Calcium regulation in endosymbiotic organelles of plants.
In plant cells calcium-dependent signaling pathways are involved in a large array of biological processes in response to hormones, biotic/abiotic stress signals and a variety of developmental cues. This is generally achieved through binding of calcium to diverse calcium-sensing proteins, which subsequently control downstream events by activating or inhibiting biochemical reactions. Regulation by calcium is considered as a eukaryotic trait and has not been described for prokaryotes. Nevertheless, there is increasing evidence indicating that organelles of prokaryotic origin, such as chloroplasts and mitochondria, are integrated into the calcium-signaling network of the cell. An important transducer of calcium in these organelles appears to be calmodulin. In this review we want to give an overview over present data showing that endosymbiotic organelles harbour calcium-dependent biological processes with a focus on calmodulin-regulation.


Endophytic Bacillus and Pseudomonas spp. Modulate Apple Shoot Growth, Cellular Redox Balance, and Protein Expression Under in Vitro Conditions.
Interactions between host plants and endophytic microorganisms play an important role in plant responses to pathogens and environmental stresses and have potential applications for plant stress management under in vitro conditions. We assessed the effect of endophytic bacteria on the growth and proliferation of domestic apple cv. Gala shoots in vitro. Further, a model apple cell suspension system was used to examine molecular events and protein expression patterns at an early stage of plant-endophyte interaction. Among the seven strains used in the study, Bacillus spp. strains Da_1, Da_4, and Da_5 and the Pseudomonas fluorescens strain Ga_1 promoted shoot growth and auxiliary shoot proliferation. In contrast, Bacillus sp. strain Oa_4, P. fluorescens strain Ga_3 and P. orientalis strain G_12 inhibited shoot development. In the cell suspension, the effects of the association between endophytic bacteria and plant cells were specific to each strain. Modulation of the cellular redox balance was monitored in the apple cells using a 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe, and strain-specific effects were observed that correlated with the in vitro shoot development results. Proteomic analysis revealed differences in protein expressions in apple cells co-cultivated with different Bacillus spp. strains that had contrasting effects on cellular redox balance and shoot development. The Bacillus sp. strain Da_4, which enhanced shoot development and oxidation of H2DCFDA, induced differential expression of proteins that are mainly involved in the defense response and regulation of oxidative stress. Meanwhile, treatment with Bacillus sp. strain Oa_4 led to strong upregulation of PLAT1, HSC70-1 and several other proteins involved in protein metabolism and cell development. Taken together, the results suggest that different cell signaling and response events at the early stage of the plant-endophyte interaction may be important for strain-dependent regulation of cellular redox balance and development of shoot phenotype.


Targeting prostate cancer based on signal transduction and cell cycle pathways.
Prostate cancer remains a leading cause of death in men despite increased capacity to diagnose at earlier stages. After prostate cancer has become hormone independent, which often occurs after hormonal ablation therapies, it is difficult to effectively treat. Prostate cancer may arise from mutations and dysregulation of various genes involved in regulation signal transduction (e.g., PTEN, Akt, etc.,) and the cell cycle (e.g., p53, p21(Cip1), p27(Kip1), Rb, etc.,). This review focuses on the aberrant interactions of signal transduction and cell cycle genes products and how they can contribute to prostate cancer and alter therapeutic effectiveness.


Lithium interactions with Na+-coupled inorganic phosphate cotransporters: insights into the mechanism of sequential cation binding.
Type IIa/b Na(+)-coupled inorganic phosphate cotransporters (NaPi-IIa/b) are considered to be exclusively Na(+) dependent. Here we show that Li(+) can substitute for Na(+) as a driving cation. We expressed NaPi-IIa/b in Xenopus laevis oocytes and performed two-electrode voltage-clamp electrophysiology and uptake assays to investigate the effect of external Li(+) on their kinetics. Replacement of 50% external Na(+) with Li(+) reduced the maximum transport rate and the rate-limiting plateau of the P(i)-induced current began at less hyperpolarizing potentials. Simultaneous electrophysiology and (22)Na uptake on single oocytes revealed that Li(+) ions can substitute for at least one of the three Na(+) ions necessary for cotransport. Presteady-state assays indicated that Li(+) ions alone interact with the empty carrier; however, the total charge displaced was 70% of that with Na(+) alone, or when 50% of the Na(+) was replaced by Li(+). If Na(+) and Li(+) were both present, the midpoint potential of the steady-state charge distribution was shifted towards depolarizing potentials. The charge movement in the presence of Li(+) alone reflected the interaction of one Li(+) ion, in contrast to 2 Na(+) ions when only Na was present. We propose an ordered binding scheme for cotransport in which Li(+) competes with Na(+) to occupy the putative first cation interaction site, followed by the cooperative binding of one Na(+) ion, one divalent P(i) anion, and a third Na(+) ion to complete the carrier loading. With Li(+) bound, the kinetics of subsequent partial reactions were significantly altered. Kinetic simulations of this scheme support our experimental data.


[Evaluation of the efficacy of recombinant human erythropoietin (rHuEPO) administration on penile erection in males undergoing hemodialysis and effect on pituitary-gonadal function].
Recombinant human erythropoietin (rHuEPO) was administered to males undergoing hemodialysis, and its effects on penile erection and hypothalamus-pituitary-gonadal hormone levels were studied. The subject consisted of 18 males undergoing hemodialysis ranging in age from 22 to 58 years (mean 45.3 years). Chronic glomerulonephritis was present in 16, and diabetic nephropathy in 2, as underlying disease. rHuEPO was administered intravenously at 1,500 U 3 times a week with a target to increase the Ht value to 25% or above. Penile erection was evaluated subjectively by a questionnaire based on a visual analogue scale and objectively by semi quantitative measurement of nocturnal penile tumescence (NPT) using an erectometer. Of the 18 patients, subjective improvements in penile erection were observed in 13 (72%), and objective improvements in NPT were observed in 10 (56%). The administration of rHuEPO may alleviate hyperprolactinemia but was found to have no effect on the FSH, LH, Zn, or HS-PTH level. rHuEPO was suggested to be fairly effective for the treatment of sexual disorders.


miR-194 as predictive biomarker of responsiveness to neoadjuvant chemoradiotherapy in patients with locally advanced rectal adenocarcinoma.
Curative surgery remains the primary form of treatment for locally advanced rectal cancer (LARC). Recent data support the use of preoperative chemoradiotherapy (pCRT) to improve the prognosis of LARC with a significant reduction of local relapse and an increase of overall survival. Unfortunately, only 20% of the patients with LARC present complete pathological response after pCRT, whereas in 20%-40%, the response is poor or absent. We investigated the expression level of miR-194 in n=38 patients with LARC using our public microRNA (miRNA) expression dataset. miR-194 expression was further validated by real-time quantitative PCR (qRT-PCR) and in situ hybridisation (ISH). Protein-protein interaction network and pathway enrichment analysis were performed on miR-194 targets. Using biopsy samples collected at diagnosis, mir-194 was significantly upregulated in patients responding to treatment (p value=0.016). The data was confirmed with qRT-PCR (p value=0.0587) and ISH (p value=0.026). Protein-protein interaction network and pathway enrichment analysis reveal a possible mechanism of susceptibility to pCRT involving Wnt pathway via its downstream mediator TRAF6. Finally, we interrogated the Comparative Toxicogenomics Database database in order to identify those chemical compounds able to mimic the biological effects of miR-194 as new possible therapeutic option in LARC treatment. The present study combining miRNA expression profiling with integrative computational biology identified miR-194 as predictive biomarker of response to pCRT. Using known and predicted drug mechanism of action, we then identified possible chemical compounds for further in vitro validation.


The origin of antiferroelectricity in PbZrO₃.
Antiferroelectrics are essential ingredients for the widely applied piezoelectric and ferroelectric materials: the most common ferroelectric, lead zirconate titanate is an alloy of the ferroelectric lead titanate and the antiferroelectric lead zirconate. Antiferroelectrics themselves are useful in large digital displacement transducers and energy-storage capacitors. Despite their technological importance, the reason why materials become antiferroelectric has remained allusive since their first discovery. Here we report the results of a study on the lattice dynamics of the antiferroelectric lead zirconate using inelastic and diffuse X-ray scattering techniques and the Brillouin light scattering. The analysis of the results reveals that the antiferroelectric state is a 'missed' incommensurate phase, and that the paraelectric to antiferroelectric phase transition is driven by the softening of a single lattice mode via flexoelectric coupling. These findings resolve the mystery of the origin of antiferroelectricity in lead zirconate and suggest an approach to the treatment of complex phase transitions in ferroics.


Aberration reduction in acoustical holography.
This paper examines the aberrations in holographic systems characterized by a ratio of reconstruction wavelength to recording wavelength of the order of 10(-3). The study is restricted to those systems using a plane reference beam and with the hologram scaled by a factor greater than the wavelength ratio. An inline hologram geometry is examined where the reconstruction beam is placed such that the image of a selected object point on the optical axis has zero aberrations. The aberrations for object points off axis then are calculated. For off-axis holograms, a technique for balancing spherical aberration and astigmatism has been modified to apply to scaled holograms. Some general rules for the optimum recording geometry are developed. The aberrations for the balanced off-axis system are calculated and compared to those of the in-line system.


Compact and stable THz vector spectroscopy using silicon photonics technology.
We present a compact and stable terahertz (THz) vector spectroscopy system using silicon photonics technology. A silicon-based integrated phase control circuit greatly reduces the physical size of the continuous-wave THz spectroscopy system and enhances environmental phase stability. Differential lightwave phase control using two carrier-injection electro-optic modulators enables fast and linear phase sweeps of THz-waves. Using the silicon-photonic circuit, we demonstrate a THz vector spectrometer; the dynamic ranges are 65 and 35 dB at 300 GHz and 1 THz with 1-ms integration time and phase variation is less than ± 10° without thermal packaging.


Interaction energies and dynamics of acid-base pairs isolated in cavitands.
The use of capsules and cavitands in physical organic chemistry is briefly reviewed, and their application to the study of salt bridges is introduced. Carboxylate/ammonium ion pairs are generated within an environment that more or less surrounds the functional groups within a synthetic fixed introverted solvent sphere. This is provided by cavitands that fold around amines and present them with a carboxylic acid function. Both organic and water-soluble versions were prepared, and their equilibrium affinities with quinuclidine bases were determined by NMR methods. The association constants range from approximately 10(3) M(-1) in water to more than 10(5) M(-1) in organic solvents. Studies of nitrogen inversion and tumbling of [2.2.2]-diazabicyclooctane within the introverted acids also illustrate the strength of the acid-base interactions. The barriers to in-out exchange of several amine guests were determined to be in the range from 15 to 24 kcal mol(-1). Some parallels with enzymes are drawn: the receptor folds around the guest species; presents them with inwardly directed functionality; and provides a generally hydrophobic environment and a periphery of secondary amide bonds.


The transcription factor Otx2 regulates choroid plexus development and function.
The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.


Using MEESTAR to Identify Ethical and Social Issues Implementing a Digital Patient-Centered Care Platform.
The PIQ research project ("Pflege im Quartier") aims for optimizing communication and patient-centered care for elderly people by implementing a digital, patient-centered care platform, with particular attention is paid to the consideration of ethical, legal and social issues. In this work, an instrument for the ethical evaluation of social-technical arrangement was used to map features of the platform with ethical concerns. The results include precise ethical questions based on scenarios identified and possible solutions to address them, regarding the ethical and privacy issues. These insights will be continuously integrated in the future system design and implementation as well as research.


In pursuit of truth: A critical examination of meta-analyses of cognitive behavior therapy.
Three recent meta-analyses have made the claim, albeit with some caveats, that cognitive-behavioral treatments (CBT) are superior to other psychotherapies, in general or for specific disorders (e.g., social phobia). The purpose of the present article was to examine four issues in meta-analysis that mitigate claims of CBT superiority: (a) effect size, power, and statistical significance, (b) focusing on disorder-specific symptom measures and ignoring other important indicators of psychological functioning, (c) problems inherent in classifying treatments provided in primary studies into classes of treatments, and (d) the inclusion of problematic trials, which biases the results, and the exclusion of trials that fail to find differences among treatments. When these issues are examined, the effects demonstrating the superiority of CBT are small, nonsignificant for the most part, limited to targeted symptoms, or are due to flawed primary studies. Meta-analytic evidence for the superiority of CBT in the three meta-analysis are nonexistent or weak.


The crystal structure of plasma gelsolin: implications for actin severing, capping, and nucleation.
The structure of gelsolin has been determined by crystallography and comprises six structurally related domains that, in a Ca2+-free environment, pack together to form a compact globular structure in which the putative actin-binding sequences are not sufficiently exposed to enable binding to occur. We propose that binding Ca2+ can release the connections that join the N- and C-terminal halves of gelsolin, enabling each half to bind actin relatively independently. Domain shifts are proposed in response to Ca2+ as bases for models of how gelsolin acts to sever, cap, or nucleate F-actin filaments. The structure also invites discussion of polyphosphoinositide binding to segment 2 and suggests how mutation at Asp-187 could initiate a series of events that lead to deposition of amyloid plaques, as observed in victims of familial amyloidosis (Finnish type).


The patterns of fetal haemoglobin production in leukaemia.
Elevated levels of haemoglobin F (Hb F) have been foudn in a wide range of haematological malignancies, but very high levels were found only in juvenile chronic myeloid leukaemia (JCML), and erythroleukaemia occurring in infancy. In both these disorders a reversion to a fetal form of erythropoiesis may occur, as judged by both the structure of the Hb F and by the disappearance of Hb A2 and the carbnoic-anhydrase isozymes during the course of the illness. The clinical picture of JCML is not always associated with a reversion to fetal erythropoiesis; there appears to be a heterogeneity of conditions with this clinical label. Thus the reversion to a completely fetal pattern of erythropoiesis seems to occur in a variety of leukaemias which start in early life. This change is associated with a uniformly bad prognosis. Of a group of 17 patients with acute myeloid leukaemia 15 developed an increase in the level of Hb F about 60 days after the commencement of treatment; significantly greater increases were observed in those achieving a clinical remission. The level of Hb F usually declined during remission but high levels persisted in a few cases. Increased levels of Hb F were found also in patients with other haematological malignancies who had undergone periods of marrow aplasia during treatment. In all cases the Hb F was heterogeneously distributed throughout the red cells. Analysis of gamma15 or gammaCB3 peptides of Hb F from a variety of leukaemias gave glycine compositions ranging from 0.20 to 0.85 residues with many values in the fetal range; all cases with a reversion to fetal erythropoiesis had values in the fetal range. Attempts to confirm the 'fetal' origin of the cells containing Hb F by means of other markers was possible only in the cases of JCML and in one child with erythroleukaemia. These studies indicate that in some forms of leukaemia there may be a genuine reversion to fetal erythropoiesis while in others the emergence of cells containing Hb F appears to be part of a rapid regeneration process occurring after a period of marrow aplasia. The diagnostic and prognostic value of these observations is discussed.


Impact of a dietary supplement containing 1,3-dimethylamylamine on blood pressure and bloodborne markers of health: a 10-week intervention study.
1,3-dimethylamylamine is a commonly used ingredient within dietary supplements. Our prior work with this agent indicates a transient increase in blood pressure (systolic in particular) following oral ingestion of a single dosage, but no significant increase in resting blood pressure following chronic ingestion. Moreover, intervention studies involving both two and eight weeks of treatment with finished products containing 1,3-dimethylamylamine indicate minimal or no change in bloodborne markers of health. The present study sought to extend these findings by using a 10-week intervention trial to determine the change in selected markers of health in a sample of men. 25 healthy men were randomly assigned to either a placebo (n = 13) or to a supplement containing 1,3-dimethylamylamine (n = 12) for a period of 10 weeks. Before and after the intervention, resting blood pressure and heart rate were measured, and blood samples were collected for determination of complete blood count, metabolic panel, and lipid panel. No significant differences were noted between conditions for blood pressure (P > 0.05), although systolic blood pressure increased approximately 6 mmHg with the supplement (diastolic blood pressure decreased approximately 4 mmHg). A main effect for time was noted for heart rate (P = 0.016), with values decreasing from pre to post intervention. There were significant main effects for time for creatinine (increased from pre to post intervention; P = 0.043) and alkaline phosphatase (decreased from pre to post intervention; P = 0.009), with no condition differences noted (P > 0.05). There was a significant interaction noted for low density lipoprotein cholesterol (LDL-C) (P = 0.043), with values decreasing in the supplement group from pre to post intervention approximately 7 mg · dL(-1) (P = 0.034). No other effects of significance were noted for bloodborne variables. These data indicate that a dietary supplement containing 1,3-dimethylamylamine does not result in a statistically significant increase in resting heart rate or blood pressure (although systolic blood pressure is increased ∼6 mmHg with supplement use). The supplement does not negatively impact bloodborne markers of health. Further study is needed involving a longer intervention period, a larger sample size, and additional measures of health and safety.


Dietary genistein and equol (4', 7 isoflavandiol) reduce oxidative stress and protect rats against focal cerebral ischemia.
High soy diets reduce injury in rat models of focal cerebral ischemia and are proposed as alternatives to hormone replacement therapy for postmenopausal women. The present study tests the hypothesis that the major soy isoflavone genistein and the daidzein metabolite equol are neuroprotective in transient focal cerebral ischemia in male and ovariectomized (OVX) female rats by inhibiting oxidative stress. Genistein is the primary circulating soy isoflavone in humans, whereas equol is the primary circulating isoflavone in rats. Male and OVX female Sprague-Dawley rats were fed an isoflavone-reduced diet alone or supplemented with genistein (500 ppm) or equol (250 ppm) for 2 wk prior to 90-min transient middle cerebral artery occlusion followed by reperfusion under isoflurane anesthesia. Indices of oxidative stress were determined 24 h after reperfusion, and cerebral injury was evaluated 3 days after reperfusion. Genistein and equol significantly reduced infarct size in both sexes. Further studies in OVX female rats revealed that this neuroprotection was accompanied by a decrease in NAD(P)H oxidase activity and superoxide levels in the brain. In addition, equol reduced plasma thiobarbituric acid reactive substances, and neurological deficits up to 7 days after injury. There were no significant differences in cerebral blood flow among treatment groups. In conclusion, dietary soy isoflavones are neuroprotective in transient focal cerebral ischemia in male and OVX female rats. These isoflavones may protect the brain via increases in endogenous antioxidant mechanisms and reduced oxidative stress.


Mapping the protein universe.
The comparison of the three-dimensional shapes of protein molecules poses a complex algorithmic problem. Its solution provides biologists with computational tools to organize the rapidly growing set of thousands of known protein shapes, to identify new types of protein architecture, and to discover unexpected evolutionary relations, reaching back billions of years, between protein molecules. Protein shape comparison also improves tools for identifying gene functions in genome databases by defining the essential sequence-structure features of a protein family. Finally, an exhaustive all-on-all shape comparison provides a map of physical attractor regions in the abstract shape space of proteins, with implications for the processes of protein folding and evolution.


Mindfulness-based cognitive therapy improves emotional reactivity to social stress: results from a randomized controlled trial.
The high likelihood of recurrence in depression is linked to a progressive increase in emotional reactivity to stress (stress sensitization). Mindfulness-based therapies teach mindfulness skills designed to decrease emotional reactivity in the face of negative affect-producing stressors. The primary aim of the current study was to assess whether Mindfulness-Based Cognitive Therapy (MBCT) is efficacious in reducing emotional reactivity to social evaluative threat in a clinical sample with recurrent depression. A secondary aim was to assess whether improvement in emotional reactivity mediates improvements in depressive symptoms. Fifty-two individuals with partially remitted depression were randomized into an 8-week MBCT course or a waitlist control condition. All participants underwent the Trier Social Stress Test (TSST) before and after the 8-week trial period. Emotional reactivity to stress was assessed with the Spielberger State Anxiety Inventory at several time points before, during, and after the stressor. MBCT was associated with decreased emotional reactivity to social stress, specifically during the recovery (post-stressor) phase of the TSST. Waitlist controls showed an increase in anticipatory (pre-stressor) anxiety that was absent in the MBCT group. Improvements in emotional reactivity partially mediated improvements in depressive symptoms. Limitations include small sample size, lack of objective or treatment adherence measures, and non-generalizability to more severely depressed populations. Given that emotional reactivity to stress is an important psychopathological process underlying the chronic and recurrent nature of depression, these findings suggest that mindfulness skills are important in adaptive emotion regulation when coping with stress.


Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)
Extracellular survival factors alter a cell's susceptibility to apoptosis, often through posttranslational mechanisms. However, no consistent relationship has been established between such survival signals and the BCL-2 family, where the balance of death agonists versus antagonists determines susceptibility. One distant member, BAD, heterodimerizes with BCL-X(L) or BCL-2, neutralizing their protective effect and promoting cell death. In the presence of survival factor IL-3, cells phosphorylated BAD on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated BAD heterodimerized with BCL-X(L) at membrane sites to promote cell death. Phosphorylated BAD was sequestered in the cytosol bound to 14-3-3. Substitution of serine phosphorylation sites further enhanced BAD's death-promoting activity. The rapid phosphorylation of BAD following IL-3 connects a proximal survival signal with the BCL-2 family, modulating this checkpoint for apoptosis.


Biomechanical topography of human articular cartilage in the first metatarsophalangeal joint.
The objective of this study was to provide a map of cartilage biomechanical properties, thickness, and histomorphometric characteristics in the human, cadaveric first metatarsophangeal joint, to determine if normal articular cartilage was predisposed topographically to biomechanical mismatches in articulating surfaces. Cartilage intrinsic material properties and thickness were obtained from seven pairs of human, freshly frozen, cadaveric, metatarsophalangeal joints using an automated creep indentation apparatus under conditions of biphasic creep. Eight sites were tested: four on the metatarsal head, two on the proximal phalanx base, and one on each sesamoid bone to obtain the aggregate modulus, Poisson's ratio, permeability, shear modulus, and thickness. Cartilage in the lateral phalanx site of the left metatarsal head had the largest aggregate modulus (1.34 MPa), whereas the softest tissue was found in the right medial sesamoid (0.63 MPa). The medial phalanx region of the right joint was the most permeable (4.56 x 10(-15) meter4/Newton-second), whereas the medial sesamoid articulation of the metatarsal head of the left joint was the least permeable (1.26 x 10(-15) meter4/Newton-second). Material properties and thickness are indicative of the tissue's functional environment. The lack of mismatches in cartilage biomechanical properties of the articulating surfaces found in this study may be supportive of clinical observations that early degenerative changes, in the absence of traumatic events, do not occur at the selected test sites in the human first metatarsophalangeal joint.


Evaluating the relationship between smartphone addiction/overuse and musculoskeletal pain among medical students at Qassim University.
Smartphone use has greatly increased in recent days, and most of the daily tasks are done through these devices. As a result, long time use may involve bad posture that may result in musculoskeletal pain. Therefore, it is important to evaluate the association between addiction/overuse of smartphones and musculoskeletal pain. To determine the prevalence of addictive/overuse of smartphones among medical students and to investigate if there is an association between smartphone addiction and musculoskeletal pain. A cross-sectional study conducted at Qassim University, medical college. The Smartphone Addiction Scale Short Version (SAS-SV) was used to measure the level of smartphone addiction while the Nordic musculoskeletal questionnaire (NMQ) was utilized to evaluate the musculoskeletal pain. The prevalence of smartphone addiction among medical students was relatively high (60.3%). The most frequent pain related to smartphone addiction was in the neck (60.8%), followed by lower back (46.8%), shoulder (40.0%). The academic year level was statistically associated with the level of smartphone addiction. Moreover, we found a significant relationship between musculoskeletal pain and smartphone addiction at certain body regions, neck, wrist/hand and knees, Other musculoskeletal parameters included in the test were found to have no statistically significant association. More than half of the medical students identified as addicted to smartphones. The most common musculoskeletal pain was the neck, lower back, and shoulder. The academic year level found to have a significant association with the level of smartphone addiction while musculoskeletal pain such as neck, wrist, and knee were the independent significant factors of smartphone addiction; therefore, it is important to educate the community about the effect of being addicted to smartphone use in order to prevent the consequences of this behavior.


Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC.
Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis. A previously reported missense mutation in the CTSC gene (NM_001814.4:c.899G>A:p.(G300D)) was identified in a homozygous state in two siblings diagnosed with PLS in a consanguineous family of Arabic ancestry. The variant was initially identified in a heterozygous state in a PLS unaffected sibling whose whole exome had been sequenced as part of a previous Primary ciliary dyskinesia study. Using this information, a proxy molecular diagnosis was made on the PLS affected siblings after consent was given to study this second disorder found to be segregating within the family. The prevalence of the mutation was then assayed in the local population using a representative sample of 256 unrelated individuals. The variant was absent in all subjects indicating that the variant is rare in Saudi Arabia. This family study illustrates how whole-exome sequencing can generate findings and inferences beyond its primary goal.


Guidelines on the management of common bile duct stones (CBDS).
The last 30 years have seen major developments in the management of gallstone-related disease, which in the United States alone costs over 6 billion dollars per annum to treat. Endoscopic retrograde cholangiopancreatography (ERCP) has become a widely available and routine procedure, whilst open cholecystectomy has largely been replaced by a laparoscopic approach, which may or may not include laparoscopic exploration of the common bile duct (LCBDE). In addition, new imaging techniques such as magnetic resonance cholangiography (MR) and endoscopic ultrasound (EUS) offer the opportunity to accurately visualise the biliary system without instrumentation of the ducts. As a consequence clinicians are now faced with a number of potentially valid options for managing patients with suspected CBDS. It is with this in mind that the following guidelines have been written.


Why rural residents migrate for family physician care.
Several studies have examined why rural residents bypass local hospitals, but few have explored why they migrate for physician care. In this study, data from a random mail survey of households in rural Iowa counties were used to determine how consumers' attitudes about their local health system, health beliefs, health insurance coverage and other personal characteristics influenced their selection of local vs. nonlocal family physicians (family physician refers to the family practice, internal medicine or other medical specialist providing an individual's primary care). Migration for family physician care was positively associated with a perceived shortage of local family physicians and use of nonlocal specialty physician care. Migration was negatively associated with a highly positive rating of the overall local health care system, living in town, Lutheran religious affiliation and private health insurance coverage. By understanding why rural residents prefer to bypass local physicians, rural health system managers, physicians and policy-makers should be better prepared to design innovative health organizations and programs that meet the needs of rural consumers.


Chemically defined conditions for human iPSC derivation and culture.
We re-examine the individual components for human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) culture and formulate a cell culture system in which all protein reagents for liquid media, attachment surfaces and splitting are chemically defined. A major improvement is the lack of a serum albumin component, as variations in either animal- or human-sourced albumin batches have previously plagued human ESC and iPSC culture with inconsistencies. Using this new medium (E8) and vitronectin-coated surfaces, we demonstrate improved derivation efficiencies of vector-free human iPSCs with an episomal approach. This simplified E8 medium should facilitate both the research use and clinical applications of human ESCs and iPSCs and their derivatives, and should be applicable to other reprogramming methods.


Molecular heterogeneity among primary motoneurons and within myotomes revealed by the differential mRNA expression of novel islet-1 homologs in embryonic zebrafish.
Zebrafish embryos have three or four identifiable primary motoneurons per hemisegment. We previously reported that, while several ventral cells initially express the zebrafish Islet-1 (Isl-1) gene, a member of the LIM/homeobox gene family, the expression of this gene becomes restricted to a single or a pair of cells slightly anterior to each segment border by 16 hr after fertilization. Double staining by in situ hybridization and immunohistochemistry strongly suggested that these cells were mainly rostral primary motoneurons. Here, we have isolated two novel zebrafish cDNA clones for more Isl-1 family genes, termed zfIsl-2 and zfIsl-3. zfIsl-2 mRNA starts to be expressed in the ventral midsegmental cells per hemisegment around 15 hr. Double labeling experiments have shown that these midsegmental cells are the caudal primary motoneuron (CaP) and its variant equivalence pair. Our results revealed the heterogeneity in the expressed genes among primary motoneurons before the fates of the primary motoneurons are irreversibly determined, and further suggest the involvement of the Isl-1 and zfIsl-2 genes in the determination of cellular identities by primary motoneurons in embryonic zebrafish. zfIsl-3 mRNA is not expressed in motoneurons but is expressed at 17 hr, mainly in the ventral myotomes. This suggests that zfIsl-3 may be involved in the regional specification of the myotome and also in target recognition by CaP. zfIsl-2 is also expressed throughout the developing eye and tectal region of the midbrain, the target for the retinal axons. In the ventral spinal cord of the spadetail mutant embryo, which has defects in the somites, the cells expressing zfIsl-2 mRNA significantly decreased in number in contrast to the increase in cells expressing Isl-1 mRNA, suggesting the influence of the somites on the expression of both genes.


OsWRKY28 Regulates Phosphate and Arsenate Accumulation, Root System Architecture and Fertility in Rice.
WRKYs are transcriptional factors involved in stress tolerance and development of plants. In the present study, we characterized OsWRKY28, a group IIa WRKY gene, in rice, because its expression was found to be upregulated by arsenate exposure in previous transcriptomic studies. Subcellular localization using YFP-OsWRKY28 fusion protein showed that the protein was localized in the nuclei. Transgenic rice plants expressing pOsWRKY28::GUS suggested that the gene was expressed in various tissues in the whole plant, with a strong expression in the root tips, lateral roots and reproductive organs. The expression of OsWRKY28 was markedly induced by arsenate and other oxidative stresses. In a hydroponic experiment, loss-of-function mutation in OsWRKY28 resulted in lower accumulation of arsenate and phosphate concentration in the shoots. The mutants showed altered root system architecture, with fewer lateral roots and shorter total root length than wild-type plants. In a soil pot experiment, the mutants produced lower grain yield than wild-type because of reduced fertility and smaller effective tiller numbers. Transcriptomic profiling using RNA-seq showed altered expression in the mutant of genes involved in the biosynthesis of phytohormones, especially jasmonic acid (JA). Exogenous JA treatments mimicked the phenotypes of the oswrky28 mutants with inhibited root elongation and decreased arsenate/phosphate translocation. Our results suggested that OsWRKY28 affected arsenate/phosphate accumulation, root development at the seedling stage and fertility at the reproductive stage possibly by influencing homeostasis of JA or other phytohormones.


Size-dependent cellular toxicity of silver nanoparticles.
Silver nanoparticles (AgNPs) have found a variety of uses including biomedical materials; however, studies of the cytotoxicity of AgNPs by size effects are only in the beginning stage. In this study, we examined the size-dependent cellular toxicity of AgNPs using three different characteristic sizes (∼ 10, 50, and 100 nm) against several cell lines including MC3T3-E1 and PC12. The cytotoxic effect determined based on the cell viability, intracellular reactive oxygen species generation, lactate dehydrogenase release, ultrastructural changes in cell morphology, and upregulation of stress-related genes (ho-1 and MMP-3) was fairly size- and dose-dependent. In particular, AgNPs stimulated apoptosis in the MC3T3-E1 cells, but induced necrotic cell death in the PC12 cells. Furthermore, the smallest sized AgNPs (10 nm size) had a greater ability to induce apoptosis in the MC3T3-E1 cells than the other sized AgNPs (50 and 100 nm). These data suggest that the AgNPs-induced cytotoxic effects against tissue cells are particle size-dependent, and thus, the particle size needs careful consideration in the design of the nanoparticles for biomedical uses.


The impact of feature selection on one and two-class classification performance for plant microRNAs.
MicroRNAs (miRNAs) are short nucleotide sequences that form a typical hairpin structure which is recognized by a complex enzyme machinery. It ultimately leads to the incorporation of 18-24 nt long mature miRNAs into RISC where they act as recognition keys to aid in regulation of target mRNAs. It is involved to determine miRNAs experimentally and, therefore, machine learning is used to complement such endeavors. The success of machine learning mostly depends on proper input data and appropriate features for parameterization of the data. Although, in general, two-class classification (TCC) is used in the field; because negative examples are hard to come by, one-class classification (OCC) has been tried for pre-miRNA detection. Since both positive and negative examples are currently somewhat limited, feature selection can prove to be vital for furthering the field of pre-miRNA detection. In this study, we compare the performance of OCC and TCC using eight feature selection methods and seven different plant species providing positive pre-miRNA examples. Feature selection was very successful for OCC where the best feature selection method achieved an average accuracy of 95.6%, thereby being ∼29% better than the worst method which achieved 66.9% accuracy. While the performance is comparable to TCC, which performs up to 3% better than OCC, TCC is much less affected by feature selection and its largest performance gap is ∼13% which only occurs for two of the feature selection methodologies. We conclude that feature selection is crucially important for OCC and that it can perform on par with TCC given the proper set of features.


Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy.
Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing. Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with β-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans. We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth. We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors.


PtyLab.m/py/jl: a cross-platform, open-source inverse modeling toolbox for conventional and Fourier ptychography.
Conventional (CP) and Fourier (FP) ptychography have emerged as versatile quantitative phase imaging techniques. While the main application cases for each technique are different, namely lens-less short wavelength imaging for CP and lens-based visible light imaging for FP, both methods share a common algorithmic ground. CP and FP have in part independently evolved to include experimentally robust forward models and inversion techniques. This separation has resulted in a plethora of algorithmic extensions, some of which have not crossed the boundary from one modality to the other. Here, we present an open source, cross-platform software, called PtyLab, enabling both CP and FP data analysis in a unified framework. With this framework, we aim to facilitate and accelerate cross-pollination between the two techniques. Moreover, the availability in Matlab, Python, and Julia will set a low barrier to enter each field.


Sonographic findings of metastatic disease to the thyroid.
The goal of this study was to evaluate the sonographic findings of thyroid metastases arising from non-thyroid primaries. The study over a 5-year period comprised nine patients who had histopathologically proven metastatic disease to the thyroid. Ultrasonography was available in all cases. Ultrasound-guided needle aspiration was performed on 10 suspected nodules as determined by ultrasound. The Ultrasonographic findings were analyzed in two different ways. The first analysis included only those nodules biopsed, and the second analysis included all the nodules, biopsed and non-biopsed. The primary neoplasms were breast carcinoma (n=6), uterine leiomyosarcoma (n=1), cervical carcinoma (n=1), and nasopharyngeal carcinoma (n=1). Excluding 2 nodules, the 8 remaining metastatic nodules exhibited ill-defined hypoechoic character with heterogeneous texture. The other two nodules showed relatively circumscribed iso- or hypo-echoic character with cystic portion. From the analysis of ultrasonographic findings including all thyroid nodules irrespective of pathologic proof, 7 cases - excluding the 2 cases from the 9 cases - showed unilateral or bilateral multiple nodules suspected of metastasis. There was no evidence of microcalcification in any thyroid nodules. In conclusion, the sonographic findings of the thyroid metastatic nodules were not specific, but unilateral or bilateral multiple suspected thyroid nodules without evidence of microcalcification may be suggestive of metastatic nodules among patients with a known primary non-thyroidal tumor.


Asynchronous carbon sink saturation in African and Amazonian tropical forests.
Structurally intact tropical forests sequestered about half of the global terrestrial carbon uptake over the 1990s and early 2000s, removing about 15 per cent of anthropogenic carbon dioxide emissions1-3. Climate-driven vegetation models typically predict that this tropical forest 'carbon sink' will continue for decades4,5. Here we assess trends in the carbon sink using 244 structurally intact African tropical forests spanning 11 countries, compare them with 321 published plots from Amazonia and investigate the underlying drivers of the trends. The carbon sink in live aboveground biomass in intact African tropical forests has been stable for the three decades to 2015, at 0.66 tonnes of carbon per hectare per year (95 per cent confidence interval 0.53-0.79), in contrast to the long-term decline in Amazonian forests6. Therefore the carbon sink responses of Earth's two largest expanses of tropical forest have diverged. The difference is largely driven by carbon losses from tree mortality, with no detectable multi-decadal trend in Africa and a long-term increase in Amazonia. Both continents show increasing tree growth, consistent with the expected net effect of rising atmospheric carbon dioxide and air temperature7-9. Despite the past stability of the African carbon sink, our most intensively monitored plots suggest a post-2010 increase in carbon losses, delayed compared to Amazonia, indicating asynchronous carbon sink saturation on the two continents. A statistical model including carbon dioxide, temperature, drought and forest dynamics accounts for the observed trends and indicates a long-term future decline in the African sink, whereas the Amazonian sink continues to weaken rapidly. Overall, the uptake of carbon into Earth's intact tropical forests peaked in the 1990s. Given that the global terrestrial carbon sink is increasing in size, independent observations indicating greater recent carbon uptake into the Northern Hemisphere landmass10 reinforce our conclusion that the intact tropical forest carbon sink has already peaked. This saturation and ongoing decline of the tropical forest carbon sink has consequences for policies intended to stabilize Earth's climate.


Evaluating the safety and operational impacts of left-turn bay extension at signalized intersections using automated video analysis.
Left-turn lanes are commonly introduced to provide space to accommodate comfortable deceleration and adequate storage of turning vehicles. Operational shortcomings may arise due to inadequate length, including overflow and blockage of left-turn entrance by queues on an adjacent through lane. This study investigates the potential safety and operational benefits of treating left-turn lanes by extending the length further upstream a signalized intersection. Video data was collected at three treated left-turn lanes as well as three matched control lanes; all in both before and after treatment conditions. Safety parameters consisted of the counts and severities of traffic conflicts occurring on the left-turn lanes and inside the intersection. There was a marked reduction in traffic conflict counts in all treated sites. The overall treatment effect, which accounts for the simultaneous change in control sites, was 63.2% (p < 0.05). There was a marked reduction in frequency of traffic conflicts at different severity levels. The mobility benefit of the treatment was demonstrated in terms of the reduction in average travel time for left-turn as well as through vehicles. The count of traffic signal cycles with blocked left-turn entrance was considerably reduced after the treatment. The use of collision data gathered from more sites is suggested as potential future work to further evaluate this treatment.


Calcium-regulated interaction of Sgt1 with S100A6 (calcyclin) and other S100 proteins.
S100A6 (calcyclin), a small calcium-binding protein from the S100 family, interacts with several target proteins in a calcium-regulated manner. One target is Calcyclin-Binding Protein/Siah-1-Interacting Protein (CacyBP/SIP), a component of a novel pathway of beta-catenin ubiquitination. A recently discovered yeast homolog of CacyBP/SIP, Sgt1, associates with Skp1 and regulates its function in the Skp1/Cullin1/F-box complex ubiquitin ligase and in kinetochore complexes. S100A6-binding domain of CacyBP/SIP is in its C-terminal region, where the homology between CacyBP/SIP and Sgt1 is the greatest. Therefore, we hypothesized that Sgt1, through its C-terminal region, interacts with S100A6. We tested this hypothesis by performing affinity chromatography and chemical cross-linking experiments. Our results showed that Sgt1 binds to S100A6 in a calcium-regulated manner and that the S100A6-binding domain in Sgt1 is comprised of 71 C-terminal residues. Moreover, S100A6 does not influence Skp1-Sgt1 binding, a result suggesting that separate Sgt1 domains are responsible for interactions with S100A6 and Skp1. Sgt1 binds not only to S100A6 but also to S100B and S100P, other members of the S100 family. The interaction between S100A6 and Sgt1 is likely to be physiologically relevant because both proteins were co-immunoprecipitated from HEp-2 cell line extract using monoclonal anti-S100A6 antibody. Phosphorylation of the S100A6-binding domain of Sgt1 by casein kinase II was inhibited by S100A6, a result suggesting that the role of S100A6 binding is to regulate the phosphorylation of Sgt1. These findings suggest that protein ubiquitination via Sgt1-dependent pathway can be regulated by S100 proteins.


Acupuncture for alcohol withdrawal: a randomized controlled trial.
Previous trials on acupuncture in alcohol addiction were in outpatients and focused on relapse prevention. Rates of dropout were high and interpretation of results difficult. We compared auricular laser and needle acupuncture with sham laser stimulation in reducing the duration of alcohol withdrawal. Inpatients undergoing alcohol withdrawal were randomly allocated to laser acupuncture (n = 17), needle acupuncture (n = 15) or sham laser stimulation (n = 16). Attempts were made to blind patients, therapists and outcome assessors, but this was not feasible for needle acupuncture. The duration of withdrawal symptoms (as assessed using a nurse-rated scale) was the primary outcome; the duration of sedative prescription was the secondary outcome. Patients randomized to laser and sham laser had identical withdrawal symptom durations (median 4 days). Patients randomized to needle stimulation had a shorter duration of withdrawal symptoms (median 3 days; P = 0.019 versus sham intervention), and tended to have a shorter duration of sedative use, but these differences diminished after adjustment for baseline differences. The data from this pilot trial do not suggest a relevant benefit of auricular laser acupuncture for alcohol withdrawal. A larger trial including adequate sham interventions is needed, however, to reliably determine the effectiveness of any type of auricular acupuncture in this condition.


Impact of integrated cerebrovascular program on outcomes in patients with intracranial aneurysms.
Recent evidence indicates that multidisciplinary care improves patient outcomes in cerebrovascular (CV) disease. A multidisciplinary integrated CV program was recently instituted at a high-volume tertiary referral center, providing the opportunity to evaluate patient outcomes before and after its introduction. To evaluate outcomes after treatment of patients with intracranial aneurysm in relation to the introduction of a CV program at our institution. A retrospective chart review was performed on all new patient encounters for a 6-month period each before and immediately after the introduction of the CV program, as well as at a more recent 6-month period to evaluate long-term results. Data were collected on demographic variables, rupture status, medical comorbidities, hospital complications, in-hospital procedures, hospital course and modified Rankin score at discharge and follow up. The total number of patients treated increased from 55 in the 6-month period before the introduction of the CV program to 112 in the most recent time period (p<0.05). Both the surgical clipping and endovascular coiling procedures increased (p<0.05). A significant increase occurred in patients with multiple comorbidities (30.5% vs 34.7%, p=0.035). The mean length of stay decreased from 12.22 ± 13.26 days before the program to 9.23 ± 12.04 days in the most current data (p<0.05). Creation of an integrated CV program at a large-volume tertiary referral center resulted in better outcomes for an increased number of more medically complicated patients with intracranial aneurysms. This study provides preliminary data for developing an integrated model of multidisciplinary care for the management of CV disease.


Altered calcium conductance in pawns, behavioural mutants of Paramecium aurelia.
Pawns are behavioural mutants (in one of three genes) of Paramecium aurelia that have lost, to varying degrees, the reversal response which is thought to depend on the calcium influx during excitation. This report shows that all of the single and double mutants have reduced active inward (calcium) current, the reduction correlating with the degree of behavioural deficit. All of the mutants display normal resting potential, input impedance and delayed rectification. Mutants in genes pwA and pwC show normal anomalous rectification, but pwB mutants do not show anomalous rectification until the membrane is hyperpolarized further. We suggest that the pwA gene plays a role in depolarization sensitivity (the 'gate') and the pwB gene a role affecting either the wall of the channel itself or the total number of channels.


No Decrease in Knee Survivorship or Outcomes Scores for Patients With HIV Infection Who Undergo TKA.
HIV is prevalent worldwide and numerous patients with this diagnosis ultimately may become candidates for TKA. Although some studies have suggested that complications are more common in patients with HIV who undergo TKA, these studies largely were done before the contemporary era of HIV management; moreover, it is unclear whether patients with HIV achieve lower patient-reported outcome scores or inferior implant survivorship. We asked whether there were any differences in the outcomes of patients with HIV without hemophilia who undergo TKA compared with a matched control cohort in terms of: (1) patient-reported outcomes; (2) implant survivorship; and (3) complication rates. Forty-five patients with HIV who had undergone 50 TKAs at three institutions with a minimum followup of 4 years between 2005 and 2011 were identified. An additional three patients were lost to followup before the fourth-year annual visit. All patients with HIV underwent thorough preoperative optimization with their primary care physician and infectious disease specialist. There were 31 men and 14 women with a mean age of 57 years and mean followup of 6 years (range, 4-10 years). These patients were compared with a matched cohort of 135 patients (one-to-three ratio) who did not have HIV and who had undergone a primary TKA by the same surgeons during this same period using the same implant. Matching criteria included patient age (within 2 years), BMI (within 2 kg/m2), surgeon performing TKA, followup (within 6 months), minimum followup of 4 years, sex ratio, and primary diagnosis (degenerative joint disease versus osteonecrosis). Approximately 10% of patients in the matching group had not returned for followup after their sixth annual visit. Outcomes evaluated included The Knee Society objective and function scores, University of California, Los Angeles (UCLA) activity scores, overall implant survivorship (free of revision) using Kaplan-Meier analysis, and complications. With the numbers available, there were no differences in preoperative Knee Society score or UCLA activity scores among the cohorts. With the numbers available, there were no differences in the mean Knee Society objective scores between patients with HIV (89 ± 11 points) and the matching cohort (91 ± 14 points) (95% CI, -7 to 3; p = 0.38). There were no differences among the Knee Society functional component as well (88 ± 12 points versus 90 ± 13 points; 95% CI, -6 to 2; p = 0.36) at latest followup. Similarly, there were no differences with the numbers available in the UCLA activity scores (6 ± 5 points [range, 4-7] versus 6 ± 7 points [range, 4-8]; p = 0.87) between the cohorts. With the numbers available, Kaplan-Meier analysis showed no significant difference in the overall implant survivorships between patients with HIV (98%; 95% CI, 94%-99%) compared with the matching group (99%; 95% CI, 98%-100%; p = 0.89). Postoperative complications were also comparable between the two groups. With the numbers available, we found that patients with HIV had no differences in clinical scores and implant survivorship compared with patients without the disease at mid-term followup. We believe practitioners should not be reluctant to perform TKA on this patient population. However, we believe the preoperative optimization process is crucial to achieving good outcomes and minimizing the risk of complications. Future comparative studies should have longer followup and a larger sample size with greater power to determine if there are differences in complications and implant survivorship. Level III, therapeutic study.


Structural and functional domains of the Rous sarcoma virus transforming protein (pp60src).
The transforming protein (pp60src) of the Rous sarcoma virus (RSV) is a phosphoprotein with the enzymatic ability to phosphorylate tyrosine in protein substrates. Previous work has indicated that the bulk of pp60src may be attached to the plasma membrane of infected cells. In an effort to better understand the mechanism by which pp60src induces the neoplastic phenotype, we have characterized further the attachment of pp60src to the plasma membrane, and we have identified separate molecular domains that are responsible for the attachment to membranes and for the protein kinase activity. Our results indicate that pp60src may be an integral membrane protein that is nevertheless synthesized on soluble polyribosomes. Subsequent to its synthesis, the protein attaches to plasma membrane without concomitant cleavage of a signal polypeptide. The amino-terminal quarter (or some portion thereof) of pp60src anchors the protein to the plasma membrane by forces that can be disrupted only with detergents. By contrast, protein kinase activity is located in the carboxyl-terminal half of the molecule. It appears that pp60src is designed on the one hand for tethering to the plasma membrane and on the other hand for enzymatic activity beyond the confines of the membrane. The fact that pp60src is but one of at least four different viral transforming proteins located on the plasma membrane implies that neoplastic transformation may commonly originate in events that occur at the periphery of the cell.


Dracunculiasis eradication: target 1995.
Substantial progress has been achieved over the past 3 years by the campaign to eradicate dracunculiasis. The target of eradication by 1995 has been set by the African Regional Office of the World Health Organization and accepted by the United Nations Children's Fund (UNICEF) and the United Nations Development Program. India and Pakistan continue to reduce their cases of the disease dramatically. In Africa, Ghana and Nigeria conducted national village-by-village searches in 1988-1990 and, between them, found greater than 800,000 cases of the disease. Most African countries have now prepared national plans of action, appointed national coordinators, and intend to use UNICEF's assistance to conduct national searches by the end of 1990. An international donors' conference held in 1989 facilitated major new assistance for the initiative by UNICEF, the United Nations Development Program, the United States Agency for International Development, the Japanese International Cooperation Agency, the Peace Corps, the American Cyanamid Company, and DuPont. The World Health Organization held a meeting early in 1990 to draft criteria and recommend the process for certifying achievement of elimination of dracunculiasis in formerly endemic countries. The major remaining obstacles to eradication of dracunculiasis by 1995 are civil wars in northeastern Africa and the apathy of some national and international officials.


The Effect of Withholding Antibiotics Prior to Bone Biopsy in Patients With Suspected Osteomyelitis: A Meta-analysis of the Literature.
The aim of this meta-analysis is to evaluate the effect of withholding antibiotics prior to obtaining a bone biopsy in the diagnosis of osteomyelitis. Literature searches on Scopus, PubMed, and Google Scholar were performed with the input antibiotic, bone, biopsy, osteomyelitis, and prior both separately and together, though initially as a combination, as key words for all study types in the English language published up until July 2018. The initial combination search (and subsequent additional search of the references) yielded 924 related articles, which ultimately resulted in 12 articles with adequate data for analysis. Data were analyzed using an inverse variance method to determine the weight of the studies in a random effects model, pooling the data for odds ratios (OR) and heterogeneity. Bias risk was determined with the Quality Assessment of Diagnostic Accuracy Studies 2 system. Of the 12 studies, 8 failed to demonstrate that antibiotics administered prior to bone biopsy have an effect on culture yield, while 4 reported a significant effect on culture yield. The total weighted OR for all studies was 2.02 (95% confidence interval [CI], 0.94-4.36; P = .04) and the prediction interval was 0.17-23.63. When vertebral osteomyelitis (VO) and nonvertebral osteomyelitis (NVO) articles were evaluated separately, the VO OR was 2.95 (95% CI, 1.40-6.24) and the prediction interval was 0.40-21.53. The OR for NVO was 0.66 (95% CI, 0.04-12.03) and the prediction interval was 0-114.53. When all studies as well as when NVO studies only were evaluated, there was no significant difference in bacterial pathogen yield based on antibiotic exposure. When VO studies were evaluated separately, there were fewer pathogens recovered than when antibiotics were administered prior to obtaining bone cultures.


Impairment of membrane phosphoinositide metabolism by aminoglycoside antibiotics: streptomycin, amikacin, kanamycin, dibekacin, gentamicin and neomycin.
Like many amphiphilic cationic drugs, aminoglycosides are able to produce phospholipidosis, mainly by inhibiting enzymes involved in phospholipid metabolism. Phosphoinositides have been suggested to function as receptors for aminoglycosides. Therefore, we investigated the influence of these drugs upon phosphoinositide metabolism by measuring the 32P-incorporation into the polyphosphoinositides, using the rat erythrocyte membrane as a model. Depending upon the experimental conditions, neomycin induced a decrease and/or an increase in the 32P-labeling of triphosphoinositides (TPI) and of diphosphoinositides (DPI), respectively. These variations were rapid and depended upon the drug concentration. At 0.3 mM, neomycin reversed the distribution of radioactivities associated with DPI and TPI without modifying the total radioactivity incorporated. This drug concentration altered neither the Mg++-activated TPI-specific phosphomonoesterase activity nor the Ca++-activated polyphosphoinositide phosphodiesterase activity. It appears likely that the drug inhibits the DPI-kinase activity, by interacting with DPI and thereby lowering the substrate availability. Over the range of concentrations studied (up to 1-2 mM), gentamicin, kanamycin and dibekacin behave as neomycin. However, their effects could be observed only at drug concentrations higher than those of neomycin. By contrast, streptomycin and amikacin did not alter the 32P-labeling of TPI and of DPI. The order of potency of aminoglycosides for the impairment of the phosphoinositide interconversion was neomycin, gentamicin, dibekacin, kanamycin. A possible relationship between the toxicity of aminoglycosides and their capacity to impair the phosphoinositide metabolism is discussed.


Concurrent renal artery stent during endovascular infrarenal aortic aneurysm repair confers higher risk for 30-day acute renal failure.
Concurrent renal artery angioplasty and stenting (RAAS) during endovascular aneurysm repair (EVAR) of infrarenal abdominal aortic aneurysm (AAA) has been practiced in an attempt to maintain renal perfusion. The aim of this study was to identify the current practice of RAAS during EVAR and its effect on perioperative renal outcome. Patients with infrarenal AAA were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP, 2011-2014) database. Baseline characteristics of patients with concurrent RAAS during EVAR were compared with those of patients who underwent EVAR only. Bivariate and multivariable logistic regression analyses controlling for patients' demographics, comorbidities, and operative factors were used to evaluate the predictors of 30-day acute renal failure (ARF). Sensitivity analysis was done to evaluate the role of RAAS in patients with prior kidney disease. Overall, 6183 patients underwent EVAR for infrarenal AAA during the study period. Of them, 281 patients had RAAS during EVAR (4.5%). The median age of the patients was 74 years; 81.7% of the cohort was male, but a higher proportion of female patients received EVAR + RAAS compared with patients who underwent EVAR only (26.3% vs 17.9%; P < .001). There was no difference between groups in terms of comorbidities, being on dialysis, or functional status, yet the EVAR + RAAS group had a higher proportion of patients with glomerular filtration rate <60 mL/min/1.73 m2 (45.2% vs 37.2%; P = .011). RAAS was associated with significantly higher odds for development of ARF (adjusted odds ratio [aOR], 4.27; 95% confidence interval [CI], 2.06-8.84; P < .001). Other highly predictive factors of 30-day ARF were glomerular filtration rate <60 (aOR, 2.92; 95% CI, 1.47-5.78; P = .002), emergency status (aOR, 2.97; 95% CI, 1.21-7.27; P = .017), and ruptured AAA as the indication for EVAR (aOR, 4.74; 95% CI, 1.80-12.50; P = .002). Patients with prior kidney disease who had EVAR + RAAS demonstrated a 12-fold higher odds for 30-day ARF (aOR, 12.37; 95% CI, 4.66-32.89; P < .001). Concurrent RAAS was found to be a significant determinant of adverse renal outcomes after EVAR for infrarenal AAA. This effect was present even after controlling for patients' risk factors that might contribute to postoperative ARF.


Taxol alleviates 2-methoxyestradiol-induced endothelial permeability.
We have previously shown that the anti-cancer agent 2-methoxyestradiol (2ME) induces hyperpermeability across endothelial monolayers. Here, we show that both microtubule disruptor, 2ME, and microtubule stabilizer, paclitaxel (taxol), increase vascular lung permeability in vitro and in vivo. Simultaneous application of 2ME and taxol alleviates 2ME-induced endothelial barrier dysfunction, which is evident by the decreased Evans Blue Dye accumulation in lung tissue and increased transendothelial resistance across monolayers. 2ME significantly increases the level of p38 and MLC phosphorylation in both endothelial monolayers and murine lungs; this increase is suppressed in the presence of taxol. Taxol treatment leads to an immediate and sustained increase in tubulin acetylation in human pulmonary artery endothelial cells (HPAEC). Surprisingly, 2ME treatment also increases tubulin acetylation; however, the onset of this process is delayed and coincides with the stage of a partial barrier restoration in HPAEC monolayer. Inhibition of histone deacetylase 6 (HDAC6) with tubacin increases tubulin acetylation level, suppresses 2ME-induced HSP27 and MLC phosphorylation, and decreases 2ME-induced barrier dysfunction, suggesting barrier-protective and/or barrier-restorative role for tubulin acetylation in vascular endothelium.


Raltegravir is a substrate for SLC22A6: a putative mechanism for the interaction between raltegravir and tenofovir.
The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEM(VBL100), and Caco-2 cells. Transport by uptake transporters was assessed by using a Xenopus laevis oocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEM(VBL100), and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The K(m) and V(max) for SLC22A6 transport were 150 μM and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentration-dependent manner. Raltegravir inhibited 1 μM tenofovir with a 50% inhibitory concentration (IC(50)) of 14.0 μM, and tenofovir inhibited 1 μM raltegravir with an IC(50) of 27.3 μM. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.


Stable isotope labeling tandem mass spectrometry (SILT): integration with peptide identification and extension to data-dependent scans.
Quantitation of relative or absolute amounts of proteins by mass spectrometry can be prone to large errors. The use of MS/MS ion intensities and stable isotope labeling, which we term stable isotope labeling tandem mass spectrometry (SILT), decreases the effects of contamination from unrelated compounds. We present a software package (SILTmass) that automates protein identification and quantification by the SILT method. SILTmass has the ability to analyze the kinetics of protein turnover, in addition to relative and absolute protein quantitation. Instead of extracting chromatograms to find elution peaks, SILTmass uses only scans in which a peptide is identified and that meet an ion intensity threshold. Using only scans with identified peptides, the accuracy and precision of SILT is shown to be superior to precursor ion intensities, particularly at high or low dilutions of the isotope labeled compounds or with low amounts of protein. Using example scans, we demonstrate likely reasons for the improvements in quantitation by SILT. The appropriate use of variable modifications in peptide identification is described for measurement of protein turnover kinetics. The combination of identification with SILT facilitates quantitation without peak detection and helps to ensure the appropriate use of variable modifications for kinetics experiments.


Single-molecule motions of oligoarginine transporter conjugates on the plasma membrane of Chinese hamster ovary cells.
To explore the real-time dynamic behavior of molecular transporters of the cell-penetrating-peptide (CPP) type on a biological membrane, single fluorescently labeled oligoarginine conjugates were imaged interacting with the plasma membrane of Chinese hamster ovary (CHO) cells. The diffusional motion on the membrane, characterized by single-molecule diffusion coefficient and residence time (tau R), defined as the time from the initial appearance of a single-molecule spot on the membrane (from the solution) to the time the single molecule disappears from the imaging focal plane, was observed for a fluorophore-labeled octaarginine (a model guanidinium-rich CPP) and compared with the corresponding values observed for a tetraarginine conjugate (negative control), a lipid analogue, and a fluorescently labeled protein conjugate (transferrin-Alexa594) known to enter the cell through endocytosis. Imaging of the oligoarginine conjugates was enabled by the use of a new high-contrast fluorophore in the dicyanomethylenedihydrofuran family, which brightens upon interaction with the membrane at normal oxygen concentrations. Taken as a whole, the motions of the octaarginine conjugate single molecules are highly heterogeneous and cannot be described as Brownian motion with a single diffusion coefficient. The observed behavior is also different from that of lipids, known to penetrate cellular membranes through passive diffusion, conventionally involving lateral diffusion followed by membrane bilayer flip-flop. Furthermore, while the octaarginine conjugate behavior shares some common features with transferrin uptake (endocytotic) processes, the two systems also exhibit dissimilar traits when diffusional motions and residence times of single constructs are compared. Additionally, pretreatment of cells with cytochalasin D, a known actin filament disruptor, produces no significant effect, which further rules out unimodal endocytosis as the mechanism of uptake. Also, the involvement of membrane potential in octaarginine-membrane interaction is supported by significant changes in the motion with high [K(+)] treatment. In sum, this first study of single transporter motion on the membrane of a living cell indicates that the mode by which the octaarginine transporter penetrates the cell membrane appears to either be a multimechanism uptake process or a mechanism different from unimodal passive diffusion or endocytosis.


Impact of diabetes on crash risks of truck-permit holders and commercial drivers.
The U.S. and some Canadian government agencies have waived commercial license restrictions for some insulin-using diabetic drivers. However, the U.S. Federal Highway Administration is no longer giving waivers. Scientific evidence to support such regulations has been sparse. This article presents detailed analyses of crash risks for users and nonusers of insulin among diabetic truck-permit holders in Québec, Canada. Diabetic truck-permit holders were group-matched by age to a random sample of healthy permit holders. Data on permits, medical conditions, and crashes involving 13,453 permit holder-years in 1987-1990 were extracted from the files of the public insurer for automobile injuries in Québec. Additional health status data were obtained from the provincial public health insurer. A telephone survey was conducted to collect data on driving patterns and exposure. Risk ratios were estimated using negative binomial regression models. Risk ratios for crashes vary by category of diabetes. Permit holders for single-unit trucks (STs) who are diabetic without complications and not using insulin have an increased crash risk of 1.68 when compared with healthy permit holders of the same permit class. When controlling for risk exposure, commercial drivers with an ST permit and the same diabetic condition have an increased risk of 1.76. Insulin use is not associated with higher crash risk. The increased crash risk for the group with uncomplicated diabetes not using insulin is a new finding. The lack of consistent increases in crash risks among diabetic commercial drivers with complications or who use insulin may be a "healthy worker effect" masking the real risk, because these licensees have a lower participation rate as professional drivers.


Determination of sample size for a multi-class classifier based on single-nucleotide polymorphisms: a volume under the surface approach.
Data on single-nucleotide polymorphisms (SNPs) have been found to be useful in predicting phenotypes ranging from an individual's class membership to his/her risk of developing a disease. In multi-class classification scenarios, clinical samples are often limited due to cost constraints, making it necessary to determine the sample size needed to build an accurate classifier based on SNPs. The performance of such classifiers can be assessed using the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for two classes and the Volume Under the ROC hyper-Surface (VUS) for three or more classes. Sample size determination based on AUC or VUS would not only guarantee an overall correct classification rate, but also make studies more cost-effective. For coded SNP data from D(≥2) classes, we derive an optimal Bayes classifier and a linear classifier, and obtain a normal approximation to the probability of correct classification for each classifier. These approximations are then used to evaluate the associated AUCs or VUSs, whose accuracies are validated using Monte Carlo simulations. We give a sample size determination method, which ensures that the difference between the two approximate AUCs (or VUSs) is below a pre-specified threshold. The performance of our sample size determination method is then illustrated via simulations. For the HapMap data with three and four populations, a linear classifier is built using 92 independent SNPs and the required total sample sizes are determined for a continuum of threshold values. In all, four different sample size determination studies are conducted with the HapMap data, covering cases involving well-separated populations to poorly-separated ones. For multi-classes, we have developed a sample size determination methodology and illustrated its usefulness in obtaining a required sample size from the estimated learning curve. For classification scenarios, this methodology will help scientists determine whether a sample at hand is adequate or more samples are required to achieve a pre-specified accuracy. A PDF manual for R package "SampleSizeSNP" is given in Additional file 1, and a ZIP file of the R package "SampleSizeSNP" is given in Additional file 2.


Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus.
Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma.Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses.Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells.Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 23(19); 5846-57. ©2017 AACR.


Peer led team learning in introductory biology: effects on peer leader critical thinking skills.
This study evaluated hypothesized effects of the Peer-Led Team Learning (PLTL) instructional model on undergraduate peer leaders' critical thinking skills. This investigation also explored peer leaders' perceptions of their critical thinking skills. A quasi-experimental pre-test/post-test with control group design was used to determine critical thinking gains in PLTL/non-PLTL groups. Critical thinking was assessed using the California Critical Thinking Skills Test (CCTST) among participants who had previously completed and been successful in a mixed-majors introductory biology course at a large, private research university in the American Northeast. Qualitative data from open-ended questionnaires confirmed that factors thought to improve critical thinking skills such as interaction with peers, problem solving, and discussion were perceived by participants to have an impact on critical thinking gains. However, no significant quantitative differences in peer leaders' critical thinking skills were found between pre- and post-experience CCTST measurements or between experimental and control groups.


Mercury in traditional Tibetan medicine - panacea or problem?
Symptoms of mercury toxicity, biochemical changes, and blood/urine mercury levels were evaluated in a small group of patients. Six patients attending Delek Hospital, Dharamsala, India, taking mercury-containing traditional Tibetan medicine (TTM) (Group I), were compared with three patients taking non-mercury containing TTM (Group II) and healthy volunteers(Group II). Quantitative estimation of mercury ingestion based on chemical analysis was compared with US regulatory standards. Group I were significantly older (mean 55 years+/-SE 6.4) range 26-69 years, than Group II (26.7 years+/-SE 5) range 17-34 years and Group III (32.5 years +/-SE 0.5) range 33-34 years (P =0.05). Group I took TTM on average for 51 months and had a mean of 2.5 non-specific, mercury-related symptoms. Group I had higher mean diastolic pressures (85 mmHg) than Group II (73 mmHg) (P=0.06) and more loose teeth. Mean daily mercury intake for Group I was 674 microg, estimated as 10 microg/kg per day. (Established reference dose for chronic oral exposure: 0.3 microg/kg per day.) Blood mercury levels were non-detectable, but mean urinary mercury levels for Group I were 67 microg/L (EPA levels <20 microg/L). Renal and liver function tests were not significantly different between groups and within normal clinical range. Prolonged ingestion of mercury containing TTM is associated with absent blood levels, but relatively high urinary levels. Further studies are needed to evaluate toxicity and therapeutic potential.


Healthy aging delays scalp EEG sensitivity to noise in a face discrimination task.
We used a single-trial ERP approach to quantify age-related changes in the time-course of noise sensitivity. A total of 62 healthy adults, aged between 19 and 98, performed a non-speeded discrimination task between two faces. Stimulus information was controlled by parametrically manipulating the phase spectrum of these faces. Behavioral 75% correct thresholds increased with age. This result may be explained by lower signal-to-noise ratios in older brains. ERP from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The fit of the model, indexed by R(2), was computed at multiple post-stimulus time points. The time-course of the R(2) function showed significantly delayed noise sensitivity in older observers. This age effect is reliable, as demonstrated by test-retest in 24 subjects, and started about 120 ms after stimulus onset. Our analyses suggest also a qualitative change from a young to an older pattern of brain activity at around 47 ± 4 years old.


Inhalation of Roman chamomile essential oil attenuates depressive-like behaviors in Wistar Kyoto rats.
The idea of aromatherapy, using essential oils, has been considered as an alternative antidepressant treatment. In the present study, we investigated the effect of Roman chamomile essential oil inhalation for two weeks on depressive-like behaviors in Wistar-Kyoto (WKY) rats. We found that inhalation of either Roman chamomile or one of its main components α-pinene, attenuated depressive-like behavior in WKY rats in the forced swim test. Using isobaric tags for relative and absolute quantitation analysis (iTRAQ), we found that inhalation of α-pinene increased expression of proteins that are involved in oxidative phosphorylation, such as cytochrome c oxidase subunit 6C-2, cytochrome c oxidase subunit 7A2, ATPase inhibitor in the hippocampus, and cytochrome c oxidase subunit 6C-2, ATP synthase subunit e, Acyl carrier protein, and Cytochrome b-c1 complex subunit 6 in the PFC (prefrontal cortex). In addition, using the quantitative real-time polymerase chain reaction technique, we confirmed an increase of parvalbumin mRNA expression in the hippocampus, which was shown to be upregulated by 2.8-fold in iTRAQ analysis, in α-pinene treated WKY rats. These findings collectively suggest the involvement of mitochondrial functions and parvalbumin-related signaling in the antidepressant effect of α-pinene inhalation.


Communicating genetics research results to families: problems arising when the patient participant is deceased.
This study explores communication within families of clinically significant genetics research results, after the death of the patient participant. BRCA2 mutations were found in several men after their death from prostate cancer. Spouses were given the results in a genetic counselling session and asked to inform relatives. Cross-sectional, qualitative exploratory study. Interviews with 13 relatives, including informers and recipients of the information, were analysed using interpretative phenomenological analysis. Dissemination was hampered when communication channels between relatives were limited, because of family rifts or socially distant or problematic relationships. When informing other branches of the family, relatives approached individuals in the generation of the deceased man, regardless of their risk status, who were then responsible for informing younger relatives. Most people informed by a relative did not seek genetic counselling. The informing relative may not have sufficient authority for the information either to be taken seriously or to challenge individual constructions about the aetiology of cancer. This impeded information transmission to further at-risk relatives. Most participants knew of relatives who had not been told about their cancer risk. The implications of this limited efficiency of information transfer among relatives are discussed in the context of a potential role for genetics services in contacting at-risk relatives directly.


Optical recoil of asymmetric nano-optical antenna.
We propose nano-optical antennas with asymmetric radiation patterns as light-driven mechanical recoil force generators. Directional antennas are found to generate recoil force efficiently when driven in the spectral proximity of their resonances. It is also shown that the recoil force is equivalent to the Poynting vector integrated over a closed sphere containing the antenna structures.


Reconciliation of diverse telepathology system designs. Historic issues and implications for emerging markets and new applications.
Telepathology, the distant service component of digital pathology, is a growth industry. The word "telepathology" was introduced into the English Language in 1986. Initially, two different, competing imaging modalities were used for telepathology. These were dynamic (real time) robotic telepathology and static image (store-and-forward) telepathology. In 1989, a hybrid dynamic robotic/static image telepathology system was developed in Norway. This hybrid imaging system bundled these two primary pathology imaging modalities into a single multi-modality pathology imaging system. Similar hybrid systems were subsequently developed and marketed in other countries as well. It is noteworthy that hybrid dynamic robotic/static image telepathology systems provided the infrastructure for the first truly sustainable telepathology services. Since then, impressive progress has been made in developing another telepathology technology, so-called "virtual microscopy" telepathology (also called "whole slide image" telepathology or "WSI" telepathology). Over the past decade, WSI has appeared to be emerging as the preferred digital telepathology digital imaging modality. However, recently, there has been a re-emergence of interest in dynamic-robotic telepathology driven, in part, by concerns over the lack of a means for up-and-down focusing (i.e., Z-axis focusing) using early WSI processors. In 2010, the initial two U.S. patents for robotic telepathology (issued in 1993 and 1994) expired enabling many digital pathology equipment companies to incorporate dynamic-robotic telepathology modules into their WSI products for the first time. The dynamic-robotic telepathology module provided a solution to the up-and-down focusing issue. WSI and dynamic robotic telepathology are now, rapidly, being bundled into a new class of telepathology/digital pathology imaging system, the "WSI-enhanced dynamic robotic telepathology system". To date, six major WSI processor equipment companies have embraced the approach and developed WSI-enhanced dynamic-robotic digital telepathology systems, marketed under a variety of labels. Successful commercialization of such systems could help overcome the current resistance of some pathologists to incorporate digital pathology, and telepathology, into their routine and esoteric laboratory services. Also, WSI-enhanced dynamic robotic telepathology could be useful for providing general pathology and subspecialty pathology services to many of the world's underserved populations in the decades ahead. This could become an important enabler for the delivery of patient-centered healthcare in the future.


Creating a "culture of research" in a community hospital: Strategies and tools from the National Cancer Institute Community Cancer Centers Program.
The value of community-based cancer research has long been recognized. In addition to the National Cancer Institute's Community Clinical and Minority-Based Oncology Programs established in 1983, and 1991 respectively, the National Cancer Institute established the National Cancer Institute Community Cancer Centers Program in 2007 with an aim of enhancing access to high-quality cancer care and clinical research in the community setting where most cancer patients receive their treatment. This article discusses strategies utilized by the National Cancer Institute Community Cancer Centers Program to build research capacity and create a more entrenched culture of research at the community hospitals participating in the program over a 7-year period. To facilitate development of a research culture at the community hospitals, the National Cancer Institute Community Cancer Centers Program required leadership or chief executive officer engagement; utilized a collaborative learning structure where best practices, successes, and challenges could be shared; promoted site-to-site mentoring to foster faster learning within and between sites; required research program assessments that spanned clinical trial portfolio, accrual barriers, and outreach; increased identification and use of metrics; and, finally, encouraged research team engagement across hospital departments (navigation, multidisciplinary care, pathology, and disparities) to replace the traditionally siloed approach to clinical trials. The health-care environment is rapidly changing while complexity in research increases. Successful research efforts are impacted by numerous factors (e.g. institutional review board reviews, physician interest, and trial availability). The National Cancer Institute Community Cancer Centers Program sites, as program participants, had access to the required resources and support to develop and implement the strategies described. Metrics are an important component yet often challenging to identify and collect. The model requires a strong emphasis on outreach that challenges hospitals to improve and expand their reach, particularly into underrepresented populations and catchment areas. These efforts build on trust and a referral pipeline within the community which take time and significant commitment to establish. The National Cancer Institute Community Cancer Centers Program experience provides a relevant model to broadly address creating a culture of research in community hospitals that are increasingly networked via systems and consortiums. The strategies used align well with the National Cancer Institute-American Society of Clinical Oncology Accrual Symposium recommendations for patient-/community-, physician-/provider-, and site-/organizational-level approaches to clinical trials; they helped sites achieve organizational culture shifts that enhanced their cancer research programs. The National Cancer Institute Community Cancer Centers Program hospitals reported that the strategies were challenging to implement yet proved valuable as they provided useful metrics for programmatic assessment, planning, reporting, and growth. While focused on oncology trials, these concepts may be useful within other disease-focused research as well.


Differentiation of induced pluripotent stem cells into dental mesenchymal cells.
Similar to embryonic stem cells, induced pluripotent stem (iPS) cells can differentiate into various cell types upon appropriate induction, and thus, may be valuable cell sources for regenerative medicine. However, iPS cells have not been reported to differentiate into odontogenic cells for tooth regeneration. Here we demonstrated that neural crest-like cells (NCLC) derived from mouse iPS cells have the potential to differentiate into odontogenic mesenchymal cells. We developed an efficient culture protocol to induce the differentiation of mouse iPS cells into NCLC. We confirmed that the cells exhibited neural crest (NC) cell markers as evidenced by immunocytochemistry, flow cytometry, and real-time reverse transcription-polymerase chain reaction. Further, in recombination cultures of NCLC and mouse dental epithelium, NCLC exhibited a gene expression pattern involving dental mesenchymal cells. Some NCLC also expressed dentin sialoprotein. Conditioned medium of mouse dental epithelium cultures further enhanced the differentiation of NCLC into odontoblasts. These results suggest that iPS cells are useful cell sources for tooth regeneration and tooth development studies.


Comparison of transmission and the 90-degree holographic recording geometry.
We compare the system performances of two holographic recording geometries using iron-doped lithium niobate: the 90-degree and transmission geometry. We find that transmission geometry is better because the attainable dynamic range (M/#) is much higher. The only drawback of transmission geometry is the buildup of fanning, particularly during readout. Material solutions that reduce fanning such as doubly-doped photerefractive crystals make transmission geometry the clear winner.