Modeling and performance analysis using extended fuzzy-timing Petri nets for networked virtual environments.
Despite their attractive properties, networked virtual environments (net-VEs) are notoriously difficult to design, implement, and test due to the concurrency, real-time and networking features in these systems. Net-VEs demand high quality-of-service (QoS) requirements on the network to maintain natural and real-time interactions among users. The current practice for net-VE design is basically trial and error, empirical, and totally lacks formal methods. This paper proposes to apply a Petri net formal modeling technique to a net-VE-NICE (narrative immersive constructionist/collaborative environment), predict the net-VE performance based on simulation, and improve the net-VE performance. NICE is essentially a network of collaborative virtual reality systems called the CAVE-(CAVE automatic virtual environment). First, we introduce extended fuzzy-timing Petri net (EFTN) modeling and analysis techniques. Then, we present EFTN models of the CAVE, NICE, and transport layer protocol used in NICE: transmission control protocol (TCP). We show the possibility analysis based on the EFTN model for the CAVE. Then, by using these models and design/CPN as the simulation tool, we conducted various simulations to study real-time behavior, network effects and performance (latencies and jitters) of NICE. Our simulation results are consistent with experimental data.


Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial.
Thioredoxin Interacting Protein (TXNIP) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes. We hypothesize that baseline DNAm level at TXNIP in blood may be associated with glycemic traits and their changes in response to weight-loss diet interventions. We included 639 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss diet intervention. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm level of TXNIP as the average methylation level over CpGs within 500 bp of cg19693031. Generalized linear regression models were used for main analyses. We found that higher regional DNAm at TXNIP was significantly correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (P < 0.05 for all). Significant interactions were observed between dietary protein intake and DNAm on changes in insulin (P-interaction = 0.007) and HOMA-IR (P-interaction = 0.009) at 6 months. In participants with the highest tertile of regional DNAm at TXNIP, average protein (15%) intake was associated with a greater reduction in insulin (β: -0.14; 95% CI: -0.24, -0.03; P = 0.011) and HOMA-IR (β: -0.15; 95% CI: -0.26, -0.03; P = 0.014) than high protein (25%) intake, whereas no significant associations were found in those with the lower tertiles (P > 0.05). The interaction was attenuated to be non-significant at 2 years, presumably related to decreasing adherence to the diet intervention. Our data indicate that higher regional DNAm level at TXNIP was significantly associated with better fasting glucose, HbA1c, and HOMA-IR; and people with higher regional DNAm levels benefited more in insulin and HOMA-IR improvement by taking the average-protein weight-loss diet.


Phase II study of docetaxel in patients with pancreatic cancer previously untreated with cytotoxic chemotherapy.
In this study, we estimated the response rate, duration of response, and type, severity and reversibility of toxicities in patients with Stage IV adenocarcinoma of the pancreas treated with docetaxel. Twenty-one patients with locally advanced or metastatic pancreatic cancer, previously untreated or treated with surgery or radiation alone, were treated with 100 mg/m2 docetaxel as a 1 hr infusion once every 21 days. All the patients were pretreated with dexamethasone and diphenhydramine. Twenty patients were assessable for both response and toxicity. One patient was assessable for toxicity alone. However, all the patients were assessed for survival. The major side effect of the drug was neutropenia, which required a dose reduction to 75 mg/m2 in approximately half of the patients. Nine patients were hospitalized with neutropenic fever. Fluid retention was not a significant problem. One patient had a partial response lasting for 21 weeks and 7 patients had stable disease. The remaining patients had progressive disease. The median survival for all the patients was 5.9 months. Docetaxel as a single agent showed limited activity against adenocarcinoma of the pancreas. Since the completion of this study, molecular predictors of in vitro response to docetaxel have been described. Confirmation of the clinical relevance of such predictors in humans could allow for the identification of a subgroup of patients with a higher rate of response to docetaxel.


Herbal administration and interaction of cancer treatment.
The widespread impact of cancer worldwide and noncurative treatment methods despite all developments drive patients towards investigating and using nonconventional treatment methods. Herbs, which have an important role in complementary and alternative medicine practices, may cause unfavorable results when used especially with chemotherapeutics in cancer patients due to the substances they contain and due to the properties of some, which still cannot be clarified. Further overshadowing the success of the treatments, patients do not talk about these issues with their doctors and physicians are unable to comprehend these properties of herbs. In this compilation we aimed to clarify the concepts of complementary and alternative medicine, to gather the properties of important and frequently used herbs, and to increase the awareness of physicians on this subject.


Challenges in treating Pompe disease: an industry perspective.
Pompe disease is a rare inherited metabolic disorder of defective lysosomal glycogen catabolism due to a deficiency in acid alpha-glucosidase (GAA). Alglucosidase alfa enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA ERT) is the only approved treatment for Pompe disease. Alglucosidase alfa has provided irrefutable clinical benefits, but has not been an optimal treatment primarily due to poor drug targeting of ERT to skeletal muscles. Several critical factors contribute to this inefficiency. Some are inherent to the anatomy of the body that cannot be altered, while others may be addressed with better drug design and engineering. The knowledge gained from alglucosidase alfa ERT over the past 2 decades has allowed us to better understand the challenges that hinder its effectiveness. In this review, we detail the problems which must be overcome for improving drug targeting and clinical efficacy. These same issues may also impact therapeutic enzymes derived from gene therapies, and thus, have important implications for the development of next generation therapies for Pompe.


The Potential Inhibitory Effects of miR-19b on Ocular Inflammation are Mediated Upstream of the JAK/STAT Pathway in a Murine Model of Allergic Conjunctivitis.
Thymic stromal lymphopoietin (TSLP) is a pro-allergic cytokine that initiates allergic inflammatory reaction between epithelial and dendritic cells (DCs). miR-19b was reported to suppress TSLP expression. The present study aimed to examine miR-19b expression, regulation, and function in allergic conjunctivitis (AC). A murine model of experimental AC was induced in BALB/c mice by short ragweed pollen. The serum, eye balls, conjunctiva, and cervical lymph nodes (CLN) were used for the study. Gene expression was determined by RT-PCR, whereas protein production and activation were evaluated by immunostaining, ELISA, and Western blotting. In the murine AC model, miR-19b was aberrantly downregulated, whereas the levels of TSLP and p-STAT3, as well as the number of CD11c+ pSTAT3+ DCs were increased. Moreover, Th2 inflammatory cytokine expression was significantly increased. These severe phenotypes could be counteracted by either applying exogenous miR-19b mimic microRNAs or the JAK/STAT inhibitor CYT387. Moreover, overexpression of miR-19b repressed p-STAT3 expression and the number of CD11c+ cells in AC eye and CLN tissues. These findings suggested that miR-19b reduced ocular surface inflammation by inhibiting Stat3 signaling via TSLP downregulation in a murine AC model. Moreover, the present study further demonstrated the clinical potential of applying miR-19b and anti-JAK/STAT therapies in the treatment of AC.


Contribution of atmospheric dry deposition to stormwater loads for PAHs and trace metals in a small and highly trafficked urban road catchment.
A deep understanding of pollutant buildup and wash-off is essential for accurate urban stormwater quality modeling and for the development of stormwater management practices, knowing the potential adverse impacts of runoff pollution on receiving waters. In the context of quantifying the contribution of airborne pollutants to the contamination of stormwater runoff and assessing the need of developing an integrated AIR-WATER modeling chain, loads of polycyclic aromatic hydrocarbons (PAHs) and metal trace elements (MTEs) are calculated in atmospheric dry deposits, stormwater runoff, and surface dust stock within a small yet highly trafficked urban road catchment (~ 30,000 vehicles per day) near Paris. Despite the important traffic load and according to the current definition of "atmospheric" source, atmospheric deposition did not account for more than 10% of the PAHs and trace metal loads in stormwater samples for the majority of the events, based on the ratio of deposition to stormwater. This result shows that atmospheric deposition is not a major source of pollutants in stormwater, and thus, linking the air and water compartment in a modeling chain to have more accurate estimates of pollutant loads in stormwater runoff might not be relevant. Comparison of road dust with water samples demonstrates that only the fine fraction of the available stock is eroded during a rainfall event. Even if the atmosphere mostly generates fine particles, the existence of other sources of fine particles to stormwater runoff is highlighted.


[Morphological changes in a chemostat culture of Candida utilis undergoing cyclic changes of pH and pO2].
The effect of cyclic pH and pO2 changes on the morphology of Candida utilis was studied with time intervals measured in minutes. The pH was varied from 4.5 to 2.6, the pO2 from 70% of the saturation to 0%. The morphology was studied both visually and using the technique of optical-structural computer analysis. The regime with pH changes increased the biomass yield. However, the averaged morphological characteristics showed that the growth was slightly inhibited. Therefore, the yeast population was very heterogeneous, some cells were inhibited while other cells were stimulated, which made the economic coefficient rise. The cells were also inhibited when they were exposed in the conditions of oxygen deficiency for a short period of time. However, the cells could not be inhibited if, at the same time, the pH was extremely low. Changes in the morphology were detected earlier than either the inhibition or stimulation of growth was recorded by measuring the weight of biomass.


Analysis of Pathogenic Variants Correctable With CRISPR Base Editing Among Patients With Recessive Inherited Retinal Degeneration.
Many common inherited retinal diseases are not easily treated with gene therapy. Gene editing with base editors may allow the targeted repair of single-nucleotide transition variants in DNA and RNA. It is unknown how many patients have pathogenic variants that are correctable with a base editing strategy. To assess the prevalence and spectrum of pathogenic single-nucleotide variants amenable to base editing in common large recessively inherited genes that are associated with inherited retinal degeneration. In this retrospective cross-sectional study, nonidentifiable records of patients with biallelic pathogenic variants of genes associated with inherited retinal degeneration between July 2013 and December 2019 were analyzed using data from the Oxford University Hospitals Medical Genetics Laboratories, the Leiden Open Variation Database, and previously published studies. Six candidate genes (ABCA4, CDH23, CEP290, EYS, MYO7A, and USH2A), which were determined to be the most common recessive genes with coding sequences not deliverable in a single adeno-associated viral vector, were examined. Data were analyzed from April 16 to May 11, 2020. Proportion of alleles with a pathogenic transition variant that is potentially correctable with a base editing strategy and proportion of patients with a base-editable allele. A total of 12 369 alleles from the Leiden Open Variation Database and 179 patients who received diagnoses through the genetic service of the Oxford University Hospitals Medical Genetics Laboratories were analyzed. Editable variants accounted for 53% of all pathogenic variants in the candidate genes contained in the Leiden Open Variation Database. The proportion of pathogenic alleles that were editable varied by gene; 63.1% of alleles in ABCA4, 62.7% of alleles in CDH23, 53.8% of alleles in MYO7A, 41.6% of alleles in CEP290, 37.3% of alleles in USH2A, and 22.2% of alleles in EYS were editable. The 5 most common editable pathogenic variants of each gene accounted for a mean (SD) of 19.1% (9.5%) of all pathogenic alleles within each gene. In the Oxford cohort, 136 of 179 patients (76.0%) had at least 1 editable allele. A total of 53 of 107 patients (49.5%) with biallelic pathogenic variants in the gene ABCA4 and 16 of 56 patients (28.6%) with biallelic pathogenic variants in the gene USH2A had 1 of the 5 most common editable alleles. This study found that pathogenic variants amenable to base editing commonly occur in inherited retinal degeneration. These findings, if generalized to other cohorts, provide an approach for developing base editing therapies to treat retinal degeneration not amenable to gene therapy.


Selective attention towards painful faces among chronic pain patients: evidence from a modified version of the dot-probe.
Evidence that patients with chronic pain selectively attend to pain-related stimuli presented in modified Stroop and dot-probe paradigms is mixed. The pain-related stimuli used in these studies have been primarily verbal in nature (i.e., words depicting themes of pain). The purpose of the present study was to determine whether patients with chronic pain, relative to healthy controls, show selective attention for pictures depicting painful faces. To do so, 170 patients with chronic pain and 40 age- and education-matched healthy control participants were tested using a dot-probe task in which painful, happy, and neutral facial expressions were presented. Selective attention was denoted using the mean reaction time and the bias index. Results indicated that, while both groups shifted attention away from happy faces (and towards neutral faces), only the control group shifted attention away from painful faces. Additional analyses were conducted on chronic pain participants after dividing them into groups on the basis of fear of pain/(re)injury. The results of these analyses revealed that while chronic pain patients with high and low levels of fear both shifted attention away from happy faces, those with low fear shifted attention away from painful faces, whereas those with high fear shifted attention towards painful faces. These results suggest that patients with chronic pain selectively attend to facial expressions of pain and, importantly, that the tendency to shift attention towards such stimuli is positively influenced by high fear of pain/(re)injury. Implications of the findings and future research directions are discussed.


Technology Based Treatment for UreteroPelvic Junction Obstruction.
Surgical management of ureteropelvic junction obstruction (UPJO) has historically been performed with open pyeloplasty. With the advent of endourology, laparoscopy, and robotics, minimally-invasive techniques have been described and accepted as alternatives to open surgery. Each of these approaches has its own advantages and disadvantages, equipment needs, degree of invasiveness, and experience of the treating urologist. Advocates and critics have their own say as to their preferred technique. In this article, we review the chronological evolution of these techniques and discuss their current role in the management of UPJO.


MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse.
Cleft lip (CL), one of the most common congenital birth defects, shows considerable geographic and ethnic variation, with contribution of both genetic and environmental factors. Mouse genetic studies have identified several CL-associated genes. However, it remains elusive how these CL-associated genes are regulated and involved in CL. Environmental factors may regulate these genes at the post-transcriptional level through the regulation of non-coding microRNAs (miRNAs). In this study, we sought to identify miRNAs associated with CL in mice. Through a systematic literature review and a Mouse Genome Informatics (MGI) database search, we identified 55 genes that were associated with CL in mice. Subsequent bioinformatic analysis of these genes predicted that a total of 33 miRNAs target multiple CL-associated genes, with 20 CL-associated genes being potentially regulated by multiple miRNAs. To experimentally validate miRNA function in cell proliferation, we conducted cell proliferation/viability assays for the selected five candidate miRNAs (miR-124-3p, let-7a-5p, let-7b-5p, let-7c-5p, and let-7d-5p). Overexpression of miR-124-3p, but not of the others, inhibited cell proliferation through suppression of CL-associated genes in cultured mouse embryonic lip mesenchymal cells (MELM cells) isolated from the developing mouse lip region. By contrast, miR-124-3p knockdown had no effect on MELM cell proliferation. This miRNA-gene regulatory mechanism was mostly conserved in O9-1 cells, an established cranial neural crest cell line. Expression of miR-124-3p was low in the maxillary processes at E10.5, when lip mesenchymal cells proliferate, whereas it was greatly increased at later developmental stages, suggesting that miR-124-3p expression is suppressed during the proliferation phase in normal palate development. Our findings indicate that upregulated miR-124-3p inhibits cell proliferation in cultured lip cells through suppression of CL-associated genes. These results will have a significant impact, not only on our knowledge about lip morphogenesis, but also on the development of clinical approaches for the diagnosis and prevention of CL.


A new clustering technique for function approximation.
To date, clustering techniques have always been oriented to solve classification and pattern recognition problems. However, some authors have applied them unchanged to construct initial models for function approximators. Nevertheless, classification and function approximation problems present quite different objectives. Therefore it is necessary to design new clustering algorithms specialized in the problem of function approximation. This paper presents a new clustering technique, specially designed for function. approximation problems, which improves the performance of the approximator system obtained, compared with other models derived from traditional classification oriented clustering algorithms and input-output clustering techniques.


Is TKA using patient-specific instruments comparable to conventional TKA? A randomized controlled study of one system.
Patient-specific CT-based instrumentation may reduce implant malpositioning and improve alignment in TKA. However, it is not known whether this innovation is an advance that benefits patients. We evaluated (1) the precision of patient-specific TKA by comparing the incidence of outliers in postoperative alignment between TKAs using patient-specific instruments and TKAs using conventional instruments, and (2) the reliability of patient-specific instruments by intraoperatively investigating whether the surgery could be completed with patient-specific instruments alone. In this randomized controlled trial, we compared patient-specific TKA instruments from one manufacturer (n = 50) with conventional TKA instruments (n = 50). Postoperative hip-knee-ankle angles, femoral component rotation, and coronal and sagittal alignments of each component were measured. The validity of the patient-specific instrument was examined using cross-checking procedures with conventional instruments during the surgeries. When the procedure could not be completed accurately with patient-specific instruments, the procedure was converted to TKA using conventional instruments, and the frequency of this occurrence was tallied. Outliers in the hip-knee-ankle angle were comparable between groups (12% in the patient-specific instrument group and 10% in the conventional instrument group). Other parameters such as sagittal alignment and femoral component rotation did not differ in terms of outliers. Patient-specific guides were abandoned in eight knees (16%) during the surgery because of malrotation of the femoral components and decreased slope of the tibia. Accuracy was comparable between TKAs done with patient-specific instruments and those done with conventional instruments. However, the patient-specific instrument procedures had to be aborted frequently, incurring expenses that did not benefit patients.


[The integrality of the attention in diabetics with periodontal disease].
The aim of this study was to evaluate the periodontal conditions of individuals with diabetes and to analyze how SUS has contributed to the health attention of these people in Belo Horizonte, Minas Gerais State. For that, a sample of 300 individuals was selected and interviews with diabetics and health unit managers were conducted. From those, 55% presented gingivitis, 35.3% periodontitis and 9.7% were healthy. As for the integral attention for diabetics in SUS, it was observed that despite the fact that most of them were under medical supervision, only 27.3% were under dental treatment in basic health care units, 3.6% had specialized dental care and only 3.4% were seen by other health workers. Interdisciplinary care and attention in all levels of the system are essential factors for the integrality of health actions.


A strategy for incorporating palliative care and end-of-life instruction into physician assistant education.
Physician assistant (PA) education has not historically taught end-of-life and palliative care in its curricula. While medical education has been reformed in the past 15 years to include palliative care, PA education lags behind. The Medical College of Georgia PA Program obtained a HRSA grant in 2009 to teach PA students about end-of-life issues and improve palliative education in the didactic and clinical years. Sparse published data exist for end-of-life/palliative education in PA programs. We built a Wiki Internet tool to help teach these concepts. We revised objectives in clinical medicine, emergency medicine, and surgery to improve instruction in end-of-life issues, including common symptom management. We extended the adult medicine clinical course from 4 weeks to 8 weeks to provide long-term care and hospice exposure. Students journaled their adult medicine experiences on the Palliative Care Wiki Discussion Forum. Students who participated in the Wiki Discussion Forum reported better understanding of end-of-life issues for patients who were near death or actively dying. Students expressed that bedside instruction, small groups, and hospice home visits were valuable venues for learning about end-of-life care. Students recommended more frequent and specific instruction in pain management and requested more time in hospice and critical care. Students appreciated learning from other students' experiences through the Wiki Discussion Forum. PA programs should incorporate palliative care and end-of-life instruction into existing curricula. Pain management and treatment of common end-of-life symptoms should be emphasized. Structured clinical experiences in critical care, hospice, and long-term-care settings should be offered.


Metabolic phases during the development of granulation tissue.
1. The metabolism of incubated slices of sponge-induced granulation tissue, harvested 4-90 days after the implantation, was studied with special reference to the capacity of collagen synthesis and to the energy metabolism. Data are also given on the nucleic acid contents during the observation period. Three metabolic phases were evident. 2. The viability of the slices for the synthesis of collagen was studied in various conditions. Freezing and homogenization destroyed the capacity of the tissue to incorporate proline into collagen. 3. Consumption of oxygen reached the maximum at 30-40 days. There was evidence that the pentose phosphate cycle was important, especially during the phases of the proliferation and the involution. The formation of lactic acid was maximal at about 20 days. 4. The capacity to incorporate proline into collagen hydroxyproline in vitro was limited to a relatively short period at 10-30 days. 5. The synthesis of collagen was dependent on the supply of oxygen and glucose, which latter could be replaced in the incubation medium by other monosaccharides but not by the metabolites of glucose or tricarboxylic acid-cycle intermediates.


Compensation strategy of shoulder synergist muscles is not stereotypical in patients with rotator cuff repair.
Rotator cuff tear is a common shoulder injury that causes shoulder dysfunction and pain. Although surgical repair is the primary treatment for rotator cuff tear, it is well recognized that impaired force exertion of muscles connecting to the involved tendon and subsequent complemental change in the force exertion of synergist muscles persist even after repair. This study aimed to identify the compensation strategy of shoulder abductors by examining how synergist muscles respond to supraspinatus (SSP) muscle force deficit in patients with rotator cuff repair. Muscle shear modulus, an index of muscle force, was assessed for SSP, infraspinatus, upper trapezius, and middle deltoid muscles in repaired and contralateral control shoulders of 15 patients with unilateral tendon repair of the SSP muscle using ultrasound shear wave elastography while the patients passively or actively held their arm in shoulder abduction. In the repaired shoulder, the shear modulus of the SSP muscle declined, whereas that of other synergist muscles did not differ relative to that of the control. To find the association between the affected SSP and each of the synergist muscles, a regression analysis was used to assess the shear moduli at the population level. However, no association was observed between them. At the individual level, there was a tendency of variation among patients with regard to a specific muscle whose shear modulus complementarily increased. These results suggest that the compensation strategy for SSP muscle force deficit varies among individuals, being nonstereotypical in patients with rotator cuff injury.


Endowing Hydrochromism to Fluorans via Bioinspired Alteration of Molecular Structures and Microenvironments and Expanding Their Potential for Rewritable Paper.
Interest and effort toward new materials for rewritable paper have increased dramatically because of the exciting advantages for sustainable development and better nature life cycle. Inspired by how nature works within living systems, herein, we have used fluorans, as a concept verification, to endow original acidochromic, basochromic or photochromic molecules with broader properties, such as switchable with solvent, water, heat, electricity, stress, other force, etc., via simplified methods (i.e., via variation of submolecular structure or microenvironments). The hydrochromic visual change and reversible behavior of selected molecules have been explored, and the primary mechanism at the atomic or subatomic level has been hypothesized. In addition, several newly demonstrated hydrochromic fluorans have been utilized for water-jet rewritable paper (WJRP), which exhibit great photostability, high hydrochromic contrast, and fast responsive rate and which can be reused at least 30 times without significant variation. The water-jet prints have good resolution and various colors and can keep legibility after a few months or years. This improved performance is a major step toward practical applications of WJRP.


Ontogenetic patterns in bluefish (Pomatomus saltatrix) feeding ecology and the effect on mercury biomagnification.
In this study, bluefish (Pomatomus saltatrix; age 0-7, n = 632) and their prey (forage fish, macroinvertebrates, zooplankton; n = 2,005) were collected from the Narragansett Bay estuary (RI, USA), and total Hg concentration was measured in white muscle and whole-body tissues, respectively. Bluefish Hg concentrations were analyzed relative to fish length, prey Hg content, and ontogenetic shifts in habitat use and foraging ecology, the latter assessed using stomach content analysis (n = 711) and stable nitrogen (δ(15)N) and carbon (δ(13)C) isotope measurements (n = 360). Diet and δ(13)C analysis showed that age 0 bluefish consumed both benthic and pelagic prey (silversides, sand shrimp, planktonic crustaceans; δ(13)C = - 16.52‰), whereas age 1 + bluefish fed almost exclusively on pelagic forage fish (Atlantic menhaden, herring; δ(13)C = - 17.33‰). Bluefish total Hg concentrations were significantly correlated with length (mean Hg = 0.041 and 0.254 ppm wet wt for age 0 and age 1 + bluefish, respectively). Furthermore, Hg biomagnification rates were maximal during bluefish early life stages and decelerated over time, resulting in relatively high Hg concentrations in age 0 fish. Rapid Hg accumulation in age 0 bluefish is attributed to these individuals occupying a comparable trophic level to age 1 + bluefish (δ(15)N = 15.58 and 16.09‰; trophic level = 3.55 and 3.71 for age 0 and age 1 + bluefish, respectively), as well as juveniles having greater standardized consumption rates of Hg-contaminated prey. Finally, bluefish larger than 30 cm total length consistently had Hg levels above the U.S. Environmental Protection Agency criterion of 0.3 ppm. As such, frequent consumption of bluefish could pose a human health risk, and preferentially consuming smaller bluefish may be an inadequate strategy for minimizing human dietary exposure to Hg.


From Augmented to Virtual Reality in Plastic Surgery: Blazing the Trail to a New Frontier.
Augmented reality (AR) and virtual reality (VR)-termed mixed reality-has shown promise in the care of operative patients. Currently, AR and VR has well-known applications for craniofacial surgery, specifically in preoperative planning. However, the application of AR/VR technology to other reconstructive challenges has not been widely adopted. Thus, the purpose of this investigation is to outline the current applications of AR and VR in the operative setting. Literature pertaining to the use of AR/VR technology in the operative setting was examined. Emphasis was placed on the use of mixed reality technology in surgical subspecialities, including plastic surgery, oral and maxillofacial surgery, colorectal surgery, neurosurgery, otolaryngology, neurosurgery, and orthopedic surgery. Presently, mixed reality is widely used in the care of patients requiring complex reconstruction of the craniomaxillofacial skeleton for pre- and intraoperative planning. For upper extremity amputees there is evidence that VR may be efficacious in the treatment of phantom limb pain. Furthermore, VR has untapped potential as a cost-effective tool for microsurgical education and for training residents on techniques surgical and non-surgical aesthetic treatment. There is utility for mixed reality in breast reconstruction for preoperative planning, mapping perforators, and decreasing operative time. VR has been especially well documented for the planning of deep inferior epigastric perforator (DIEP) by creating 3D immersive simulation based on a patient's preoperative CT angiogram. The benefits of AR and VR are numerous to both patients and surgeons. Virtual reality has been shown to increase surgical precision and decrease operative time. Furthermore, it is effective for patient specific rehearsal (PsR) which uses the patient's exact anatomical data to rehearse the procedure before performing it on the actual patient. Taken together, AR/VR technology can improve patient outcomes, decrease operative times, and lower the burden of care on both patients and healthcare institutions.


Serum Levels of IL-4, IL-10, IL-12, IL-13 and IFN-gamma in Behçet's disease.
Behçet's disease (BD) is an inflammatory disease of unknown etiology. Although its pathogenesis is not fully understood, recent studies have suggested that immunological abnormalities and neutrophil hyperfunction may be involved in its etiology and pathophysiology. The immune system in BD can be characterized as a divergent cytokine production profile of the mixed Th1/Th2 cell type. In this study, we investigated the levels of interleukin (IL)-4, IL-10, IL-12, IL-13 and interferon-g in the sera of patients with BD, in comparison with recurrent aphthous stomatitis and healthy controls, to determine the Th1/Th2 profile of the disease. The levels of IL-4, IL-10 and IL-13 were found to be high in active BD patients, and IL-12 and interferon-gamma levels were lower in active BD patients than in inactive BD, recurrent aphthous stomatitis, and control patients.


Improving the speech function of maxillary complete dentures: a pilot study.
The aim of this pilot study was to investigate a universal and easy method for improving the speech function of complete maxillary dentures. Specifically, it was analyzed whether sandblasting could improve speech performance, since this process increases the tactile surface area in the region of tongue-to-denture contact. Fourteen volunteers with complete maxillary dentures in a geriatric rehabilitation center (7 men, 7 women, mean age 81.2) were recruited. Speech samples (normal conversation, logopedic standard text, and a word list) were recorded for all subjects. In 11 cases, a specific area of the denture was sandblasted, while the remaining 3 cases served as controls. After 1 week of service, the same speech samples were recorded again. The rating of the speech samples was performed by 2 experienced speech therapists. The rater did not know whether the sample was a control case or whether it was before or after intervention. The speech therapists found no difference between the 2 speech samples in all 3 cases in the control group. For 8 of 11 subjects, the speech sample after sandblasting was rated better by both therapists (P = .002). In 2 subjects, no difference was observed, and deterioration was found in only 1 subject by 1 speech therapist. Taking into account the limited number of subjects, the results show that sandblasting may lead to moderate improvements in speech performance in most cases. Deterioration is not expected, but in such cases, it is easy to restore the denture with simple polishing.


STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice.
Efferocytosis, or phagocytic clearance of dead/dying cells by brain-resident microglia and/or infiltrating macrophages, is instrumental for inflammation resolution and restoration of brain homeostasis after stroke. Here, we identify the signal transducer and activator of transcription 6/arginase1 (STAT6/Arg1) signaling axis as a potentially novel mechanism that orchestrates microglia/macrophage responses in the ischemic brain. Activation of STAT6 was observed in microglia/macrophages in the ischemic territory in a mouse model of stroke and in stroke patients. STAT6 deficiency resulted in reduced clearance of dead/dying neurons, increased inflammatory gene signature in microglia/macrophages, and enlarged infarct volume early after experimental stroke. All of these pathological changes culminated in an increased brain tissue loss and exacerbated long-term functional deficits. Combined in vivo analyses using BM chimeras and in vitro experiments using microglia/macrophage-neuron cocultures confirmed that STAT6 activation in both microglia and macrophages was essential for neuroprotection. Adoptive transfer of WT macrophages into STAT6-KO mice reduced accumulation of dead neurons in the ischemic territory and ameliorated brain infarction. Furthermore, decreased expression of Arg1 in STAT6-/- microglia/macrophages was responsible for impairments in efferocytosis and loss of antiinflammatory modality. Our study suggests that efferocytosis via STAT6/Arg1 modulates microglia/macrophage phenotype, accelerates inflammation resolution, and improves stroke outcomes.


Electroviscous Dissipation in Aqueous Electrolyte Films with Overlapping Electric Double Layers.
We use dynamic atomic force microscopy (AFM) to investigate the forces involved in squeezing out thin films of aqueous electrolyte between an AFM tip and silica substrates at variable pH and salt concentration. From amplitude and phase of the AFM signal we determine both conservative and dissipative components of the tip sample interaction forces. The measured dissipation is enhanced by up to a factor of 5 at tip-sample separations of ≈ one Debye length compared to the expectations based on classical hydrodynamic Reynolds damping with bulk viscosity. Calculating the surface charge density from the conservative forces using Derjaguin-Landau-Verwey-Overbeek (DLVO) theory in combination with a charge regulation boundary condition we find that the viscosity enhancement correlates with increasing surface charge density. We compare the observed viscosity enhancement with two competing continuum theory models: (i) electroviscous dissipation due to the electrophoretic flow driven by the streaming current that is generated upon squeezing out the counterions in the diffuse part of the electric double layer, and (ii) visco-electric enhancement of the local water viscosity caused by the strong electric fields within the electric double layer. While the visco-electric model correctly captures the qualitative trends observed in the experiments, a quantitative description of the data presumably requires more sophisticated simulations that include microscopic aspects of the distribution and mobility of ions in the Stern layer.


Automatic, sequential power generation for prolonging the net lifetime of a miniature biofuel cell stack.
A sequential power generation system for prolonging the net lifetime of a miniature biofuel cell stack has been developed. The system consists of layered chambers of enzyme fuel cells designed to be exposed sequentially to fuel solution by automatically switched fuel flow. The cell chambers were initially separated by magnetized plastic covers sealed with a degradable glue, poly(lactic-co-glycolic acid) (PLGA). The time that the cover was opened by attraction with an external magnet, thereby activating the following cell, was adjustable from a few hours to a few weeks by controlling the weight ratio of Fe(3)O(4) in the covers and the molecular weight of PLGA. By using sequential power generation in this way, the power output of the system was stable for longer periods, and therefore the net lifetime of the stack has been extended as compared with that of a single biofuel cell.


Inference of an Integrative, Executable Network for Rheumatoid Arthritis Combining Data-Driven Machine Learning Approaches and a State-of-the-Art Mechanistic Disease Map.
Rheumatoid arthritis (RA) is a multifactorial, complex autoimmune disease that involves various genetic, environmental, and epigenetic factors. Systems biology approaches provide the means to study complex diseases by integrating different layers of biological information. Combining multiple data types can help compensate for missing or conflicting information and limit the possibility of false positives. In this work, we aim to unravel mechanisms governing the regulation of key transcription factors in RA and derive patient-specific models to gain more insights into the disease heterogeneity and the response to treatment. We first use publicly available transcriptomic datasets (peripheral blood) relative to RA and machine learning to create an RA-specific transcription factor (TF) co-regulatory network. The TF cooperativity network is subsequently enriched in signalling cascades and upstream regulators using a state-of-the-art, RA-specific molecular map. Then, the integrative network is used as a template to analyse patients' data regarding their response to anti-TNF treatment and identify master regulators and upstream cascades affected by the treatment. Finally, we use the Boolean formalism to simulate in silico subparts of the integrated network and identify combinations and conditions that can switch on or off the identified TFs, mimicking the effects of single and combined perturbations.


[Prion diseases: what is the role of dendritic cells in the pathogenesis of transmissible prion diseases?].
Prion diseases are caused by the transconformation of a normal cellular protein, PrPc, into an infectious isoform, PrPsc, which ultimately triggers neuronal death. They are always fatal and, after transmission, they feature long incubation periods, during which prions accumulate in lymphoid tissues, infect nerves and progress to the central nervous system. In lymphoid organs, prions replicate and accumulate in follicular dendritic cells. Suppressing these cells slows down the neuro-invasion but does not totally abrogate it. This review examines the current knowledge in the roles of hematopoietic dendritic cells at different steps of the pathogenesis of prion diseases. Dendritic cells endocytose inoculated prions, permit their crossing of the intestinal epithelium and then migrate and transport them to lymphoid organs. They can carry prions to sites of neuroinvasion, and establish contacts with axons in peripheral lymph nodes or even after passage of the blood-brain barrier. However, results in the literature on the role of dendritic cells differ according to the host or the prion strain.


Handedness for bimanual coordinated actions in infants as a function of grip morphology.
We investigated the emergence of bimanual handedness in tasks involving complementary roles for the two hands, one hand holding a base object and the other hand removing several pieces from the base object. Infants aged 12, 16, and 20 months were tested on bimanual tasks differing mainly in the precision of the movement required to remove the pieces. The results show that the right hand was more often used than the left hand not only to grasp the base object but also to remove the pieces, often after transferring the base object from the right to the left hand. As of 12 months of age, right hand preference for the active part of the bimanual task was stronger in the precision grip than in the whole-hand grip tasks. These results indicate that even though infants often do not anticipate that they will need their preferred hand to remove the pieces, they show clear handedness in such coordinated repeated bimanual actions, and do so to a greater degree on tasks requiring precision grip than on ones requiring whole-hand grip. These results agree with the notion that handedness develops very early and is related to the precision required from the active hand.


A cross-country time and motion study to measure the impact of electronic medication management systems on the work of hospital pharmacists in Australia and England.
Qualitative studies have provided important insights into how hospital pharmacists' work changes when electronic medication management (EMM) systems are introduced. Quantitative studies of work practice change are rare. Despite the use of EMM systems internationally, there are no cross-country comparative studies of their impact on health professionals' work. We aimed to quantify and compare the type and magnitude of changes in hospital pharmacists' work pre- and post-EMM implementation in two countries. Parallel, direct observational, time and motion studies of pharmacists in Australia and England pre- and post-EMM implementation. 20 pharmacists were observed: 9 in an Australian 440-bed hospital (155 h); and 11 pharmacists in a 500-bed English hospital (258 h). The Work Observation Method By Activity Timing (WOMBAT) software was used to collect observational data. Proportions of observed time in 11 tasks by study period (pre- versus post-EMM) and site, time spent with others or alone, and using different tools (e.g computers, paper) were calculated. Magnitude of changes between pre- and post-EMM by task and country were determined using z-tests for proportions adjusting for multiple testing. At baseline, Australian and English pharmacists spent the greatest proportion of time in medication review. Post-EMM, time in medication review (Australia 21.6%-27.5%; England 27.1%-33.8%) and history-taking (Australia 7.6%-13.3%; England 19.5%-28.9%) significantly increased. Despite country differences in these tasks at baseline, the magnitude of changes did not significantly differ. English pharmacists increased time engaged in medication discussions with patients post-EMM (from 5.9% to 10.8%; p = 0.01). The Australian rate did not change (18.0%-27.2%; p = 0.09), but was higher at baseline. Post-EMM, Australian pharmacists spent 63.4% of time working alone, compared to 92.0% for English pharmacists. EMM systems impacted the same core areas of work and had a similar magnitude of effect on pharmacists' work in both countries. Anticipated reductions in medication review and history taking were not observed.


[Postoperative analgesia with nonsteroid anti-inflammatory drugs in children].
The purpose of the case-study was to evaluate the efficiency of non-steroid antiinflammatory drugs (NAD) for postoperative analgesia in children after small-scope surgical interventions. Diclofenac, 1 mg/kg per day administered as rectal suppositories or intramuscular injections after initial narcosis, was used for postoperative analgesia in children of the main group; postoperative analgesia made by analgin and promedol in the control group was compared with the former. Forty-seven children and 10 children with identical diseases like groin hernia, varicocele and dropsy of testicular membranes, were respectively in the main and control groups. Clinical examinations and registration of functional parameters were made in patients during certain time periods, i.e. before surgery (in the standing and lying postures) and after surgery (in 20 minutes, as well as in 1, 2, and 3 hours after surgical interventions). The efficiency of postoperative analgesia was evaluated by means of cardiointervalography according to Bayevsky method as well as by a state of central hemodynamics and by clinical examinations, including the visual-analogue 10-point scale and the 0-4 point verbal pain assessment scale. The postoperatively obtained data revealed a pronounced misbalance between the main and control groups, which is indicative of that the application of NAD for preventive and postoperative analgesia in children improves essentially the postoperative course and contributes to a fast rehabilitation of patients. A comparative analysis of the efficiency of postoperative analgesia by the discussed drugs showed that diclofenac possesses a sufficient analgetic activity and is free of any side-effects inherent in narcotic analgetics.


Estrogen up-regulates neuropeptide Y Y1 receptor expression in a human breast cancer cell line.
Normal breast tissue mainly expresses the neuropeptide Y (NPY) Y2 receptor whereas primary human breast carcinomas express the Y1 receptor (Y1R) subtype. We hypothesized that activation of estrogen signaling systems plays a role in the induction of Y1R. To investigate this possibility, we used estrogen receptor-positive (ER+) human breast carcinoma cell line, MCF-7, and examined the effect of estrogen on Y1R gene expression and its signaling pathways. Saturation binding studies revealed that MCF-7 cells express high-affinity NPY receptor. NPY inhibited forskolin-stimulated adenosine 3'5'-cyclic monophosphate (cAMP) accumulation and mobilized intracellular Ca(2+) in MCF-7 cells. Chronic estrogen treatment enhanced NPY-mediated inhibition of cAMP accumulation by 4-fold and caused a significant increase in Y1R mRNA expression through ERalpha. Similarly, estrogen increased Y1R mRNA expression in T-47D (ER+) but not in MDA-MB231 or MDA-MB468 (ER-) cell lines. Cycloheximide decreased basal Y1R mRNA expression; however, it did not affect its increase by estrogen. Moreover, estrogen treatment of MCF-7 cells did not increase Y1R mRNA stability. The up-regulation of Y1R expression by estrogen is prevented by hydroxyurea but not by nocodazole or IB-MECA (cell cycle inhibitors). Lastly, NPY inhibited estrogen-induced cell proliferation through Y1R. In conclusion, MCF-7 cells express a functional Y1R coupled to both Ca(2+) and cAMP pathways. Estrogen up-regulates Y1R expression through ERalpha. This effect is independent of increased Y1R mRNA stability or new protein synthesis, and likely occurs during S phase completion of the cell cycle. Estrogen plays an important role in the up-regulation of Y1R, which in turn regulates estrogen-induced cell proliferation in breast cancer cells.


Supplementing neonatal Jersey calves with a blend of probiotic bacteria improves the pathophysiological response to an oral Salmonella enterica serotype Typhimurium challenge.
The objectives of the current study were to determine the effects of supplementing a blend of probiotic bacteria (Provida Calf, MB Nutritional Sciences, Lubbock, TX) on the pathophysiological response to an oral Salmonella enterica serotype Typhimurium challenge in neonatal Jersey calves. Twenty-four Jersey bull calves within 24 h of birth were acquired from a local calf ranch, blocked by total serum protein and initial body weight, and randomly assigned to 1 of 3 treatments (n = 8). Calves were assigned to either (1) Control (CON); base milk replacer, (2) Control + Salmonella Typhimurium (CON+ST); base milk replacer and challenged with Salmonella Typhimurium on d 7; or (3) Provida Calf probiotics + Salmonella Typhimurium (PRO+ST); same milk replacer supplemented with a proprietary blend of Lactobacillus casei and Enterococcus faecium strains and challenged with Salmonella Typhimurium on d 7. The PRO+ST calves were supplemented for the first 3 d with 2 × 1010 cfu/d and then with 2 × 109 cfu/d for the remainder of the study. The CON+ST and PRO+ST calves were each challenged with approximately 5 × 106 cfu of Salmonella Typhimurium (ATCC# 14028), which was a mild challenge that did not cause scours in the calves. Peripheral blood samples were collected on d 0, 7, 10, 14, and 21 and analyzed for hematology; serum was collected and analyzed for haptoglobin, glucose, and urea N. Rectal temperatures were collected daily from d 6 to 21, when all calves were killed, so that persistent colonization of Salmonella Typhimurium and histomorphology of both the duodenum and ileum could be determined. Serum haptoglobin and urea N concentrations were increased among CON+ST on d 10. In contrast, the peak rectal temperature on d 10 in PRO+ST calves was 40.4°C, which was greater than that for CON and CON-ST (38.9°C and 39.7°C, respectively). The neutrophil percentage in peripheral circulation in PRO+ST calves was 55.4%, which was greater than that for CON and CON+ST (34.8 and 41.8%, respectively). Seven of the 8 PRO+ST calves had elevated neutrophil percentages on d 10 compared with d 7, whereas 4 of the 8 CON+ST calves had reduced neutrophil percentages on d 10 compared with d 7. Villus height-to-crypt depth ratios in the duodenum were greater among CON and PRO+ST calves, being 1.38, 0.84, and 1.43 for CON, CON+ST, and PRO+ST, respectively. In the ileum, the PRO+ST calves had greater villus height-to-crypt depth ratios than both the CON and CON+ST calves (1.64, 1.53, and 2.43 for CON, CON+ST, and PRO+ST, respectively). These data indicate that supplementing neonatal calves with the blend of probiotic bacteria used in the current study can influence the pathophysiological response to a mild enteric Salmonella Typhimurium challenge.


A single nucleotide substitution converts potato spindle tuber viroid (PSTVd) from a noninfectious to an infectious RNA for nicotiana tabacum.
Mechanical inoculation of Nicotiana tabacum with the PSTVd isolate KF 440-2 from the host plant tomato resulted in the de novo emergence, replication, and accumulation of a new "tobacco variant," designated PSTVd NT. It produces no symptoms in tobacco but, like PSTV KF 440-2, severe ones in tomato. The sequence analysis of PSTVd NT revealed a single nucleotide substitution from C-->U at position 259. Autonomous viroid replication was also induced in tobacco by genomic integration of oligomeric cDNA copies of PSTVd KF 440-2. Although these cDNAs contained the original tomato-specific C259, the circular PSTVd RNA subsequently accumulating in tobacco also exhibited the C259-->U259 substitution. In the secondary structure of PSTVd, nucleotide 259 is part of an internal loop analogous to loop E of eukaryotic 5S rRNA and presumed to be the only bulged extrahelical nucleotide of this loop. The C259 in PSTVd KF 440-2 and in practically all other isolates and the U259 in PSTVd NT of the loop E-like structure might be involved in protein binding and in viroid processing. The new variant PSTVd NT is genetically stable in both tobacco and tomato.


In-channel printing-device opening assay for micropatterning multiple cells and gene analysis.
Herein we report an easy but versatile method for patterning different cells on a single substrate by using a microfluidic approach that allows not only spatial and temporal control of multiple microenvironments but also retrieval of specific treated cells to profile their expressed genetic information at around 10-cell resolution. By taking advantages of increased surface area of gold nanoparticles on a poly(dimethylsiloxane) (PDMS) coated substrate, cell adhesive-promotive protein, human fibronectin (hFN) can be significantly accumulated on designed regions where cells can recognize the protein and spread out. Moreover, the whole device can be easily opened by hand without any loss of patterned cells which could be retrieved by mouth-pipet. Consequently, we demonstrate the possibility of analyzing the difference of gene expression patterns between wild type MCF-7 cell and MCF/Adr (drug-resistant cell line) from less than 400 cells in total for a single comprehensive assay, including parallel experiments, controls, and multiple dose treatments. Certain genes, especially the P-glycoprotein coding gene (ABCB1), show high expression level in resistant cells compared with the wild type, suggesting a possible pathway that may contribute to the antidrug mechanism.


Chorioamnionitis induces hepatic inflammation and time-dependent changes of the enterohepatic circulation in the ovine fetus.
Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes. These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. An ovine chorioamnionitis model was used in which circulatory cytokines and outcomes of the liver and EHC of preterm lambs were longitudinally assessed following IA administration of 10 mg LPS at 5, 12 or 24h or 2, 4, 8 or 15d before preterm birth. Hepatic inflammation was observed, characterized by increased hepatic cytokine mRNA levels (5h - 2d post IA LPS exposure) and increased erythropoietic clusters (at 8 and 15 days post IA LPS exposure). Besides, 12h after IA LPS exposure, plasma BA levels were increased, whereas gene expression levels of several hepatic BA transporters were decreased. Initial EHC alterations normalized over time. Concluding, IA LPS exposure induces significant time-dependent changes in the fetal liver and EHC. These chorioamnionitis induced changes have potential postnatal consequences and the duration of IA LPS exposure might be essential herein.


Profile of Helicobacter pylori cytotoxin derived from two areas of Japan with different prevalence of atrophic gastritis.
To clarify the roles of Helicobacter pylori cytotoxin in gastric atrophy, the cytotoxin positive rate and cytotoxin activity in Fukui and Okinawa, where the prevalence of atrophic gastritis and gastric cancer risk are quite different, were studied. Seventy three strains from Fukui and 51 from Okinawa were examined. The validation of atrophy was done by endoscopy, being confirmed with histology. The supernatant of liquid H pylori culture media was concentrated 20-fold, serially diluted, using doubling dilutions, and scored from 1 to 8. The semi-quantitated cytotoxin activity was expressed as the maximum dilution score yielding > 50% A431 cell vacuolation, being standardised with bacterial density. The cytotoxin activity of the strains from Fukui was highly diverse compared with that from Okinawa, although the cytotoxin positive rate was not different. In Fukui strains, the grade of atrophy and the cytotoxin activity were correlated (p < 0.05). In addition, the cytotoxin activity of the strains from all patients in Okinawa, most of whom showed closed-type/mild atrophy, was significantly lower than that of the strains from the patients with open-type/severe atrophy in Fukui (6.46 (5.53) v 9.76 (8.80), p < 0.05), (mean (SEM)). The difference in profile of the cytotoxin activity in the two areas was related to the difference in the prevalence of atrophic gastritis.


GeneCards Version 3: the human gene integrator.
GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org.


Design-based texture feature fusion using Gabor filters and co-occurrence probabilities.
A design-based method to fuse Gabor filter and grey level co-occurrence probability (GLCP) features for improved texture recognition is presented. The fused feature set utilizes both the Gabor filter's capability of accurately capturing lower and mid-frequency texture information and the GLCP's capability in texture information relevant to higher frequency components. Evaluation methods include comparing feature space separability and comparing image segmentation classification rates. The fused feature sets are demonstrated to produce higher feature space separations, as well as higher segmentation accuracies relative to the individual feature sets. Fused feature sets also outperform individual feature sets for noisy images, across different noise magnitudes. The curse of dimensionality is demonstrated not to affect segmentation using the proposed the 48-dimensional fused feature set. Gabor magnitude responses produce higher segmentation accuracies than linearly normalized Gabor magnitude responses. Feature reduction using principal component analysis is acceptable for maintaining the segmentation performance, but feature reduction using the feature contrast method dramatically reduced the segmentation accuracy. Overall, the designed fused feature set is advocated as a means for improving texture segmentation performance.


Intrastriatal microinjection of sodium nitroprusside induces cell death and reduces binding of dopaminergic receptors.
Rat striatum was microinjected with 50 nmol sodium nitroprusside (SNP) and neural cell death as well as the binding of dopaminergic receptors were followed for 24 h after the infusion using TTC staining, cresyl violet staining, and quantitative autoradiography. Striatal cell death was observed 3 h after the infusion of SNP. A widespread area of cell death, including part of the cerebral cortex, was seen at 24 h after the infusion. A decrease of more than 80% in dopamine D1 receptor binding was seen in rat brain slices prepared 2 h after the infusion of SNP, whereas only a slight decrease in dopamine D2 receptor binding and almost no changes in dopamine transporter binding were observed. One day after the infusion, less than 10% of the binding of all three types of dopaminergic receptors remained in a widespread area in the infused side of the striatum and part of the cerebral cortex. Microinjection of either NOC-18 (50 nmol), another type of NO donor, or sodium cyanide (50 nmol) did not caused cell death. In addition, microinjection of FeCl2 (50 nmol) into the striatum caused cell death and reduction in dopamine D() receptor binding. These results suggest that iron-related radical reactions, but not NO itself, might have important roles on SNP-caused cell death. The current receptor binding study also indicated that dopamine D1 receptor binding is the most sensitive indicator for detection of cell death or cell damage induced by radical reactions in the rat striatum.


The dynamic evolutionary history of genome size in North American woodland salamanders.
The genus Plethodon is the most species-rich salamander genus in North America, and nearly half of its species face an uncertain future. It is also one of the most diverse families in terms of genome sizes, which range from 1C = 18.2 to 69.3 pg, or 5-20 times larger than the human genome. Large genome size in salamanders results in part from accumulation of transposable elements and is associated with various developmental and physiological traits. However, genome sizes have been reported for only 25% of the species of Plethodon (14 of 55). We collected genome size data for Plethodon serratus to supplement an ongoing phylogeographic study, reconstructed the evolutionary history of genome size in Plethodontidae, and inferred probable genome sizes for the 41 species missing empirical data. Results revealed multiple genome size changes in Plethodon: genomes of western Plethodon increased, whereas genomes of eastern Plethodon decreased, followed by additional decreases or subsequent increases. The estimated genome size of P. serratus was 21 pg. New understanding of variation in genome size evolution, along with genome size inferences for previously unstudied taxa, provide a foundation for future studies on the biology of plethodontid salamanders.


Comparison of upper and lower lip position, length and thickness in sagittal and vertical malocclusion.
This study aimed to compare the upper and lower lips position, length, and thickness in different malocclusions, in randomly selected 180 patients' pre-treatment lateral cephalograms. The subjects were grouped sagittally by using Steiner's analysis and Wits appraisal and vertically based on Frankfort horizontal and mandibular plane (FHMP) angle and lower facial height. One-way ANOVA was applied to compare the upper and lower lip positions, thickness, and length in sagittal and vertical malocclusion and independent sample T test was applied for comparison between genders among soft tissue variables. Post-hoc Dunnett T3 was performed for comparison of lip variables in adjacent malocclusion groups. The level of significance was not less than or equal to 0.05. The anteroposterior position of the upper and lower lips with respect to E and S planes and upper and lower lip thickness varied significantly (p < 0.05) in all classes of sagittal malocclusion, whereas the anteroposterior (AP) position of the LL with respect to both planes and UL length between vertical malocclusion groups was statistically significant (p < 0.05). AP position and fullness of both lips have a significant association with sagittal malocclusion, whereas the AP position of the lower lip's and the length of upper lip is significantly associated with vertical malocclusion.


Anesthetic dreaming, anesthesia awareness and patient satisfaction after deep sedation with propofol target controlled infusion: A prospective cohort study of patients undergoing day case breast surgery.
Anesthetic dreaming and anesthesia awareness are well distinct phenomena. Although the incidence of intraoperative awareness is more common among patients who reported a dream after surgery, the exact correlation between the two phenomena remains an unsolved rebus. The main purpose of this study was to investigate anesthetic dreaming, anesthesia awareness and psychological consequences eventually occurred under deep sedation. Intraoperative dreaming experiences were correlated with dream features in natural sleep. Fifty-one patients, undergoing surgical excision of fibroadenomas under a Bispectral index-guided deep sedation anesthesia with propofol target controlled infusion, were enrolled into this prospective study. Psychological assessment was performed through the State Trait Anxiety Inventory. A questionnaire was adopted to register dreaming and anesthesia awareness. Data were collected after emergence (t0), 24 hours (t1), 1 month (t2), 6 months (t3). Six patients (12%) reported anesthetic dreaming at t0 confirming the response at each subsequent evaluation. One patient (2%) confirmed dreaming during anesthesia in all, but denied it at t0. There was a high correlation between the intraoperative dream contents and the features of dreams in natural sleep. No cases of anesthesia awareness were detected. A similar level of satisfaction was observed in dreaming and no-dreaming patients. Anesthetic dreaming does not seem to influence satisfaction of patients undergoing deep sedation with propofol target controlled infusion. A psychological assessment would seem to improve the evaluation of possible psychological consequences in dreamer patient.


Evaluation of the precision of fit between the Procera custom abutment and various implant systems.
It has been suggested that the CAD/CAM Procera custom abutment may be universally applied with multiple implant systems. An acceptable fit between the internal hexagon of an abutment and the external hexagon of various implant systems, along with true interchangeability of the Procera abutment screw, would support this concept. This study determined the precision of fit of the CAD/CAM-produced Procera abutment onto the external hexagon and bearing surfaces of implants from 6 implant manufacturers and the interchangeability of the Procera abutment screw with these systems. This investigation consisted of 3 parts: (1) direct measurement of the internal hexagon and bearing surface of each Procera abutment and the external hexagon and the bearing surface of 6 implants from 6 different systems, (2) radiographic examination of 30 Procera abutment-implant junctions following tightening to 32 Ncm to determine the precision of fit between the bearing surfaces and the top of the external hexagon of the implant with the superior surface of the internal hexagon of the abutment, and (3) examination of 3 abutment screws and 3 implants from the various manufacturers for interchangeability based on American National Standards. The mean flat-to-flat external hexagons of the implants measured between 2.67 and 2.69 mm. The Procera abutment's flat-to-flat internal hexagon measured 2.73 mm. The height of the various implant systems' external hexagon ranged from 0.69 to 0.81 mm. The height of the Procera abutment blanks was 0.90 mm. Radiographic examination demonstrated that not all of the manufacturers' screws fit appropriately within the internal screw bore of the Procera abutment. The internal bore of all implant systems studied had a metric thread designation of M2 x 0.4 - 6H. The metric thread designation of all abutment screws examined was M2 x 0.4 - 6g. The greatest variations in the dimensions of the abutment screws measured were seen in the diameter of the screw head, which ranged from 2.12 to 2.69 mm. The Procera abutment's internal hexagon fit the external hexagon of all implant systems evaluated. The Procera abutment screw fit the internal screw bore of the implant systems tested. The Procera abutment with its screw can be universally applied to the implant systems studied. This fact, plus the CAD/CAM feature of this system, would thus provide a dynamic approach to satisfying the design and spatial needs of implant placements observed clinically.


Locally formed 5-hydroxytryptamine stimulates phosphate transport in cultured opossum kidney cells and in rat kidney.
Renal proximal tubular cells have been shown to express aromatic L-amino acid decarboxylase (L-AAAD), which converts L-dopa into dopamine and 5-hydroxytryptophan [(OH)Trp] into 5-hydroxytryptamine (5-HT; serotonin). Because 5-HT receptors have been demonstrated in proximal cells, we hypothesized that 5-HT may act as an autocrine/paracrine modulator of proximal transport. We evaluated this possibility in opossum kidney (OK) cells, a renal epithelial cell line with a proximal phenotype expressing 5-HT1B receptors, and in intact anaesthetized rats. 5-HT synthesis by OK cells increased with incubation time and (OH)Trp concentration, and was abolished by benserazide, an L-AAAD inhibitor. 5-HT reversed parathyroid hormone (PTH)-induced cAMP accumulation in a pertussis toxin-sensitive manner and reduced the PTH inhibition of P(i) uptake without affecting the NaP(i)-4 mRNA level. The effects of 5-HT on cAMP generation and Na-P(i) co-transport were reproduced by (OH)Trp, except in the presence of benserazide, and by L-propranolol and dihydroergotamine, two 5-HT1B receptor agonists. In rats, (OH)Trp and dihydroergotamine decreased fractional P(i) excretion. Benserazide abolished the effect of (OH)Trp but not that of dihydroergotamine. (i) locally generated 5-HT blunts the inhibitory effect of PTH on Na-P(i) co-transport in OK cells; (ii) endogenous 5-HT decreases P(i) excretion in rats; and (iii) 5-HT is a paracrine modulator involved in the physiological regulation of renal P(i) transport.


Energy metabolism in rat mast cells in relation to histamine secretion.
1. The relation between the energy metabolism and the secretory activity of rat peritoneal mast cells has been studied by determination of the cellular content of ATP and the rate of lactate production reflecting the rate of ATP synthesis under various experimental conditions. Secretion of histamine was induced by the antigen-antibody reaction, the polymeric amine compound 48/80, and the divalent ionophore A23187. 2. In presence of low concentrations of metabolic inhibitors (oligomycin or antimycin A) a linear relation between the secretion of histamine induced by all three liberators and the cellular ATP content at the time of cell activation was demonstrated. This may indicate a direct link between ATP and the secretory mechanism. 3. The possibility of an increased utilization of ATP during histamine secretion was explored in mast cells exposed to metabolic inhibitors. Incubation of mast cells with 2-deoxyglucose (2-DG) decreased the ATP content of the cells, and a long-lasting and stable level of mast cell ATP was observed. This is explained by a small decrease in the rate of ATP-synthesis by 2-DG. In 2-DG-treated cells secretion of histamine in response to compound 48/80 or the antigen-antibody reaction could still occur, and the secretion is shown to be associated with a decrease of the cellular ATP level. This ATP decrease indicates that secretion occurs by an ATP-requiring mechanism, that causes an increased cellular utilization of ATP in association with the secretory response. 4. The possibility has been considered that increased cytosol concentration of calcium in association with secretion may decrease the rate of ATP-synthesis due to accumulation of calcium by the mitochondria. This possibility can be excluded by the observation that in presence of respiratory inhibitors an identical ATP decrease was found during the secretion as in the case of the glycolytic inhibitor alone. This indicates that increased utilization of ATP by the cells was related directly to the secretory response. This observation was made with all three secretagogues. 5. A quantitative evaluation of the increased amount of ATP utilized by the cells in relation to the secretory response was performed by use of metabolic inhibitors. The ATP requirement of compound 48/80-induced secretion was 0.15 pmol/10(3) cells. This was observed when the ATP-synthesis was decreased to a negligible value.(ABSTRACT TRUNCATED AT 400 WORDS)


"So, what is a psychopath?" Venireperson perceptions, beliefs, and attitudes about psychopathic personality.
This study surveyed over 400 individuals attending jury duty regarding various perceptions, attitudes, and beliefs they had concerning psychopathic personality (psychopathy). The protocol included (a) prototype ratings of what participants considered to be core features, using the Comprehensive Assessment of Psychopathic Personality (CAPP) prototype rating scale; (b) questions concerning knowledge and beliefs about psychopathy (e.g., prevalence in society); and (c) attitudinal scales concerning potential associated features (e.g., criminality, rehabilitation potential), etiological underpinnings, and moral judgments and legal sanctions. Consistent with results of earlier studies using expert raters, jury panel members rated most of the 33 individual CAPP items and all 6 CAPP scales as at least moderately prototypical, with Self and Dominance domains obtaining the highest mean ratings. Many participants also strongly endorsed symptoms of psychosis (e.g., delusions) as prototypical of psychopathy. Despite this, they viewed psychopaths as responsible for their own actions, as capable of determining right from wrong, and as generally not "insane." Our findings indicate that jury panel members view the prototypical psychopath as highly dominant, self-focused, and lacking in remorse and empathy and reinforce the need for expert witnesses to clearly differentiate between psychopathy and psychotic-spectrum disorders.


The impact of socioenvironmental characteristics on domains of oral health-related quality of life in Brazilian schoolchildren.
Recent researches have pointed out the need to consider the functional and psychosocial dimensions of oral health, such as Oral Health-related Quality of Life (OHRQoL). The aim of this study was to investigate the influence of oral health status, socioeconomic factors and home environment of children on the four health domains of Child Perceptions Questionnaire (CPQ11-14). A cross-sectional study was conducted in Brazil with a sample of 286 schoolchildren aged 12 years and their parents. The schoolchildren were clinically examined, and participants were asked to complete the CPQ11-14, as well as a questionnaire about home environment. In addition, a questionnaire was sent to each child's parents asking them about family socioeconomic status. The chi-square test and Poisson's regression analysis were performed. After adjusting for potential confounders, variables sex, monthly family income, mothers' education showed a statistically significant association with all health domains of the CPQ11-14. The family structure and presence of bleeding impacted on emotional (p = 0.0135), and social (p = 0.0010) well-being health domain scores. Orthodontic treatment need showed a strong negative effect on functional limitations domain score (p = 0.0021). Clinical and socio-environmental factors had different impacts on domains of oral health-related quality of life, demonstrating the need to consider these conditions in planning strategies for the oral health of schoolchildren.


[Effects of the population density on growth of SD-JCL rats (author's transl)].
The effects of the population density on growth and life span of 21 to 26 months in SD-JCL-rats were investigated. The mean life spans of males and females were 23 and 24 months, respectively. The population density had no definite influence on increase in body weight of females, whereas a most accelerated growth of males was seen with 2 rats per cage. The total amounts of food intake of each animal throughout its life were about 15 and 11 kg for males and females, respectively, and those of water intake were about twice the food. No correlation was observed between the population density and the weights of the liver, kidney, heart and femur, though mals reared at 5 animals per cage had lightest adrenals among all the animals.


Stevens-Johnson syndrome in a boy with macrolide-resistant Mycoplasma pneumoniae pneumonia.
Mycoplasma pneumoniae is a highly specialized parasitic bacterium that is a significant cause of community-acquired pneumonia in children. Although most such respiratory infections are mild, a minor percentage of patients require hospitalization and, occasionally, intensive treatment for respiratory failure. A variety of extrapulmonary sequelae of M pneumoniae infections have been described, including Stevens-Johnson syndrome. Macrolide resistance in M pneumoniae has developed rapidly in Asia, particularly in China, over the past decade and is now appearing in the United States. Emerging resistance to macrolides creates a therapeutic conundrum, particularly for pediatricians caring for young children in whom absolute or relative contraindications exist for the use of tetracyclines or fluoroquinolones, the 2 other main classes of drugs shown to be efficacious for M pneumoniae. We describe here the case of a child with a prolonged febrile illness associated with Stevens-Johnson-like mucocutaneous involvement who was found to have a respiratory infection with macrolide-resistant M pneumoniae.


Circadian rhythm and response to an acute stressor of urinary corticosterone, testosterone, and creatinine in adult male mice.
In small laboratory species, steroid measures can be obtained more frequently and less invasively from urine than blood. Insofar as urinary levels reflect systemic levels, they could provide advantages particularly for measurement of glucocorticoids, whose blood levels react rapidly to handling and stress. In Experiment 1, urinary samples were collected from male mice every second hour over a 14:10 h light:dark cycle. Samples were analyzed via enzyme immunoassay for corticosterone, testosterone, and creatinine. Corticosterone had peak concentrations 1 h after light offset and a trough 1 h after light onset. Testosterone showed peak concentrations 5-7 h after light onset and lowest concentrations during the dark phase of the cycle. Creatinine showed some variation over the light-dark cycle, but steroid measures showed similar trends with and without adjustment for creatinine. In Experiment 2, mice were stressed via an injection at times close to the determined peak and trough levels of corticosterone. In urinary samples taken 90 min after injection, corticosterone was significantly higher in injected animals at both times relative to levels in control animals, but testosterone was unaffected by injection stress. In Experiment 3, serum and urine samples were collected from mice every sixth hour across the diurnal cycle. Corticosterone peaked in urine and serum immediately after light offset, and urinary measures predicted those in serum. These data indicate that urinary corticosterone reflects systemic levels in mice, document circadian variation in urinary testosterone, and indicate that circadian variation in creatinine is minimal, but potentially relevant in stressed animals.


Uridylation of the histone mRNA stem-loop weakens binding interactions with SLBP while maintaining interactions with 3'hExo.
Histone mRNA degradation is controlled by the unique 3' stem-loop of histone mRNA and the stem-loop binding protein (SLBP). As part of this process, the 3' stem-loop is trimmed by the histone-specific 3' exonuclease (3'hExo) and uridylated by the terminal uridylyl transferase 7 (TUT7), creating partially degraded intermediates with short uridylations. The role of these uridylations in degradation is not fully understood. Our work examines changes in the stability of the ternary complex created by trimming and uridylation of the stem-loop to better understand the role of this process in the histone mRNA life cycle. In this study, we used fluorescence polarization and electrophoretic mobility shift assays to demonstrate that both SLBP and 3'hExo can bind to uridylated and partially degraded stem-loop intermediates, although with lower affinity. We further characterized this complex by performing 1-µs molecular dynamics simulations using the AMBER force field and Nanoscale Molecular Dynamics (NAMD). These simulations show that while uridylation helps maintain the overall shape of the stem-loop, the combination of uridylation and dephosphorylation of the TPNK motif in SLBP disrupts key RNA-protein interactions. They also demonstrate that uridylation allows 3'hExo to maintain contact with the stem-loop after partial degradation and plays a role in disrupting key base pairs in partially degraded histone mRNA intermediates. Together, these experiments and simulations suggest that trimming by 3'hExo, uridylation, and SLBP dephosphorylation weakens both RNA-protein interactions and the stem-loop itself. Our results further elucidate the role of uridylation and SLBP dephosphorylation in the early stages of histone mRNA degradation.


Medicaid eligibility policy and the crowding-out effect: did women and children drop private health insurance to enroll in Medicaid.
In the late 1980s and early 1990s, the federal government expanded Medicaid eligibility for children and pregnant women. By 1992, nearly a third of all children in the United States were eligible for Medicaid, and between 40 and 50 percent of women of childbearing age were eligible for Medicaid coverage for pregnancy-related services. During this period, the number of persons with employment-based insurance coverage declined, leading researchers to investigate whether Medicaid expansions have contributed to this decline--a so-called crowding-out effect. This Issue Brief discusses research findings and the health policy implications of the crowding-out effect.


Evaluating Sampling Biases from Third-party Reporting as a Method for Improving Survey Measures of Sensitive Behaviors.
Survey participants often misreport their sensitive behaviors (e.g., smoking, drinking, having sex) during interviews. Several studies have suggested that asking respondents to report the sensitive behaviors of their friends or confidants, rather than their own, might help address this problem. This is so because the "third-party reporting" (TPR) approach creates a surrogate sample of alters that may be less subject to social desirability biases. However, estimates of the prevalence of sensitive behaviors based on TPR assume that the surrogate sample of friends is representative of the population of interest. We used sociometric data on social networks in Likoma, Malawi to examine this assumption. Specifically, we use friendship network data to investigate whether friends have similar socio-economic characteristics as index respondents, and to measure possible correlations between the likelihood of inclusion in the surrogate sample and sensitive behaviors. From these results, we suggest approaches to strengthen estimates of the prevalence of sensitive behaviors obtained from TPR.


Steroids as pain relief adjuvants.
Mr. C. is a married, 80-year-old man with a straight posture and a sharp wit. Ten years ago he was diagnosed with a pancreatic carcinoid tumour and underwent a Whipple procedure. Since then, his symptoms have been well controlled with intermittent chemotherapy despite his known liver and multiple spinal metastases.One year ago, Mr. C. developed bony pain from his cervical spine disease and was started on hydromorphone. Despite escalating doses, he presents to your office with increasing pain. The pain is moderate in severity and described as aching and constant in his neck, with intermittent, sharp, shooting pain through his left upper back and shoulder. You consider adding a corticosteroid as an adjuvant analgesic to Mr. C.'s hydromorphone regimen.


[An objective method for isolating globular protein domains].
Regions of more stability and nearest environs were localized on the basis of the calculation of intramolecular interactions in the frame of pair-wise approach. A criterium for definition of domains boundary in globular proteins is establishing if residues from k to l are included into one domain and residues from l+1 to l+1+m are included into another domain. According to this criterium, the boundary between two domains is set between two residues in the case when the interaction energy is minimal when first residue is included into the first domain and the second one into another. Structural domains are founded and probability of existing of domains boundary is studied for the binase, barnase, and complex of barnase with dioxy-dinucleotide inhibitor. It is determinated that the biggest structural interaction between domains coinsiders with location of domains at 1-43, 44-110 residues correspondently.


Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material.
Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein's poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed; however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations.


Low bend loss in tightly-bent fibers through adiabatic bend transitions.
We demonstrate low bend loss for tightly bent optical fibers by winding the fiber around a mandrel designed to follow an adiabatic transition path into the bend. Light in the fundamental core-guided mode is smoothly transferred to a single cladding mode of the bent fiber, and back to the core mode as it leaves the bent region again. Design of the transition is based on modeling of the propagation and coupling characteristics of the core and cladding modes, which clearly illustrate the physical processes involved.


AFRbase: a database of protein mutations responsible for antifungal resistance.
Fungal pathogens are known to cause life threatening invasive infections with rising global mortality rates. Besides, the indiscriminate use of antifungals in both clinics and agriculture has promoted antifungal drug resistance in the last decade. Fungi can show drug resistance by a variety of mechanisms. But primary driver in all these hitherto documented mechanisms is stable and heritable point mutations in the key proteins. Therefore, cataloguing mutations that can confer resistance is the first step toward understanding the mechanisms leading to the emergence of antifungal resistance. In the present, work we have described a database of all the mutations responsible for antifungal resistance. Named as antifungal resistance database (AFRbase), it is better than the existing databases of antifungal resistance namely, FunResDB and MARDy which have a limited scope and inadequate information. Data of AFRbase was collected using both text mining and manual curation. AFRbase provides a separate window for visualization of mutations in the 2D and 3D formats making it easy for researchers to analyze the mutation data and ensures interoperability with other standard molecular biology databases like NCBI and UniProtKB. We hope AFRbase can be useful to both clinicians and basic biomedical scientists as we envision it as an important resource for genotypic susceptibility testing of fungi and to study/predict the course of evolution of antifungal resistance. The current version of AFRbase contains manually curated 3691 unique mutations present in 29 proteins of 32 fungal species along with the information of drugs against which resistance is caused. AFRbase is an open access database available at http://proteininformatics.org/mkumar/afrbase/.


Overproduction of human M₃ muscarinic acetylcholine receptor: an approach toward structural studies.
Human M(3) muscarinic acetylcholine receptor (M3R), present in both the central and the peripheral nervous system, is involved in several neurodegenerative and autoimmune diseases. Recently, M3R overexpression has been suggested to play a role in certain forms of cancer, showing promise as a new potential pharmacological target. However, the lack of structural information hampered to develop a new potent selective and potent antagonist. We describe here different strategies for overexpressing functional M3R on the perspective of future biophysical studies. To achieve this goal, four tagged M3R genes were engineered and codon optimized. Different heterologous expression systems, including mammalian cells and viral transfection, were employed to overexpress M3R. Although codon optimization resulted in only twofold to threefold increase of M3R expression, we found that epitope tagging of the synthetic M3R, especially with hemagglutinin and Flag epitope tags, could improve M3R expression levels. On the other hand, viral transfection led to a yield of 27 pmol/mg protein that is the highest level reported so far for this receptor subtype in mammalian cells. Taking together several of the strategies used can help increasing M3R expression, not only to start purification efforts but also for secondary structural analysis trial and functional analyses.


Preparation and characterization of fine and stable short amylose nanocarriers for curcumin using a highly efficient and convenient method.
To prepare fine and stable nanocarriers for curcumin using a highly efficient and convenient method, nanoprecipitation combined with ultrasonication and a high-speed dispersion (US+HSS) method were used to prepare short amylose nanoparticles with pre-formed helical structures. Their morphology, structural characteristics, and embedding effects for curcumin were investigated. The results showed that the optimal ratio of ethanol to short amylose solution and ultrasonic time was 4:1 and 4 min, respectively. The nanoparticles showed a small size (82.43 nm), relatively high loading capacity (11.57 %), and a peak gelatinization temperature of 97.74 °C. Compared to the nanoprecipitation method, the short amylose nanoparticles prepared using the US+HSS method possessed a higher V-type crystalline structure ratio. In addition, the US+HSS method was easier to use to prepare nanoparticles with high stability against NaCl, and the stable nanoparticles showed the best in vitro sustained release effect for curcumin. The Peppas-Sahlin model was the optimal model that matched curcumin release from nanoparticles during digestion.


James Joyce: steps towards a diagnosis.
Authors whose scholarship is in the golden realm of English literature have not hesitated to make pronouncements on James Joyce's health. A publication in this genre claims he had tabes dorsalis. One feels that an authoritative comment, accepting or rejecting a diagnosis of neurosyphilis, should be provided by the Journal of the History of the Neurosciences.


The use of a mono-fluted reamer results in decreased enlargement of the tibial tunnel when using a transtibial ACL reconstruction technique.
To evaluate whether femoral tunnel preparation using a mono-fluted reamer rather than an acorn reamer would result in less tibial tunnel deformation when using a transtibial technique for anterior cruciate ligament reconstruction. Tibial and femoral tunnel preparation was performed in four matched pairs of cadaveric knees. The tibial tunnel was drilled using a standard acorn reamer. The femoral tunnel was prepared using a transtibial technique with a mono-fluted reamer, and then, the same femoral tunnel was re-reamed using an acorn reamer. The anterior-posterior (AP) and medial-lateral (ML) dimensions of the tibial tunnel were recorded after each reamer. We then compared the measurements following the use of each reamer using a paired two-sample t test. There was a significantly larger degree of tibial tunnel deformation following femoral tunnel preparation with the acorn reamer when compared with the mono-fluted reamer. The initial tibial tunnel measured 10.5 and 10.1 mm in the AP and ML dimensions, respectively. The resultant AP diameter of the tibial tunnel after femoral reaming was 16.7 mm (p < 0.001) for the acorn reamer compared with 11.6 mm (p < 0.001) for the mono-fluted reamer. The ML diameters were 11.3 mm (p = 0.003) versus 10.2 mm (p = 0.07) for the acorn and mono-fluted reamer, respectively. The use of a mono-fluted reamer for femoral tunnel preparation results in less tibial tunnel deformation during transtibial reaming.


The fast and the tendinous? Locomotor modifications of the caudal peduncle in Gila spp. from the American Southwest.
In the American Southwest, the fishes within the genus Gila evolved in an environment with seasonal rainstorms that caused stochastic flooding. Some species within this genus, such as bonytail (Gila elegans), possess locomotor morphologies that are similar to those seen in high-performance swimmers such as tuna and lamnid sharks. These shared features include a shallow caudal peduncle, lunate tail, and mechanisms to transmit force from the anterior musculature to the tail fin. We compared the skeletal anatomy of the caudal region of bonytail to roundtail chub (Gila robusta) and humpback chub (Gila cypha) to determine which vertebral elements have been modified to create a shallow peduncle. We also tested the tensile strength of the red (slow oxidative) axial muscle by performing a standard stress test. If the muscle can withstand a large load, this suggests it may play a tendon-like role in transmitting force from the anterior muscle to the hypural plate of the tail. Lastly, we measured the collagen content of the red axial muscle (visualized using serial sections and Masson's trichrome stain) to determine if increased tensile strength is associated with increased collagen content. We found bonytail caudal peduncles are characterized by acute vertebral spines and have red axial muscle that can resist tearing under tension. Roundtail chub peduncles are characterized by relatively more obtuse angles and the red muscle tears easily under tension. Humpback chub possess an intermediate morphology, with relatively obtuse vertebral spine angles and the red muscle can resist tearing under tension. Bonytail have increased collagen content in posterior red axial muscle compared to the anterior musculature also suggesting a tendon-like role of the posterior red muscle. In combination with previous studies of swimming performance, our findings suggest that the axial musculature of bonytail may play a role in transmitting force directly to the shallow peduncle in a manner similar to that of the great lateral tendon of scombrids.