DNA-binding properties of an adenovirus 289R E1A protein.
An adenovirus 2 289 amino acid (289R) E1A protein purified from Escherichia coli has been shown to interact with DNA by two independent methods. UV-crosslinking of complexes containing unmodified, uniformly 32P-labelled DNA and purified E1A protein induced efficient labelling of the protein with covalently attached oligonucleotides, indicating that the E1A protein itself contacts DNA. Discrete nucleoprotein species were also observed when E1A protein--DNA complexes were analysed by gel electrophoresis. Although the 289R E1A protein exhibited no significant binding to single-stranded DNA or to RNA, no evidence for its sequence-specific binding to double-stranded DNA was obtained with either assay. Identification of the sites of covalent attachment of 32P-labelled oligonucleotides by partial proteolysis of the crosslinked E1A protein indicated that the interaction of this protein with DNA is mediated via domain(s) in the C-terminal half of the protein. Such previously unrecognized DNA-binding activity is likely to contribute to the regulatory activities of this important adenoviral protein.


Direct numerical simulation and Reynolds-averaged Navier-Stokes modeling of the sudden viscous dissipation for multicomponent turbulence.
Simulations of a turbulent multicomponent fluid mixture undergoing isotropic deformations are carried out to investigate the sudden viscous dissipation. This dissipative mechanism was originally demonstrated using simulations of an incompressible single-component fluid [S. Davidovits and N. J. Fisch, Phys. Rev. Lett. 116, 105004 (2016)10.1103/PhysRevLett.116.105004]. By accounting for the convective and diffusive transfer of various species, the current work aims to increase the physical fidelity of previous simulations and their relevance to inertial confinement fusion applications. Direct numerical simulations of the compressed fluid show that the sudden viscous dissipation of turbulent kinetic energy is unchanged from the single-component scenario. More importantly, the simulations demonstrate that the mass fraction variance and covariance for the various species also exhibit a sudden viscous decay. Reynolds-averaged Navier-Stokes simulations were carried out using the k-l model to assess its ability to reproduce the sudden viscous dissipation. Results show that the standard k-l formulation does not capture the sudden decay of turbulent kinetic energy, mass-fraction variance, and mass-fraction covariance for simulations with various compression and expansion rates, or different exponents for the power-law model of viscosity. A new formulation of the k-l model that is based on previous improvements to the k-ε family of models is proposed, which leads to consistently good agreement with the direct numerical simulations for all the isotropic deformations under consideration.


An audit of prosthodontics undertaken in general dental practice in the South East of England.
Before embarking upon changes to teaching in prosthodontics it is important to identify what techniques are being used in general practice. The aim of this study was to assess the current range and quantity of fixed and removable prosthodontics reported in general dental practice in the South East of England. Structured questionnaires were sent to 191 randomly selected dentists from the GDC list in the South East of England, with 71% of the dentists completing the questionnaire. The questionnaire included demographic data, NHS/private and the range and quantity of fixed and removable prosthodontics. The reported number of removable prostheses undertaken was low; most metal dentures were made in private specialist practices, whereas most acrylic partial and complete dentures were made in NHS general practices. The number of bridges, in particular minimal preparation bridges, was low as opposed to the number of crowns, which was high in all types of practices. Implants were provided mainly by the specialists. Dentists reported prescribing low numbers of removable and fixed prostheses with the exception of crowns. Metal dentures and implants were mainly provided by specialists. The implications of this study emphasise the importance in teaching crowns to undergraduates.


3D Printing Technology for Smart Clothing: A Topic Review.
Clothing is considered to be an important element of human social activities. With the increasing maturity of 3D printing technology, functional 3D printing technology can realize the perfect combination of clothing and electronic devices while helping smart clothing to achieve specific functions. Furthermore, the application of functional 3D printing technology in clothing not only provides people with the most comfortable and convenient wearing experience, but also completely subverts consumers' perception of traditional clothing. This paper introduced the progress of the application of 3D printing from the aspect of traditional clothing and smart clothing through two mature 3D printing technologies normally used in the field of clothing, and summarized the challenges and prospects of 3D printing technology in the field of smart clothing. Finally, according to the analysis of the gap between 3D-printed clothing and traditionally made clothing due to the material limitations, this paper predicted that the rise in intelligent materials will provide a new prospect for the development of 3D-printed clothing. This paper will provide some references for the application research of 3D printing in the field of smart clothing.


An ensemble approach to accurately detect somatic mutations using SomaticSeq.
SomaticSeq is an accurate somatic mutation detection pipeline implementing a stochastic boosting algorithm to produce highly accurate somatic mutation calls for both single nucleotide variants and small insertions and deletions. The workflow currently incorporates five state-of-the-art somatic mutation callers, and extracts over 70 individual genomic and sequencing features for each candidate site. A training set is provided to an adaptively boosted decision tree learner to create a classifier for predicting mutation statuses. We validate our results with both synthetic and real data. We report that SomaticSeq is able to achieve better overall accuracy than any individual tool incorporated.


[Effects of reserpine and 5-HT on analgesia induced by lappaconitine and N-deacetyllappaconitine].
In the rat tail-flick test it was shown that ip lappaconitine (LA) 1-6 mg/kg, N-deacetyllappaconitine (DLA) 4-10 mg/kg or icv DLA 20-60 micrograms/rat exhibited a dose-dependent analgesic activity, but icv LA 20-40 micrograms/rat was inactive. The analgesic potency of ip LA was a little more potent than that of DLA and slightly weaker than that of morphine (P less than 0.05). Combined ip of subanalgesic doses of morphine and LA or DLA produced significant analgesic action. Analgesia mediated by LA was not antagonized by naloxone. The analgesic effect induced by LA or DLA was abolished and restored 3 and 120 h, respectively, after ip reserpine 3 mg/kg. Concomitant administration of 1-tryptophan or 5-HT as well as premedication of alpha-methyldopa prevented reserpine-induced decrease on LA or DLA analgesia. The elevation of brain 5-HT level by icv 5-HT significantly enhanced the analgesia of LA and DLA. LA- or DLA-induced analgesia was attenuated by pretreatment of p-chlorophenylalanine but this attenuation was reversed by icv 5-HT. p-Chloroamphetamine also markedly reduced LA- or DLA-induced analgesia. It is concluded that the central serotoninergic system is involved in the modulation of LA- or DLA-induced analgesia.


Individualization of attention-deficit/hyperactivity disorder treatment: pharmacotherapy considerations by age and co-occurring conditions.
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests in childhood and can persist into adolescence and adulthood. Impairments associated with ADHD can impact quality of life, social interactions, and increase the risk of morbidity and mortality; however, for many patients, effective treatment can lessen these effects. Pharmacotherapy with stimulants or nonstimulants is recommended in conjunction with psychosocial therapy for most patients. Determining the optimal pharmacotherapy can be complex, and the clinician needs to consider many factors such as the patient's age, comorbidities, and lifestyle. Furthermore, the needs of the patient with ADHD will change over time, with specific challenges to consider at each stage of life. A variety of Food and Drug Administration (FDA)-approved stimulant and nonstimulant formulations are available with different modes of delivery and durations of effect. This armamentarium of ADHD medications can be used to individualize ADHD treatment for each patient's needs. This article combines current information from the literature and the first-hand experience of the authors to provide guidance on ADHD treatment options for patients of different ages and for some of the more common comorbidities.


Delayed Autoimmune Toxicity Occurring Several Months After Cessation of Anti-PD-1 Therapy.
Treatment with anti-programmed cell death protein 1 (PD-1) antibodies has demonstrated clinical efficacy in a whole range of malignancies including advanced melanoma, renal cell cancer, bladder cancer, and non-small cell lung cancer. Immune-related adverse events are a unique side effect of checkpoint regulator therapy including anti-PD-1 antibodies. Treatment-related autoimmunity can occur in any organ system, with the median onset usually within 5-15 weeks from the commencement of therapy, depending on the organ system involved. This study describes for the first time a case of delayed autoimmunity occurring 8 months after discontinuing treatment with the anti-PD-1 antibody nivolumab in a patient with metastatic melanoma. The case highlights the need for ongoing surveillance of patients treated with immune checkpoint inhibitors even after cessation of therapy, especially as patients increasingly stop treatment after achieving durable responses.


Dynamics of Disagreement: Large-Scale Temporal Network Analysis Reveals Negative Interactions in Online Collaboration.
Disagreement and conflict are a fact of social life. However, negative interactions are rarely explicitly declared and recorded and this makes them hard for scientists to study. In an attempt to understand the structural and temporal features of negative interactions in the community, we use complex network methods to analyze patterns in the timing and configuration of reverts of article edits to Wikipedia. We investigate how often and how fast pairs of reverts occur compared to a null model in order to control for patterns that are natural to the content production or are due to the internal rules of Wikipedia. Our results suggest that Wikipedia editors systematically revert the same person, revert back their reverter, and come to defend a reverted editor. We further relate these interactions to the status of the involved editors. Even though the individual reverts might not necessarily be negative social interactions, our analysis points to the existence of certain patterns of negative social dynamics within the community of editors. Some of these patterns have not been previously explored and carry implications for the knowledge collection practice conducted on Wikipedia. Our method can be applied to other large-scale temporal collaboration networks to identify the existence of negative social interactions and other social processes.


Bilateral orbital dysmorphology in unicoronal synostosis.
Orbital dysmorphology is believed to cause ipsilateral ocular abnormalities in unicoronal synostosis. Recently, there has been increasing evidence of visual problems in the contralateral eye. The purpose of this study was to explore morphology of both the ipsilateral and contralateral unicoronal synostosis orbit. Demographic data and computed tomographic information were recorded. Three-dimensional computed tomographic renderings were created digitally and analyzed (SurgiCase). Craniometric analysis was conducted for orbital volume, horizontal and vertical orbital cone angle, orbital depth, and corneal projection. Twenty-one unicoronal synostosis infants and 10 matched controls were examined. The orbital volume ratio between ipsilateral and contralateral sides was 93.8 ± 5.3 in unicoronal synostosis infants and 99.3 ± 2.1 (p = 0.001) in the control group. The horizontal orbital cone angle of the contralateral eye was significantly greater than that of both the ipsilateral side (p < 0.0001) and the control orbits (p = 0.0011, p = 0.0004). The vertical cone angle of the ipsilateral eye was significantly greater than that of the ipsilateral (p < 0.0001) and control orbits (p = 0.0326, p = 0.0030). There was no difference in orbital depth between ipsilateral and contralateral orbits. The ipsilateral globe projected 27 percent farther past the orbital aperture than the contralateral side. There was no difference between right and left orbits of a control in any analysis. In addition to ipsilateral orbital deformity, the contralateral orbit is highly dysmorphic. As orbital asymmetry may underlie visual abnormalities, future reconstructive efforts may necessitate bilateral correction. Risk, II.


Damping of Josephson Oscillations in Strongly Correlated One-Dimensional Atomic Gases.
We study Josephson oscillations of two strongly correlated one-dimensional bosonic clouds separated by a localized barrier. Using a quantum-Langevin approach and the exact Tonks-Girardeau solution in the impenetrable-boson limit, we determine the dynamical evolution of the particle-number imbalance, displaying an effective damping of the Josephson oscillations which depends on barrier height, interaction strength, and temperature. We show that the damping originates from the quantum and thermal fluctuations intrinsically present in the strongly correlated gas. Because of the density-phase duality of the model, the same results apply to particle-current oscillations in a one-dimensional ring where a weak barrier couples different angular momentum states.


Severe ocular trauma-The hidden danger of plastic bottles when throwing out the rubbish.
This is the first reported case of ocular trauma caused by a plastic bottle cap occurring accidentally without misuse. The mechanism involved an un-emptied plastic bottle containing orange juice being thrown away with other rubbish. The combination of this minor impact and the pressure built up within the bottle through fermentation caused expulsion of the cap at high velocity. This cap caused severe ocular trauma requiring urgent ophthalmic assessment and intervention. Our simple recommendation is that plastic bottles have their caps removed and are emptied before being thrown away.


Factors influencing adrenocortical suppression during long-term triamcinolone acetonide therapy in asthma.
The causes for an abnormal five-hour tetracosactrin test in 14 out of 75 patients (18.5% of the entire group), treated continuously with triamcinolone acetonide long-term (mean 3.2 years) for asthma or related syndromes, were investigated. The average daily dosage, duration of treatment and age of the patients were analyzed. Statistical analysis indicated that the risk of adrenocortical suppression was increased by the patient's age and the average patients under the age of 50, receiving less than 1.2 mg triamcinolone acetonide daily, only rarely develop adrenocortical functional impairment.


Transmission potential of modified measles during an outbreak, Japan, March‒May 2018.
A recent outbreak of measles in Okinawa Prefecture, Japan ended with 33 measles cases whose symptoms were masked because of insufficient protection against the disease (modified measles). Using quantitative modelling, we determined the transmission potential of measles by clinical presentation (classic vs modified measles). We found low ascertainment probabilities among modified measles cases, indicating that intensified public health interventions that specifically target this group should be implemented to better contain outbreaks with modified measles cases.


Calcium as a crucial cofactor for low density lipoprotein receptor folding in the endoplasmic reticulum.
The family of low density lipoprotein (LDL) receptors mediate uptake of a plethora of ligands from the circulation and couple this to signaling, thereby performing a crucial role in physiological processes including embryonic development, cancer development, homeostasis of lipoproteins, viral infection, and neuronal plasticity. Structural integrity of individual ectodomain modules in these receptors depends on calcium, and we showed before that the LDL receptor folds its modules late after synthesis via intermediates with abundant non-native disulfide bonds and structure. Using a radioactive pulse-chase approach, we here show that for proper LDL receptor folding, calcium had to be present from the very early start of folding, which suggests at least some native, essential coordination of calcium ions at the still largely non-native folding phase. As long as the protein was in the endoplasmic reticulum (ER), its folding was reversible, which changed only upon both proper incorporation of calcium and exit from the ER. Coevolution of protein folding with the high calcium concentration in the ER may be the basis for the need for this cation throughout the folding process even though calcium is only stably integrated in native repeats at a later stage.


[Rhytidectomy and Raynaud's phenomenon: about two cases].
Raynaud's phenomenon is a currently vascular syndrome (8 to 10% of women and 3 to 5% of men). It was defined as episodic ischaemia of the fingers, toes, nose, ears and nipples, which presents clinically as pallor, cyanosis, and often rubor of the skins, in response to cold, emotional stimuli and vasoconstriction agents. The phenomenon is caused by a vasoconstriction of arterials skin. In severe forms of the phenomenon, we can see ulcerations and necrosis. We report here two cases of rhytidectomy flap necrosis in Raynaud's Phenomenon. After review of literature, we explain the elements of physiopathology whose can explain these complications and we try to establish recommendations to these complications.


Student-Reported Attitudes during an Interprofessional Palliative Care Learning Experience: Implications for Dual-Professional Identity, Interdisciplinary Bias, and Patient Outcomes.
Background: The geriatric population in the United States is in need of palliative care (PC), yet it is not consistently established in the curriculum across health care training programs. There is a clarion call to reform the education of health care students using interprofessional education (IPE). The Joint Commission reported that communication errors represent two-thirds of the causes behind provider sentinel events in health care. Objective: The purpose of this study was to design, implement, and assess an IPE curriculum on PC to understand interprofessional student attitudes. Design/Setting: Three professors conducted a mixed-methods study at a California university involving an IPE PC event for 40 nursing and speech-language pathology students, and administered the Interprofessional Attitudes Survey (IPAS) and reflective questions. Results: Qualitative findings indicated that students increased their knowledge about PC and the purpose/value of IPE. Four out of the five IPAS subscales had positive outcomes: teamwork and roles/responsibilities, patient-centeredness, diversity/ethics, and community-centeredness. Interprofessional-biases subscale revealed that 33% of the participants reported biases toward students from other health care disciplines, and 35% reported that students from other health care disciplines held similar biases toward them. However, only 25% did not believe that the interdisciplinary biases interfered with patient outcomes. Conclusion: The study identified the existence of interprofessional biases and prejudices that may impede collaboration among health care professionals resulting in reduced health care outcomes. Faculty and health educators are encouraged to embed IPE into a multidisciplinary curriculum that dismantles preexisting interdisciplinary biases and stereotypes, and constructs dual-professional identity. IRB ID #904203-1.


Immunoassays for the detection of parathyroid hormone.
Biologically active parathyroid hormone (PTH) in humans with normal renal function circulates predominantly as an 84 amino acid peptide. PTH fragments of varying length arise either from metabolism of the intact hormone within the parathyroid glands or in peripheral tissues, such as liver, and the resulting carboxyl-terminal peptides are eliminated mainly by glomerular filtration and subsequent tubular degradation. Most of the initially raised anti-PTH antisera were directed against epitopes within the mid- or carboxyl-terminal regions of the hormone. These antibodies were used for the development of conventional, displacement-type radioimmunoassays, but provided only an index of the biologically active PTH(1-84) in the circulation. Subsequently developed immunometric assays use two distinct antibodies, a capture antibody usually directed against a carboxyl-terminal portion of PTH(1-84) and a radio- or enzyme-labeled detection antibody usually directed against the amino-terminal portion of the hormone. Such assays were thought to detect largely, if not exclusively, intact PTH, thus providing the concentration of biologically active hormone in blood, which is especially important for establishing the diagnosis of hyperparathyroidism. However, serum samples from normal subjects and patients with primary or secondary hyperparathyroidism have demonstrated that most immunometric two-site sandwich assays detect, besides PTH(1-84), one or more recently discovered large carboxyl-terminal PTH fragments that lack a portion of the amino-terminal end of the molecule. Some of these amino-terminally truncated PTH molecules [ntPTH(1-84)] exhibit an elution profile on high performance liquid chromatography (HPLC) that is indistinguishable from that of synthetic PTH(784). Such peptides were previously thought to be of minimal if any biological activity, but recent studies have shown that synthetic PTH(7-84) has hypocalcemic properties in vivo and that it inhibits osteoclastic bone resorption and the formation of mature osteoclasts in vitro. It is currently unclear whether important differences in disease states can be revealed by comparing results obtained with older immunometric assays that measure the full-length hormone and ntPTH(1-84) versus newer assays that measure only PTH(1-84). Therefore, whereas most immunometric PTH assay systems are appropriate for the diagnosis of primary hyperparathyroidism, it is possible that immunometric assays designed to detect only PTH(1-84) will be more useful in certain diagnostic studies, for intraoperative PTH monitoring and for assessing the pulsatility of PTH secretion. In addition, the ability to distinguish between the relative concentrations of ntPTH(1-84) versus PTH(1-84) may reveal previously unsuspected roles for the ntPTH(1-84) fragments in the pathophysiology of patients with end-stage renal disease and/or other disorders involving parathyroid hormone.


[Antitumor effect of BCG on growth of transplanted human myeloid leukemia HL-60 cells in nude mice].
This study was purposed to explore the anti-leukemia effect of bacillus calmette-guerin vaccine (BCG) on the human myeloid leukemia cell xenograft models. An animal model was established by inoculating the human myeloid leukemia HL-60 cells into the BALB/c (8 - 10 weeks of age) nude mice. The mice were randomly divided into two groups: control group and experimental group. Nude mice in control group were injected with physiological saline, while those of experimental group were given BCG and inactivated BCG respectively. The tumor growth was assayed by using caliper. The survival time of nude mice was determined. Necrotic extent and morphological changes of tumor were observed and examined by HE staining and immunohistochemical method. The results indicated that on 5th-7th days after tumor inoculated, 2 - 3 mm tumor mass could be observed. The tumor volume increased over the time. HE staining of tumor tissues showed that there were different degrees of tumor necrosis in BCG group and inactivated BCG group. Immunohistochemistry results demonstrated that CD20 positive cells were obviously observed in the necrotic area of BCG group, compared with the control group and inactivated BCG group. It is concluded that human myeloid leukemia HL-60 cells have been successfully transplanted in nude mice, and the systemic metastasis occurs along with the prolongation of time. BCG inoculation can delay the tumor growth and prolong the survival time of nude mice with leukemia, suggesting that BCG has an antitumor effect.


Expression of heat shock proteins in tissues from young pigs exposed to transport stress.
The objective of the present study was to investigate the role of heat shock proteins (Hsps) as potential stress response marker in several organs of transported pigs. Constitutive (Hsp90, Hsp70 and Hsp27) and inducible (Hsp72 and Hsp86) Hsps expressed in skeletal muscle, heart, liver and kidney of transported young pigs were investigated. The study comprised 13 German Landrace line pigs (mean weight, approx. 35 +/- 1 kg). Eight animals (n = 8) were transported for a period of 6 h, whereas the control group (n = 5) was kept under normal housing conditions. Identification of Hsps was performed by immunoblot using porcine specific antibodies. Although the 5 Hsps were regularly detected in all porcine tissues, no clear up-regulation could be observed due to transportation. Densitometrical analysis of the immunoblots revealed an unexpected result. Every tissue had a significant reduction of at least 2 Hsp members: Kidney (Hsp90 and Hsp70), M. longissimus dorsi (Hsp90 and Hsp72) and M. gluteus maximus superficialis (Hsp90 and Hsp86), liver (Hsp90, Hsp86 and Hsp27). The heart was most affected, all Hsps were significantly reduced by 26% to 41% after 6 h of transportation. The regular reduction of the large Hsp90 and Hsp86 in nearly all tissues examined point to a new and critical role these Hsps might have in counteracting short-term stress reactions. The fast reduction of Hsps in fatal organs such as heart and kidney may have a relation to organ failure. Hsp90 level may therefore serve as a potential marker for the stress pigs are suffering during transportation.


Novel solid lipid nanoparticles as carriers for oral administration of insulin.
The aim of this study was to propose novel solid lipid nanoparticles (SLNs) loaded with cell-penetrating peptide (CPP), and to evaluate their potential for oral administration of insulin. Octaarginine (R8) was used as the CPP. SLNs loaded with insulin and R8 (Ra-Ins-SLNs) were prepared using the spontaneous emulsion solvent diffusion method. The morphological study of R8-Ins-SLNs showed its spherical shape using transmission electron microscopy (TEM) photography. The mean particle size, zeta potential, encapsulation efficiency (EE %) of insulin and R8 were 150.8 +/- 23.4 nm, 32.65 +/- 2.02 mV, 62.29 +/- 0.52% and 58.05 +/- 0.66%, respectively. The in vitro release of insulin or R8 from R8-Ins-SLNs was characterized by an initial rapid release and subsequent sustained release in pH 6.8 dissolution media. In vivo absorption experiments provided a relative pharmacological bioavailability (PA%) value of R8-Ins-SLN of 10.39 +/- 0.46%. These results suggest that SLNs loaded with CPP could be a promising perioral carrier for insulin.


The protective effect of apolipoprotein in models of trophoblast invasion and preeclampsia.
Preeclampsia is a hypertensive disorder of pregnancy. It is associated with abnormal placentation via poor placental invasion of the uterine vasculature by trophoblast cells, leading to poor placental perfusion, oxidative stress, and inflammation, all of which are implicated in its pathogenesis. A dyslipidemia characterized by low plasma levels of high-density lipoproteins (HDL) and elevated triglycerides has been described in preeclampsia. Apolipoprotein A-I (apoA-I), a constituent of HDL is an anti-inflammatory agent. This study investigated whether apoA-I protects against hypertension and adverse placental changes in a proinflammatory cytokine (TNF-α)-induced model of preeclampsia. Further, this study investigated whether apoA-I protects against the inhibitory effect of TNF-α in a human in vitro model of trophoblast invasion. Administration of apoA-I to pregnant mice before infusion with TNF-α resulted in a significant reduction in the cytokine-induced increase in systolic blood pressure. MRI measurement of T2 relaxation, a parameter that is tissue specific and sensitive to physiological changes within tissues, showed a reversal of TNF-α-induced placental changes. Preincubation of endothelial cells with apoA-I protected against the TNF-α-induced inhibition of HTR-8/SVneo (trophoblast) cell integration into endothelial (UtMVEC) networks. These data suggest that a healthy lipid profile may affect pregnancy outcomes by priming endothelial cells in preparation for trophoblast invasion.


A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues.
We report a general and facile method that provides rapid entry into 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under palladium-copper catalysis. The methodology utilises simple and easily available substrates of broad range. The applicability of this reaction for the synthesis of optically active products has been demonstrated. A plausible reaction mechanism has also been proposed.


Endogenous methylarginines modulate superoxide as well as nitric oxide generation from neuronal nitric-oxide synthase: differences in the effects of monomethyl- and dimethylarginines in the presence and absence of tetrahydrobiopterin.
The endogenous methylarginines asymmetric dimethylarginine (ADMA) and N(G)-monomethyl-L-arginine (L-NMMA) regulate nitric oxide (NO) production from neuronal NO synthase (nNOS). Under conditions of L-arginine or tetrahydrobiopterin (BH(4)) depletion, nNOS also generates superoxide, O(2)(.); however, the effects of methylarginines on this O(2)(.) generation are poorly understood. Therefore, we measured the dose-dependent effects of ADMA and L-NMMA on the rate and amount of O(2)(.) production from nNOS under conditions of L-arginine and/or BH(4) depletion, using electron paramagnetic resonance spin trapping. In the absence of L-arginine, ADMA (1 microm) inhibited O(2)(.) generation by approximately 60% from a rate of 56 to 23 nmol/mg/min, whereas L-NMMA (0.1-100 microm) had no effect. L-Arginine markedly decreased the observed O(2)(.) adduct formation; however, O(2)(.) generation from the enzyme still occurs at a low rate (12.1 nmol/mg/min). This O(2)(.) leak is NOS-derived as it is not seen in the absence of calcium and calmodulin and demonstrates that O(2)(.) generation from NOS occurs even when normal substrate/ cofactor levels are present. Under conditions of BH(4) depletion, ADMA had no effect on O(2)(.), whereas L-NMMA increased O(2)(.) production almost 3-fold. This O(2)(.) generation was >90% inhibited by imidazole, indicating that it occurred at the heme center. Thus, methylarginines can profoundly shift the balance of NO and O(2)(.) generation from nNOS. These observations have important implications with regard to the therapeutic use of methylarginine-NOS inhibitors in the treatment of disease.


A rare late complication of traumatic diaphragmatic hernia repair.
We report a case of sudden cardiovascular collapse several weeks following surgical repair of a traumatic diaphragmatic hernia. The patient presented with features of circulatory shock without a clear diagnosis, therefore an urgent computed tomography scan of the chest and abdomen was undertaken, which revealed a pericardial effusion with evidence of cardiac tamponade. Ultrasound-guided needle pericardiocentesis with aspiration of blood from the pericardial sac in the Emergency Department provided an immediate response and her cardiac output improved. On review of the imaging, it is likely a surgically-placed permanent metallic fixation device, sitting near the pericardium, caused bleeding into the pericardial sac due to local trauma as a delayed postoperative complication.


Multiple domains are required for the toxic activity of Pseudomonas aeruginosa ExoU.
Expression of ExoU by Pseudomonas aeruginosa is correlated with acute cytotoxicity in a number of epithelial and macrophage cell lines. In vivo, ExoU is responsible for epithelial injury. The absence of a known motif or significant homology with other proteins suggests that ExoU may possess a new mechanism of toxicity. To study the intracellular effects of ExoU, we developed a transient-transfection system in Chinese hamster ovary cells. Transfection with full-length but not truncated forms of ExoU inhibited reporter gene expression. Inhibition of reporter activity after cotransfection with ExoU-encoding constructs was correlated with cellular permeability and death. The toxicity of truncated versions of ExoU could be restored by coexpression of the remainder of the molecule from separate plasmids in trans. This strategy was used to map N- and C-terminal regions of ExoU that are necessary but not sufficient for toxicity. Disruption of a middle region of the protein reduces toxicity. This portion of the molecule is postulated to allow the N- and C-terminal regions to functionally complement one another. In contrast to ExoS and ExoT, native and recombinant ExoU molecules do not oligomerize or form aggregates. The complex domain structure of ExoU suggests that, like other P. aeruginosa-encoded type III effectors (ExoS and ExoT), ExoU toxicity may result from a molecule that possesses more than one activity.


The relationship of nitrogen and C/N ratio with secondary metabolites levels and antioxidant activities in three varieties of Malaysian kacip Fatimah (Labisia pumila Blume).
Kacip Fatimah (Labisia pumila Blume), one of the most famous and widely used herbs, especially in Southeast Asia, is found to have interesting bioactive compounds and displays health promoting properties. In this study, the antioxidant activities of the methanol extracts of leaves, stems and roots of three varieties of L. pumila (var. alata, pumila and lanceolata) were evaluated in an effort to compare and validate the medicinal potential of this indigenous Malaysian herb species. The antioxidant activity determined by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, as well as the total amount of phenolics and flavonoids were the highest in the leaves, followed by the stems and roots in all the varieties. A similar trend was displayed by the ferric reducing antioxidant potential (FRAP) activity, suggesting that the L. pumila varieties possess high foliar antioxidant properties. At low FRAP activity concentrations, the values of the leaves' inhibition activity in the three varieties were significantly higher than those of the stems and roots, with var. alata exhibiting higher antioxidant activities and total contents of phenolics and flavonoids compared to the varieties pumila and lanceolata. The high production of secondary metabolites and antioxidant activities in var. alata were firmly related to low nitrogen content and high C/N ratio in plant parts. The study also demonstrated a positive correlation between secondary metabolite content and antioxidant activities, and revealed that the consumption of L. pumila could exert several beneficial effects by virtue of its antioxidant activity.


Effects of emotion and emotional ambiguity on early visual event-related potentials.
The modulation of early sensory event-related potentials such as the P1, N1, and N170 by emotion and emotional ambiguity is still controversial. Some studies have found a modulation of one or all of these components by one or both of these factors, whereas others have failed to show such results. The objective of this study was to investigate the effects of emotion and ambiguity on the behavioral and electrophysiological responses to a morphed emotion recognition task. Thirty-seven healthy participants (19 men) completed an emotion recognition task where photographs of a male face expressing the six basic emotions morphed with another emotion (in a proportion ranging from 26% to 74%) were randomly presented while electroencephalography was recorded. After each face presentation, participants were asked to identify the facial emotion. We found an emotional effect on the P1, N1, and N170, with greater amplitudes for some emotional facial expressions than for others. However, we found no significant emotional ambiguity effect or interaction between emotion and ambiguity for any of these components. These findings suggest that computation of emotional facial expressions (regardless of their ambiguity) occurs from the early stages of brain processing. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Hizentra for the treatment of primary immunodeficiency.
Immunoglobulin (IgG) replacement therapy has been the cornerstone of treatment for primary immunodeficiency disease for nearly 60 years. During this time, research has continually refined the target IgG trough level and IgG replacement dosages to allow patients with primary immunodeficiency disease to achieve effective protection from infection. Manufacturers have also improved IgG formulations to allow patients to receive clinically beneficial dosages of IgG replacement with improved safety and tolerability. This review will introduce Hizentra(®), a highly concentrated (20%) IgG solution for subcutaneous (sc.) infusion, discuss its manufacturing process and pharmacokinetic profile and review its tolerability and efficacy data as evaluated in clinical trials. New highly concentrated sc. IgG products may improve patient quality of life and adherence to therapy because of the flexible dosing options, fewer infusion sites and less infusion time, compared with less concentrated sc. IgG products, resulting in favorable patient outcomes consistent with higher steady-state IgG levels.


Collision course? Donald Trump, Paul Ryan, and the fate of Medicare.
The election of Donald Trump as president of the United States raises questions about the future of Medicare. How will Medicare fare under Republican-led government? There are several compelling reasons that the Trump administration and Congressional Republicans might avoid Medicare reform, including the political risks of taking on a popular program, the difficulties the party has encountered in trying to dismantle the Patient Protection and Affordable Care Act (ACA), the importance of older Americans to the GOP coalition, and President Trump's views about Medicare. However, because of fiscal pressures and the commitment of Speaker of the House Paul Ryan and other Republicans to entitlement reform, the GOP nonetheless could end up attempting to make major changes in Medicare. Alternatively, Republican efforts to repeal and undermine the ACA could unintentionally enhance the political fortunes of proposals to expand Medicare. Consequently, the fate of Medicare during the Trump administration remains highly uncertain.


Barriers to care for children with orofacial clefts in North Carolina.
Little is known about the barriers faced by families of children with birth defects in obtaining healthcare. We examined reported perceived barriers to care and satisfaction with care among mothers of children with orofacial clefts. In 2006, a validated barriers to care mail/phone survey was administered in North Carolina to all resident mothers of children with orofacial clefts born between 2001 and 2004. Potential participants were identified using the North Carolina Birth Defects Monitoring Program, an active, state-wide, population-based birth defects registry. Five barriers to care subscales were examined: pragmatics, skills, marginalization, expectations, and knowledge/beliefs. Descriptive and bivariate analyses were conducted using chi-square and Fisher's exact tests. Results were stratified by cleft type and presence of other birth defects. Of 475 eligible participants, 51.6% (n = 245) responded. The six most commonly reported perceived barriers to care were all part of the pragmatics subscale: having to take time off work (45.3%); long waits in the waiting rooms (37.6%); taking care of household responsibilities (29.7%); meeting other family members' needs (29.5%); waiting too many days for appointments (27.0%); and cost (25.0%). Most respondents (72.3%, 175/242) felt "very satisfied" with their child's cleft care. Although most participants reported being satisfied with their child's care, many perceived barriers to care were identified. Due to the limited understanding and paucity of research on barriers to care for children with birth defects, including orofacial clefts, additional research on barriers to care and factors associated with them are needed.


Ecobiological approach to research regarding ageing and diseases.
Ageing and age-related diseases (ARD) share a common biological clock that appears as their root cause: protein damage. A majority of proteins have evolved into native structures resistant to oxidative damage but any folding imperfections, including those due to "silent" amino acid substitutions, reduce oxidation resistance. Damaged proteins accumulate with age and trigger ageing-like phenotypes reversible by their turnover, while acquired genome alterations remain as stable consequences of protein malfunction. Ageing and ARD display species-specific latency in phenotypic expression. Disease latency may be proposed as to be due to phenotypic suppression of cellular defects by molecular traffic among neighbouring cells. Such cross-complementation of functional deficiencies acts as a kind of tissue-based cellular "solidarity", called cellular parabiosis. Chronic inflammation reveals dormant cell phenotypes and shortens disease latency by the breakdown of cell-cell communication, as in tumour promotion and inflammation. At the present time, predictive diagnostics, prognostics, prevention and even cure of disease by phenotypic reversion become conceivable.


CC16 as an Inflammatory Biomarker in Induced Sputum Reflects Chronic Obstructive Pulmonary Disease (COPD) Severity.
The progression of an abnormal inflammatory response plays a crucial role in the lung function decline of chronic obstructive pulmonary disease (COPD) patients. Compared to serum biomarkers, inflammatory biomarkers in induced sputum would be a more reliable reflection of inflammatory processes in the airways. A total of 102 COPD participants were divided into a mild-to-moderate group (FEV1%pred≥ 50%, n=57) and a severe-to-very-severe group (FEV1%pred<50%, n=45). We measured a series of inflammatory biomarkers in induced sputum and analyzed their association with lung function and SGRQ in COPD patients. To evaluate the relationship between inflammatory biomarkers and the inflammatory phenotype, we also analyzed the correlation between biomarkers and airway eosinophilic phenotype. We found increased mRNA levels of MMP9, LTB4R, and A1AR and decreased levels of CC16 mRNA in induced sputum in the severe-to-very-severe group. After adjustment for age, sex and other biomarkers, CC16 mRNA expression was positively associated with FEV1%pred (r=0.516, p=0.004) and negatively correlated with SGRQ scores (r=-0.3538, p=0.043). As previously known, decreased CC16 was related to the migration and aggregation of eosinophils in airway. It was also found that CC16 had a moderate negative correlation with the eosinophilic inflammation in airway (r=-0.363, p=0.045) in our COPD patients. Low CC16 mRNA expression levels in induced sputum were associated with low FEV1%pred and a high SGRQ score in COPD patients. Sputum CC16 as a potential biomarker for predicting COPD severity in clinical practice might attribute to the involvement of CC16 in airway eosinophilic inflammation.


Risk factors for musculoskeletal symptoms among crawfish farmers in Louisiana--a pilot study.
The prevalence of musculoskeletal symptoms (MSS) among crawfish farmers is unknown. The purpose of this study was to assess the prevalence of MSS in nine body regions among crawfish farmers, and to examine associations between MSS and crawfish farm work activities. Questionnaires were mailed to randomly selected crawfish farmers in the State of Louisiana, USA. Site-specific MSS, demographics, and crawfish farm work information was obtained from the previous six months. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression adjusting for potential confounders. Among the participants (N = 184), shoulder MSS were reported most frequently (62%). Wrist/hand and low back MSS were significantly associated with tractor use (OR(adj) = 2.89; 95% CI = 1.28-6.56) and (OR(adj) = 2.41; 95% CI = 1.03-5.67), respectively. Also, upper back MSS were associated with the number of years working on a crawfish farm (OR(adj) = 3.07; 95% CI = 1.17-8.04). Shoulder and low back MSS were common. Tractor use may increase the risk of wrist/hand and low back MSS. Future studies need accurately assess exposures to physical risk factors for MSS so ergonomic interventions can be developed.


Age-dependent changes in thiamin concentrations in whole blood and cerebrospinal fluid in infants and children.
We determined pediatric age-specific normative ranges for total, phosphorylated, and nonphosphorylated thiamin in whole blood (n = 323) and cerebrospinal fluid (CSF; n = 208). Whole-blood total thiamin decreased from 258 +/- 63 (mean +/- SD; age 0-3 mo group) to 214 +/- 44 nmol/L (age 3-12 mo group) in the first year of life and was stable at 187 +/- 39 nmol/L after 12 mo of age. The overall decline in whole-blood total thiamin was mainly due to a drop in phosphorylated thiamin, the biologically active form. Mean CSF total thiamin decreased from 135 +/- 42 (age 0-9-mo group) to 107 +/- 34 nmol/L (age 9-18-mo group) in the first 1.5 y of life and was stable at 84 +/- 51 nmol/L thereafter. This overall decline was due initially to a drop in nonphosphorylated thiamin and later to a drop in phosphorylated thiamin. The changes in whole blood and CSF occurred independently and probably represent metabolic and neurological maturation of the infant. Whole-blood total and phosphorylated thiamin concentrations were lower in blacks only after pubarche. Age-specific norms should be used for determining the thiamin status in infancy because thiamin concentrations are significantly higher in the first few months of life.


Cytotoxicity of tetraplatin and cisplatin for human and rodent cell lines cultured as monolayers and multicellular spheroids.
The cytotoxicity of tetraplatin (dl-trans), its d- and l-isomers, and cisplatin for four human tumor cell lines (myeloma 8226, ovarian 2008, A2780, and OVCAR-3), their cisplatin-resistant variants, and three rodent cell lines (V79, EMT6/Ro, and L1210) were compared. Tetraplatin was more, or equally as, potent as cisplatin for the human cell lines and for L1210 but was clearly less potent for V79 and EMT6/Ro. The d-trans tetraplatin was more potent than the l-trans. Cisplatin resistant human tumor cells were less resistant to tetraplatin. On comparing sensitivity of V79 and EMT6/Ro cells in two growth models, we observed that all of the platinum compounds were more cytotoxic to cells in multicellular spheroids than in exponentially growing monolayers. Uptake studies, however, showed that tetraplatin was more cytotoxic to spheroids because spheroids accumulated more drug than monolayers.


Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics.
The ubiquitin‑specific protease 9X (USP9X) is a conserved deubiquitinase that has been investigated in several types of human cancer. However, the clinical significance and the biological roles of USP9X in prostate cancer remain unexplored. In the present study, an investigation into the expression and clinical significance of USP9X in prostate cancer revealed that USP9X expression was downregulated in prostate cancer tissues compared with that in healthy tissues. In addition, decreased USP9X expression was associated with a higher Gleason score and local invasion. Depletion of USP9X in prostate cancer LNCaP and PC‑3 cells by small interfering RNA promoted cell invasion and migration. Furthermore, USP9X depletion upregulated matrix metalloproteinase 9 (MMP9) and the phosphorylation of dynamin‑related protein 1 (DRP1). Notably, a significant increase in phosphorylated extracellular signal‑regulated kinase (ERK), an upstream activator of MMP9 and DRP1, was observed. To investigate whether ERK activation was able to increase MMP9 protein levels and induce DRP1 phosphorylation, an ERK inhibitor was used, demonstrating that ERK‑mediated MMP9 production and change in mitochondrial function was critical for the biological function of USP9X in prostate cancer cells. In conclusion, the present study demonstrated that USP9X is downregulated in prostate cancer and functions as an inhibitor of tumor cell invasion, possibly through the regulation of the ERK signaling pathway.


Environment and individual: a dialectic relationship.
The role of development in current neo-Darwinian evolutionary theory is still underestimated. Only a few experimental and theoretical efforts have been made to bridge the gap, among which the theories of genetic assimilation, stabilising selection and autopoiesis. The relationship between the organism and its environment is a focal point for understanding development. The organism itself determines which environmental features are relevant to it, what represents a stimulus that would trigger its behaviour, and continuously affects the environment through its activities, in a dialectic relationship. Such a relationship is unique and diachronic, changing with time and defining the individual. Development in the broad sense and behavioural plasticity refer to the individual unlike evolution, which refers to populations.


Reversible right ventricular dysfunction in patients with HIV infection.
Human immunodeficiency virus-related cardiomyopathy is characterized by global left ventricular (LV) dysfunction commonly associated with biventricular dilation. Human immunodeficiency virus (HIV) cardiomyopathy carries a poor prognosis, and the role of antiretroviral therapy in the reversal of heart failure is not very clear. We report two patients with HIV infection who presented with severe right ventricular (RV) dysfunction in the absence of pulmonary parenchymal, pulmonary arterial and left ventricular myocardial involvement. During the period of intensive antiretroviral therapy, the symptoms of right heart failure progressively and remarkably improved. This was accompanied by normalization of right ventricular size and RV function documented by repeat echocardiograms. Given that the serologic tests for opportunistic infections were negative, and the RV function improvement correlated with a decrement in the viral load, it is likely that the cardiomyopathy was due to direct infection by HIV. These cases illustrate that there can be isolated involvement of the right heart in the absence of lung, significant pulmonary vascular and left ventricular disease, and also that the antiretroviral therapy might reverse the cardiomyopathy.


Rat liver cytochrome P450IA2 synthesized by transfected COS-1 cells efficiently activates food-derived promutagens.
A standard calcium phosphate technique was used to obtain transient expression of cDNAs for rat liver cytochrome P450s in COS-1 cells. Cells transfected with a pMT2-based vector expressing P450IA2 cDNA (pMT2-IA2) had high acetanilide-4-hydroxylase activity and very low aryl hydrocarbon hydroxylase (AHH) activity. Cells transfected with a hybrid expression vector, pMT2-IA2/IA1, coding for a P450IA2/IA1 fusion protein (consisting of the amino-terminal region of P450IA2 and the central and carboxy-terminal regions of P450IA1) had high AHH activity. This result and other data indicate that the P450IA2/IA1 fusion protein has the substrate specificity of P450IA1. Extracts of cells transfected with pMT2-IA2 readily converted 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and related food-derived promutagens into mutagenic forms. Extracts of cells transfected with pMT2-IA2/IA1 showed efficient activation of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp P-2). To facilitate comparison of activities of P450s synthesized from cDNA expression vectors, the promutagen activation assays were carried out with limiting enzyme and saturating or nearly saturating substrate concentrations. The transient expression system described here uses a standard expression vector and requires only microgram quantities of cell extract protein for activation of food-derived promutagens such as MeIQ and Trp P-2. It will be useful for identifying P450s active in promutagen activation and for analyzing structure-function relationships of different P450 molecules.


Event-triggered model predictive control of positive systems with random actuator saturation.
This paper investigates the event-triggered model predictive control of positive systems with actuator saturation. Interval and polytopic uncertainties are imposed on the systems, respectively. First, a new model with actuator saturation obeying Bernoulli distribution is established, which is more general and powerful for describing the saturation phenomenon than the saturation in a deterministic way. Then, a linear event-triggering condition is constructed based on the state and error signal. Under the event-triggering condition, an interval estimate approach is presented to reach the positivity and stability of the systems. The saturation part in the controller is technically transformed into a non-saturation part. Thus, a linear programming approach is proposed to compute the event-triggered controller gain and the corresponding gain of attraction domain. A predictive algorithm is introduced for the computation of the event-triggered controller parameters. Finally, an example is provided to illustrate the validity of the design.


[Chronic arthroses in children: practical approach and epidemiological data].
Osteo-articular symptoms are frequent in pediatrics, but chronic arthritis is rare in childhood. Arthritis may be difficult to recognize in children and there is a large differential diagnosis including infectious and neoplastic diseases. Even if juvenile arthritis has often a favourable course, significant functional damage may occur. The diagnosis and the follow-up of chronic arthritis should be performed in collaboration with a specialized consultation in pediatric rheumatology, in order to allow access to multidisciplinary medical care and help to increase the clinical and epidemiological knowledge in these rare diseases. A study is starting this fall aimed at collecting epidemiological datas on childhood arthritis in the french part of Switzerland.


Examining positive and negative perceptions of older workers: a meta-analysis.
This article presents an updated meta-analysis of field and laboratory studies that examine the influence of age on a number of evaluative workplace outcomes (advancement, selection, general evaluations, interpersonal skills, and reliability). Method. A random effects meta-analytic procedure was used. In line with the perspective that perceptions of older workers are multidimensional, the observed meta-analytic correlations indicate that age has medium-sized negative effects on majority of the outcomes investigated (r(advancement) = -.21, r(selection) = -.30, r(general evaluations) = -.24, and r(interpersonal skills) = -.23, and a medium-sized positive effect on perceptions of reliability (r(reliability) = .31). Additionally, evidence of moderation by study design for the selection outcome is presented, such that within-subjects designs elicit stronger effects of age than between-subjects designs. Discussion. The present study demonstrates that it is likely that older workers are not viewed entirely negatively or entirely positively in the workplace; rather, the perceptions of older workers are more are varied, and even positive in some cases.


Rapid, hand-held paper diagnostic for measuring Fibrinogen Concentration in blood.
Critical bleeding causes over 2 million deaths a year. Early hypofibrinogenemia is a strong predictor of mortality in critically bleeding patients. The early replenishment of fibrinogen can significantly improve outcomes. However, over replenishment can also be dangerous. Furthermore, there is no rapid, cheap, hand-held diagnostic that can aid critically bleeding patients in fibrinogen replacement therapy. In this study, we have developed a hand-held paper diagnostic that measures plasma fibrinogen concentrations. The diagnostic has the potential to be used as a point of care device both inside and outside of hospital settings. It can vastly reduce the time to treatment for fibrinogen replacement therapy. The diagnostic is a two-step process. First, thrombin and plasma are added onto horizontially-orientated paper strips where the fibrinogen is converted into fibrin, drastically increasing the plasma's hydrophobicity. Second, an aqueous blue dye is pipetted onto the strips and allowed to wick through the fibrin. The distance the blue dye wicks through the strip correlates precisely to the fibrinogen concentration. The diagnostic can provide results within a minute. It can distinguish low fibrinogen concentrations (ie. <2 g/L) from normal fibrinogen concentrations. It shows remarkable reproducibility between healthy individuals. It is unaffected by common blood conditions such as acidosis, blood alcohol, severe hypertriglyceridemia, severe haemolysis and warfarin administration. Finally, it is unaffected by humidity and can withstand cold temperatures.


Preferential oxidation-induced etching of zigzag edges in nanographene.
We investigated the thermal oxidation process of nanographene using activated carbon fibers (ACFs) by thermogravimetry (TG), X-ray photoemission spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS), and electrical conductance measurements. The oxidation process started from the edge of nanographene with the formation of phenol (-OH) or ether (C-O-C) groups attached to edge carbon atoms, as verified by the XPS and NEXAFS results. While the TG results indicated a decrease in the size of the nanographene sheet during the oxidation process, the intensity of the edge-state peak, i.e., the signature of the zigzag edge, decreased in the C K-edge NEXAFS spectra. This suggests that the zigzag edge preferentially reacted with oxygen and that the nanographene terminated with the thermodynamically unstable zigzag edges converted to one terminated with stable armchair edges. As the oxidation temperature increased, the activation energy for the electron hopping transport governed by the Coulomb gap variable range hopping between the nanographene sheets increased, and the tunneling barrier decreased. This change can be understood on the basis of the decrease in the size of the nanographene sheets together with the preferential etching of nanographene edges and the decrease in the inter-nanographene-sheet distance.


Magnetically driven micro-optical choppers fabricated by two-photon polymerization.
In this Letter, a series of magnetically driven micro-optical choppers based on customized photoresist were fabricated by two-photon polymerization (TPP) technology. Synthetic Fe3O4 nanoparticles (NPs) were modified and dispersed in the original photoresist to achieve magnetic field response. After accurately formulating a magnetic photoresist containing Rhodamine B to reduce the light transmittance, four micro-optical choppers with different slot widths were printed using optimized processing parameters. The micro-optical choppers were remotely manipulated to rotate by the external magnetic field. More importantly, the function demonstration of the micro-optical choppers with an excellent chopping effect was achieved at a given light wavelength of 515 nm. The magnetically driven micro-optical choppers provide a new approach, to the best of our knowledge, for the fabrication of external field-responsive optical components.


A learning theory perspective on lapse, relapse, and the maintenance of behavior change.
Behavior change processes studied in the learning laboratory, such as extinction and counterconditioning, do not involve destruction of the original learning. Instead, they often result in new behavior that is strongly dependent on the current context, whether provided by external cues, internal state, recent events, or time. Lapse and relapse effects may therefore occur after various manipulations of the context. Theory and preliminary evidence suggests that long-term maintenance of changed behavior may be promoted by a number of factors, including situating the new learning in the most relevant contexts, providing retrieval cues after the new learning is complete, and varying the contexts in which the new learning takes place. Furthermore, because original learning is often more context free than the learning that replaces it, the most efficient way to reduce risk behavior in the general population may be to find ways to ensure that healthy behaviors and attitudes are learned first.


A unique resting position of the ATP-synthase from chloroplasts.
The chloroplast ATP-synthase catalyzes ATP synthesis coupled to transmembrane proton transport. The enzyme consists of two parts, a membrane-embedded F(0) part and an extrinsic F(1) part, which are linked by two connectors. One of these rotates during catalysis and the other remains static. Although the atomic structures of various sub-complexes and individual subunits have been reported, only limited structural information on the complex, as a whole, is available. In particular, information on the static connector is lacking. We contribute a three-dimensional map at about 20-A resolution, derived from electron cryomicroscopy of enzymes embedded in vitrified buffer followed by single particle image analysis. In the three-dimensional map both connectors, between the F(1) part and the F(0) part, are clearly visible. The static connector is tightly attached to an alpha subunit and faces the side of the neighboring beta subunit. The three-dimensional map provides a scaffold for fitting in the known atomic structures of various subunits and sub-complexes, and suggests that the oxidized, non-activated ATP-synthase from chloroplasts adopts a unique resting position.


High Corrosion Resistance of NiFe-Layered Double Hydroxide Catalyst for Stable Seawater Electrolysis Promoted by Phosphate Intercalation.
Sustainable production of hydrogen from seawater electrolysis has attracted much attention in recent years. Considering that Cl- might corrode metal substrate by crossing through the covered catalyst, the conventional Ni(II)Fe(III)-layered double hydroxide (NiFe-LDH) loaded on metal substrate, as a favorable oxygen evolution catalyst, cannot be directly used for seawater electrolysis. Herein, an anti-corrosion strategy of PO4 3- intercalation in NiFe-LDH is proposed, in which the highly negatively charged PO4 3- in the interlayers can prevent the Ni substrate from Cl- corrosion by electrostatic repulsion. In order to verify the anti-corrosion effect, the two electrodes of the pristine NiFe-LDH and the PO4 3- intercalated NiFe-LDH are evaluated in a solution with high Cl- concentration. PO4 3- can effectively hinder the migration of Cl- between the interlayers of NiFe-LDH, thus the corrosion life of the PO4 3- intercalated NiFe-LDH is more than 100 times longer than that of the pristine NiFe-LDH. The improvement of stability is attributed to the inhibition effect of Cl- passing through the interlayers of NiFe-LDH, leading to the protection of Ni substrate. This work provides a design strategy for the catalysts loaded on the metal substrate, which has excellent Cl- -corrosion resistance and can be widely used in hydrogen generation from seawater electrolysis.


Biomechanical properties of anuran long bones: correlations with locomotor modes and habitat use.
Long bones are subjected to mechanical loads during locomotion that will influence their biomechanical properties through a feedback mechanism (the bone mechanostat). This mechanism adapts the spatial distribution of the mineralized tissue to resist compression, bending and torsion. Among vertebrates, anurans represent an excellent group to study long bone properties because they vary widely in locomotor modes and habitat use, which enforce different skeletal loadings. In this study, we hypothesized that (a) the cortical bone mass, density and design of anuran femur and tibiofibula would reflect the mechanical influences of the different locomotor modes and habitat use, and (b) the relationships between the architectural efficiency of cortical design (cross-sectional moments of inertia) and the intrinsic stiffness of cortical tissue [cortical mineral density; the 'distribution/quality' (d/q) relationship] would describe some inter-specific differences in the efficiency of the bone mechanostat to improve bone design under different mechanical loads. To test this hypothesis, we determined tomographic (peripheral quantitative computed tomography) indicators of bone mass, mineralization, and design along the femur and tibiofibula of four anuran species with different modes of locomotion and use of habitat. We found inter-specific differences in all measures between the distal and proximal ends and mid-diaphysis of the bones. In general, terrestrial-hopper species had the highest values. Arboreal-walker species had the lowest values for all variables except for cortical bone mineral density, which was lowest in aquatic-swimmer species. The d/q relationships showed similar responses of bone modeling as a function of cortical stiffness for aquatic and arboreal species, whereas terrestrial-hoppers had higher values for moments of inertia regardless of the tissue compliance to be deformed. These results provide new evidence regarding the significant role of movement and habitat use in addition to the biomechanical properties of long bones within a morpho-functional and comparative context in anuran species.


Mercury content in commercially available finfish in the United States.
Seventy-seven finfish species (300 composites of three fish) were obtained from commercial vendors in six regions of the United States: Great Lakes, mid-Atlantic, New England, northwest, southeast, and southwest. Total mercury in fish muscle tissue ranged from 1 ppb (channel catfish) to 1,425 ppb (king mackerel). Of the top 10 most commonly consumed seafoods in the United States, all finfish species, including salmon species (13 to 62 ppb), Alaskan pollock (11 ppb), tilapia (16 ppb), channel catfish (1 ppb), Atlantic cod (82 ppb), and pangasius (swai) (2 ppb), had low total mercury concentrations. However, two large predatory species, king mackerel and swordfish (1,107 ppb), contained mercury concentrations above the current U.S. Food and Drug Administration action level of 1,000 ppb, indicating that consumers may be unaware that species that are high in mercury are being sold in the marketplace.


Current approaches to advanced-stage non-small-cell lung cancer: first-line therapy in patients with a good functional status.
Lung cancer is the leading cause of cancer-related death among men and women in the United States. Approximately 80-85% of lung cancer cases are non-small-cell lung cancer (NSCLC), and approximately 65% of these patients have advanced-stage (IIIB/IV) disease at diagnosis. The median survival for patients with advanced-stage NSCLC treated with platinum-based chemotherapy is a disappointing 8-10 months. This article reviews the current status of chemotherapy in patients with a good functional status and evaluates the treatments in terms of efficacy, toxicity, survival, and impact on quality of life in the first-line treatment. Biologic agents such as bevacizumab and erlotinib have been investigated in phase III trials in the first- and second-line setting. These agents could play a role in select patient populations. This article also highlights some of the more promising new strategies, such as advances in pharmacogenomics and immune-based therapy. There is a clear need for improvement in the current standard of care. Well-designed clinical trials with appropriate patient selection, as well as continued efforts in translational research and pharmacogenomics, are crucial for progress in this disease.


Atrial standstill in sinus node disease due to extensive atrial fibrosis: impact on dual chamber pacemaker implantation.
Atrial standstill is characterized by the absence of atrial activity. We report about a series of cases, in which conventional atrial pacemaker lead implantation in patients with symptomatic sinus node disease failed due to lack of excitable right atrial tissue, thus, prompting the diagnosis of atrial standstill. We hypothesized that mapping of the atria with subsequent identification of myocardium still amenable to atrial pacing would allow dual chamber pacemaker implantation. In four patients, atrial lead implantation failed. In these patients, spontaneous or fibrillatory electrical activity was absent but the atria could not be captured despite high stimulation voltages at conventional atrial sites. We suspected partial or complete atrial standstill and subsequently confirmed this hypothesis by conventional (n = 1) or electroanatomical mapping (n = 3). Areas of fibrotic tissue were present in all patients as identified by lack of spontaneous electrical activity and inability of local electrical capture via the mapping catheter. Surviving atrial tissue, which could be electrically captured with subsequent conduction of activity to the atrioventricular (AV) node, was present in three patients. Successful targeted atrial lead implantation at these sites was achieved in all these patients. Isolated sinus node activity without conduction to the atria was found in one patient. Partial atrial standstill may be present and prevent atrial lead implantation in patients with sinus node disease. In these patients, recognition of partial atrial standstill and identification of surviving muscular islets with connection to the AV node by mapping studies may still allow synchronous AV sequential pacing.


Cell chip to detect effects of graphene oxide nanopellet on human neural stem cell.
The graphene oxide (GO) nanopellet, a potentially useful carbon-based material, recently started being applied in cell-based research areas. Its toxicity assessment using the neural-stem-cell-based chip has not been thoroughly reported yet, though. Herein, a cell chip was fabricated to electrochemically detect the toxic effects of GO nanopellets on HBl.F3 cells. The RGD peptide was immobilized on the gold electrode surface to enhance the binding affinity of the HBl.F3 cells to the electrode surface. A clear redox peak appeared when the HB1.F3 cells were analyzed via cyclic voltammetry. The GO nanopellet was analyzed via Raman spectroscopy to confirm its distinct structural characteristics that normally differ from those of graphite oxide. After GO was added to the HB1.F3 cells, differential pulse voltammetry was performed to discover the toxic effects of GO nanopellets on HB1.F3 cells. A negative correlation was achieved between the concentration of the GO nanopellets and the cell viability, which was verified via both MTT assay and a microscopic imaging tool. Thus, these electrochemical tools can be usefully applied to the toxicity assessment of various kinds of carbon-based materials.


Identification of inhibitors of bacterial RNA polymerase.
Very few clinically available antibiotics target bacterial RNA polymerase (RNAP) suggesting it is an underutilized target. The advent of detailed structural information of RNAP holoenzyme (HE) has allowed the design and in silico screening of novel transcription inhibitors. Here, we describe our approach for the design and testing of small molecule transcription inhibitors that work by preventing the interaction between the essential transcription initiation factor σ and RNAP. With the appropriate structural information this approach can be easily modified to other essential protein-protein interactions.


Urolithiasis--medical therapies.
This review paper provides a summary of medical therapies available for urolithiasis. The summary includes general medical advice, prophylactic medications, dissolution therapy and medical expulsion therapy. The paper is designed to provide a management strategy for all physicians who treat urolithiasis, from general practitioners, to emergency physicians, to urologists. • To provide an up to date review of the literature in relation to the medical management of stone disease. This will encompass prophylaxis, dissolution therapy and medical expulsion therapy. • First-time stone formers do not regularly have a full urine and electrolyte evaluation due to the low incidence of a reversible metabolic cause. • However, stone disease is common and over a lifetime urolithiasis can affect up to 10-15% of the population. • Medical management of stone disease encompasses preventative measures, medical dissolution and medical expulsion therapy. • Recurrent stone formers should have dietary optimization to decrease the risk of further stones. • Furthermore, the correct use of prophylactic and therapeutic medications can decrease the morbidity associated with ureteric calculi.


A note of feature screening via a rank-based coefficient of correlation.
Feature screening is a useful and popular tool to detect informative predictors for ultrahigh-dimensional data before developing statistical analysis or constructing statistical models. While a large body of feature screening procedures has been developed, most methods are restricted to examine either continuous or discrete responses. Moreover, even though many model-free feature screening methods have been proposed, additional assumptions are imposed in those methods to ensure their theoretical results. To address those difficulties and provide simple implementation, in this paper we extend the rank-based coefficient of correlation to develop a feature screening procedure. We show that this new screening criterion is able to deal with continuous and binary responses. Theoretically, the sure screening property is established to justify the proposed method. Simulation studies demonstrate that the predictors with nonlinear and oscillatory trajectories are successfully retained regardless of the distribution of the response. Finally, the proposed method is implemented to analyze two microarray datasets.


Effect of Intraoperative Computed Tomography on Ventriculoperitoneal Shunt Survival.
In patients with hydrocephalus who undergo ventriculoperitoneal shunt placement, the ventricular catheter tip position is one of the most important prognostic factors influencing shunt survival. The aim of this study was to present our findings of ventriculoperitoneal shunt placement performed with intraoperative computed tomography (CT) and to evaluate the effect of intraoperative CT-based image guidance on optimal catheter positioning and overall shunt survival. Of the study enrolled 345 patients with hydrocephalus who underwent ventriculoperitoneal shunt placement for the first time between 2008 and 2018. Ventricular catheters were inserted freehand via the Kocher point into the lateral ventricle in all patients. In 163 patients, intraoperative CT was performed to confirm the tip position. In this group of patients, if the tip position was nonoptimal, the catheter was ejected and reinserted during the surgery. In the remaining 182 patients, the tip position was assessed with routine postoperative CT. The effect of performing intraoperative CT on catheter tip positioning and shunt failure was investigated. Nonoptimal tip position was significantly correlated with shunt dysfunction even when excluding nonobstructive causes (P < 0.001). In the intraoperative CT group, 11 ventricular catheters (6.7%) were intraoperatively repositioned. The repositioning significantly improved the optimal tip position rate from 54% to 58.3% (P = 0.007). Intraoperative CT usage also showed direct correlation with shunt survival (P = 0.006). Intraoperative CT is an effective tool for increasing the rate of optimal tip positioning and thereby overall shunt survival.


Eyes and negative phototaxis in juvenile crown-of-thorns starfish, Acanthaster species complex.
As a corallivore, the crown-of-thorns starfish (COTS; Acanthaster species complex), has significant impacts on coral mortality and community structure on tropical reefs throughout its Indo-Pacific range. COTS form aggregations which systematically move through and across reefs causing significant loss in hard coral cover. Previous work has shown that their behaviours on the reef are influenced by rheotaxis, olfaction and vision, with vision guiding adult animals to their coral habitat at short distances. As the compound eye of starfish grows throughout life the visual capacity of juvenile eyes is putatively less than for adult animals. Here we show this to be the case. Juvenile eyes have approximately the same visual field as adult eyes but significantly lower spatial resolution. They display negative phototaxis, as observed in adults, but we found no direct proof for the use of spatial resolution in this behaviour. Our results show that juveniles are able to use their eyes to locate their habitat: the coral reef. However, their putatively lower spatial resolution would make this visual task more difficult than for the adults.This article has an associated First Person interview with the first author of the paper.


High-Fat Diet Alters Immunogenic Properties of Circulating and Adipose Tissue-Associated Myeloid-Derived CD45+DDR2+ Cells.
Chronic inflammation is evident in the adipose tissue and periphery of patients with obesity, as well as mouse models of obesity. T cell subsets in obese adipose tissue are skewed towards Th1- and Th17-associated phenotypes and their secreted cytokines contribute to obesity-associated inflammation. Our lab recently identified a novel, myeloid-derived CD45+DDR2+ cell subset that modulates T cell activity. The current study sought to determine how these myeloid-derived CD45+DDR2+ cells are altered in the adipose tissue and peripheral blood of preobese mice and how this population modulates T cell activity. C57BL/6 mice were fed with a diet high in milkfat (60%·kcal, HFD) ad libitum until a 20% increase in total body weight was reached, and myeloid-derived CD45+DDR2+ cells and CD4+ T cells in visceral adipose tissue (VAT), mammary gland-associated adipose tissue (MGAT), and peripheral blood (PB) were phenotypically analyzed. Also analyzed was whether mediators from MGAT-primed myeloid-derived CD45+DDR2+ cells stimulate normal CD4+ T cell cytokine production. A higher percentage of myeloid-derived CD45+DDR2+ cells expressed the activation markers MHC II and CD80 in both VAT and MGAT of preobese mice. CD4+ T cells were preferentially skewed towards Th1- and Th17-associated phenotypes in the adipose tissue and periphery of preobese mice. In vitro, MGAT from HFD-fed mice triggered myeloid-derived CD45+DDR2+ cells to induce CD4+ T cell IFN-γ and TNF-α production. Taken together, this study shows that myeloid-derived CD45+DDR2+ cells express markers of immune activation and suggests that they play an immune modulatory role in the adipose tissue of preobese mice.


Patterns of Potentially Inappropriate Bladder Antimuscarinic Use in People with Dementia: A Retrospective Cohort Study.
Emergency department (ED) visits or hospitalizations should prompt review of the patient's medications after discharge and targeted deprescribing to reduce ongoing risks. To see if this is happening, we sought to examine the proportion of serious falls and delirium that were followed by a prescription fill for a bladder antimuscarinic. Our secondary objective was to identify concurrent use of other anticholinergics, cholinesterase inhibitors (ChEIs), and diuretics among people with dementia taking bladder antimuscarinics. Retrospective descriptive study using data from the National Health and Aging Trends Study (2011-2014) linked with Medicare claims from 2010-2014. The primary outcome was the proportion of serious falls or delirium that were followed by a bladder antimuscarinic prescription fill within 12 months. The secondary outcome was the proportion of individuals concurrently receiving prescriptions for bladder antimuscarinics, other strong anticholinergics, ChEIs, and diuretics. During the observation period, 8.88% of people with dementia filled a bladder antimuscarinic prescription. Over one-third (35%) initiated use after being identified as having dementia. Many used bladder antimuscarinics concurrently with other strong anticholinergics (19%), diuretics (42%), and ChEIs (32%). The majority (76%) of serious falls or delirium among people with dementia and bladder antimuscarinic use were followed by a bladder antimuscarinic prescription within 12 months. In this descriptive study, bladder antimuscarinic prescriptions were often filled irrespective of dementia status, serious falls, or delirium. Concurrent use of other anticholinergics, diuretics, and ChEIs was common. Falls and delirium should trigger review of the medication list after discharge and targeted deprescribing in people with dementia.


Gastrointestinal basidiobolomycosis in a patient suffering from duodenal ulcer with perforation: First case report from Italy.
Gastrointestinal basidiobolomycosis (GIB), an unusual fungal infection caused by the fungus Basidiobolus ranarum, is rarely reported in the medical literature. GIB is difficult to diagnose because its clinical presentation is non-specific and has no identifiable risk factors. We report here the first case of GIB diagnosed in Italy in a patient suffering from a duodenal ulcer with perforation. The patient was successfully treated with itraconazole. The absence of non-specific signs and symptoms of GIB may delay a definitive diagnosis and treatment. A microbiological investigation should always be requested in order to reach a rapid and definitive diagnosis and to rule out other intestinal diseases.


Bio-Functional and Structural Properties of Pasta Enriched with a Debranning Fraction from Purple Wheat.
A colored and fiber-rich fraction from the debranning of purple wheat was incorporated at 25% into semolina- and flour-based pasta produced on a pilot-plant scale, with the aim of increasing anthocyanin and total phenolic content with respect to pasta obtained from whole pigmented grains. The debranning fraction impaired the formation of disulfide-stabilized protein networks in semolina-based systems. Recovery of phenolics was impaired by the pasta making process, and cooking decreased the phenolic content in both enriched samples. Cooking-related losses in anthocyanins and total phenolics were similar, but anthocyanins in the cooked semolina-based pasta were around 20% of what was expected from the formulation. HPLC (High Performance Liquid Chromatography) profiling of phenolics was carried out on extracts from either type of enriched pasta both before and after cooking and indicate possible preferential retention of specific compounds in each type of enriched pasta. Extracts from cooked samples of either enriched pasta were tested as inhibitors of enzymes involved in glucose metabolism and uptake, as well as for their capacity of suppressing the response to inflammatory stimuli. Results of both biological tests indicate that the phenolics in extracts from both cooked pasta samples had inhibitory capacities higher than extracts of the original debranning fraction at identical concentrations of total bioactives.


Identification and Validation of Hub Genes with Poor Prognosis in Hepatocellular Carcinoma by Integrated Bioinformatical Analysis.
Hepatocellular carcinoma (HCC) is the reason for the world's second largest cancer-related death. It is clinically valuable to study the molecular mechanisms of HCC occurrence and development for formulating more effective diagnosis and treatment strategies. The five microarray data sets GSE45267, GSE101685, GSE84402, GSE62232 and GSE45267 were downloaded from Gene Expression Omnibus (GEO) database, including 165 HCC tissues and 73 normal tissues. Differential expressed genes (DEGs) between HCC tissues and normal tissues were determined by GEO2R. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and the protein-protein interaction network (PPI) network analysis were employed to identify DEGs and to evaluate the clinical significance in prognosis of HCC. A total of 152 genes differentially expressed in HCC tissues and normal tissues were identified. GO and KEGG functional enrichment analysis revealed that 39 up-regulated genes were mainly enriched in mitosis, cell cycle and oocyte meiosis, while those down-regulated genes (113) were concentrated in exogenous drug catabolism and the metabolism of cytochrome P450 on exogenous drugs. Totally, 19 hub genes were chosen by PPI network and module analysis and verified by The Cancer Genome Atlas (TCGA) database. Finally, 8 hub genes were selected, including CDK1, CYP2C8, CCNB1, AURKA, CYP2C9, BUB1B, MAD2L1 and TTK, which were associated with the overall survival rate of HCC patients. This study presented eight target genes connected to the prognosis of HCC patients. Those mainly exists in cell cycle and drug catabolism, which may be latent targets for clinical treatment.


Psoriasis and pentoxifylline: a clinical, histopathologic, and immunohistochemical evaluation.
The aim of this study was to examine the clinical and histopathologic effects of pentoxifylline on psoriasis, compared with placebo. Sixty-one outpatients with active psoriasis were randomly assigned to either of 2 groups: one was given pentoxifylline 400 mg tid PO, and the other, placebo. Fifty-six patients concluded the study. They were evaluated clinically and by laboratory parameters before and after 8 weeks of treatment. Pretreatment and posttreatment biopsies were taken. Initial sections were stained with hematoxylin-eosin. Further cuts were immunostained for cytokeratins 10, 14, and 16. Clinical and histologic improvement did not show statistically significant differences between the groups. No laboratory abnormalities or serious reactions related to the drug were observed. No statistical difference was seen when the treatment group was compared with the control group. Pentoxifylline is a well tolerated and safe drug, but its efficacy in psoriasis appears to be limited.


Cytokine Circuits in Cardiovascular Disease.
Arterial inflammation is a hallmark of atherosclerosis, and appropriate management of this inflammation represents a major unmet therapeutic need for cardiovascular disease patients. Here, we review the diverse contributions of immune cells to atherosclerosis, the mechanisms of immune cell activation in this context, and the cytokine circuits that underlie disease progression. We discuss the recent application of these insights in the form of immunotherapy to treat cardiovascular disease and highlight how studies on the cardiovascular co-morbidity that arises in autoimmunity might reveal additional roles for cytokines in atherosclerosis. Currently, data point to interleukin-1β (IL-1β), tumor necrosis factor (TNF), and IL-17 as cytokines that, at least in some settings, are effective targets to reduce cardiovascular disease progression.


Association Between Early-Onset Osteoporosis With Hearing Loss and Benign Paroxysmal Positional Vertigo (BPPV): A Systematic Review and Meta-Analysis.
Osteoporosis is a chronic systemic disease characterized by low bone mass, progressive microarchitectural deterioration and increased bone fragility. Hearing loss and benign paroxysmal positional vertigo (BPPV) have been found in patients diagnosed with osteoporosis over 65 years, however, there is lack of information about these conditions in young patients. Herein, we conducted a systematic review and meta-analysis to provide evidence of the association between osteoporosis and audio-vestibular findings in young subjects. Systematic review and meta-analysis were performed according to PRISMA guidelines. Searches were conducted in PubMed, Embase, and Web of Science Core Collection. Mean age, proportion of patients with low mineral density, hearing loss, and BPPV were calculated for the systematic review and meta-analysis. Odds Ratio (OR) with their corresponding 95% confidence intervals (CI) were calculated. A total of 26 articles were reviewed. Only 10 studies met inclusion criteria for the meta-analysis. Six were assessed pursuing the association between osteoporosis and hearing loss. Pooled evidence suggested in patients with osteoporosis, an increased risk for developing hearing loss (OR = 1.52, 95% CI 1.06-2.19; P = .02) compared to controls. Another 6 studies reported the association between osteoporosis and BPPV. A significant increased risk for BPPV was found in individuals with osteoporosis (OR = 1.58, 95% CI 1.02-2.4; P = .04). There was no publication bias. Subjects younger than 65 years with osteoporosis have an increase odds for hearing loss and BPPV compared to controls. These conditions could be associated with early inner or middle ear bone morphologic changes.


Importin beta is transported to spindle poles during mitosis and regulates Ran-dependent spindle assembly factors in mammalian cells.
Spatial control is a key issue in cell division. The Ran GTPase regulates several fundamental processes for cell life, largely acting through importin molecules. The best understood of these is protein import through the nuclear envelope in interphase, but roles in mitotic spindle assembly are also established. In mammalian cells, in which centrosomes are major spindle organizers, a link is emerging between the Ran network, centrosomes and spindle poles. Here, we show that, after nuclear envelope breakdown, importin beta is transported to the spindle poles in mammalian cells. This localization is temporally regulated from prometaphase until anaphase, when importin beta dissociates from poles and is recruited back around reforming nuclei. Importin beta sediments with mitotic microtubules in vitro and its accumulation at poles requires microtubule integrity and dynamics in vivo. Furthermore, RNA interference-dependent inactivation of TPX2, the major Ran-dependent spindle organizer, abolishes importin beta accumulation at poles. Importin beta has a functional role in spindle pole organization, because overexpression yields mitotic spindles with abnormal, fragmented poles. Coexpression of TPX2 with importin beta mitigates these abnormalities. Together, these results indicate that the balance between importins and spindle regulators of the TPX2 type is crucial for spindle formation. Targeting of TPX2/importin-beta complexes to poles is a key aspect in Ran-dependent control of the mitotic apparatus in mammalian cells.


Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis.
Thrombospondin 2 (TSP2), a matricellular protein with a primary role in modulating cell-matrix interactions, has been implicated in tissue repair and foreign body responses. Here we show that TSP2 has regulatory function in the chronic inflammatory lesions of rheumatoid arthritis. Tissue TSP2, produced by synovial fibroblasts, endothelial cells, and macrophages correlated not only with the intensity of angiogenesis but also with the architecture of lymphoid infiltrates. Synovial tissues with diffuse inflammatory infiltrates had high levels of TSP2, whereas synovial tissues with ectopic germinal center reactions and T cell-B cell aggregates produced low levels. Cell-based gene therapy with TSP2 was used to examine the in vivo effects of the matrix protein on neoangiogenesis and lymphoid organization. Human synovium-severe combined immunodeficiency (SCID) mouse chimeras were treated with TSP2-transfected fibroblasts deposited into the peritoneum. Overexpression of TSP2 led to the accumulation of TSP2 protein in the inflamed synovium and resulted in a prompt inhibition of lesional vascularization. Beside its anti-angiogenic activity, TSP2 also suppressed the production of the proinflammatory mediators, interferon-gamma and tumor necrosis factor-alpha, and induced the depletion of tissue-residing T cells. We propose that TSP2 is an endogenous regulator of angiogenesis and autoimmune inflammation in the synovium and represents a protective mechanism preventing ectopic lympho-organogenesis and persistent inflammation in this tissue site.


Restriction endonuclease patterns of the omp1 gene of reference Chlamydia trachomatis strains and characterization of isolates from Cameroonian students.
Eighteen reference strains of Chlamydia trachomatis were differentiated by omp1 PCR- and nested PCR-based RFLP analysis, using two restriction digestions, one with AluI and the other with the three enzymes HpaII, EcoRI and HinfI. AluI digestion allowed the differentiation of 12 different profiles after CT1/CT5 PCR and 13 different profiles after the nested PCR. The triple hydrolysis permitted the identification of 15 different patterns. In all, 16/18 reference strains were clearly identified. These reference patterns were successfully used to genotype 34 of 35 (28 strains and 7 clinical specimens) samples from infected students, collected during a screening programme in Yaounde (Cameroon). Genotypes D, Da, E, F, G and J were found. The most prevalent omp1 genotype was E (n = 14; 40 %), followed by F (n = 7; 20 %). As RFLP patterns of reference strains are essential for typing clinical isolates, they will greatly facilitate C. trachomatis characterization in many resource-limited laboratories.


Formation of a metastable phase due to the presence of impurities.
Phase transitions into a new phase that is itself metastable are common; instead of the equilibrium phase nucleating, a metastable phase does so. When this occurs the system is sometimes said to be obeying Ostwald's rule. We show how this can happen when there are impurities present that reduce the barrier to heterogeneous nucleation of the metastable phase. We do so by studying a Potts lattice model using Monte Carlo simulation. Thus, which phase forms depends not only on the properties of the different phases but also on the impurities present. Understanding why systems obey Ostwald's rule may therefore require a study of the impurities present.


Combining propensity score matching and group-based trajectory analysis in an observational study.
In a nonrandomized or observational study, propensity scores may be used to balance observed covariates and trajectory groups may be used to control baseline or pretreatment measures of outcome. The trajectory groups also aid in characterizing classes of subjects for whom no good matches are available and to define substantively interesting groups between which treatment effects may vary. These and related methods are illustrated using data from a Montreal-based study. The effects on subsequent violence of gang joining at age 14 are studied while controlling for measured characteristics of boys prior to age 14. The boys are divided into trajectory groups based on violence from ages 11 to 13. Within trajectory group, joiners are optimally matched to a variable number of controls using propensity scores, Mahalanobis distances, and a combinatorial optimization algorithm. Use of variable ratio matching results in greater efficiency than pair matching and also greater bias reduction than matching at a fixed ratio. The possible impact of failing to adjust for an important but unmeasured covariate is examined using sensitivity analysis.


Effect of polyhexanide and gentamycin on human osteoblasts and endothelial cells.
Infection of total joint replacements is painful, disabling and difficult to treat because of the increasing bacterial resistance against antibiotics. In view of this, antiseptics show limited bacterial tolerance and have a broad-spectrum antimicrobial activity. However, the application of antiseptics to bone is insufficiently studied in literature. Therefore, we investigated the biocompatibility of the antiseptic polyhexanide with bone related cells and asked whether supplementation to bone cement is appropriate in the management of total arthroplasty infections. We performed an in vitro study with immortalised human foetal osteoblast cells (hFOB 1.19) and human endothelial cells (EAhy 926). The cultured cells were exposed to media containing various concentrations of gentamicin (12.5-800 microg/ml) and polyhexanide (0.0006-0.01%) for six hours. We measured the phase-contrast microscopy images, the cell viability, cell number and the alkaline phosphatase activity as a parameter for osteogenic function. The exposure of hFOB and endothelial cells to polyhexanide showed a severe reduction of viability and cell number. Gentamicin did not have negative effects on hFOB and endothelial cell number and viability. The alkaline phosphatase activity of hFOB showed a significant decrease after exposure to polyhexanide and gentamicin. The viability and the cell number of endothelial cells seem more negatively affected by polyhexanide than the parameters of the hFOB-cells. The exposure of human osteoblasts and endothelial cells to polyhexanide at concentrations with questionable antibacterial activity resulted in severe cell damage whereas exposure to high dosed gentamicin did not. These results raise questions as to the feasibility of using antiseptics in bone cement for the treatment of total arthroplasty infections. Further in vivo studies are necessary to show the in vivo relevance of these in vitro findings.