Serum Amyloid P inhibits single stranded RNA-induced lung inflammation, lung damage, and cytokine storm in mice.
SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. In this report, we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1β, IL-6, IL-12p70, IL-23, and IL-27 in serum. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms as well as diseases that generate a cytokine storm.


A new model of soft tissue with constraints for interactive surgical simulation.
An accurate and real-time model of soft tissue is critical for surgical simulation for which a user interacts haptically and visually with simulated patients. This paper focuses on the real-time deformation model of brain tissue for the interactive surgical simulation, such as neurosurgical simulation. A new Finite Element Method (FEM) based model with constraints is proposed for the brain tissue in neurosurgical simulation. A new energy function of constraints characterizing the interaction between the virtual instrument and the soft tissue is incorporated into the optimization problem derived from the implicit integration scheme. Distance and permanent deformation constraints are introduced to describe the interaction in the convexity meningioma dissection and hemostasis. The proposed model is particularly suitable for GPU-based computing, making it possible to achieve real-time performance. Simulation results show that the simulated soft tissue exhibits the behaviors of adhesion and permanent deformation under the constraints. Experiments show that the proposed model is able to converge to the exact solution of the implicit Euler method after 96 iterations. The proposed model was implemented in the development of a neurosurgical simulator, in which surgical procedures such as dissection of convexity meningioma and hemostasis were simulated.


Effects of shift rotation and the flexibility of a shift system on daytime alertness and cardiovascular risk factors.
A controlled intervention study was conducted to evaluate the effects of two changes in shift characteristics on alertness and cardiovascular risk factors: a change in shift rotation (direction and speed) and a change in the flexibility of the shift system. Altogether 84 male workers currently working in a backward-rotating shift system volunteered for the study. A total of 40 men changed to a rapidly forward-rotating shift system, 22 changed to a more flexible shift system, and 22 remained with the old shift system. Health effects were studied with the use of clinical measurements, blood tests, and questionnaires before and after the shift changes. Analyses of variance were used with repeated measures to study associations of cardiovascular risk factors and daytime sleepiness according to the change in shift systems. The mean number of days on which the workers reported sleepiness decreased in the group with the forward-rotating shift system when compared with that of the group on the old shift system (from 2.9 to 2.1 days/week, P=0.02). Systolic blood pressure decreased (from 142 to 136 mm Hg, P=0.049), and heart rate showed a declining trend (from 66 to 60 beats/minute, P=0.06) in the flexible shift system when the three groups were compared. The study indicates that a faster speed, together with a change to the forward direction, in shift rotation alleviates daytime sleepiness. Combining individual flexibility with company-based flexibility in a shift system may have favorable effects on shift workers' blood pressure.


The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity.
We recently reported the cloning of a novel alpha 1-adrenergic receptor (AR), the alpha 1CAR. By transient and stable expression of the alpha 1CAR and the previously cloned alpha 1BAR in COS-7 and HeLa cells, respectively, we have now compared their ability to interact with major signal-transduction pathways (including polyphosphoinositide hydrolysis, intracellular calcium, and cAMP metabolism), as well as their mammalian tissue localization. Both alpha 1C- and alpha 1BARs primarily couple to phospholipase C via a pertussis toxin-insensitive GTP-binding protein, leading to the release of calcium from intracellular stores. Even though alpha 1C- and alpha 1BARs activate polyphosphoinositide hydrolysis by similar biochemical mechanisms, the alpha 1CAR couples to phospholipase C more efficiently than does the alpha 1BAR; activation of the alpha 1CAR results in a 2-3-fold greater increase in inositol phosphates, compared with the alpha 1BAR. Both alpha 1AR subtypes can also increase intracellular cAMP, by a mechanism that does not involve direct activation of adenylyl cyclase. In agreement with ligand binding data, the agonist methoxamine and the antagonist WB4101 are 10-fold more potent in activating or inhibiting, respectively, the ability of the alpha 1CAR to stimulate phospholipase C, compared with the alpha 1BAR. In addition, methoxamine is almost a full agonist at the alpha 1CAR, whereas it can only weakly activate the alpha 1BAR. Tissue localization, using Northern blot analysis of total and poly(A)+-selected RNA from rabbit tissues, revealed striking mammalian species heterogeneity. As previously described, the alpha 1BAR is present in several rat tissues, including heart, liver, brain, kidney, lung, and spleen, whereas the alpha 1CAR is not present in any rat tissue studied. The alpha 1BAR is also present in rabbit aorta, heart, spleen, and kidney (and absent in rabbit liver), whereas the alpha 1CAR is present in rabbit liver. Our results indicate that the cloning and expression of different alpha 1AR subtypes represents a valuable tool to elucidate functional correlates of alpha 1AR heterogeneity.


A five-step "microskills" model of clinical teaching.
Teaching family practice residents in a clinical setting is a complex and challenging endeavor, especially for community family physicians teaching part-time and junior faculty members beginning their academic careers. We present a five-step model of clinical teaching that utilizes simple, discrete teaching behaviors or "microskills." The five microskills that make up the model are (1) get a commitment, (2) probe for supporting evidence, (3) teach general rules, (4) reinforce what was done right, and (5) correct mistakes. The microskills are easy to learn and can be readily used as a framework for most clinical teaching encounters. The model has been well received by both community family physicians interested in teaching and newer residency faculty members.


Prediction by clinicians of quality of life for children and adolescents with cardiac disease.
To determine whether clinicians could reliably predict health-related quality of life (HRQOL) for children with cardiac disease, the level of agreement in predicted HRQOL scores between clinician sub-types, and agreement between clinician-predicted HRQOL scores and patient and parent-proxy reported HRQOL scores. In this multicenter, cross-sectional study, a random sample of clinical summaries of children with cardiac disease and related patient and parent-proxy reported HRQOL scores were extracted from the Pediatric Cardiac Quality of Life Inventory data registry. We asked clinicians to review each clinical summary and predict HRQOL. Experienced pediatric cardiac clinicians (n = 140), including intensive care physicians, outpatient cardiologists, and intensive care, outpatient, and advanced practice nurses, each predicted HRQOL for the same 21 pediatric cardiac patients. Reliability within clinician subspecialty groups for predicting HRQOL was poor (intraclass correlation coefficients, 0.34-0.38). Agreement between clinician groups was low (Pearson correlation coefficients, 0.10-0.29). When comparing the average clinician predicted HRQOL scores to those reported by patients and parent-proxies by Bland Altman plots, little systematic bias was present, but substantial variability existed. Proportional bias was found, in that clinicians tended to overestimate HRQOL for those patients and parent-proxies who reported lower HRQOL, and underestimate HRQOL for those reporting higher HRQOL. Clinicians perform poorly when asked to predict HRQOL for children with cardiac disease. Clinicians should be cognizant of these data when providing counseling. Incorporating reported HRQOL into clinical assessment may help guide individualized treatment decision-making.


Closing the DNA replication cycle: from simple circular molecules to supercoiled and knotted DNA catenanes.
Due to helical structure of DNA, massive amounts of positive supercoils are constantly introduced ahead of each replication fork. Positive supercoiling inhibits progression of replication forks but various mechanisms evolved that permit very efficient relaxation of that positive supercoiling. Some of these mechanisms lead to interesting topological situations where DNA supercoiling, catenation and knotting coexist and influence each other in DNA molecules being replicated. Here, we first review fundamental aspects of DNA supercoiling, catenation and knotting when these qualitatively different topological states do not coexist in the same circular DNA but also when they are present at the same time in replicating DNA molecules. We also review differences between eukaryotic and prokaryotic cellular strategies that permit relaxation of positive supercoiling arising ahead of the replication forks. We end our review by discussing very recent studies giving a long-sought answer to the question of how slow DNA topoisomerases capable of relaxing just a few positive supercoils per second can counteract the introduction of hundreds of positive supercoils per second ahead of advancing replication forks.


DNA charge neutralization by linear polymers. II. Reversible binding.
We model the way in which polymers bind to DNA and neutralize its charged backbone by analyzing the dynamics of the distribution of gaps along the DNA. We generalize existing theory for irreversible binding to construct deterministic models which include polymer removal, movement along the DNA, and allow for binding with overlaps. We show that reversible binding alters the capacity of the DNA for polymers by allowing the rearrangement of polymer positions over a longer time scale than when binding is irreversible. When the polymers do not overlap, allowing reversible binding increases the number of polymers adhered and hence the charge that the DNA can accommodate; in contrast, when overlaps occur, reversible binding reduces the amount of charge neutralized by the polymers.


Sample Size Requirements for Traditional and Regression-Based Norms.
Test norms enable determining the position of an individual test taker in the group. The most frequently used approach to obtain test norms is traditional norming. Regression-based norming may be more efficient than traditional norming and is rapidly growing in popularity, but little is known about its technical properties. A simulation study was conducted to compare the sample size requirements for traditional and regression-based norming by examining the 95% interpercentile ranges for percentile estimates as a function of sample size, norming method, size of covariate effects on the test score, test length, and number of answer categories in an item. Provided the assumptions of the linear regression model hold in the data, for a subdivision of the total group into eight equal-size subgroups, we found that regression-based norming requires samples 2.5 to 5.5 times smaller than traditional norming. Sample size requirements are presented for each norming method, test length, and number of answer categories. We emphasize that additional research is needed to establish sample size requirements when the assumptions of the linear regression model are violated.


Functionalized TiO2 nanoparticles by single-step hydrothermal synthesis: the role of the silane coupling agents.
A simple, robust and versatile hydrothermal synthesis route to in situ functionalized TiO2 nanoparticles was developed using titanium(IV) isopropoxide as Ti-precursor and selected silane coupling agents (3-aminopropyltriethoxysilane (APTES), 3-(2-aminoethylamino)propyldimethoxymethylsilane (AEAPS), and n-decyltriethoxysilane (DTES)). Spherical nanoparticles (ca. 9 nm) with narrow size distribution were obtained by using DTES or by synthesis performed without silane coupling agents. Rod-like nanoparticles along with 9 nm spherical nanoparticles were formed using aminosilane coupling agents because of a combination of oriented attachment of nanoparticles and specific adsorption of the aminosilane on crystallographic faces of anatase nanoparticles. The nanoparticles were functionalized in situ and became hydrophobic as silanes reacted to form covalent bonds on the surface of TiO2. The versatility of the aqueous synthesis route was demonstrated, and by selecting the type of silane coupling agent the surface properties of the TiO2 nanoparticles could be tailored. This synthesis route has been further developed into a two-step synthesis to TiO2-SiO2 core-shell nanoparticles. Combustion of the silane coupling agents up to 700 °C leads to the formation of a nanometric amorphous SiO2 layer, preventing growth and phase transition of the in situ functionalized nanoparticles.


Protic Ionic Liquids Based on the Alkyl-Imidazolium Cation: Effect of the Alkyl Chain Length on Structure and Dynamics.
Protic ionic liquids are known to form extended hydrogen-bonded networks that can lead to properties different from those encountered in the aprotic analogous liquids, in particular with respect to the structure and transport behavior. In this context, the present paper focuses on a wide series of 1-alkyl-imidazolium bis(trifluoromethylsulfonyl)imide ionic liquids, [HC nIm][TFSI], with the alkyl chain length ( n) on the imidazolium cation varying from ethyl ( n = 2) to dodecyl ( n = 12). A combination of several methods, such as vibrational spectroscopy, wide-angle X-ray scattering (WAXS), broadband dielectric spectroscopy, and 1H NMR spectroscopy, is used to understand the correlation between local cation-anion coordination, nature of nanosegregation, and transport properties. The results indicate the propensity of the -NH site on the cation to form stronger H-bonds with the anion as the alkyl chain length increases. In addition, the position and width of the scattering peak q1 (or the pre-peak), resolved by WAXS and due to the nanosegregation of the polar from the nonpolar domains, are clearly dependent on the alkyl chain length. However, we find no evidence from pulsed-field gradient NMR of a proton motion decoupled from molecular diffusion, hypothesized to be facilitated by the longer N-H bonds localized in the segregated ionic domains. Finally, for all protic ionic liquids investigated, the ionic conductivity displays a Vogel-Fulcher-Tammann dependence on inverse temperature, with an activation energy Ea that also depends on the alkyl chain length, although not strictly linearly.


Molecular interactions of alanine-rich and proline-rich regions of cell surface protein antigen c in Streptococcus mutans.
Streptococcus mutans has been implicated as a primary causative agent of dental caries in humans, and its cell surface protein antigen c (PAc) is known to be associated with sucrose-independent adhesion to tooth surfaces. PAc is composed of several domains, including an N-terminal signal sequence, an alanine-rich repeat region (A-region), a proline-rich repeat region (P-region), and an anchor region. To investigate the functions of each domain, an A-region-deficient mutant strain of S. mutans was constructed, and recombinant PAc and A- and P-region proteins were also constructed. The interactions of each domain with the recombinant proteins were analyzed using surface plasmon resonance spectroscopy with a biomolecular interaction analyzing system. The A-region-deficient mutant strain showed the lowest levels of adherence to saliva-coated hydroxyapatite. Furthermore, findings in an immunoblot assay indicated that the A-region protein reacted strongly with proline-rich proteins in saliva, while the recombinant P-region protein interacted more quickly with PAc than the recombinant A-region protein. These results suggest that the A-region has a strong relationship with adhesion to tooth surfaces, while the P-region has a high affinity for PAc.


Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis: a placebo-controlled, randomized study.
In patients with severe aortic stenosis (AS), treatment with angiotensin-converting enzyme inhibitors has previously been considered contraindicated. However, there is a lack of clinical evidence to confirm these potential hemodynamic risks and benefits. Forty-four patients with severe AS (aortic valve area <1 cm(2)) were randomized to treatment with trandolapril 22 mg daily/placebo (1:1). Right heart catheterization and echocardiography were performed at rest and during exercise at baseline and on day 3. Follow-up was performed before valve replacement or after a maximum of 8 weeks, when exercise echocardiography was repeated. Compared with placebo, systolic blood pressure and systemic arterial compliance significantly changed at day 3 (-14 ± 11 vs -5 ± 13 mm Hg, P = .02, and 0.08 ± 0.16 vs -0.05 ± 0.86 mL/m(2) per mm Hg, P = .03, respectively). Changes in left ventricular end systolic volume (LVESV) was nonsignificant (-8 ± 9 vs -3 ± 11 mL, P = .17). At a median of 49 days of follow-up, changes in LVESV and N-terminal pro-brain natriuretic peptide were even lower revealing significant differences between the groups (-7.8 ± 2.6 vs -0.5 ± 2.5 mL, P = .04, and -19 ± 7 vs 0.8 ± 6 pmol/L, P = .04, respectively). No episodes of symptomatic hypotension were noted, and other hemodynamic parameters remained unchanged. Angiotensin-converting enzyme inhibition in severe AS caused a decrease in LVESV and N-terminal pro-brain natriuretic peptide with other hemodynamic parameters preserved both at rest and during exercise implying hemodynamic improvement with left ventricular unloading.


Protein phosphorylation patterns during aestivation in the land snail Otala lactea.
Protein phosphorylation patterns were investigated in whole tissues and subcellular fractions of active and aestivating Otala lactea (Müller) (Pulmonata, Helicidae). Measurement of overall protein phosphorylation showed that incorporation of 32P increased until the second day after injection and remained constant for the remaining 4 days of the time course. Comparison of tissues from aestivating and active snails on day 3 showed a decreased protein phosphorylation in aestivating snails (44% of active). No differences in total and protein-associated radioactivity for foot, mantle or haemolymph were observed. Subcellular fractionation of the hepatopancreas localized the changes to plasma membrane, microsomal, and cytosolic fractions: values for aestivating animals were reduced to 71, 37 and 58% of the corresponding active values. Separation of the individual subcellular fractions on isoelectric focusing columns revealed differences in the phosphate incorporation patterns. Plasma membrane from aestivating animal hepatopancreas had a lower overall level of incorporation and fewer radioactive peaks in the pH 7-10 region than did the plasma membrane fraction from active animals. SDS-PAGE analysis of plasma membrane fractions from active and aestivating snails showed a relative decrease in phosphorylation between 60-80 kDa and 30-40 kDa. IEF analysis of cytosolic proteins from aestivating snail hepatopancreas also showed peaks of radioactivity that were apparently shifted by 0.3 pH units toward higher pI values. Increased phosphate incorporation was observed at a peak that corresponded to the pI value for pyruvate kinase in aestivating snails but definite assignment of peaks was not possible. SDS-PAGE analysis of cytosolic proteins showed an aestivation-related decrease in relative protein phosphorylation between 30-35 kDa and 40-45 kDa. A relative increase in phosphorylation during aestivation was observed for proteins between 16-22 kDa.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories.
Inhalation is the main pathway of ZnO exposure in the occupational environment but only few studies have addressed toxic effects after pulmonary exposure to ZnO nanoparticles (NP). Here we present results from three studies of pulmonary exposure and toxicity of ZnO NP in mice. The studies were prematurely terminated because interim results unexpectedly showed severe pulmonary toxicity. High bolus doses of ZnO NP (25 up to 100 μg; ≥1.4 mg/kg) were clearly associated with a dose dependent mortality in the mice. Lower doses (≥6 μg; ≥0.3 mg/kg) elicited acute toxicity in terms of reduced weight gain, desquamation of epithelial cells with concomitantly increased barrier permeability of the alveolar/blood as well as DNA damage. Oxidative stress was shown via a strong increase in lipid peroxidation and reduced glutathione in the pulmonary tissue. Two months post-exposure revealed no obvious toxicity for 12.5 and 25 μg on a range of parameters. However, mice that survived a high dose (50 μg; 2.7 mg/kg) had an increased pulmonary collagen accumulation (fibrosis) at a similar level as a high bolus dose of crystalline silica. The recovery from these toxicological effects appeared dose-dependent. The results indicate that alveolar deposition of ZnO NP may cause significant adverse health effects.


The human environment and the vitamin D compromise: Scotland as a case study in human biocultural adaptation and disease susceptibility.
Year-round human habitation of environments with highly seasonal regimes of ultraviolet B radiation (UVB) depended on adaptive complexes of biological and cultural traits to ensure adequacy of vitamin D. Perturbations of such adaptive complexes resulting from changes in the physical environment, human behavior and culture, or both have had unexpected and untoward consequences for health. Scotland is an excellent case study of the changing nature of human biocultural adaptation to low-UVB environments. Occupation of Scotland after the last Pleistocene glaciation event about 14,000 YBP was made possible by maximally depigmented skin, which facilitated cutaneous biosynthesis of vitamin D3, and by a diet that emphasized foods rich in vitamin D. Changes in human subsistence and diet began with the introduction of agriculture and grazing about 5,000 YBP and accelerated greatly in the last 200 years through industrialization and urbanization. The resulting changes in domiciles, patterns of daily activity and behavior, and diet have led to reduced exposure to UVB and reduced consumption of vitamin D-rich foods. This has perturbed the "vitamin D compromise," an adaptive complex established in Scotland during the Mesolithic and Neolithic. We describe the UVB environment of Scotland from remotely sensed data and combine these data with information from the archaeological record to describe the vitamin D compromise in Scotland. Changes in human exposure to UVB and vitamin D consumption, which occurred as the result of urbanization and the dietary shift away from the consumption of oily fish, are traced. Vitamin D deficiency contributes to increased disease prevalence in Scotland, including that of the autoimmune disease multiple sclerosis, a debilitating neurodegenerative disease caused by demyelination of the central nervous system. These conditions have created an "imperfect storm" of poor health that should command the attention of public health experts and policy makers.


High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma.
The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P = .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P = .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02). In conclusion, high Treg numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to DLBCL.


Whole-Genome Resequencing of Red Junglefowl and Indigenous Village Chicken Reveal New Insights on the Genome Dynamics of the Species.
The red junglefowl Gallus gallus is the main progenitor of domestic chicken, the commonest livestock species, outnumbering humans by an approximate ratio of six to one. The genetic control for production traits have been well studied in commercial chicken, but the selection pressures underlying unique adaptation and production to local environments remain largely unknown in indigenous village chicken. Likewise, the genome regions under positive selection in the wild red junglefowl remain untapped. Here, using the pool heterozygosity approach, we analyzed indigenous village chicken populations from Ethiopia, Saudi Arabia, and Sri Lanka, alongside six red junglefowl, for signatures of positive selection across the autosomes. Two red junglefowl candidate selected regions were shared with all domestic chicken populations. Four candidates sweep regions, unique to and shared among all indigenous domestic chicken, were detected. Only one region includes annotated genes (TSHR and GTF2A1). Candidate regions that were unique to each domestic chicken population with functions relating to adaptation to temperature gradient, production, reproduction and immunity were identified. Our results provide new insights on the consequence of the selection pressures that followed domestication on the genome landscape of the domestic village chicken.


Analyses of dolichol pyrophosphate-linked oligosaccharides in cell cultures and tissues by fluorophore-assisted carbohydrate electrophoresis.
Lipid-linked oligosaccharides (LLOs) are the precursors of asparagine (N)-linked glycans, which are essential information carriers in many biological systems, and defects in LLO synthesis cause Type I congenital disorders of glycosylation. Due to the low abundance of LLOs and the limitations of the chemical and physical methods previously used to detect them, simple and sensitive nonradioactive methods for LLO analysis are lacking. Thus, almost all studies of LLO synthesis have relied on metabolic labeling of the oligosaccharides with radioactive sugar precursors. We report that LLOs in cell cultures and tissues can be easily detected and quantified with a sensitivity of 1-2 pmol by fluorophore-assisted carbohydrate electrophoresis (FACE). These analyses required efficient removal of contaminants, most likely trace quantities of glycogen breakdown products, that interfered with FACE. Studies with CHO-K1 cells showed that LLOs detected by FACE and by metabolic labeling had similar turnover rates. Glc(3)Man(9)GlcNAc(2)-P-P-dolichol was the most prominent LLO detected by FACE in normal cultured cells and mouse tissues. However, the relative amounts of Glc(0-2)Man(5-9)GlcNAc(2)-P-P-dolichol intermediates in tissues, such as liver and kidney, were unexpectedly greater than for cultured cells. IV injection of D-mannose, raising the circulatory concentration by three- to fourfold, did not affect LLO composition. Thus, the relative accumulation of LLO intermediates in mouse liver and kidney is not likely due to inadequate D-mannose in the circulation. In summary, FACE is a facile, accurate, and sensitive method for LLO analysis, permitting investigations not feasible by metabolic labeling.


Targeting IL-13Rα2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models.
OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.METHODSThe authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.RESULTSIL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.CONCLUSIONSThe current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.


A tick protein with a modified Kunitz fold inhibits human tryptase.
TdPI, a tick salivary gland product related to Kunitz/BPTI proteins is a potent inhibitor of human beta-tryptase. Kinetic assays suggest that three of the four catalytic sites of tryptase are blocked by TdPI, and that the inhibition of one of these involves a peptide flanking the Kunitz head. In the course of the inhibition, tryptase cleaves TdPI at several positions. Crystal structures of the TdPI head, on its own and in complex with trypsin, reveal features that are not found in classical Kunitz/BPTI proteins and suggest the mode of interaction with tryptase. The loop of TdPI connecting the beta-sheet with the C-terminal alpha-helix is shortened, the disulphide-bridge pattern altered and N and C termini separated to produce a highly pointed molecule capable of penetrating the cramped active sites of tryptase. TdPI accumulates in the cytosolic granules of mast cells, presumably suppressing inflammation in the host animal's skin by tryptase inhibition.


Double exchange in a mixed-valent octanuclear iron cluster, [Fe8(μ4-O)4(μ-4-Cl-pz)12Cl4](-).
A combination of SQUID and pulsed high-field magnetometry is used to probe the nature of mixed valency in an Fe(II)Fe7(III) cluster. DFT-computed spin Hamiltonian parameters suggest that antiferromagnetic coupling dominates, and that electron transfer both between the four irons of the cubane core (t1) and between a cubane and three neighboring irons (t2) is significant. Simulations using the computed parameters are able to reproduce the key features of the measured effective magnetic moment, μeff(T), over the 2 < T < 300 K temperature range. In contrast, the field dependence of the molar magnetization, Mmol, measured at 0.4 K is inconsistent with substantial electron transfer: only values of t2∼ 0 place the separation between ground and first excited states in the region indicated by experiment. The apparent quenching of the cubane-outer electron transfer at very low temperatures indicates that vibronic coupling generates one or more shallow minima on the adiabatic potential energy surfaces that serve to trap the itinerant electron in the cubane core.


Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics.
The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.


Two-year outcomes of bioresorbable vascular scaffold versus drug-eluting stents in coronary artery disease: a meta-analysis.
Data regarding long-term clinical outcomes with everolimus-eluting bioresorbable vascular scaffold (BVS) versus second-generation drug-eluting stents (DES) are scarce. We searched online databases until October 2016 for studies comparing BVS versus DES reporting outcomes at 2 years of follow-up. We performed a meta-analysis comparing BVS with DES across the spectrum of coronary artery disease (CAD). Random effects model OR was calculated for outcomes of interest including device-oriented composite events (DOCE; defined as composite of cardiac mortality, target vessel myocardial infarction (TV-MI), and ischaemia-driven target lesion revascularisation (TLR)), all-cause mortality, definite stent thrombosis, TV-MI and TLR. A total of 2360 patients enrolled in five studies met criteria for inclusion in this analysis. At 2 years, BVS was associated with higher rates of DOCE (6.9% vs 4.5%, OR=1.53; 95% CI 1.06 to 2.23; p=0.02), absolute risk increase (ARI) 2.4%, relative risk increase (RRI) 53%, TV-MI (4% vs 1.8%, OR=1.94; 95% CI 1.02 to 3.67; p=0.04), ARI 2.2%, RRI 122% and definite stent thrombosis (2.1% vs 0.6%, OR=3.39; 95% CI 1.46 to 7.88; p=0.005), ARI 1.5%, RRI 250% compared with DES. No differences in all-cause mortality (OR=0.86; 95% CI 0.26 to 2.81; p=0.80) and TLR (OR=1.44; 95% CI 0.81 to 2.54; p=0.21) were observed between both groups. BVS may be associated with worse long-term clinical outcomes compared with DES. Randomised clinical trials are encouraged to expeditiously report long-term safety and efficacy outcomes and identify predictors of adverse events with BVS compared with DES.


Short (8-mm) dental implants in the rehabilitation of partial and complete edentulism: a 3- to 14-year longitudinal study.
This study aimed to evaluate the clinical effectiveness of different implant sizes (8- and 10-mm lengths with 3.75-, 4.1-, and 4.8-mm diameters) in diverse host bone sites in a selected sample of partially and completely edentulous patients. Over a 14-year period, 129 patients (68 women and 61 men) were consecutively treated with a fixed prosthesis (single or multiunit, screw or cement retained) supported by 265 different-sized implants (154 standard 10-mm; 111 shorter 8-mm). Two types of implants were used (141 titanium plasma-sprayed and 124 Sand-blasted, large-grit, acid-etched). Dropouts were recorded for 23 patients with 23 prostheses supported by 42 implants. In the remaining 106 patients (223 implants), 8 implants failed (4 standard and 4 shorter), in type 3 or 4 bone. Mean marginal bone loss and gingival crevice probing depth associated with either implant length were statistically comparable (P> .05). The 14-year cumulative survival rates for all short and standard implants were 97.9% and 97.1%, respectively. Survival rates were 92.3% and 95.9% for titanium plasma-sprayed short and standard implants, respectively, and 100% and 98.5% for the Sand-blasted, large-grit, acid-etched short and standard implants, respectively. Six of the 8 lost implants required implant replacement after the host sites' healing period. The remaining 2 lost implants were managed by converting the distal unit of the fixed partial prosthesis to a cantilever. Within the limits of the study design and observation period, a mix of implant sizes did not appear to compromise the effectiveness of implant therapy in this particular population group.


Contrast-enhanced coded phase-inversion harmonic sonography of knee synovitis correlates with histological vessel density: 2 automated digital quantifications.
To use contrast-enhanced coded phase-inversion harmonic B-mode sonography to assess the acoustic enhancement of the synovial area of the knee; and to compare the data with the histological vessel density. Eleven patients eligible for a knee arthroscopy were studied. Acoustic quantification was carried out by a digital image analysis program that detects the time-dependent increase [intensity (time) = k x time + C] of gray-level intensity in all the pixels of a specific region of interest (ROI) following intravenous injection of the microbubble contrast agent sulfur hexafluoride. Echo-guided synovial biopsies were carried out in the same ROI. Synovial vessel areas were quantified after Factor VIII immunostaining of synovial biopsies using an automated digital image analysis. Significant (p < 0.05) correlations were observed between histological vessel density and percentage of the synovial area with a k value > 0.01 (r = 0.93) and k(max) values (r = 0.79), as well as between the 2 latter parameters (r = 0.72). The histological vessel density and the 2 acoustic parameters were also significantly correlated with the logarithm of erythrocyte sedimentation rate (r = 0.77, r = 0.87, r = 0.67, respectively) and with log C-reactive protein serum concentration (r = 0.69, r = 0.83, r = 0.62, respectively). Contrast-enhanced coded phase-inversion harmonic B-mode sonography coupled with an appropriate data analysis method is a new tool to identify and quantify vessel density in knee synovitis.


Leptin inhibits the proliferation of vascular smooth muscle cells induced by angiotensin II through nitric oxide-dependent mechanisms.
This study was designed to investigate whether leptin modifies angiotensin (Ang) II-induced proliferation of aortic vascular smooth muscle cells (VSMCs) from 10-week-old male Wistar and spontaneously hypertensive rats (SHR), and the possible role of nitric oxide (NO). NO and NO synthase (NOS) activity were assessed by the Griess and (3)H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS) and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs.


Ancient horizontal transfers of retrotransposons between birds and ancestors of human pathogenic nematodes.
Parasite host switches may trigger disease emergence, but prehistoric host ranges are often unknowable. Lymphatic filariasis and loiasis are major human diseases caused by the insect-borne filarial nematodes Brugia, Wuchereria and Loa. Here we show that the genomes of these nematodes and seven tropical bird lineages exclusively share a novel retrotransposon, AviRTE, resulting from horizontal transfer (HT). AviRTE subfamilies exhibit 83-99% nucleotide identity between genomes, and their phylogenetic distribution, paleobiogeography and invasion times suggest that HTs involved filarial nematodes. The HTs between bird and nematode genomes took place in two pantropical waves, >25-22 million years ago (Myr ago) involving the Brugia/Wuchereria lineage and >20-17 Myr ago involving the Loa lineage. Contrary to the expectation from the mammal-dominated host range of filarial nematodes, we hypothesize that these major human pathogens may have independently evolved from bird endoparasites that formerly infected the global breadth of avian biodiversity.


Laparoscopic totally extra-peritoneal hernia repair for bilateral Spigelian hernias and coincident inguinal hernia: A case report.
Spigelian hernia (SH) is a rare ventral hernia occurring near the lateral border of the rectus muscle. The treatment remains controversial and depends on institutional expertise. Although laparoscopic surgery is a good adaptation for the repair of ventral hernias, only a few cases have been reported in the literature. Here, we report a case of totally extra-peritoneal (TEP) repair for bilateral SHs. A 74-year-old Japanese man presented with asymptomatic bulges in the right lower abdominal quadrant. On physical examination, the bulges were located to the right of the lateral border of the abdominal rectus muscle and the right inguinal region in an upright position. We diagnosed right SH and coincident homonymous ipsilateral inguinal hernia (IH) by abdominal computed tomography and planned a curative operation by laparoscopy. By first laparoscopic exploration, we found an asymptomatic SH to the left of the lateral border of the abdominal rectus muscle and performed TEP repair for all hernias. The second laparoscopic exploration after fixing the mesh in place revealed that the orifice of the right SH was scarred and stiffened by repeated prolapse. We finally eliminated the sac by ligation because of a fear causing of reduction en masse of the SH. The use of laparoscopy simplified the diagnosis and facilitates the subsequent repair of the hernia. TEP approach is the ideal treatment for the simultaneous laparoscopic repair of SH and IH.


Accuracy of administrative data in trauma: splenic injuries as an example.
Accurate data are needed to evaluate clinical outcomes, therapeutic modalities, and quality of care in trauma. Administrative data, usually used for billing, have been used to evaluate performance and assess therapy in other medical specialties. This study was performed to determine whether administrative databases are accurate in the recording of information about trauma patients with splenic injuries. Patients who had blunt splenic injuries were identified using a state trauma registry. The medical records of those patients were reviewed. The data collected by chart review were compared with data in the statewide administrative database of patients who had splenic injuries at the same four Level I and II trauma centers in the same 5-year period. Age, sex, admission date, and hospital were matched to assure comparison of the identical cohort. chi2 analysis was used to compare dichotomous data and Student's t test continuous data. The administrative database identified 641 and the trauma registry identified 529 patients with a diagnosis of splenic injury. A total of 401 patients were found in both databases. Of these, 120 (22.7%) patients were not recorded in the administrative database. Injury Severity Score was underreported by the administrative database (25.74 +/- 14.7 vs. 19.52 +/- 11, p < 0.0001). The administrative database underreported orthopedic, chest, and head injuries (317 vs. 215, 325 vs. 228, and 234 vs. 155, respectively; all p < 0.0001). Use of abdominal computed tomographic scan and diagnostic peritoneal lavage were also underreported (260 vs. 56 and 104 vs.17, both p < 0.0001). The number of operations on the spleen and number of orthopedic procedures were underreported (259 vs. 225, p < 0.014 and 147 vs. 94, p < 0.0001). Complications were markedly underreported by the administrative database (200 vs. 47, p < 0.0001) This study shows that administrative data lack accuracy in the recording of associated injuries, injury severity, diagnostics, procedures, and outcomes data in patients with splenic injuries. Whether these data should be used to evaluate treatment modalities or quality of care in trauma is questionable.


Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.
Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1(+/-)), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1(+/-) mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1(+/-) mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.


Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence.
There has been growing interest in disrupting bacterial virulence mechanisms as a form of infectious disease control through the use of 'anti-infective' drugs. Pseudomonas aeruginosa is an opportunistic pathogen noted for its intrinsic antibiotic resistance that causes serious infections requiring new therapeutic options. In this study, an analysis of the P. aeruginosa PAO1 deduced proteome was performed to identify pathogen-associated proteins. A computational screening approach was then used to discover drug repurposing opportunities, i.e. identifying approved drugs that bind and potentially disrupt the pathogen-associated protein targets. The selective oestrogen receptor modulator raloxifene, a drug currently used in the prevention of osteoporosis and/or invasive breast cancer in post-menopausal women, was predicted from this screen to bind P. aeruginosa PhzB2. PhzB2 is involved in production of the blue pigment pyocyanin produced via the phenazine biosynthesis pathway. Pyocyanin is toxic to eukaryotic cells and has been shown to play a role in infection in a mouse model, making it an attractive target for anti-infective drug discovery. Raloxifene was found to strongly attenuate P. aeruginosa virulence in a Caenorhabditis elegans model of infection. Treatment of P. aeruginosa wild-type strains PAO1 and PA14 with raloxifene resulted in a dose-dependent reduction in pyocyanin production in vitro; pyocyanin production and virulence were also reduced for a phzB2 insertion mutant. These results suggest that raloxifene may be suitable for further development as a therapeutic for P. aeruginosa infection and that such already approved drugs may be computationally screened and potentially repurposed as novel anti-infective/anti-virulence agents.


Protein identification using customized protein sequence databases derived from RNA-Seq data.
The standard shotgun proteomics data analysis strategy relies on searching MS/MS spectra against a context-independent protein sequence database derived from the complete genome sequence of an organism. Because transcriptome sequence analysis (RNA-Seq) promises an unbiased and comprehensive picture of the transcriptome, we reason that a sample-specific protein database derived from RNA-Seq data can better approximate the real protein pool in the sample and thus improve protein identification. In this study, we have developed a two-step strategy for building sample-specific protein databases from RNA-Seq data. First, the database size is reduced by eliminating unexpressed or lowly expressed genes according to transcript quantification. Second, high-quality nonsynonymous coding single nucleotide variations (SNVs) are identified based on RNA-Seq data, and corresponding protein variants are added to the database. Using RNA-Seq and shotgun proteomics data from two colorectal cancer cell lines SW480 and RKO, we demonstrated that customized protein sequence databases could significantly increase the sensitivity of peptide identification, reduce ambiguity in protein assembly, and enable the detection of known and novel peptide variants. Thus, sample-specific databases from RNA-Seq data can enable more sensitive and comprehensive protein discovery in shotgun proteomics studies.


The prevalence of medical nomadism of the followed patients in rheumatology.
The nomads are defined as patients related to multiple practicians of the same speciality or different specialities for the same symptomatology during a certain period. The objectives of this investigation were to evaluate the prevalence of medical nomadism of the followed patients in rheumatology and compare their profile with those patients followed in neurology and gastroenterology. A multicentric transverse study (September 2009-March 2010) was conducted in three departments of CHU Ibn Sina Rabat-Salé, Morocco; rheumatology, gastroenterology and neurology. Only patients seen in external consultations were included. Patients' socio-economic and demographic background (familial status, instruction level, monthly revenue, social assistance) were recorded, as well as the clinical parameters related to the pathology (pathology, duration of the illness, diagnosis final time). A questionnaire containing variables on the patients' state concerning diagnosis, satisfaction degree of the patients and other variables evaluated the notion of taking medication and the practice of alternative medicine. Medical nomadism has been defined by the consultation for the same symptomatology of three different practicians, either of the same speciality or of different specialities during the study period of 6 months. There were 250 patients included in this study (150 patients in rheumatology, 50 in gastroenterology and 50 in neurology), the mean age was 46 ± 13 years and females dominated (65.6%). The average duration of the evolution was 7 ± 5 years, 35% of the patients were illiterate, 30% had a primary school education, 22% had a secondary school education and 13% had a university-level education. Sixty-two percent of the patients were jobless, 27% were workers, 9% were the functionary and 2% were the based liberal. Fifty-six percent had no social assistance. Rheumatoid arthritis and degenerative pathology were the most frequent diagnoses in rheumatology, being 20% and 40%, respectively. In gastroenterology, the most frequent pathologies were functional colopathy (25%) and proctology (20%), and migraine (42%) in neurology. The global prevalence of nomadism was 51%; 36% in rheumatology, 58% in neurology and 86% in gastroenterology. The associated factors of nomadism phenomena in rheumatology were: the satisfaction degree of the patient (P = 0.001), the wrong beliefs (P = 0.007), the practice of alternative medicine (P = 0.009), the pathology (P = 0.01) and the psychic profile (P = 0.001). Our study suggests that medical nomadism is frequent. It seems to be more frequent in the gastroenterology area, was linked with the degree of the patients' satisfaction, the alternative medicine practice and the type of the pathologies. Other studies of a high level would be necessary.


Comparative performance of five commercially available serologic assays to detect antibodies to SARS-CoV-2 and identify individuals with high neutralizing titers.
Accurate serological assays to detect antibodies to SARS-CoV-2 are needed to characterize the epidemiology of SARS-CoV-2 infection and identify potential candidates for COVID-19 convalescent plasma (CCP) donation. This study compared the performance of commercial enzyme immunoassays (EIAs) to detect IgG or total antibodies to SARS-CoV-2 and neutralizing antibodies (nAb). The diagnostic accuracy of five commercially available EIAs (Abbott, Euroimmun, EDI, ImmunoDiagnostics, and Roche) to detect IgG or total antibodies to SARS-CoV-2 was evaluated from cross-sectional samples of potential CCP donors that had prior molecular confirmation of SARS-CoV-2 infection for sensitivity (n=214) and pre-pandemic emergency department patients for specificity (n=1,102). Of the 214 potential CCP donors, all were sampled >14 days since symptom onset and only a minority had been hospitalized due to COVID-19 (n=16 [7.5%]); 140 potential CCP donors were tested by all five EIAs and a microneutralization assay. When performed according to the manufacturers' protocol to detect IgG or total antibodies to SARS-CoV-2, the sensitivity of each EIA ranged from 76.4% to 93.9%, and the specificity of each EIA ranged from 87.0% to 99.6%. Using a nAb titer cutoff of ≥160 as the reference positive test (n=140 CCP donors), the empirical area under receiver operating curve of each EIA ranged from 0.66 (Roche) to 0.90 (Euroimmun). Commercial EIAs with high diagnostic accuracy to detect SARS-CoV-2 antibodies did not necessarily have high diagnostic accuracy to detect high nAbs. Some but not all commercial EIAs may be useful in the identification of individuals with high nAbs in convalescent individuals.


Internal lamin structures within G1 nuclei of human dermal fibroblasts.
The nuclear lamina is a mesh-like network of fibres subjacent to the inner nuclear membrane that is believed to be involved in the specific spatial reorganisation of chromatin after mitosis. To determine how the lamina might be involved in chromatin reorganisation, we have performed indirect immunofluorescence studies on quiescent and proliferating human dermal fibroblasts (HDF). Two monoclonal antibodies recognising human lamins A and C and three different fixation methods were employed. In indirect immunofluorescence studies, cultures of quiescent cells displayed a uniform perinuclear distribution of the antibodies. In proliferating cultures two distinct populations of cells were observed: one population displayed a typical perinuclear antibody distribution, while the second population displayed an unusual pattern consisting of a series of spots and fibres within the nucleus. By inducing cell-cycle synchrony in cultures we were able to determine that the unusual internal distribution of the lamin antibodies was restricted to cells in G1. Optical sectioning and 3-D reconstruction of the lamina structures in G1 nuclei was performed with a confocal laser scanning microscope (CLSM). This revealed that the internal lamin structures consisted of small foci and fibres proliferating throughout the nucleus. These structures were shown to be closely associated with areas of condensed chromatin but not nuclear membrane. As cells progress towards S phase the internal lamin foci disappear.


Load transfer at the distal ulna following simulated distal radius fracture malalignment.
To measure the effects of distal radius malalignment on loading at the distal ulna. Using an adjustable mechanism to simulate angulated and translated malalignments, clinically relevant distal radius deformities were simulated in a cadaveric model. A custom-built load cell was inserted just proximal to the native ulna head to measure the resultant force and torque in the distal ulna. Loads were measured before and after transecting the triangular fibrocartilage complex (TFCC). There was an increase in distal ulna load and torque with increasing dorsal translation and angulation. Combined conditions of angulation and translation increased force and torque in the distal ulna to a greater extent than with either condition in isolation. Transecting the TFCC resulted in a reduction in distal ulna load and torque. A progressive increase in load at the distal ulna was observed with increasing severity of malalignment, which may be an important contributor to residual ulnar wrist pain and dysfunction. However, no clear-cut threshold of malalignment of a dorsally angulated and translated distal radius fracture was identified. These observations suggest that radius deformities cause articular incongruity, which increases TFCC tension and distal radioulnar joint load. Cutting of the TFCC decreased distal ulna loading, likely by releasing the articular constraining effect of the TFCC on the distal radioulnar joint, allowing the radius to rotate more freely with respect to the ulna. Anatomical reduction of a distal radius fracture minimizes the forces in the distal ulna and may reduce residual ulnar wrist pain and dysfunction.


Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits.
Spinal muscular atrophy (SMA), caused by the deletion of the SMN1 gene, is the leading genetic cause of infant mortality. SMN protein is present at high levels in both axons and growth cones, and loss of its function disrupts axonal extension and pathfinding. SMN is known to associate with the RNA-binding protein hnRNP-R, and together they are responsible for the transport and/or local translation of β-actin mRNA in the growth cones of motor neurons. However, the full complement of SMN-interacting proteins in neurons remains unknown. Here we used mass spectrometry to identify HuD as a novel neuronal SMN-interacting partner. HuD is a neuron-specific RNA-binding protein that interacts with mRNAs, including candidate plasticity-related gene 15 (cpg15). We show that SMN and HuD form a complex in spinal motor axons, and that both interact with cpg15 mRNA in neurons. CPG15 is highly expressed in the developing ventral spinal cord and can promote motor axon branching and neuromuscular synapse formation, suggesting a crucial role in the development of motor axons and neuromuscular junctions. Cpg15 mRNA previously has been shown to localize into axonal processes. Here we show that SMN deficiency reduces cpg15 mRNA levels in neurons, and, more importantly, cpg15 overexpression partially rescues the SMN-deficiency phenotype in zebrafish. Our results provide insight into the function of SMN protein in axons and also identify potential targets for the study of mechanisms that lead to the SMA pathology and related neuromuscular diseases.


Arab-migrant Cancer Survivors' Experiences of Using Health-care Interpreters: A Qualitative Study.
This paper is drawn from a larger mixed-method study that sought to explore the cancer experiences of Jordanian and Australian Arab cancer survivors and their family caregivers. This paper specifically focuses on the experiences of the Australian cancer survivors and their use of interpreter services to communicate with health-care providers (HCPs). Individual face-to-face interviews were conducted using a semi-structured interview guide. Data were manually thematically analyzed using an inductive approach. Three key themes were identified which highlighted the communication issues the Arab-migrant cancer survivors experienced when using health-care interpreters: (1) "My language is weak" - needing someone to help them when communicating with their HCPs; (2) "I had a problem in the dialect" - the need to understand and to be understood by the interpreters; and (3) "I felt all the time that there is something missing" - not being heard by the interpreter. Low confidence in engaging and using the English language meant many cancer survivors were reluctant to seek support from cancer services or to attend workshops conducted in the English language. Despite the presence of professionally trained health-care interpreters in health-care communications, cancer survivors were frustrated when provided with interpreters who did not speak the same dialect, causing linguistic and cultural discord. This created confusion as information was often misinterpreted, resulting in the delivery and receipt of mixed messages. Despite the availability of professionally trained health-care interpreters, our findings identified the need for HCPs to ascertain linguistic and cultural congruence when arranging interpreter services.


Efficacy of Sharapunkhadi powder (a polyherbal formulation) and lifestyle modification in the management of nonalcoholic fatty liver disease-A randomized placebo-controlled clinical trial.
Nonalcoholic fatty liver disease (NAFLD) is an expanding health problem, which varies in prevalence among ethnic groups, occurring with an estimated global prevalence of 25%. In high-risk populations, the prevalence of NAFLD may be as high as 70%-90%. No established pharmacological treatment is available for NAFLD in modern medicine and hence, there is a search for alternative treatment modalities in other systems of medicine, which is safe and cost-effective. The aim is to evaluate the efficacy of Sharapunkhadi powder and lifestyle modification in the management of NAFLD. Patients suffering from any of the components of metabolic syndrome, i.e. hypertension, diabetes mellitus, hypertriglyceridemia, elevated body mass index (>25 kg/m2), truncal obesity, or presenting with the symptoms of indigestion, abdominal discomfort, flatulence. were screened with liver function tests and ultrasonography (USG) of the abdomen. A total of 93 patients confirmed with fatty liver Grade 1-3 were selected for the present trial and were randomly divided into two groups. After Mridu Virechana (mild purgation) with Haritaki powder (6-8 g) according to Koshtha, in group A (n = 46), 2 capsules (500 mg each) filled with Sharapunkhadi powder thrice a day before food with warm water along with lifestyle modification were administered for 8 weeks. In group B (n = 47), capsules filled with roasted Sooji powder in the same dose as mentioned for group A was given along with lifestyle modification and were maintained as a placebo. Relief in subjective parameters such as indigestion, abdominal discomfort, and flatulence and improvement in the grades of fatty liver evident from USG was considered for the overall assessment of the therapy in both the groups. SigmaStat 3.1 software was used for statistical calculation. Wilcoxon signed-rank test for subjective criteria and Student's paired t-test for objective criteria were applied to check the level of significance in a single group before and after treatment, while Student's unpaired t-test for objective criteria was applied to assess the level of significance of difference observed between two groups. After 8 weeks of treatment, it was found from USG findings that there was a statistically significant improvement by about 39.25% in group A and 31.82% in group B, in the grade of fatty liver. The combination of Sharapunkhadi powder along with lifestyle modification provided comparatively better relief in subjective and objective parameters over the placebo control group. Sharapunkhadi powder is a promising herbal preparation for the management of NAFLD and the combination of Sharapunkhadi powder along with lifestyle modification can yield more significant results in the management of NAFLD than lifestyle modification alone.


Effect of preventive and curative interventions on hepatitis C virus transmission in Egypt (ANRS 1211): a modelling study.
Most hepatitis C virus (HCV) transmission in Egypt is related to medical injections and procedures. To control the spread of HCV, the Egyptian Ministry of Health initiated awareness and education campaigns, strengthened infection control in health-care facilities, and subsidised anti-HCV treatment. We aimed to investigate the effect of these interventions on the spread of HCV by mathematical modelling. We developed a mathematical model of HCV transmission in Zawyat Razin, a typical rural community. Our model assumes that each individual has two distinct types of medical procedures: injections and more invasive medical procedures. To quantify the severity of the spread of HCV, we used the notion of the basic reproduction number R0, a standard threshold parameter signalling whether transmission of an infectious disease is self-sustained and maintains an epidemic. If R0 is greater than 1, HCV is self-sustained; if R0 is 1 or less, HCV transmission is not self-sustained. We investigated whether heterogeneity in the rate of injection or invasive medical procedures is the determinant factor for HCV transmission and whether most iatrogenic transmission is caused by a small group of individuals who receive health-care interventions frequently. We then assessed whether interventions targeted at this group could reduce the spread of HCV. The R0 of the spread of HCV without treatment was 3·54 (95% CI 1·28-6·18), suggesting a self-sustained spread. Furthermore, the present national treatment programme only decreased R0 from 3·54 to 3·03 (95% CI 1·10-5·25). Individuals with high rates of medical injections seem to be responsible for the spread of HCV in Egypt; the R0 of the spread of HCV without treatment would be 0·64 (95% CI 0·41-0·93) if everybody followed the average behaviour. The effect of treatment on HCV transmission is greatly enhanced if treatment is provided a mean of 2·5 years (95% CI 0·1-9·2) after chronic infection and with drug regimens with more than 80% efficacy. With these treatment parameters, preventive and curative interventions targeting individuals with high rates of medical injections might decrease R0 below 1 for treatment coverage lower than 5%. Targeting preventive and curative interventions to individuals with high rates of medical injections in Egypt would result in a greater reduction the spread of HCV than would untargeted allocation. Such an approach might prove beneficial in other resource-limited countries with health-care-driven epidemics. Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS 1211), ANR grant Labex Integrative Biology of Emerging Infectious Diseases.


Simulation model for cost estimation of integrated care concepts of heart failure patients.
As a direct result of the population growing older the total number of chronic illnesses increases. The future expenditure for care of chronically ill patients is an ever-present challenge for the health care system. New solutions based on integrated care or the inclusion of telemedical systems in the treatment procedure can be essential for reducing the future financial burden. Therefore a detailed economic model was developed, which enables the comparison of health and cost outcomes for conventional medical care and different integrated care concepts in heart failure treatment. F0r modelling, the discrete event technique was used. The model takes outpatient care as well as inpatient care into account to estimate the total occurring costs. It enables the treatment of patients by a physician, a specialist or a clinical ambulance for the simulation of the outpatient care. For inpatient care the model considers the total-costs of the hospitalization and rate of re-admission and furthermore the costs which occur because of special medical treatments or necessary stay at intensive care units. To rate the severity of symptoms patients can be classified using NYHA groups. To outline some of the potential model results, two scenarios have been simulated to compare both methods of care regarding overall costs. The developed simulation model allows comparing health and cost outcomes of different integrated care concepts for the treatment of heart failure patients. Additionally to the simulation of standard outpatient and inpatient care procedures in Austria the approach of a telemedical monitoring system for heart failure patients was implemented in this economic model. With the simulated scenarios it could be shown that under the given simulation parameters the telemedical system can lead to cost savings of up to 8% within the first three years. The developed model represents a comprehensive tool, which opens a wide field of possible simulation scenarios for the treatment of heart failure patients with special focus on overall cost estimations and reimbursement strategies. The simulated scenarios show that telemedical care has the potential of improved health outcomes and economic benefits.


Long-Term Response to Vasoactive Treatment in a Case of Kyphoscoliosis-Associated Pulmonary Hypertension.
BACKGROUND Kyphoscoliosis is an anatomical deformity of the spine often accompanied by an array of respiratory complications, pulmonary hypertension being among the most severe ones. At present, evidence-based treatment options for kyphoscoliosis-related pulmonary hypertension remain limited to the correction of hypoxemia through ventilatory support and long-term oxygenation. CASE REPORT We report a case of a 61-year-old female with severe kyphoscoliosis-related pulmonary hypertension who was admitted to a university hospital in September 2018 due to progressive dyspnea and respiratory failure. She was diagnosed with pulmonary hypertension in 2016 and had been on endothelin receptor antagonist (ambrisentan) and oxygen therapy ever since. Upon admission, the patient presented with severe depression of peripheral oxygen saturation (SpO₂ at 75%). The patient declined further treatment hours after hospitalization, despite optimized supportive oxygen therapy. Ambrisentan was discontinued and replaced by inhaled iloprost. Over the course of the next 4 days, the patient showed symptomatic improvement and was discharged on Day 5. Right heart catheterization follow-up in February 2019 showed no worsening in pulmonary hemodynamic parameters compared to the time of initial diagnosis. CONCLUSIONS Managing the respiratory decline in kyphoscoliosis-related pulmonary hypertension can be challenging since these patients tend to deteriorate despite current treatment options. Our case reports on the use of vasoactive agents as a safe and effective treatment option in addition to established therapeutic regimen.


Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross.
Transmission ratio distortion (TRD), defined as statistically significant deviation from expected 1:1 Mendelian ratios of allele inheritance, results in a reduction of the expected progeny of a given genotype. Since TRD is a common occurrence within interspecific crosses, a mouse interspecific backcross was used to genetically map regions showing TRD, and a developmental analysis was performed to identify the timing of allele loss. Three independent events of statistically significant deviation from the expected 50:50 Mendelian inheritance ratios were observed in an interspecific backcross between the Mus musculus A/J and the Mus spretus SPRET/EiJ inbred strains. At weaning M. musculus alleles are preferentially inherited on Chromosome (Chr) 7, while M. spretus alleles are preferentially inherited on Chrs 10 and 11. Furthermore, alleles on Chr 3 modify the TRD on Chr 11. All TRD loci detected at weaning were present in Mendelian ratios at mid-gestation and at birth. Given that Mendelian ratios of inheritance are observed for Chr 7, 10 and 11 during development and at birth, the underlying causes for the interspecific TRD events are the differential post-natal survival of pups with specific genotypes. These results are consistent with the TRD mechanism being deviation from Mendelian inheritance rather than meiotic drive or segregation distortion.


Prevalence and predictors of proteinuria in HIV-infected and uninfected pregnant women in Cameroon.
Proteinuria during pregnancy has been associated with increased pregnancy complications. Furthermore, even low-grade proteinuria has been associated with increased mortality in the general population and in non-pregnant HIV-infected women. Urine dipstick protein was measured prospectively on HIV-infected and trace protein or more and quantified by urine protein:creatinine measurement (P:C). Logistic regression modeling was used to identify factors associated with proteinuria. About 199 human immunodeficiency virus (HIV)-infected and 190 HIV-uninfected normotensive pregnant women were evaluated. The median age was 27 years in both groups and 37% presented in the third trimester. Among HIV-infected women, median CD4 cell count was 417 cells/mm(3); 27% were on combination antiretroviral therapy (cART). Proteinuria was present in 39.2% of HIV-infected and 20.9% of uninfected women (P < 0.001). HIV infection was independently associated with proteinuria [adjusted odds ratio (OR) = 2.45; confidence interval (CI) = 1.56-3.85]. Among HIV-infected pregnant women, cART was protective (adjusted OR = 0.39; CI = 0.19-0.82). Results were qualitatively similar when urine P:C was evaluated as a continuous outcome variable. The prevalence of low-grade proteinuria in both HIV-infected and -uninfected Cameroonian pregnant women is high. HIV-infected pregnant women are at increased risk for proteinuria, and cART appears to exert a protective effect. Further studies are needed to elucidate the causes of increased proteinuria in African pregnant women, both HIV-infected and -uninfected.


A review of the impacts of degradation threats on soil properties in the UK.
National governments are becoming increasingly aware of the importance of their soil resources and are shaping strategies accordingly. Implicit in any such strategy is that degradation threats and their potential effect on important soil properties and functions are defined and understood. In this paper, we aimed to review the principal degradation threats on important soil properties in the UK, seeking quantitative data where possible. Soil erosion results in the removal of important topsoil and, with it, nutrients, C and porosity. A decline in soil organic matter principally affects soil biological and microbiological properties, but also impacts on soil physical properties because of the link with soil structure. Soil contamination affects soil chemical properties, affecting nutrient availability and degrading microbial properties, whilst soil compaction degrades the soil pore network. Soil sealing removes the link between the soil and most of the 'spheres', significantly affecting hydrological and microbial functions, and soils on re-developed brownfield sites are typically degraded in most soil properties. Having synthesized the literature on the impact on soil properties, we discuss potential subsequent impacts on the important soil functions, including food and fibre production, storage of water and C, support for biodiversity, and protection of cultural and archaeological heritage. Looking forward, we suggest a twin approach of field-based monitoring supported by controlled laboratory experimentation to improve our mechanistic understanding of soils. This would enable us to better predict future impacts of degradation processes, including climate change, on soil properties and functions so that we may manage soil resources sustainably.


The neglected neglect: auditory neglect.
Whereas visual and somatosensory forms of neglect are commonly recognized by clinicians, auditory neglect is often not assessed and therefore neglected. The auditory cortical processing system can be functionally classified into 2 distinct pathways. These 2 distinct functional pathways deal with recognition of sound ("what" pathway) and the directional attributes of the sound ("where" pathway). Lesions of higher auditory pathways produce distinct clinical features. Clinical bedside evaluation of auditory neglect is often difficult because of coexisting neurological deficits and the binaural nature of auditory inputs. In addition, auditory neglect and auditory extinction may show varying degrees of overlap, which makes the assessment even harder. Shielding one ear from the other as well as separating the ear from space is therefore critical for accurate assessment of auditory neglect. This can be achieved by use of specialized auditory tests (dichotic tasks and sound localization tests) for accurate interpretation of deficits. Herein, we have reviewed auditory neglect with an emphasis on the functional anatomy, clinical evaluation, and basic principles of specialized auditory tests.


On the impact of Vertical Alignment of MoS2 for Efficient Lithium Storage.
Herein, we report energy storage devices, which are based on densely packed, vertically aligned MoS2 (VA-MoS2) or planar oriented MoS2 (PO-MoS2) and compare their electrochemical performances. The VA-MoS2 films have been processed by chemical vapor deposition (CVD) to reach unprecedented micron-scale thick films while maintaining the vertical alignment for the whole thickness. The VA-MoS2 and the PO-MoS2 films form a high-performance Li-ion electrode, reaching the theoretical limits of reversible capacity for this material (800 mAh/g; twice the specific capacity of graphite). The vertical alignment allows faster charge-discharge rates while maintaining a high specific capacity (C-rate measurements). Noteworthy, the reversible cycling of the Li-ion electrode also benefits from the vertical alignment. In this article, we present the full synthesis, structural and electrochemical characterization of VA-MoS2 along with the properties of PO-MoS2 to deconvolute the intrinsic properties of MoS2 from the influence of the layers' orientation.


Changes in stool frequency following chicory inulin consumption, and effects on stool consistency, quality of life and composition of gut microbiota.
Inulin is a soluble dietary fibre, also classified as a prebiotic, extracted from chicory roots. The present study aimed to determine the effect of consumption of native chicory inulin on the stool frequency of middle-aged to older adults (40-75 years old) with uncomfortably but not clinically relevant low stool frequency, specified as two to four days without bowel movements per week. Two randomised, double blind, placebo-controlled crossover trials were conducted using similar protocols in differing populations. Trial A was conducted in Amsterdam, The Netherlands and subsequently Trial B was conducted in Newcastle, United Kingdom. Both trials involved supplementation for 5 weeks with 10 g per day of inulin or placebo, a washout period of 2 weeks, and then crossed over to receive the other treatment. In Trial B, faecal gut microbiota composition was assessed using 16S rRNA gene sequencing. In Trial A, which 10 volunteers completed, the stool frequency was significantly increased to an average 4.9 ± 0.23 (SEM) times per week during inulin periods versus 3.6 ± 0.25 in the periods with placebo (p = 0.01). In contrast, in Trial B which 20 volunteers completed, there was no significant effect of the inulin on stool frequency (7.5 ± 2.1 times per week with inulin, 8.1 ± 3.0 with placebo, p = 0.35). However, many subjects in Trial B had a stool frequency >5 per week also for the placebo period, in breach of the inclusion criteria. Combining the data of 16 low stool frequency subjects from Trials A and B showed a significant effect of inulin to increase stool frequency from 4.1 to 5.0 per week (p = 0.032). Regarding secondary outcomes, stool consistency was significantly softer with inulin treatment compared to placebo periods, it increased 0.29 on the Bristol stool scale (p = 0.008) when data from all subjects of Trials A and B were combined. No other differences in bowel habit parameters due to inulin consumption were significant. None of the differences in specific bacterial abundance, alpha or beta diversity were significant, however the trends were in directions consistent with published studies on other types of inulin. We conclude that 10 g per day of native chicory inulin can increase stool frequency in subjects with low stool frequency.


R-rated film viewing and adolescent smoking.
As smoking is very common in R-rated films, we sought to determine if viewing R-rated films is associated with adolescent smoking. Three annual cross-sectional surveys conducted of 88,505 Year 10 students of largely European, Maori, Asian or Pacific Islander ethnicity in secondary schools in New Zealand between 2002 and 2004. Outcomes of interest were: intention to smoke among never smokers; past experimentation with smoking among current non-smokers; current smoking status; and current frequency of smoking. Dose-response relationships were observed between the frequency of viewing R-rated films and all outcome measures controlling for age, gender, ethnicity, peer smoking, parental smoking, socioeconomic status, pocket money and household smoking rules. Compared to never viewing R-rated films, viewing at least weekly nearly tripled the relative risk (2.81; 95% confidence interval 2.57, 3.09) of never smokers being susceptible to smoking, and more than doubled the risk of both past experimentation (2.28; 95% CI 2.12, 2.45) and smoking>/=monthly (2.31; 95% CI 2.10, 2.54). Each of these risks was seen across all ethnic groups. Our results extend the association that has been demonstrated between viewing R-rated films and current smoking in American youth by demonstrating the same association in youth of different ethnic and cultural backgrounds in New Zealand.


Single nucleotide polymorphisms associated with coronary heart disease predict incident ischemic stroke in the atherosclerosis risk in communities study.
Ischemic stroke and coronary heart disease (CHD) may share genetic factors contributing to a common etiology. This study investigates whether 51 single nucleotide polymorphisms (SNPs) associated with CHD in multiple antecedent studies are associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. From the multiethnic ARIC cohort of 14,215 individuals, 495 validated ischemic strokes were identified. Cox proportional hazards models, adjusted for age and gender, identified three SNPs in Whites and two SNPs in Blacks associated with incident stroke (p <or= 0.05). The rs11628722 polymorphism in SERPINA9 was associated with incident stroke in Whites and Blacks, even after taking into account traditional risk factors. The idea that ischemic stroke and CHD may share some common genetic factors, such as variation in SERPINA9, should be investigated in other studies.


The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population.
Mutations in HFE, a gene defect that can disrupt iron metabolism, have been implicated in increasing the risk of developing amyotrophic lateral sclerosis (ALS). To further establish the association between ALS and HFE mutations by investigating whether HFE mutations are associated with an increased risk of developing ALS in a population in The Netherlands and by pooling our results with those from previous studies. Retrospective study. Tertiary referral center for neuromuscular disorders. Genotyping for 2 common HFE mutations was performed in 289 patients with ALS and 5886 population-based controls in The Netherlands between January 1, 2000, and December 31, 2004. Development of ALS and clinical phenotype were compared among the different HFE genotypes, adjusting for known prognostic factors such as age at onset and sex. Homozygosity for H63D was associated with an increased risk of developing ALS (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.1). After pooling our results with those from previous studies, a positive association between H63D homozygotes (OR, 2.7; 95% CI, 1.7-4.4), heterozygotes (OR, 1.5; 95% CI, 1.0-2.1), and mutation carriers (OR, 1.7; 95% CI, 1.1-2.5) was found. Within the patient group, heterozygosity for the H63D mutation was associated with a higher age at onset. These findings suggest that H63D mutations in HFE play a role in the pathogenesis of ALS in various populations. This association might involve a later-onset subset of ALS.


Salivary Proteins-A Barrier on Enamel Demineralization: An in vitro Study.
The aim of this study is to evaluate the protective effect of the salivary proteins on the demineralization of enamel. Twenty freshly extracted human molar teeth were used in this study. Enamel samples (2 mm thickness) were prepared from the buccal and lingual surfaces of the teeth selected. An acid-resistant nail varnish was used to cover every aspect of the sample, except an area of 5 * 5 mm limited by an adhesive tape. After drying, the adhesive tape was removed, exhibiting a rectangular area on the enamel surface. Samples were divided into two groups: Group I (10 samples): Each sample was coated by 100 μg of albumin for 2 hours at 37°C. Group II (10samples): Each sample was exposed to 100 μL of deionized water.Samples were washed by dipping once in deionized water. They were then disposed into individual tubes containing demineralization solution for 1, 2, 3, and 4 minutes at 37°C with gentle agitation. The demineralization solution was utilized to determine the calcium loss from specimens at 1, 2, 3, 4 minutes using an ultraviolet-visible spectrophotometer. Calcium loss was less from the albumin-coated samples than control group at all times and was statistically significant (p < 0.05). Also, calcium loss was maximum at the end of 1 minute, and it decreased as time interval increased and was statistically significant (p < 0.001). Albumin has provided a strong protection against enamel demineralization at all times compared to the one without it. Hegde MN, Sajnani AR. Salivary Proteins-A Barrier on Enamel Demineralization: An in vitro Study. Int J Clin Pediatr Dent 2017;10(1):10-13.


Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.
Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A (VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.


Standard anatomical and visual space for the mouse retina: computational reconstruction and transformation of flattened retinae with the Retistruct package.
The concept of topographic mapping is central to the understanding of the visual system at many levels, from the developmental to the computational. It is important to be able to relate different coordinate systems, e.g. maps of the visual field and maps of the retina. Retinal maps are frequently based on flat-mount preparations. These use dissection and relaxing cuts to render the quasi-spherical retina into a 2D preparation. The variable nature of relaxing cuts and associated tears limits quantitative cross-animal comparisons. We present an algorithm, "Retistruct," that reconstructs retinal flat-mounts by mapping them into a standard, spherical retinal space. This is achieved by: stitching the marked-up cuts of the flat-mount outline; dividing the stitched outline into a mesh whose vertices then are mapped onto a curtailed sphere; and finally moving the vertices so as to minimise a physically-inspired deformation energy function. Our validation studies indicate that the algorithm can estimate the position of a point on the intact adult retina to within 8° of arc (3.6% of nasotemporal axis). The coordinates in reconstructed retinae can be transformed to visuotopic coordinates. Retistruct is used to investigate the organisation of the adult mouse visual system. We orient the retina relative to the nictitating membrane and compare this to eye muscle insertions. To align the retinotopic and visuotopic coordinate systems in the mouse, we utilised the geometry of binocular vision. In standard retinal space, the composite decussation line for the uncrossed retinal projection is located 64° away from the retinal pole. Projecting anatomically defined uncrossed retinal projections into visual space gives binocular congruence if the optical axis of the mouse eye is oriented at 64° azimuth and 22° elevation, in concordance with previous results. Moreover, using these coordinates, the dorsoventral boundary for S-opsin expressing cones closely matches the horizontal meridian.


Molecular recognition in the selective oxygenation of saturated C-H bonds by a dimanganese catalyst.
Although enzymes often incorporate molecular recognition elements to orient substrates selectively, such strategies are rarely achieved by synthetic catalysts. We combined molecular recognition through hydrogen bonding with C-H activation to obtain high-turnover catalytic regioselective functionalization of sp3 C-H bonds remote from the -COOH recognition group. The catalyst contains a Mn(mu-O)2Mn reactive center and a ligand based on Kemp's triacid that directs a -COOH group to anchor the carboxylic acid group of the substrate and thus modify the usual selectivity for oxidation. Control experiments supported the role of hydrogen bonding in orienting the substrate to achieve high selectivity.


Cystic ameloblastoma: a clinico-pathologic review.
Cystic ameloblastoma represent 10-15% of all intra osseous ameloblastomas and appear to be less aggressive than the solid ameloblastomas. The aim of this study was to examine the clinico-pathologic characteristics of cystic ameloblastomas seen at a tertiary health care centre. All cases diagnosed as cystic ameloblastoma in the Oral Pathology Department of University College Hospital, Ibadan over a 10 year period were investigated for age, gender, location of lesion, treatment, and follow-up. The cases were classified as luminal, intraluminal or mural, based on Ackermann classification. The data was entered into the statistical package for the social sciences version 18 (SPSS 18) and results expressed as percentages. Fifteen cystic ameloblastomas, representing 14.3% of a total of 105 ameloblastoma cases were seen. The mean age was 28.9(±14.5) years with 73.4% occurring in the second and third decades. The male:female ratio was 2:3. Fourteen (93.3%) of the lesions were in the mandible while only one (6.7%) was in the maxilla. The mural variant was the most common histological variant with 6(40%) cases while the luminal and intra-luminal had 4(26.7%) and 5(33.3%) respectively. The multilocular radiologic appearance was more common than the unilocular in this study (ratio 8:4). Cystic ameloblastoma with multilocular appearance occurred in a higher age group (mean age 31yrs) when compared with the unilocular type which had a mean age of 16.3years. This study shows similar findings with previous studies but shows a higher multilocular radiological appearance as compared to unilocular variant and no case of recurrence.


Zn Isotope Fractionation during Sorption onto Kaolinite.
In this study, we quantify zinc isotope fractionation during its sorption onto kaolinite, by performing experiments under various pH, ionic strength, and total Zn concentrations. A systematic enrichment in heavy Zn isotopes on the surface of kaolinite was measured, with Δ(66)Znadsorbed-solution ranging from 0.11‰ at low pH and low ionic strength to 0.49‰ at high pH and high ionic strength. Both the measured Zn concentration and its isotopic ratio are correctly described using a thermodynamic sorption model that considers two binding sites: external basal surfaces and edge sites. Based on this modeling approach, two distinct Zn isotopic fractionation factors were calculated: Δ(66)Znadsorbed-solution = 0.18 ± 0.06‰ for ion exchange onto basal sites, and Δ(66)Znadsorbed-solution = 0.49 ± 0.06‰ for specific complexation onto edge sites. These two distinct factors indicate that Zn isotope fractionation is dominantly controlled by the chemical composition of the solution (pH, ionic strength).


Stable helical peptoids via covalent side chain to side chain cyclization.
Peptoids are oligomeric N-substituted glycines with potential as biologically relevant compounds. Helical peptoids provide an attractive fold for the generation of protein-protein interaction inhibitors. The generation of helical peptoid folds in organic and aqueous media has been limited to strict design rules, as peptoid-folding is mainly directed via the steric direction of alpha-chiral side-chains. Here a new methodology is presented to induce helical folds in peptoids with the aid of side chain to side chain cyclization. Cyclic peptoids were generated via solid-phase synthesis and their folding was studied. The cyclization induces significant helicity in peptoids in organic media, aids the folding in aqueous media, and requires the incorporation of only relatively few chiral aromatic side chains.


Global conservation priorities for marine turtles.
Where conservation resources are limited and conservation targets are diverse, robust yet flexible priority-setting frameworks are vital. Priority-setting is especially important for geographically widespread species with distinct populations subject to multiple threats that operate on different spatial and temporal scales. Marine turtles are widely distributed and exhibit intra-specific variations in population sizes and trends, as well as reproduction and morphology. However, current global extinction risk assessment frameworks do not assess conservation status of spatially and biologically distinct marine turtle Regional Management Units (RMUs), and thus do not capture variations in population trends, impacts of threats, or necessary conservation actions across individual populations. To address this issue, we developed a new assessment framework that allowed us to evaluate, compare and organize marine turtle RMUs according to status and threats criteria. Because conservation priorities can vary widely (i.e. from avoiding imminent extinction to maintaining long-term monitoring efforts) we developed a "conservation priorities portfolio" system using categories of paired risk and threats scores for all RMUs (n = 58). We performed these assessments and rankings globally, by species, by ocean basin, and by recognized geopolitical bodies to identify patterns in risk, threats, and data gaps at different scales. This process resulted in characterization of risk and threats to all marine turtle RMUs, including identification of the world's 11 most endangered marine turtle RMUs based on highest risk and threats scores. This system also highlighted important gaps in available information that is crucial for accurate conservation assessments. Overall, this priority-setting framework can provide guidance for research and conservation priorities at multiple relevant scales, and should serve as a model for conservation status assessments and priority-setting for widespread, long-lived taxa.