immunologic agents in both grain and animal production. Animal confinement gases, particularly ammonia and hydrogen sulfide, have been implicated as additional sources of respiratory irritants. It has become evident that a significant percentage of agricultural workers have clinical symptoms associated with long-term exposure to organic dusts and animal confinement gases. Respiratory diseases and syndromes, including hypersensitivity pneumonitis, organic dust toxic syndrome, chronic bronchitis, mucous membrane inflammation syndrome, and asthmalike syndrome, result from ongoing acute and chronic exposures. In this review we focus upon the emerging respiratory health issues in a changing agricultural economic and technologic environment. Environmental and occupational hazards and exposures will be emphasized rather than clinical diagnosis and treatment. Methods of prevention, from both engineering controls and personal respiratory perspectives, are also addressed.


[Search for propionic acid bacteria in the human intestine].
The possibility of detecting propionic acid-producing bacteria in the intestine of healthy humans with a view to obtaining a strain which is physiologically most suitable for therapeutic purposes has been studied. The selective conditions for the isolation of propionic acid-producing bacteria from the large intestine have been experimentally established. Analysis of 70 puncture biopsy specimens of parietal mucus and luminal contents from different sections of the intestine has not shown the presence of the representatives of propionic acid-producing bacteria. The strains isolated under the conditions selective for such bacteria have been found to belong to the family Enterobacteriaceae. These strains have proved capable of synthesizing vitamin B12, but the synthesis of propionic acid has not been observed.


Intestinal permeability in patients after surgical trauma and effect of enteral nutrition versus parenteral nutrition.
To study the intestinal permeability (IP) following stress of abdominal operation and the different effects on IP of enteral nutrition (EN) and parenteral nutrition (PN). Forty patients undergoing abdominal surgery were randomized into EN group and PN group. Each group received nutritional support of the same nitrogen and calorie from postoperative day (POD) 3 to POD 11. On the day before operation (POD-1), POD 7 and POD 12, 10 g of lactulose and 5 g of mannitol were given orally, and urine was collected for 6 hours. Urine excretion ratios of lactulose and mannitol (L/M) were measured. L/M ratios of EN group on POD-1, POD 7 and POD 12 were 0.026+/-0.017, 0.059+/-0.026, 0.027+/-0.017, respectively, and those of PN group were 0.025+/-0.013, 0.080+/-0.032, 0.047+/-0.021, respectively. Patients of both groups had elevated L/M ratios on POD 7 vs. POD-1. However the ratio returned toward control level in EN group by POD 12. In contrast, PN group still had elevated L/M ratios on POD 12. L/M ratio increases for a period of time after surgical trauma and the loss of gut mucosal integrity can be reversed by substitution of enteral nutrition.


Sodium and potassium fluxes and membrane potential of human neutrophils: evidence for an electrogenic sodium pump.
Sodium and potassium ion contents and fluxes of isolated resting human peripheral polymorphonuclear leukocytes were measured. In cells kept at 37 degrees C, [Na]i was 25 mM and [K]i was 120 mM; both ions were completely exchangeable with extracellular isotopes. One-way Na and K fluxes, measured with 22Na and 42K, were all approximately 0.9 meq/liter cell water . min. Ouabain had no effect on Na influx or K efflux, but inhibited 95 +/- 7% of Na efflux and 63% of K influx. Cells kept at 0 degree C gained sodium in exchange for potassium ([Na]i nearly tripled in 3 h); upon rewarming, ouabain-sensitive K influx into such cells was strongly enhanced. External K stimulated Na efflux (Km approximately 1.5 mM in 140-mM Na medium). The PNa/PK permeability ratio, estimated from ouabain insensitive fluxes, was 0.10. Valinomycin (1 microM) approximately doubled PK. Membrane potential (Vm) was estimated using the potentiometric indicator diS-C3(5); calibration was based on the assumption of constant-field behavior. External K, but not Cl, affected Vm. Ouabain caused a depolarization whose magnitude dependent on [Na]i. Sodium-depleted cells became hyperpolarized when exposed to the neutral exchange carrier monensin; this hyperpolarization was abolished by ouabain. We conclude that the sodium pump of human peripheral neutrophils is electrogenic, and that the size of the pump-induced hyperpolarization is consistent with the membrane conductance (3.7-4.0 microseconds/cm2) computed from the individual K and Na conductances.


Targeted genetic and viral therapy for advanced head and neck cancers.
Head and neck cancers usually present with advanced disease and novel therapies are urgently needed. Genetic therapy aims at restoring malfunctioned tumor suppressor gene(s) or introducing proapoptotic genes. Oncolytic virotherapeutics induce multiple cycles of cancer-specific virus replication, followed by oncolysis, virus spreading and infection of adjacent cancer cells. Oncolytic viruses can also be armed to express therapeutic transgene(s). Recent advances in preclinical and clinical studies are revealing the potential of both therapeutic classes for advanced head and neck cancers, including the approval of two products (Gendicine and H101) by a governmental agency. This review summarizes the available clinical data to date and discusses the challenges and future directions.


Inter-limb asymmetries are associated with decrements in physical performance in youth elite team sports athletes.
Actually, there is scarce literature looking for the relationship between inter-limb asymmetries and performance in youth elite team sports. The main purpose of this cross-sectional study was to examine the relationships between inter-limb asymmetries and physical performance in youth elite team-sports players. A secondary objective was to evaluate the presence of between-sexes differences in inter-limb asymmetries in elite youth team sports players. Eighty-one young elite team-sports athletes (age: u-14 to u-18) performed the star excursion balance test in the anterior direction (SEBT ANT), a single leg vertical countermovement jump test (SLCMJ), the one leg hop test for distance (OLHT), a 30 m sprint test, and the V-cut test. Inter-limb asymmetries were calculated for SEBT ANT, SLCMJ and OLHT. Pearson r was used to analyse the relationships between inter-limb asymmetries and physical performance. Results showed significant (p < 0.05) but small (r = 0.26) relationships between SLCMJ asymmetries and 30 m sprint time for the total group. Significant negative correlations with small to moderate magnitude of correlation were also found between SLCMJ asymmetries and SLCMJ performance on the lowest performing limb for the total group (p < 0.05; r = -0.26), males (p < 0.01; r = -0.48) and females (p < 0.05; r = -0.30). Moreover, significant negative correlations with moderate and large magnitude were also present between OLHT asymmetries and OLHT performance on the lowest performing limb for the total group (p < 0.01; r = -0.44), males (p < 0.01; r = -0.56) and females (p < 0.01; r = -0.64). No correlations were observed between asymmetries and either the V-cut test or SEBT ANT performance. No correlation were observed between SEBT ANT asymmetries and physical performance. In addition, when comparing asymmetry values between sexes there were no significant differences in vertical (p = 0.06) and horizontal (p = 0.61) jumping tests. However, there were significant differences in asymmetry between sexes in the ANT SEBT (p = 0.04). In conclusion, the current study indicated that jumping asymmetries were associated with decrements in sprint speed and jumping performance. Therefore, assessing inter-limb asymmetries would be recommended to improve training interventions for youth elite team-sports athletes.


Differential Virulence of Aggregatibacter actinomycetemcomitans Serotypes Explained by Exoproteome Heterogeneity.
Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative bacterial pathogen associated with periodontitis and nonoral diseases like rheumatoid arthritis and Alzheimer´s disease. Aa isolates with the serotypes a, b, and c are globally most prevalent. Importantly, isolates displaying these serotypes have different clinical presentations. While serotype b isolates are predominant in severe periodontitis, serotypes a and c are generally encountered in mild periodontitis or healthy individuals. It is currently unknown how these differences are reflected in the overall secretion of virulence factors. Therefore, this study was aimed at a comparative analysis of exoproteomes from different clinical Aa isolates with serotypes a, b, or c by mass spectrometry, and a subsequent correlation of the recorded exoproteome profiles with virulence. Overall, we identified 425 extracellular proteins. Significant differences in the exoproteome composition of isolates with different serotypes were observed in terms of protein identification and abundance. In particular, serotype a isolates presented more extracellular proteins than serotype b or c isolates. These differences are mirrored in their virulence in infection models based on human salivary gland epithelial cells and neutrophils. Remarkably, serotype a isolates displayed stronger adhesive capabilities and induced more lysis of epithelial cells and neutrophils than serotype b or c isolates. Conversely, serotype c isolates showed relatively low leukotoxicity, while provoking NETosis to similar extents as serotype a and b isolates. Altogether, we conclude that the differential virulence presentation by Aa isolates with the dominant serotypes a, b, or c can be explained by their exoproteome heterogeneity. IMPORTANCE Periodontitis is an inflammatory disease that causes progressive destruction of alveolar bone and supporting tissues around the teeth, ultimately resulting in tooth loss. The bacterium Aggregatibacter actinomycetemcomitans (Aa) is a prevalent causative agent of periodontitis, but this oral pathogen is also associated with serious extraoral diseases like rheumatoid arthritis and Alzheimer's disease. Clinical Aa isolates are usually distinguished by serotyping, because of known serotype-specific differences in virulence. Aa with serotype b is associated with aggressive forms of periodontitis, while isolates with serotypes a or c are usually encountered in cases of mild periodontitis or healthy individuals. The molecular basis for these differences in virulence was so far unknown. In the present study, we pinpoint serotype-specific differences in virulence factor production by clinical Aa isolates. We consider these findings important, because they provide new leads for future preventive or therapeutic approaches to fight periodontitis and associated morbidities.


Interaction of the maize and Arabidopsis kinase interaction domains with a subset of receptor-like protein kinases: implications for transmembrane signaling in plants.
The kinase interaction (KI) domain of kinase-associated protein phosphatase (KAPP) interacts with the phosphorylated form of an Arabidopsis thaliana receptor-like protein kinase (RLK). The KI domain may recruit KAPP into an RLK-initiated signaling complex. To examine additional roles that this domain may play in plant signal transduction, a search was conducted for other KI domain-containing proteins. One gene was isolated which encodes a KI domain, the maize homolog of KAPP. To test whether the maize KI domain associates with other maize proteins, it was used as a probe in a protein-protein interaction cloning strategy. A new maize RLK, KI domain interacting kinase 1 (KIK1), was identified by its interaction with the maize KI domain. The maize KI domain and the KIK1 kinase domain association required phosphorylation of the kinase. This work establishes that the KI domain phosphorylation-dependent signaling mechanism is present in both monocots and dicots. Additionally, it was determined that both the maize and Arabidopsis KI domains interact with several but not all of the active RLKs assayed. These multiple associations imply that KAPP may function in a number of RLK-initiated signaling pathways.


Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies.
Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV) in the delivery room is one of the least controlled interventions a preterm infant will likely face. Varying pressures and volumes administered shortly after birth are sufficient to trigger pathways of ventilation-induced lung and brain injury. The pathways involved in ventilation-induced brain injury include a complex inflammatory cascade and haemodynamic instability, both of which have an impact on the brain. However, regardless of the strategy employed to deliver IPPV, any ventilation has the potential to have an impact on the immature brain. This is particularly important given that preterm infants are already at a high risk for brain injury simply due to immaturity. This highlights the importance of improving the initial respiratory support in the delivery room. We review the mechanisms of ventilation-induced brain injury and discuss the need for, and the most likely, current therapeutic agents to protect the preterm brain. These include therapies already employed clinically, such as maternal glucocorticoid therapy and allopurinol, as well as other agents, such as erythropoietin, human amnion epithelial cells and melatonin, already showing promise in preclinical studies. Their mechanisms of action are discussed, highlighting their potential for use immediately after birth.


Where is all the research software? An analysis of software in UK academic repositories.
This research examines the prevalence of research software as independent records of output within UK academic institutional repositories (IRs). There has been a steep decline in numbers of research software submissions to the UK's Research Excellence Framework from 2008 to 2021, but there has been no investigation into whether and how the official academic IRs have affected the low return rates. In what we believe to be the first such census of its kind, we queried the 182 online repositories of 157 UK universities. Our findings show that the prevalence of software within UK Academic IRs is incredibly low. Fewer than 28% contain software as recognised academic output. Of greater concern, we found that over 63% of repositories do not currently record software as a type of research output and that several Universities appeared to have removed software as a defined type from default settings of their repository. We also explored potential correlations, such as being a member of the Russell group, but found no correlation between these metadata and prevalence of records of software. Finally, we discuss the implications of these findings with regards to the lack of recognition of software as a discrete research output in institutions, despite the opposite being mandated by funders, and we make recommendations for changes in policies and operating procedures.


Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse.
Defects in cilia are associated with several human disorders, including Kartagener syndrome, polycystic kidney disease, nephronophthisis and hydrocephalus. We proposed that the pleiotropic phenotype of Bardet-Biedl syndrome (BBS), which encompasses retinal degeneration, truncal obesity, renal and limb malformations and developmental delay, is due to dysfunction of basal bodies and cilia. Here we show that individuals with BBS have partial or complete anosmia. To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, we examined mice with deletions of Bbs1 or Bbs4. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement.


Sphincter preservation techniques during radical prostatectomies: Lessons learned.
Prolonged urinary incontinence represents one of the most severe complications after a radical prostatectomy procedure, significantly affecting patients' quality of life. In an attempt to ameliorate postprostatectomy continence rates, several sphincter preservation techniques have been reported. The purpose of this article is to report several different sphincter preservation techniques and identify the ones which affect postoperative outcomes the most. For our narrative review, PubMed was searched using the keywords "sphincter," "continence," "preservation," "techniques," and "prostatectomy." Other potentially eligible studies were identified using the reference lists of included studies. Sphincter preservation techniques can be summarized into bladder neck preservation, minimizing injury to the external urethral sphincter, and preserving the maximal length of the external sphincter and of the membranous urethra. Three anatomical structures must be recognized and protected in an attempt to maintain the sphincter complex: the bladder neck, the external urethral sphincter and the musculature of the membranous urethra. While there is strong evidence supporting the importance of bladder neck preservation, the role of maximal preservation of the external sphincter and of the intraprostatic part of the membranous urethra in improving continence rates has not yet been reported in a statistically significant manner by high-quality studies.


Food allergy knowledge, attitudes, and beliefs of parents with food-allergic children in the United States.
Parents of food-allergic children are responsible for risk assessment and management of their child's condition. Such practices are likely informed by parental knowledge, attitudes, and beliefs of food allergy. Our objective was to characterize food allergy knowledge and perceptions among parents with food-allergic children. Parents were recruited nationally between January 2008 and 2009 to complete the validated, web-based Chicago Food Allergy Research Survey for Parents of Children with Food Allergy. Findings were analyzed to provide composite/itemized knowledge scores, describe attitudes and beliefs, and examine the effects of participant characteristics on response. A sample of 2945 parents was obtained. Participants had an average knowledge score of 75% correct (range 19-100%). Strengths were observed in each content domain; e.g., 95% of participants accurately identified the signs of a milk-induced reaction. Weaknesses were limited to items assessing food allergy triggers/environmental risks and perceptions of susceptibility/prevalence; e.g., 52% of parents incorrectly believed young children are at higher risk for fatal anaphylaxis than adolescents. Parental attitudes/beliefs were diverse, although 85% agreed children should carry an EpiPen at school and 91% felt schools should have staff trained in food allergy. One in four parents reported food allergy caused a strain on their marriage/relationship, and 40% reported experiencing hostility from other parents when trying to accommodate their child's food allergy. In conclusion, parents in our study exhibited solid baseline knowledge although several important misconceptions were identified. While a broad spectrum of parental perceptions was observed, a large proportion of parents reported that their child's food allergy had an adverse impact on personal relationships and also agreed on certain policies to address food allergy in schools.


Patent review.
The section on patent review will be focused in the areas of interest to the readers of CCHTS. The search was conducted using the following key words: combinatorial chemistry, high throughput screening, drug repurposing, chemical library, high content screening, drug discovery and natural products. All patents highlighted here are identified by the patent number issued either by the World Intellectual Property Organization or by a regional patent office.


Molecular characterization of an H1N2 swine influenza virus isolated in Miyazaki, Japan, in 2006.
Swine influenza virus (SIV) was isolated from a farm in Miyazaki Prefecture in Japan in July 2006. An isolate was genetically subtyped as H1N2 and was designated A/swine/Miyazaki/1/2006 (H1N2). The nucleotide sequences of all eight viral RNA segments were determined, and then phylogenetic analysis was performed using the neighbor-joining method. All segments were shown to be closely related to those of Japanese SIV H1N2 isolates, which have been circulating since the 1980s. The results indicate the persistence of the SIV H1N2 subtype in the Japanese pig population for more than two decades and emphasize the importance of continuous surveillance for SIV.


Recombination in adenovirus. I. Analysis of recombinant viruses under non-selective conditions.
A method is described, based on an approach previously employed for the mapping of adenovirus ts mutants (Grodzicker et al. 1975), for the identification of recombinant viruses in the progeny of mixed infections of human HeLa cells with wild-type adenovirus types 2 and 5 under non-selective conditions. Differences in restriction enzyme sites for the endonuclease HpaI could be used to detect new recombinant DNA fragments in a yield of 3 to 6% after single mixed infections and yields up to 25% following three successive mixed infections. The recombinant nature of the new fragments was proved by the clonal isolation of recombinant viruses in similar yields. Analysis of one cloned recombinant pointed to the occurrence of multiple crossover events at different sites along the virus chromosome. The results are discussed in terms of a biochemical approach towards the study of the mechanism of general genetic recombination in human cells as well as with respect to the evolution of adenoviruses.


Development and maturation of the occupational health services research field in the United States over the past 25 years: Challenges and opportunities for the future.
Work is an important social determinant of health; unfortunately, work-related injuries remain prevalent, can have devastating impact on worker health, and can impose heavy economic burdens on workers and society. Occupational health services research (OHSR) underpins occupational health services policy and practice, focusing on health determinants, health services, healthcare delivery, and health systems affecting workers. The field of OHSR has undergone tremendous expansion in both definition and scope over the past 25 years. In this commentary, focusing on the US, we document the historical development and evolution of OHSR as a research field, describe current doctoral-level OHSR training, and discuss challenges and opportunities for the OHSR field. We also propose an updated definition for the OHSR field: Research and evaluation related to the determinants of worker health and well-being; to occupational injury and illness prevention and surveillance; to healthcare, health programs, and health policy affecting workers; and to the organization, access, quality, outcomes, and costs of occupational health services and related health systems. Researchers trained in OHSR are essential contributors to improvements in healthcare, health systems, and policy and programs to improve worker health and productivity, as well as equity and justice in job and employment conditions. We look forward to the continued growth of OHSR as a field and to the expansion of OHSR academic training opportunities.


Intestinal phospholipase A and triglyceride lipase: localization and effect of fasting.
We investigated the distribution of phospholipase A and triglyceride lipase in the rat small intestine and the effects of heparin and hormones on enzyme release. Phospholipase A activity was 10 times higher in the ileum than in the jejunum; triglyceride lipase activity was threefold higher in the jejunum than in the ileum. Activities of both enzymes were much greater in villus than in crypt cells. The specific activity of phospholipase A was highest in microsomes and least in cytosol. The crude nuclei and brush-border fraction contained 40.5% of total phospholipase A activity; mitochondria contained 33.8%; and microsomes, 17.4%. Phospholipase A activity increased significantly in the distal intestinal mucosa in fasted rats compared with controls. Heparin did not increase the release of phospholipase A by isolated intestinal cells or perfused intestinal vasculature. Thus, the small intestine probably does not contribute significantly to the phospholipase A activity of postheparin plasma. Hormones and cAMP, which inhibit the secretion of phospholipase A and triglyceride lipase from isolated hepatocytes, had no effect on the release of either enzyme from intestinal cells.


Transformer with convolution and graph-node co-embedding: An accurate and interpretable vision backbone for predicting gene expressions from local histopathological image.
Inferring gene expressions from histopathological images has long been a fascinating yet challenging task, primarily due to the substantial disparities between the two modality. Existing strategies using local or global features of histological images are suffering model complexity, GPU consumption, low interpretability, insufficient encoding of local features, and over-smooth prediction of gene expressions among neighboring sites. In this paper, we develop TCGN (Transformer with Convolution and Graph-Node co-embedding method) for gene expression estimation from H&E-stained pathological slide images. TCGN comprises a combination of convolutional layers, transformer encoders, and graph neural networks, and is the first to integrate these blocks in a general and interpretable computer vision backbone. Notably, TCGN uniquely operates with just a single spot image as input for histopathological image analysis, simplifying the process while maintaining interpretability. We validate TCGN on three publicly available spatial transcriptomic datasets. TCGN consistently exhibited the best performance (with median PCC 0.232). TCGN offers superior accuracy while keeping parameters to a minimum (just 86.241 million), and it consumes minimal memory, allowing it to run smoothly even on personal computers. Moreover, TCGN can be extended to handle bulk RNA-seq data while providing the interpretability. Enhancing the accuracy of omics information prediction from pathological images not only establishes a connection between genotype and phenotype, enabling the prediction of costly-to-measure biomarkers from affordable histopathological images, but also lays the groundwork for future multi-modal data modeling. Our results confirm that TCGN is a powerful tool for inferring gene expressions from histopathological images in precision health applications.


Natural history of de novo high grade glioma: first description of growth parabola.
Etiopathogenesis and physiopathology of gliomas are largely unknown. Recently, many authors have proved a strict correlation between the velocity of diametric expansion (VDE) on the magnetic resonance imaging (MRI) and the biological behavior of these tumors, especially in low grade gliomas (LGGs). Unfortunately, natural history of High Grade Gliomas (HGGs) has not been well clarified because of its fast progression, late diagnoses and early surgical intervention. We describe, for the first time to our knowledge, the case of asymptomatic patient with an incidentally discovered de novo HGG with a total of 17 months of follow-up. A male patient was referred to our consultation for routinely follow-up after meningioma resection 5 years before. He underwent MRI every year without any neuroradiological alterations. A new MRI image presented a non-enhancing lesion in the right temporal lobe with 3.55 cm of mean tumor diameter (MTD) and 35.6 mm/year of VDE. After two months interval, the lesion had 3.97 cm of MTD and 27.8 mm/year of VDE. Although we have strongly suggested surgical resection, patient have delayed the operation for personal issues. After other 3 months, the tumor showed enhancement with 4.5 of MTD and 17.4 mm/year of VDE. We speculate that the descending parabola is due to initial mass effect and hypoxia of the tumor core. We also underline the crucial role of the VDE determining, in order to predict the nature of the lesion and address the most effective treatment for each patient.


Hepatocyte growth factor regulates E box-dependent plasminogen activator inhibitor type 1 gene expression in HepG2 liver cells.
We sought to determine the etiologic mechanism of pleiotropic growth factor, hepatocyte growth factor (HGF), as a regulator of hepatic synthesis of plasminogen activator inhibitor (PAI)-1, the physiological inhibitor of fibrinolysis and a potential inducer of atherothrombosis. HGF increased PAI-1 mRNA expression and PAI-1 protein accumulation in the conditioned media of human liver-derived HepG2 cells, and increased hepatic PAI-1 mRNA expression in vivo in mice. HGF-inducible PAI-1 mRNA was attenuated by U0126, a specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, and genistein, an inhibitor of tyrosine kinase. HGF increased the human PAI-1 promoter (-829 to +36 bp) activity, and deletion and mutation analysis uncovered a functional E box (5'-CACATG-3') at positions -158 to -153 bp. Electrophoretic mobility shift assays demonstrated that this E box binds upstream stimulatory factors (USFs). HGF phosphorylated USFs through MAPK and tyrosine kinase pathways. Co-transfection of USF1 expression vector increased PAI-1 promoter activity. Sterol regulatory element-binding protein-1 attenuated HGF-inducible PAI-1 promoter activity. Because USFs are involved in the regulation of carbohydrates and lipid metabolism, HGF-mediated PAI-1 production may provide a novel link between atherothrombosis and metabolic derangements. Targeting HGF signaling pathway may modulate the thrombotic risk in high-risk patients.


Outcomes of Conservative Management of Acute Appendicitis during COVID-19 Pandemic.
To measure the outcomes of conservative treatment of acute appendicitis. Observational study. Fauji Foundation Hospital, Rawalpindi from April to July 2020. All 58 patients (n=58) presenting with acute appendicitis (AA) were included. Assessment was done with Alvarado score (AS) and ultrasound. Treatment was initiated according to the algorithm corresponding with AS. Those with AS score of 4 or less were started on outpatient oral antibiotics. Patients with AS score of 5 or more were admitted for IV antibiotics. If the symptoms and signs resolved, they were sent home on oral antibiotics to complete a course of 5 days. If their condition did not improve in 72 hours or deteriorated at any time, appendectomy was done. Outcomes were recorded and analysed on SPSS. Out of 58 patients, 16 were treated with oral, while 42 with IV antibiotics. This yielded a statistically significant difference on the course of disease (p=0.028). Resolution of symptoms was seen in 27.6% (n=16) with conservative management; whereas, 72.4% (n=42) patients needed a subsequent appendectomy. The difference in operative findings between patients, who had been given oral or IV antibiotics was statistically insignificant (p=0.536). Diagnostic value of leukocyte count (TLC), ultrasound and AS was not found to be significant. Non-operative management is successful in about a quarter of the patients of AA. There is very limited value of sonography, laboratory parameters, or AS in confirming the diagnosis of AA. Key Words: Appendicitis, Conservative treatmen, COVID-19.


One-component self-etching primer: a seventh generation of orthodontic bonding system?
The purpose of this study was to compare the bond strengths and to evaluate the debonding site using the adhesive remnant index (ARI) provided by a conventional acid-etch conditioner and a new self-etching adhesive system, Xeno IV (Dentsply Caulk). One hundred and eighty bovine lower incisors were randomly divided into six groups (n = 30). In groups 1, 2, and 3, Transbond XT (3M Unitek) composite was used to bond the brackets to enamel samples conditioned with 37 per cent phosphoric acid + XT primer (3M Unitek), Xeno IV + XT primer, or Xeno IV only, respectively. In groups 4, 5, and 6, the bonding procedures were performed using Fuji Ortho LC (GC Corp.) resin-modified glass ionomer cement unconditioned, enamel conditioned with 37 per cent phosphoric acid, or Xeno IV, respectively. All samples underwent thermocycling and then shear bond strength (SBS) testing was performed using a universal testing machine (Emic DL 10.000). Analysis of variance was applied. For the post hoc test, the Tukey's test was used. Kruskal-Wallis and Mann-Whitney U-tests were used to assess ARI scores. The results demonstrated no statistical differences between groups 1, 2, and 3. However, statistically significant differences were found between these samples and groups 4, 5, and 6. With regard to ARI score, the highest mean value was found in group 5 (Fuji Ortho LC + 37 per cent acid conditioning), whereas group 4 (Fuji Ortho LC + no conditioning) had the lowest SBS. Xeno IV self-etching bonding agent was able to bond orthodontic brackets in association with Transbond XT composite as well as with Fuji Ortho LC, thus maximizing bracket bonding.


S100A14 interacts with S100A16 and regulates its expression in human cancer cells.
Both S100A14 and S100A16 are members of the multifunctional S100 protein family. Formation of homo/heterodimers is considered to be one of the major mechanisms for S100 proteins to execute their diverse cellular functions. By employing a classical Yeast two hybrid (Y-2 H) screen, we identified S100A16 as the single interaction partner of S100A14. This interaction was verified by co-immunoprecipitation, double indirect immunofluorescence and double immunostaining in specimens of oral squamous cell carcinoma and normal oral mucosa. The functional significance of this interaction was examined by employing retroviral mediated over-expression and knock-down of these proteins in several cancer cell-lines. Over-expression and knock-down of S100A14 led to concomitant up- and down-regulation of S100A16 protein in the cell-lines examined. However, there was no up-regulation of S100A16 mRNA upon S100A14 over-expression, indicating that modulation of S100A16 expression was not due to enhanced transcriptional activity but possibly by post-transcriptional regulation. In contrary, over-expression of S100A16 was associated neither with the up-regulation of S100A14 mRNA nor its protein, suggesting a unidirectional regulation between S100A14 and S100A16. Cellular treatment with protein synthesis inhibitor cycloheximide demonstrated a time-dependent intracellular degradation of both S100A16 and S100A14 proteins. Additionally, regulation of S100A16 and S100A14 degradation was found to be independent of the classical proteasomal and lysosomal pathways of protein degradation. Further studies will therefore be necessary to understand the functional significance of this interaction and the mechanisms on how S100A14 is involved in the regulation of S100A16 expression.


Fine mapping of qPAA8, a gene controlling panicle apical development in rice.
In rice, one detrimental factor influencing single panicle yield is the frequent occurrence of panicle apical abortion (PAA) under unfavorable climatic conditions. Until now, no detailed genetic information has been available to avoid PAA in rice breeding. Here, we show that the occurrence of PAA is associated with the accumulation of excess hydrogen peroxide. Quantitative trait loci (QTLs) mapping for PAA in an F(2) population derived from the cross of L-05261 (PAA line) × IRAT129 (non-PAA variety) identified seven QTLs over a logarithm of the odd (LOD) threshold of 2.5, explaining approximately 50.1% of phenotypic variance for PAA in total. Five of the QTLs with an increased effect from L-05261, were designated as qPAA3-1, qPAA3-2, qPAA4, qPAA5 and qPAA8, and accounted for 6.8%, 5.9%, 4.2%, 13.0% and 12.2% of phenotypic variance, respectively. We found that the PAA in the early heading plants was mainly controlled by qPAA8. Subsequently, using the sub-populations specific for qPAA8 based on marker-assisted selection, we further narrowed qPAA8 to a 37.6-kb interval delimited by markers RM22475 and 8-In112. These results are beneficial for PAA gene clone.


Inhibitory Effect of Garlic, Purple Onion, and White Onion on Key Enzymes Linked with Type 2 Diabetes and Hypertension.
Spices are used in soup preparation in many homes and serve as ingredients in the preparation of several traditional delicacies endowed with natural antioxidants such as polyphenols. The aim of this study is to evaluate the effect of aqueous extract of garlic, white onion, and purple onion on angiotensin-converting enzyme, α-amylase, and α-glucosidase activity in vitro and determine their antioxidant properties via various antioxidant assays such as OH*, Fe2+ chelation, and 2, 2'-azino-bis 3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical-scavenging assays. The results reveal that aqueous extract of garlic, purple onion, and white onion inhibited angiotensin-converting enzyme, α-amylase, and α-glucosidase in a concentration-dependent manner (0-4 mg/ml). However, purple onion (IC50 = 0.59 mg/ml) had higher inhibitory effect on angiotensin-converting enzyme than white onion (IC50 = 0.66 mg/ml) and purple onion (IC50 = 0.96 mg/ml). Furthermore, white onion had significantly (p < .05) stronger inhibitory effect on α-amylase (IC50 = 3.93 mg/mL) than garlic (IC50 = 8.19 mg/ml) and purple onion (IC50 = 8.27 mg/ml). Conversely, garlic (IC50 = 4.50 mg/ml) had no significantly higher inhibitory effect on α-glucosidase activity than white onion and purple onion. In addition, the aqueous extracts were able to scavenge 2,2- diphenyl-1-picrylhydrazyl (DPPH*) free radical and reduce Fe3+ to Fe2+ in a dose-dependent manner. Therefore, a possible mechanism by which garlic, white onion, and purple onion exert antidiabetes and antihypertensive properties could be through the inhibitory effect on ACE, α-amylase, and α-glucosidase coupled with their ability to prevent lipid peroxidation in the pancreas and heart, which justify their strong antioxidant properties.


Tuning path tracking controllers for autonomous cars using reinforcement learning.
This article proposes an adaptable path tracking control system, based on reinforcement learning (RL), for autonomous cars. A four-parameter controller shapes the behaviour of the vehicle to navigate lane changes and roundabouts. The tuning of the tracker uses an 'educated' Q-Learning algorithm to minimize the lateral and steering trajectory errors, this being a key contribution of this article. The CARLA (CAR Learning to Act) simulator was used both for training and testing. The results show the vehicle is able to adapt its behaviour to the different types of reference trajectories, navigating safely with low tracking errors. The use of a robot operating system (ROS) bridge between CARLA and the tracker (i) results in a realistic system, and (ii) simplifies the replacement of CARLA by a real vehicle, as in a hardware-in-the-loop system. Another contribution of this article is the framework for the dependability of the overall architecture based on stability results of non-smooth systems, presented at the end of this article.


Salmonella Typhimurium gastroenteritis leading to chronic prosthetic vascular graft infection.
Introduction. It is estimated up to 6 % of prosthetic vascular grafts become infected. Staphylococcus aureus is predominant in early infection and coagulase-negative staphylococci are predominant in late infections. Enterobacteriaceae cause 14-40 % of prosthetic vascular graft infections. This is, to our knowledge the first reported case of Salmonella gastroenteritis causing chronic prosthetic vascular graft infection (PVGI). Case presentation. A 57 years old lady presented with signs and symptoms of prosthetic vascular graft infection. Three years earlier, she had undergone a prosthetic axillo-femoral bypass graft for critical limb ischaemia. The infected prosthetic vascular graft was removed and Salmonella Typhimurium was isolated on culture. In the intervening period, Salmonella Typhimurium was isolated from a faecal specimen, collected during an episode of acute gastroenteritis. Whole-genome sequencing (WGS) showed that the respective Salmonella Typhimurium isolates differed by only a single nucleotide polymorphism (SNP). Salmonella Typhimurium was not isolated on culture of a faecal specimen collected five days following cessation of antimicrobial therapy. Six months after removal of the prosthetic graft, the patient remains under follow-up for her peripheral vascular disease, which currently requires no further surgical intervention. Conclusion. This case has clear implications for the management of chronic PVGI. It is vital to collect high-quality surgical specimens for microbiological analysis and empirical choices of antibiotics are unlikely to cover all potential pathogens. It may also be prudent to enquire about a history of acute gastroenteritis when assessing patients presenting with chronic PVGI.


Sympathetic innervation of human tracheal and bronchial smooth muscle.
We have assessed functional and structural evidence for sympathetic innervation of human tracheal and bronchial smooth muscles. In the bronchus, functional evidence for such innervation was shown by the following results: a leftward shift in the noradrenaline inhibitory dose-response curve by the neuronal uptake blocker imipramine; the inhibition of uptake of 3H-L-noradrenaline by the neuronal uptake blockers imipramine, cocaine and phenoxybenzamine; and the induced release of noradrenaline and its metabolites by tyramine and electrical field stimulation using nerve-specific parameters; and selective inhibition of field-stimulated contractions by isoprenaline. Structural evidence was shown by the presence of small dense-cored vesicles containing nerve varicosities, occasionally in close proximity to morphologically characteristic cholinergic nerve-endings. This suggests the possibility of presynaptic modulation of acetylcholine release by noradrenaline.


Counting RNA pseudoknotted structures.
In 2004, Condon and coauthors gave a hierarchical classification of exact RNA structure prediction algorithms according to the generality of structure classes that they handle. We complete this classification by adding two recent prediction algorithms. More importantly, we precisely quantify the hierarchy by giving closed or asymptotic formulas for the theoretical number of structures of given size n in all the classes but one. This allows us to assess the tradeoff between the expressiveness and the computational complexity of RNA structure prediction algorithms.


Effects of ouabain, amiloride, monensin, and other agents on ovine parotid secretion.
Secretion by the parotid gland of Na-replete and -depleted sheep was investigated by examining the effects of modifiers of ionic transfer on salivary composition and flow rate. These agents were infused into the arterial blood supply of the vascularly isolated gland in anesthetized sheep. Ouabain inhibited Na+-K+ exchange in the ducts caused by Na depletion and restored the [Na+], [K+], and osmolality to close to those of Na-replete saliva. Ouabain also inhibited Cl- -HCO3- exchange in the ducts in Na repletion and depletion. Amiloride partially inhibited Na+-K+ exchange in Na depletion without affecting Cl- -HCO3- exchange. Monensin potentiated Na+-K+ exchange in Na repletion and depletion. Amiloride and monensin gained access to the saliva, but furosemide and ethacrynic acid were almost totally excluded, and, up to 10(-3) M in blood, they did not affect salivary composition or flow rate. Methazolamide gained free access to saliva but was without effect. 4-Acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid at 10(-3) M slightly increased salivary [Na+] and [HPO4(2-)]. The results indicate potent effects of ouabain on basolateral Na+-K+ pumps and of amiloride and monensin on transcellular delivery of Na+ to these pumps, but ouabain had no effect on salivary flow rate until O2 consumption approached zero and secretion failed. The findings do not support a proposal that the salivary secretion depends on a Cl- -dependent furosemide-sensitive system energized by Na+-K+-ATPase-dependent Na pumps.


Molecular, anatomical, and functional organization of the Drosophila olfactory system.
Olfactory receptor neurons (ORNs) convey chemical information into the brain, producing internal representations of odors detected in the periphery. A comprehensive understanding of the molecular and neural mechanisms of odor detection and processing requires complete maps of odorant receptor (Or) expression and ORN connectivity, preferably at single-cell resolution. We have constructed near-complete maps of Or expression and ORN targeting in the Drosophila olfactory system. These maps confirm the general validity of the "one neuron--one receptor" and "one glomerulus--one receptor" principles and reveal several additional features of olfactory organization. ORNs in distinct sensilla types project to distinct regions of the antennal lobe, but neighbor relations are not preserved. ORNs grouped in the same sensilla do not express similar receptors, but similar receptors tend to map to closely appositioned glomeruli in the antennal lobe. This organization may serve to ensure that odor representations are dispersed in the periphery but clustered centrally. Integrated with electrophysiological data, these maps also predict glomerular representations of specific odorants. Representations of aliphatic and aromatic compounds are spatially segregated, with those of aliphatic compounds arranged topographically according to carbon chain length. These Or expression and ORN connectivity maps provide further insight into the molecular, anatomical, and functional organization of the Drosophila olfactory system. Our maps also provide an essential resource for investigating how internal odor representations are generated and how they are further processed and transmitted to higher brain centers.


Couple Simulation: A Novel Approach for Evaluating Models of Human Mate Choice.
Choosing a mate is perhaps the most important decision a sexually reproducing organism makes in its lifetime. And yet, psychologists lack a precise description of human mate choice, despite sustained attention from several theoretical perspectives. Here, I argue this limited progress owes to the complexity of mate choice and describe a new modeling approach, called "couple simulation," designed to compare models of mate choice by challenging them to reproduce real couples within simulated mating markets. I present proof-of-concept simulations that demonstrate couple simulation can identify a population's true model of mate choice. Furthermore, I apply couple simulation to two samples of real couples and find that the method (a) successfully reconstructs real-world couples, (b) discriminates between models of mate choice, and (c) predicts a wide range of dimensions of relationship quality. Collectively, these results provide evidence that couple simulation offers a framework useful for evaluating theories of human mate choice.


[Ontogenetic peculiarities of hemostasis in newborn children].
A total of 25 newborns (15 full-term and 10 preterm babies) were examined. The coagulative and summary lytic blood activity with regard for the aggregategram and hemocoagulagram findings was studied. The following was established: the neonatal period of healthy babies is characterized by changing stages in the hemostasis system, i.e. hypocoagulation is followed by the normalized coagulation fibrinolytic activity. Preterm babies have more pronounced changes and become normal later.


Effects of L-arginine on vascular smooth muscle cell proliferation and apoptosis after balloon injury.
Nitric oxide (NO) inhibits neointimal formation in experimental models of restenosis, but the mechanisms have not been fully elucidated. This study examined whether the beneficial effect of L-arginine, the physiological NO precursor, was associated with alteration of the apoptotic and proliferative activities of vascular smooth muscle cells (VSMCs) in the vessel wall after arterial injury. Balloon injury was performed in the rat carotid-artery injury model. Rats were treated with L-arginine (2.25% in the drinking water) or normal drinking water, and sacrificed at 1, 2 and 14 days postinjury. Apoptosis was assessed by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL), and proliferation by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Treatment with L-arginine increased the luminal area at 14 days postinjury (0.26 +/- 0.03 mm2 vs 0.14 +/- 0.04 mm2; p < 0.05), and this effect was attributable to a reduction in neointimal formation (0.11 +/- 0.03 mm2 vs 0.23 +/- 0.04 mm2; p < 0.05), while L-arginine did not affect vascular remodeling, as indicated by the total vessel area. The decreased neointimal area at 14 days after balloon injury contained a reduced percentage of TUNEL positive (0.1 +/- 0.1% vs 2.0 +/- 0.6%; p < 0.05), and PCNA positive (13.0 +/- 2.6% vs 27.2 +/- 5.9%; p < 0.05) nuclei, respectively. L-arginine did not influence the apoptotic or proliferative activities of VSMCs at earlier time points postinjury. The favourable effect of L-arginine in the rat model of arterial injury is associated with inhibition of VSMC proliferative activity in the vessel wall and is not explained by increased VSMC apoptosis.