TLR2 utilization of Borrelia does not induce p38- and IFN-beta autocrine loop-dependent expression of CD38, resulting in poor migration and weak IL-12 secretion of dendritic cells.
Lyme borreliosis is a tick-borne bacterial infection that in many cases is limited to the skin. However, in some patients the bacterium evades the immune response and disseminates into various organs. Dendritic cells (DCs) are among the first cells to meet invading pathogens in the skin. We have previously shown that CD38, an ectoenzyme involved in the migration of DCs and generally upregulated by microbial stimuli, is not upregulated in Borrelia garinii-stimulated DCs. In this paper, we characterize the cellular events that lead to the absence of CD38 on the DC surface after B. garinii stimulation and investigate the consequences of absent CD38 expression for the migration of DCs in vitro and in vivo. The data show that 1) effective signaling via p38 MAPK (and STAT1 and NF-kappaB) is needed for CD38 expression and 2) TLR2 stimulation, as opposed to TLR4 stimulation, does not induce IFN-beta autocrine loop-dependent expression of CD38 and secretion of IL-12. Further, we show that 3) B. garinii-stimulated DCs do not migrate effectively toward CCL19 and CCL21 and 4) after B. garinii infection of mice, the number of DCs migrating from the infection site to draining lymph nodes is only half that induced by Escherichia coli infection. Our results provide evidence for the first time that different TLR use results in different CD38 expression, which correlates with the migratory potential of DCs.


DNA-dependent RNA polymerase detects hidden giant viruses in published databanks.
Environmental metagenomic studies show that there is a "dark matter," composed of sequences not linked to any known organism, as determined mainly using ribosomal DNA (rDNA) sequences, which therefore ignore giant viruses. DNA-dependent RNA polymerase (RNAP) genes are universal in microbes and conserved in giant viruses and may replace rDNA for identifying microbes. We found while reconstructing RNAP subunit 2 (RNAP2) phylogeny that a giant virus sequenced together with the genome of a large eukaryote, Hydra magnipapillata, has been overlooked. To explore the dark matter, we used viral RNAP2 and reconstructed putative ancestral RNAP2, which were significantly superior in detecting distant clades than current sequences, and we revealed two additional unknown mimiviruses, misclassified as an euryarchaeote and an oomycete plant pathogen, and detected unknown putative viral clades. We suggest using RNAP systematically to decipher the black matter and identify giant viruses.


Assessment of sleep in children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.
Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most common cause of periodic fever in childhood. This study aimed to investigate sleep patterns and possible factors that are associated with sleep disturbances among children with PFAPA syndrome. Sixty-two patients with PFAPA and 68 age and sex matched healthy controls were enrolled in the study. Patients who had an attack during the former 2 weeks were not included. Demographic and anthropometric data, duration of fever episodes, laboratory results, and clinical manifestations of patients were recorded. The Children`s Sleep Habits Questionnaire was administered. The total sleep scores of patients with PFAPA were significantly higher than the control group (49.6 ± 10.7 vs. 38.3 ± 7.5, p = 0.002 ). Children with PFAPA had significantly higher scores regarding sleep-onset delay, sleep anxiety and night wakening (p=0.003, p=0.007, and p=0.014, respectively). Total sleep durations were similar between children with PFAPA and the control group. There was a significant positive correlation between the total sleep score and disease duration (r=0.425, p=0.002). Also there was a significant positive correlation between disease duration and sleep onset delay (r=0.561, p < 0.001) and night wakening (r=0.327, p=0.003). This study showed for the first time that patients with PFAPA have significantly disturbed sleep when compared to otherwise normal children. This study emphasized the need to assess sleep problems in children with PFAPA.


Identification of Split-GAL4 Drivers and Enhancers That Allow Regional Cell Type Manipulations of the Drosophila melanogaster Intestine.
The Drosophila adult midgut is a model epithelial tissue composed of a few major cell types with distinct regional identities. One of the limitations to its analysis is the lack of tools to manipulate gene expression based on these regional identities. To overcome this obstacle, we applied the intersectional split-GAL4 system to the adult midgut and report 653 driver combinations that label cells by region and cell type. We first identified 424 split-GAL4 drivers with midgut expression from ∼7300 drivers screened, and then evaluated the expression patterns of each of these 424 when paired with three reference drivers that report activity specifically in progenitor cells, enteroendocrine cells, or enterocytes. We also evaluated a subset of the drivers expressed in progenitor cells for expression in enteroblasts using another reference driver. We show that driver combinations can define novel cell populations by identifying a driver that marks a distinct subset of enteroendocrine cells expressing genes usually associated with progenitor cells. The regional cell type patterns associated with the entire set of driver combinations are documented in a freely available website, providing information for the design of thousands of additional driver combinations to experimentally manipulate small subsets of intestinal cells. In addition, we show that intestinal enhancers identified with the split-GAL4 system can confer equivalent expression patterns on other transgenic reporters. Altogether, the resource reported here will enable more precisely targeted gene expression for studying intestinal processes, epithelial cell functions, and diseases affecting self-renewing tissues.


[Croatian Catholic Movement and Vladimir Hudolin (1922-1996): formation of one world known alcohologist].
Vladimir Hudolin was born in Ogulin in 1922 and died in Zagreb in 1996. He was one of the best students of the Susak grammar school and distinguished himself in a Catholic youth association Domagoj. In 1940, he moved to Zagreb to study medicine. In 1948 he graduated, and in 1951 specialised in psychiatry. His field of expertise was social psychiatry, alcohology in particular. In developing his own original preventive and remedial programmes, he much relied on the concepts of Community Psychiatry and alike, and managed to encourage their implementation on a variety of community levels, from local to national. His concept was recognised in a number of countries around the world; over 650 articles speak about how successful it was. This article focuses on Vladimir Hudolin's grammar school years in Susak, proposing that particular circumstances and figures from his formative years played a key role in his humanistic and scientific development. Early on it was his social activity in the Catholic youth association Domagoj and Bonifacije Perović, a theologist-sociologist who was a member of the Croatian Catholic Movement. The key figures who made him aware of the alcoholism issue were Fran Gudrum, Mirko Cunko, Maksimilijan Benković, Andrija Stampar, Josip Silović, and the Bishop of Senj Josip Marusić. Regardless of the controversies and controversial activities of some of the members of the Croatian Catholic Movement between the two world wars, there is no doubt that this movement has played a major role in the development of one of the most distinct figures in world alcohology, Vladimir Hudolin.


Validation of a one year fracture prediction tool for absolute hip fracture risk in long term care residents.
Frail older adults living in long term care (LTC) homes have a high fracture risk, which can result in reduced quality of life, pain and death. The Fracture Risk Scale (FRS) was designed for fracture risk assessment in LTC, to optimize targeting of services in those at highest risk. This study aims to examine the construct validity and discriminative properties of the FRS in three Canadian provinces at 1-year follow up. LTC residents were included if they were: 1) Adults admitted to LTC homes in Ontario (ON), British Columbia (BC) and Manitoba (MB) Canada; and 2) Received a Resident Assessment Instrument Minimum Data Set Version 2.0. After admission to LTC, one-year hip fracture risk was evaluated for all the included residents using the FRS (an eight-level risk scale, level 8 represents the highest fracture risk). Multiple logistic regressions were used to determine the differences in incident hip or all clinical fractures across the provinces and FRS risk levels. We examined the differences in incident hip or all clinical fracture for each FRS level across the three provinces (adjusted for age, BMI, gender, fallers and previous fractures). We used the C-statistic to assess the discriminative properties of the FRS for each province. Descriptive statistics on the LTC populations in ON (n = 29,848), BC (n = 3129), and MB (n = 2293) are: mean (SD) age 82 (10), 83 (10), and 84 (9), gender (female %) 66, 64, and 70% respectively. The incident hip fractures and all clinical fractures for FRS risk level were similar among the three provinces and ranged from 0.5 to 19.2% and 1 to 19.2% respectively. The overall discriminative properties of the FRS were similar between ON (C-statistic = 0.673), BC (C-statistic = 0.644) and MB (C-statistic = 0.649) samples. FRS is a valid tool for identifying LTC residents at different risk levels for hip or all clinical fractures in three provinces. Having a fracture risk assessment tool that is tailored to the LTC context and embedded within the routine clinical assessment may have significant implications for policy, service delivery and care planning, and may improve care for LTC residents across Canada.


Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion.
The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this is accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release. In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines). However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later. Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization). Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days. This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios. These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH 'challenge.' In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity. It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH 'runs' common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity.


Preparation and preliminary evaluation of novel beta-cyclodextrin/IUDR prodrug formulations.
Iododeoxyuridine (IUdR) has a very short in vivo half-life and consequently achieves low target-tissue concentrations with concomitant lower efficacy than would be predicted from in vitro studies. This work reports the preparation of IUdR:beta-cyclodextrin (beta-CyD) inclusion complexes designed to reduce in vivo inactivation of IUdR. IUdR was derivatized with either 1-adamantanecarbonyl chloride or 4-(1-adamantyl-carbamoyl)butanoic acid, to prepare 5'-O-(1-adamantoyl)-5-iodo-2'-deoxyuridine 1 and 5'-O-(4-(1-adamantylcarbamoyl)butoyl)-5-iodo-2'-deoxy-uridine 4, respectively. beta-CyD complexes 5 and 6 were formed by vigorous stirring of 1:1 solutions of beta-CyD and 1 or 4, respectively, in D2O under argon. Complexation was inferred from DSC, powder x-ray diffractometry and NMR spectrometry. The dissociation of 5 in water and under cholesterol challenge, and the effect of complexation on the stability of 1 was determined by incubation in plasma. IUdR coupling with adamantanecarbonyl chloride proceeded smoothly to afford 1 (69 %) and the di-substituted derivative, 3',5'-di-O-(1-adamantoyl)-5-iodo-2'-deoxyuridine 2 (8 %); 4 was obtained in 42 % yield. The formation of 1:1 complexes 5 and 6 was inferred from NMR chemical shift data. In serum, 1 was 90 % hydrolyzed to IUdR in 30 min, compared to 10 % hydrolysis of 1 to IUdR when from complex 5. Inclusion complexes were formed between beta-CyD and adamantamine-IUdR conjugates at 1:1 molar ratios. The complex 5 was resistant to dissociation by cholesterol challenge, and 5 was more slowly converted to IUdR than non-complexed 1. In vivo studies are required to further exploit the beta-CyD inclusion complex approach for improved delivery of nucleoside derivatives.


From ferrocene to fluorine-containing penta-substituted derivatives and all points in-between; or, how to increase the available chemical space.
In spite of the growing interest in fluorine-containing compounds, and the improvements in materials, optical and biological properties that can arise from substitution of a phenyl ring by ferrocene within a molecular scaffold, synthetic strategies that allow the efficient preparation of fluoroferrocene derivatives are scarce. Following conversion of ferrocene to fluoroferrocene, we have developed routes to fluorine-containing di-, tri-, tetra- and penta-substituted ferrocene derivatives to extend the available chemical space. Our approach is based on the identification of suitable reagents and conditions to achieve fluorine-directed deprotometalation, and exploitation of the halogen 'dance' rearrangement in the ferrocene series.


The double life of the ribosome: When its protein folding activity supports prion propagation.
It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation. In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.


Estimation of the Malthusian parameter in an stochastic epidemic model using martingale methods.
Data, on the number of infected, gathered from a large epidemic outbreak can be used to estimate parameters related to the strength and speed of the spread. The Malthusian parameter, which determines the initial growth rate of the epidemic is often of crucial interest. Using a simple epidemic SEIR model with known generation time distribution, we define and analyze an estimate, based on martingale methods. We derive asymptotic properties of the estimate and compare them to the results from simulations of the epidemic. The estimate uses all the information contained in the epidemic curve, in contrast to estimates which only use data from the start of the outbreak.


Drinking in social groups. Does 'groupdrink' provide safety in numbers when deciding about risk?
To investigate the impact of alcohol consumption on risk decisions taken both individually and while part of a four- to six-person ad-hoc group. A 2 (alcohol: consuming versus not consuming alcohol) × 2 (decision: individual, group) mixed-model design; decision was a repeated measure. The dependent variable was risk preference, measured using choice dilemmas. Opportunity sampling in campus bars and a music event at a campus-based university in the United Kingdom. A total of 101 individuals were recruited from groups of four to six people who either were or were not consuming alcohol. Participants privately opted for a level of risk in response to a choice dilemma and then, as a group, responded to a second choice dilemma. The choice dilemmas asked participants the level of accident risk at which they would recommend someone could drive while intoxicated. Five three-level multi-level models were specified in the software program HLM 7. Decisions made in groups were less risky than those made individually (B = -0.73, P < 0.001). Individual alcohol consumers opted for higher risk than non-consumers (B = 1.27, P = 0.025). A significant alcohol × decision interaction (B = -2.79, P = 0.001) showed that individual consumers privately opted for higher risk than non-consumers, whereas risk judgements made in groups of either consumers or non-consumers were lower. Decisions made by groups of consumers were less risky than those made by groups of non-consumers (B = 1.23, P < 0.001). Moderate alcohol consumption appears to produce a propensity among individuals towards increased risk-taking in deciding to drive while intoxicated, which can be mitigated by group monitoring processes within small (four- to six-person) groups.


Dehydrogenation of secondary amines: synthesis, and characterization of rare-earth metal complexes incorporating imino- or amido-functionalized pyrrolyl ligands.
The dehydrogenation of pyrrolyl-functionalized secondary amines initiated by rare-earth metal amides was systematically studied. Reactions of the rare-earth metal amides [(Me(3)Si)(2)N](3)RE(μ-Cl)Li(THF)(3) with pyrrolyl-functionalized secondary amines 2-(t)BuNHCH(2)-5-R-C(4)H(2)NH (R = H (1), R = (t)Bu (2)) led to dehydrogenation of the secondary amines with isolation of imino-functionalized pyrrolyl rare-earth metal complexes [2-(t)BuN=CH-5-R-C(4)H(2)N](2)REN(SiMe(3))(2) (R = H, RE = Y (3a), Dy (3b), Yb (3c), Eu (3d); R = (t)Bu, RE = Y (4a), Dy (4b), Er (4c)). The mixed ligands erbium complex [2-(t)BuNCH(2)-5-(t)Bu-C(4)H(2)N]Er[2-(t)BuN=CH-5-(t)BuC(4)H(2)N](2)ClLi(2)(THF) (4c') was isolated in a short reaction time for the synthesis of complex 4c. Reaction of the deuterated pyrrolyl-functionalized secondary amine 2-((t)BuNHCHD)C(4)H(3)NH with yttrium amide [(Me(3)Si)(2)N](3)Y(μ-Cl)Li(THF)(3) further proved that pyrrolyl-amino ligands were transferred to pyrrolyl-imino ligands. Treatment of 2-((t)BuNHCH(2))C(4)H(3)NH (1) with excess (Me(3)Si)(2)NLi gave the only pyrrole deprotonated product {[η(5):η(2):η(1)-2-((t)BuNHCH(2))C(4)H(3)N]Li(2)N(SiMe(3))(2)}(2) (5), indicating that LiN(SiMe(3))(2) could not dehydrogenate the secondary amines to imines and rare-earth metal ions had a decisive effect on the dehydrogenation. The reaction of the rare-earth metal amides [(Me(3)Si)(2)N](3)RE(μ-Cl)Li(THF)(3) with 1 equiv. of more bulky pyrrolyl-functionalized secondary amine 2-[(2,6-(i)Pr(2)C(6)H(3))NHCH(2)](C(4)H(3)NH) (6) in toluene afforded the only amine and pyrrole deprotonated dinuclear rare-earth metal amido complexes {(μ-η(5):η(1)):η(1)-2-[(2,6-(i)Pr(2)C(6)H(3))NCH(2)]C(4)H(3)N]LnN(SiMe(3))(2)}(2) (RE = Nd (7a), Sm (7b), Er (7c)), no dehydrogenation of secondary amine to imine products were observed. On the basis of experimental results, a plausible mechanism for the dehydrogenation of secondary amines to imines was proposed.


Sox9 Is Crucial for Mesenchymal Stem Cells to Enhance Cutaneous Wound Healing.
Human umbilical cord mesenchymal stem cells (HUC-MSCs) are promising candidates for cell-based therapy in regenerative medicine or other diseases due to their superior characteristics, including higher proliferation, faster self-renewal ability, lower immunogenicity, a noninvasive harvest procedure, easy expansion in vitro, and ethical access, compared with stem cells from other sources. In the present study, we knocked down the expression of SOX9 in HUC-MSCs by lentivirus interference and found that knockdown of SOX9 inhibited the proliferation and migration of HUC-MSCs and influenced the expression of cytokines (IL-6 and IL-8), growth factors (GM-CSF and VEGF) and stemness-related genes (OCT4 and SALL4). In addition, the repair effect of skin with burn injury in rats treated with HUC-MSCs transfected with sh-control was better than that rats treated with HUC-MSCs transfected with shSOX9 or PBS, and the accessory structures of the skin, including hair follicles and glands, were greater than those in the other groups. We found that knockdown of the expression of SOX9 obviously inhibited the expression of Ki67, CK14 and CK18. In conclusion, this study will provide a guide for modifying HUC-MSCs by bioengineering technology in the future.


Determination of surface area and porosity of small, nanometer-thick films by quartz crystal microbalance measurement of gas adsorption.
The Brunauer-Emmett-Teller (BET) surface area of 15 nm-thick films made of TiO2/polyelectrolyte bilayer was determined by quartz crystal microbalance (QCM) measurement of N2 and Ar adsorption isotherms at 77 K. The measurements were carried out using a home-built vacuum chamber that includes built-in 9 MHz QCM and cryostat units. As little as 1 ng of the adsorbed gas could be detected, and the BET surface area of a flat Au film (ca. 0.5 cm2) on an oscillator was determined within an experimental error of +/-5%. The titania/polymer composite film gives N2 and Ar adsorption isotherms consisting of a less-pronounced type-I curve and a break at around p/p0 = 0.7. This behavior is ascribed to the presence of irregular micropores and 6 nm phi-mesopores in the composite film. An analysis of the isotherms shows that the porosity of the composite film is about 12%, which is much smaller than that of bulk titania gel powder. The greater density appears to be related to the reported superior properties (robustness and resistance to electrical breakdown) of the organic/inorganic multilayer film. We conclude that the QCM-based, high-precision measurement of gas adsorption is a powerful tool for investigation of the detailed morphology of nanometer-thick films.


Temporally dependent accelerated failure time model for capturing the impact of events that alter survival in disease mapping.
The introduction of spatial and temporal frailty parameters in survival models furnishes a way to represent unmeasured confounding in the outcome of interest. Using a Bayesian accelerated failure time model, we are able to flexibly explore a wide range of spatial and temporal options for structuring frailties as well as examine the benefits of using these different structures in certain settings. A setting of particular interest for this work involved using temporal frailties to capture the impact of events of interest on breast cancer survival. Our results suggest that it is important to include these temporal frailties when there is a true temporal structure to the outcome and including them when a true temporal structure is absent does not sacrifice model fit. Additionally, the frailties are able to correctly recover the truth imposed on simulated data without affecting the fixed effect estimates. In the case study involving Louisiana breast cancer-specific mortality, the temporal frailty played an important role in representing the unmeasured confounding related to improvements in knowledge, education, and disease screenings as well as the impacts of Hurricane Katrina and the passing of the Affordable Care Act. In conclusion, the incorporation of temporal, in addition to spatial, frailties in survival analysis can lead to better fitting models and improved inference by representing both spatially and temporally varying unmeasured risk factors and confounding that could impact survival. Specifically, we successfully estimated changes in survival around the time of events of interest.


Greek nursing students' immunization coverage: data from central continental Greece.
Nursing students are at risk of acquiring vaccine-preventable diseases. To estimate the vaccination rates for nursing students, a cross-sectional survey was conducted in a major district of central continental Greece with an anonymous and self-administered questionnaire in a sample of 432 nursing students (the response rate was 97%). The eligible nursing students completed the questionnaire after informed consent was obtained. The vaccination rates of the nursing students ranged from 65.2% for the oral polio (SABIN) vaccine and 65.7% for the hepatitis B virus vaccine to 74.6% for the diphtheria-tetanus-pertussis (DTP) vaccine. The parents' level of education did not correlate with the students' underimmunization. The t-test showed that the senior students were more knowledgeable about the compulsory vaccines. Almost half of the nursing students were somewhat satisfied with the available information on vaccination, while 9.5% were not at all satisfied and 38.5% were underimmunized. The proportion of male students who had completed the SABIN and DTP vaccination schedules was higher compared to the female students. More health education programs could increase the vaccination rates among nursing students.


Reactions of Neutral Scandium/Phosphorus Lewis Pairs with Small Molecules.
Treating a scandium mixed alkyl/diaryloxide complex with phosphino-substituted alcohols resulted in the formation of scandium mixed alkoxyl/diaryloxide complexes Sc[OC(CH3)2CH2PR2][O-2,6- tBu2-C6H3]2[THF] (6, R = Ph; 8, R = tBu). The reactivity of Sc-based Lewis pair complexes 6 and 8 toward a wide range of substrates was investigated. A ligand substitution reaction occurred when complex 6 was treated with benzophenone. The reaction of complex 6 with sulfur afforded a phosphane oxidative product. Complexes 6 and 8 also exhibited typical Sc/P frustrated Lewis pair (FLP) reactivity. They added to the carbonyl group of phenyl isocyanate to form seven-membered metallacycles. Complex 6 underwent selective Sc/P 1,4-addition reactions with α,β-unsaturated carbonyl compounds to give the corresponding nine-membered metallacyclic products. The reaction of 6 with 0.5 mol of dimethyl acetylenedicarboxylate led to the formation of bicyclo[7.7.0]cetane-derived metallacycle 16 in a distinctive double 1,4-addition pattern. With benzil complex 6 underwent a 1,4-addition reaction to afford a cis-enediolate which was coordinated to the Sc/P FLP through Sc-O and P-O bonds. Treatment of complex 6 with cyclopropyl phenyl ketone afforded the 10-membered metallaheterocycle 18, in which a scandium Lewis acid added to the oxygen atom and the phosphine Lewis base attacked the cyclopropyl group with ring opening. A ring-opening reaction also took place when epoxycyclohexane was employed as a substrate. Complex 6 successfully cleaved the C-Br bond of benzyl bromide to give zwitterionic complex 20 with newly formed Sc-Br and P-C bonds. Scandium phosphazine complex 21 was generated by a Sc/P 1,1-addition to the terminal nitrogen atom of (trimethylsilyl)diazomethane. Aided by the phosphorus Lewis base, scandium Lewis acid was able to abstract chloride from (Ph3P)AuCl to produce heterobimetallic Sc/Au complexes 22 and 23. Many complexes in this study were characterized by single-crystal X-ray diffraction.


Lattice distortion stabilizes the photoinduced metallic phase in the charge-ordered organic salts (BEDT-TTF)3X2 (X=ReO4, ClO4).
Photoinduced effects caused by intramolecular excitation were investigated by simultaneous optical and transport measurement in two charge-ordered organic salts, (BEDT-TTF)3X2 (X=ReO4, ClO4) [BEDT-TTF=bis(ethylenedithio)tetrathiafulvalene]. Although the two salts have the same molecular (average) charge and arrangement, they showed different photoinduced effects. A photoinduced insulator-to-metal phase transition with a metastable charge order-melting state was observed in the ReO4 salt where the charge ordered state is associated with the lattice distortion. On the other hand, no photoinduced insulator-to-metal phase transition was noted in the ClO4 salt where the charge ordered state is not accompanied by the lattice distortion. This comparative study suggested that the lattice distortion plays a key role in the stabilization of the photoinduced phase.


The antifungal effects of cinnamaldehyde against Aspergillus niger and its application in bread preservation.
Cinnamaldehyde (CIN) is a promising replacement for chemical synthetic preservatives, which has exhibited effective antimicrobial activities in food applications. In this study we examined the antifungal efficiency of CIN against Aspergillus niger in vitro. In addition, we explored its mode of action and evaluated its application potential in bread preservation in situ. The results showed that CIN exerted different levels of antifungal activity through different treatments, wherein it showed the highest antifungal activity in the liquid broth test, followed by solid contact and gas diffusion methods. On the other hand, ultrastructure observation, propyl iodide staining and ergosterol detection showed that CIN may damage the cell ultrastructure and membrane integrity in a dose dependent manner. Besides, the content of reactive oxygen species and malondialdehyde were, respectively, 2.74 and 2.07 times higher in fungi treated with 100 μg/mL of CIN, compared with those in untreated fungi. Finally, shelf life experiment showed that, in the vapor phase, CIN can efficiently prolong the shelf life of bread. Altogether, these results indicate that CIN can be used as an alternative food preservative due to its antifungal effects that are exerted, at least in part in A. niger, through the induction of oxidative stress, which caused cell damage and increased membrane permeability.


Pancreatic fate of 6-deoxy-6-[125I]iodo-D-glucose: in vitro experiments.
The apparent distribution space of 6-deoxy-6-[125I]iodo-D-glucose, recently proposed as a tracer of D-glucose transport, was measured in rat isolated islets, acinar tissue, and pieces of pancreas. While such a space reached a steady-state value corresponding to the 3HOH volume in pancreatic islets within 5 min, it slowly increased in pieces of pancreas and, even after 60-min incubation, remained lower than the 3HOH volume. Moreover, the net uptake of 6-deoxy-6-[125I]iodo-D-glucose by pancreatic pieces was inhibited by unlabeled 6-deoxy-6-iodo-D-glucose, D-glucose, and cytochalasin B, while being less or not affected by these agents in isolated islets. A preferential labeling of the endocrine, relative to exocrine, moiety of the pancreas was documented both by comparing, after 2 min incubation, the uptake of 6-deoxy-6-[125I]iodo-D-glucose by pieces of pancreas from normal vs streptozotocin-injected rats and by comparing the radioactive content of pancreatic islets and acinar tissue obtained from normal rats injected intravenously 3 min before sacrifice with 6-deoxy-6-[125I]iodo-D-glucose. It is proposed, therefore, that advantage could conceivably be taken from the vastly different time course for the uptake of selected monosaccharides by pancreatic islets vs acinar cells in the perspective of imaging of the endocrine pancreas by a non invasive method.


Dietary Modulation of Oxidative Stress in Alzheimer's Disease.
Cells generate unpaired electrons, typically via oxygen- or nitrogen-based by-products during normal cellular respiration and under stressed situations. These pro-oxidant molecules are highly unstable and may oxidize surrounding cellular macromolecules. Under normal conditions, the reactive oxygen or nitrogen species can be beneficial to cell survival and function by destroying and degrading pathogens or antigens. However, excessive generation and accumulation of the reactive pro-oxidant species over time can damage proteins, lipids, carbohydrates, and nucleic acids. Over time, this oxidative stress can contribute to a range of aging-related degenerative diseases such as cancer, diabetes, macular degeneration, and Alzheimer's, and Parkinson's diseases. It is well accepted that natural compounds, including vitamins A, C, and E, β-carotene, and minerals found in fruits and vegetables are powerful anti-oxidants that offer health benefits against several different oxidative stress induced degenerative diseases, including Alzheimer's disease (AD). There is increasing interest in developing anti-oxidative therapeutics to prevent AD. There are contradictory and inconsistent reports on the possible benefits of anti-oxidative supplements; however, fruits and vegetables enriched with multiple anti-oxidants (e.g., flavonoids and polyphenols) and minerals may be highly effective in attenuating the harmful effects of oxidative stress. As the physiological activation of either protective or destructive pro-oxidant behavior remains relatively unclear, it is not straightforward to relate the efficacy of dietary anti-oxidants in disease prevention. Here, we review oxidative stress mediated toxicity associated with AD and highlight the modulatory roles of natural dietary anti-oxidants in preventing AD.


Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease.
Autosomal dominant polycystic liver disease (PCLD) is characterized by progressive development of multiple (> 20) liver cysts. Two separate genes, PRKCSH and SEC63, have been identified to cause familial PCLD. We designed this study with two goals: to assess the relative contribution of PRKCSH and SEC63 mutations in a cohort of unrelated patients with a variable number of liver cysts, and to assess the effect of these mutations on the severity of the PCLD phenotype. We selected patients with two or more liver cysts on radiological studies and excluded those with renal cysts. A total of 51 patients entered the study and three groups were distinguished: A, 2-10 cysts (18 patients); B, 11-20 cysts (nine patients); and C, more than 20 cysts (24 patients). In total we found that eight patients with multiple liver cysts (16%) had PRKCSH (5) or SEC63 (3) mutations. Two patients (11%) from group A had missense mutations (1 PRKCSH and 1 SEC63). Six patients (25%) with more than 20 liver cysts had mutations (4 PRKCSH and 2 SEC63), of which five mutations were chain-terminating. In conclusion, both PRKCSH and SEC63 mutations are associated with polycystic liver disease. Frequency and severity of mutations is higher among patients with more than 20 liver cysts, but also patients with as few as eight liver cysts can be mutation carriers.


Laboratory assessment of thyroid disorders - which test should be used?
There are a variety of laboratory investigations which have been used in the assessment of thyroid function and it is obvious that not all of these tests can be used on each occasion. Which, therefore, provides the best diagnostic index? Each test is designed to assess a particular aspect of the thyroid gland and it is often not possible to select a single test as an ideal and exclude the others. The data presented in this paper indicate the advantages of using a combination of various procedures as a screening profile to cover all thyroid abnormalities. The results of several thyroid tests accumulated over the past five years are critically examined to assess their diagnostic value separately and in selected groups. Introduction.


Cannabidiol Marketing Strategies in the United States: An Analysis of Three Prominent Companies.
Introduction: The popularity and market for cannabidiol (CBD) products have expanded. Materials and Methods: Using Numerator advertising data from 2017 to 2021 regarding three popular CBD companies in the United States (Charlotte's Web, Green Roads, Medterra), we examined (1) general advertising characteristics (e.g., media channel, year); (2) ad content (i.e., themes of headlines and imagery); (3) themes of prominent sources (i.e., specific websites, magazines, etc.); and (4) ad expenditures. Results: Across companies during the study timeframe, there were 475 unique ads (i.e., unique content), 4767 ad occurrences, and $1,471,944 total expenditures. Charlotte's Web accounted for the greatest proportion of unique ads, ad occurrences, and expenditures (53.3%, 62.8%, and 70.3%, respectively), followed by Medterra (40.4%, 33.9%, and 28.5%) and Green Roads (6.3%, 3.3%, and 1.2%). The largest proportion of occurrences and expenditures were via online display (83.5%, 54.8%), followed by mobile (15.9%, 24.8%) and print (0.4%, 20.1%). Per ad occurrences and expenditures, ads prominently featured headline themes focused on brand/trust/quality (27.5%, 18.3%, respectively), wellness (17.5%, 17.7%), pain/sport (9.9%, 20.0%), and promotions (13.2%, 11.6%), in addition to visual themes of the product itself (74.3%, 78.5%) or with women (5.3%, 10.0%). The most prominent source themes were focused on health/wellness (21.0% of ad occurrences, 18.1% of expenditures), followed by other websites and search engines (18.3%, 11.2%), news/weather (12.9%, 21.3%), and entertainment/lifestyle/culture (12.6%, 28.0%). Despite some distinctions between companies, ad and source themes were similar. Conclusions: Regulatory efforts must be informed by ongoing surveillance of CBD marketing and how specific consumer subgroups are impacted by marketing exposure.


Caveolin-1 and Sox-2 are predictive biomarkers of cetuximab response in head and neck cancer.
The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse-phase protein array molecular profiles from patient-derived xenograft (PDX) tumors and revealed 2 PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors according to cetuximab response with 88% accuracy. Next, a support vector machine classifier algorithm identified a minimalist biomarker signature consisting of 8 proteins - caveolin-1, Sox-2, AXL, STING, Brd4, claudin-7, connexin-43, and fibronectin - with expression that strongly predicted cetuximab response in PDXs using either protein or mRNA. A combination of caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in tumor samples from patients with HNSCC with known clinical response to cetuximab. These results support further investigation into the combined use of caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.


Null mutations in a Nudix gene, ygdP, implicate an alarmone response in a novel suppression of hybrid jamming.
Induction of the toxic LamB-LacZ protein fusion, Hyb42-1, leads to a lethal generalized protein export defect. The prlF1 suppressor causes hyperactivation of the cytoplasmic Lon protease and relieves the inducer sensitivity of Hyb42-1. Since prlF1 does not cause a detectable change in the stability or level of the hybrid protein, we conducted a suppressor screen, seeking factors genetically downstream of lon with prlF1-like phenotypes. Two independent insertions in the ygdP open reading frame relieve the toxicity of the fusion protein and share two additional properties with prlF1: cold sensitivity and the ability to suppress the temperature sensitivity of a degP null mutation. Despite these similarities, ygdP does not appear to act in the same genetic pathway as prlF1 and lon, suggesting a fundamental link between the phenotypes. We speculate that the common properties of the suppressors relate to secretion defects. The ygdP gene (also known as nudH) has been shown to encode a Nudix protein that acts as a dinucleotide oligophosphate (alarmone) hydrolase. Our results suggest that loss of ygdP function leads to the induction of an alarmone-mediated response that affects secretion. Using an epitope-tagged ygdP construct, we present evidence that this response is sensitive to secretion-related stress and is regulated by differential proteolysis of YgdP in a self-limiting manner.


910-m propagation of THz ps pulses through the Atmosphere.
We measured the atmospheric propagation of ps THz pulses with a 0.4-THz bandwidth through a 910-m distance; the pulse delay corresponded to 255 pulses down the pulse train of the mode-locked ring laser excitation pulses. The complexity of the atmosphere requires the use of the complete theory of Essen and Froome to compare the measured time shifts due to both the dry atmosphere and water vapor with theoretical calculations. A new procedure involving the measurement of phase in the frequency domain is introduced and achieves comparable results for the calculated time shifts, compared to the previous direct measurements of time shifts. When the THz pulses were sequentially measured for a distance of 186 and 910 m at the same weather condition, the time variation due to atmospheric turbulence between the two pulses of the 910 m measurement was up to 4 times larger than that between the two pulses of the 186 m measurement. THz long path WVD studies are necessary to evaluate proposed applications in the atmosphere, such as communications and monitoring pollutants and dangerous gases.


On the use of motion-based frame rejection in temporal averaging denoising for segmentation of echocardiographic image sequences.
We have recently introduced an algorithm for semi-automatic segmentation of the left ventricular wall in short-axis echocardiographic images (EMBC 30:218-221). In its preprocessing stage, the algorithm uses temporal averaging for image denoising. Motion estimation is used to detect and reject frames that do not correlate well with the set of images being averaged. However, the process of estimating motion vectors is computationally intense, which increases the algorithm's computation time. In this work, we evaluate the viability of replacing the motion estimation stage with less computationally intense approaches. Two alternative techniques are evaluated. The ventricular contours obtained from each of the three algorithm variants were quantitatively and qualitatively compared with contours manually-segmented by a specialist. We show that it is possible to reduce the algorithm's computational load without significantly reducing the segmentation quality. The proposed algorithms are also compared with three other techniques from the literature.


Myostatin mediates abdominal aortic atherosclerosis progression by inducing vascular smooth muscle cell dysfunction and monocyte recruitment.
Myostatin (Mstn) is a skeletal muscle growth inhibitor involved in metabolic disorders and heart fibrosis. In this study we sought to verify whether Mstn is also operative in atherosclerosis of abdominal aorta. In human specimens, Mstn expression was almost absent in normal vessels, became detectable in the media of non-progressive lesions and increased with the severity of the damage. In progressive atherosclerotic lesions, Mstn was present in the media, neointima, plaque shoulder and in infiltrating macrophages. Mstn co-localized with α-smooth muscle actin (α-SMA) staining and with some CD45+ cells, indicating Mstn expression in VSMCs and bloodstream-derived leukocytes. In vitro, Mstn was tested in VSMCs and monocytes. In A7r5 VSMCs, Mstn downregulated proliferation and Smoothelin mRNA, induced cytoskeletal rearrangement, increased migratory rate and MCP-1/CCR2 expression. In monocytes (THP-1 cells and human monocytes), Mstn acted as a chemoattractant and increased the MCP-1-dependent chemotaxis, F-actin, α-SMA, MCP-1 and CCR2 expression; in turn, MCP-1 increased Mstn mRNA. Mstn induced JNK phosphorylation both in VSMCs and monocytes. Our results indicate that Mstn is overexpressed in abdominal aortic wall deterioration, affects VSMCs and monocyte biology and sustains a chronic inflammatory milieu. These findings propose to consider Mstn as a new playmaker in atherosclerosis progression.


Diet and hyperkinesis: a review of the controversy.
Controlled scientific evaluation of the efficacy of the Kaiser-Permanente diet has just begun and no studies have proved or disproved its usefulness in controlling the hyperkinetic syndrome. Further studies with good controls are needed. The best studies done so far tend to support the thesis that control of diet may influence the disorder. It has not been shown that diet is the most important variable; nor have the effective substances been identified. The Kaiser-Permanente diet appears to be basically sound and perhaps superior to a normal diet, with the exception of its low Vitamin C content. Careful monitoring of the child on this diet by a professional would be advisable. The hyperkinetic syndrome may represent more than one disease entity and may, therefore, require different forms of therapy. A careful evaluation of the individual case should be made, considering diet; behavioral, psychological, and physical problems; and learning disabilities, before the diagnosis of hyperkinetic syndrome is established. Cooperation of the physician, educator, and psychologist is required. The best form of treatment (dietetic, psychiatric, behavioral, or pharmaceutic) should be predicated upon the assessment by these professionals.


Photoactive hybrid material based on pyrene functionalized PbS nanocrystals decorating CVD monolayer graphene.
A simple and facile solution-based procedure is implemented for decorating a large area, monolayer graphene film, grown by chemical vapor deposition, with size-tunable light absorbing colloidal PbS nanocrystals (NCs). The hybrid is obtained by exposing a large area graphene film to a solution of 1-pyrene butyric acid surface coated PbS NCs, obtained by a capping exchange procedure onto presynthesized organic-capped NCs. The results demonstrate that at the interface, multiple and cooperative π-π stacking interactions promoted by the pyrene ligand coordinating the NC surface lead to a successful anchoring of the nano-objects on the graphene platform which concomitantly preserves its aromatic structure. Interligand interactions provide organization of the nano-objects in highly interconnected nanostructured multilayer coatings, where the NCs retain geometry and composition. The resulting hybrid exhibits a sheet resistance lower than that of bare graphene, which is explained in terms of electronic communication in the hybrid, due to the interconnection of the NC film and to a hole transfer from photoexcited PbS NCs to graphene, channelled at the interface by pyrene. Such a direct electron coupling makes the manufactured hybrid material an interesting component for optoelectronics, sensors and for optical communication and information technology.


Ltv1 is required for efficient nuclear export of the ribosomal small subunit in Saccharomyces cerevisiae.
In eukaryotes, 40S and 60S ribosomal subunits are assembled in the nucleus and exported to the cytoplasm independently of one another. Nuclear export of the 60S requires the adapter protein Nmd3, but no analogous adapter has been identified for the 40S. Ltv1 is a nonessential, nonribosomal protein that is required for 40S subunit biogenesis in yeast. Cells lacking LTV1 grow slowly, are hypersensitive to inhibitors of protein synthesis, and produce about half as many 40S subunits as do wild-type cells. Ltv1 interacts with Crm1, co-sediments in sucrose gradients with 43S/40S subunits, and copurifies with late 43S particles. Here we show that Ltv1 shuttles between nucleus and cytoplasm in a Crm1-dependent manner and that it contains a functional NES that is sufficient to direct the export of an NLS-containing reporter. Small subunit export is reduced in Deltaltv1 mutants, as judged by the altered distribution of the 5'-ITS1 rRNA and the 40S ribosomal protein RpS3. Finally, we show a genetic interaction between LTV1 and YRB2, a gene that encodes a Ran-GTP-, Crm1-binding protein that facilitates the small subunit export. We propose that Ltv1 functions as one of several possible adapter proteins that link the nuclear export machinery to the small subunit.


The Construct of the Schizophrenia Quality of Life Scale Revision 4 for the Population of Taiwan.
This study examines the factor structure of the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4) for inpatients with schizophrenia in a psychiatric hospital in southern Taiwan. All the participants (n = 100) filled out the SQLS-R4, Mini Mental Status Examination (MMSE), and Brief Psychiatric Rating Scale (BPRS) under the supervision of one experienced occupational therapist. Using confirmatory factor analysis, we first determined that a 29-item model was more satisfactory than the original 33-item model based on the findings of better fit indices for the 29-item model. We then found that a three-correlated-factor structure was best for the SQLS-R4 after four models (namely, two-correlated-factor, three-correlated-factor, seven-correlated-factor, and second-order models) had been compared. In addition, the three constructs (psychosocial, physical, and vitality) were moderately to highly correlated with the constructs of the World Health Organization Quality of Life- (WHOQOL-) BREF (r = -0.38 to -0.69), except for one low correlation between the vitality construct of the SQLS-R4 and the psychological construct of the WHOQOL-BREF (r = -0.26). We tentatively conclude that the SQLS-R4 with a three-correlated-factor structure is a valid and reliable instrument for examining the quality of life of people with schizophrenia.


Comparison of different sampling types across the rearing period in broiler flocks for isolation of Campylobacter spp.
Campylobacter is the most common bacterial cause of human gastrointestinal disease in most developed countries. It is generally accepted that poultry products are a significant source of foodborne Campylobacter infections in humans. Assessing the effectiveness of any potential intervention at farm level requires monitoring of the Campylobacter status of broiler flocks, using appropriate sampling methods. The aim of this study was to assess the influence of the sample type across the rearing period for the detection of Campylobacter spp. at farm level. During this study, 21 commercial broiler farms were intensively sampled. Each farm was visited and sampled at different times during the rearing period (d 1, 7, 14, 21, 28, 35, and 42). On the first day of rearing, the status of the house and the day-old flock was evaluated, and environmental and cecal samples were collected. During rearing, 4 different sample types were collected: feces with sock swabs (sock swabs), feces directly from the litter (feces), cloacal swabs, and cecal content. All samples were analyzed according to ISO 10272-1:2006 (Annex E) and also by direct culture. The results of this study showed that Campylobacter spp. were detected in all of the sample types on d 14 of rearing. From this point on, the detection increased significantly, with a maximum detection rate by the end of rearing, regardless of the sample type. All samples that were negative upon direct culture were also negative after pre-enrichment. At the end of rearing, the percentage of samples positive for Campylobacter spp. was 71.4% for cecal samples, 61.9% for cloacal swabs, 45.2% for sock swabs, and 69.1% for fecal samples. C. jejuni was detected in all the sample types, with positive rates ranging from 67.1 to 76.0% for cecal samples and cloacal content, respectively. Cecal samples, cloacal swabs, and fecal samples cultured by direct plating onto modified charcoal cefoperazone deoxycholate agar (mCCDA) without pre-enrichment have the same sensitivity for detection of Campylobacter spp. in broiler flocks independent of the day of rearing.


A novel ferroptosis-related gene signature can predict prognosis and influence immune microenvironment in acute myeloid leukemia.
Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy that strongly correlates with poor clinical outcomes. Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death which plays an important role in various human cancers. Nevertheless, the prognostic significance and functions of ferroptosis-related genes (FRGs) in AML have not received sufficient attention. The aim of this article was to evaluate the association between FRGs levels and AML prognosis using publicly available RNA-sequencing datasets. The univariate Cox regression analysis identified 20 FRGs that correlate with patient overall survival. The LASSO Cox regression model was used to construct a prognostic 12-gene risk model using a TCGA cohort, and internal and external validation proved the signature efficient. The 12-FRGs signature was then used to assign patients into high- and low-risk groups, with the former exhibiting markedly reduced overall survival, compared to the low-risk group. ROC curve analysis verified the predictive ability of the risk model. Functional analysis showed that immune status and drug sensitivity differed between the 2 risk groups. In summary, FRGs is a promising candidate biomarker and therapeutic target for AML.


Renin activity solid phase radioimmunoassay.
A solid-phase radioimmunoassay for measurement of generation angiotensin I (renin activity) in plasma is reported. The angiontensin I antisera were attached to diazotized arylamine and N-hydroxy succinimide controlled pore glass, and reacted with labelled and unlabelled angiotentin I for saturation analysis before and after one hour incubation. Chelating agents were used to inhibit the conversion of angiotensin I to angiotensin II in vitro. The assay is accurate, rapid and reproducible.


Nocturia and its clinical implications in older women.
The aim of this study is to demonstrate the relationship between nocturia and geriatric syndromes, and comprehensive geriatric assessment parameters (CGA) in older women. 858 older outpatient women were included in this cross-sectional study. For the nocturia variable, the question, "Generally, during the past 30 days, how many times did you usually urinate after you have gone to sleep at night until the time you got up in the morning?'' was used. The relationships between nocturia status and common geriatric syndromes, and CGA parameters were determined. The mean age of patients was 74.1 ± 8.0 years. The prevalence of patients who reported average of 0, ≥1, ≥2, ≥3, and ≥4 nocturnal episodes was 14.7%, 85.3%, 66.3%, 42.13%, and 24.1%, respectively. When all the covariates including age, education, Charlson Comorbidities Index score, glomerular filtration rate, antimuscarinic drugs and alpha-blockers use, diabetes mellitus, chronic obstructive pulmonary disease, and incontinence were adjusted, there were higher rates of insomnia, recurrent falls and higher scores of Timed Up-Go test in older women with ≥2 nocturia episodes (p < 0.05). There was a significant correlation between ≥3 nocturia episodes and lower Instrumental Activities of Daily Living scores and a significant correlation between ≥4 nocturnal episodes and frailty and polypharmacy (p < 0.05). Nocturia is quite common and associated with insomnia, frailty, polypharmacy, incontinence, falls, lower gait speed, and functionality in older women.Therefore, nocturia is very important for geriatric practice and ≥2 nocturia episodes can be a marker of poor health status in older women.


Meiosis-specific gene discovery in plants: RNA-Seq applied to isolated Arabidopsis male meiocytes.
Meiosis is a critical process in the reproduction and life cycle of flowering plants in which homologous chromosomes pair, synapse, recombine and segregate. Understanding meiosis will not only advance our knowledge of the mechanisms of genetic recombination, but also has substantial applications in crop improvement. Despite the tremendous progress in the past decade in other model organisms (e.g., Saccharomyces cerevisiae and Drosophila melanogaster), the global identification of meiotic genes in flowering plants has remained a challenge due to the lack of efficient methods to collect pure meiocytes for analyzing the temporal and spatial gene expression patterns during meiosis, and for the sensitive identification and quantitation of novel genes. A high-throughput approach to identify meiosis-specific genes by combining isolated meiocytes, RNA-Seq, bioinformatic and statistical analysis pipelines was developed. By analyzing the studied genes that have a meiosis function, a pipeline for identifying meiosis-specific genes has been defined. More than 1,000 genes that are specifically or preferentially expressed in meiocytes have been identified as candidate meiosis-specific genes. A group of 55 genes that have mitochondrial genome origins and a significant number of transposable element (TE) genes (1,036) were also found to have up-regulated expression levels in meiocytes. These findings advance our understanding of meiotic genes, gene expression and regulation, especially the transcript profiles of MGI genes and TE genes, and provide a framework for functional analysis of genes in meiosis.


Pharmacologic modulation of nasal epithelium augments neural stem cell targeting of glioblastoma.
Glioblastoma (GBM) remains the most lethal and untreatable central nervous system malignancy. The challenges to devise novel and effective anti-tumor therapies include difficulty in locating the precise tumor border for complete surgical resection, and rapid regrowth of residual tumor tissue after standard treatment. Repeatable and non-invasive intranasal application of neural stem cells (NSCs) was recently shown to enable clinically relevant delivery of therapy to tumors. Treatment with chemotactic NSCs demonstrated significant survival benefits when coupled with radiation and oncolytic virotherapy in preclinical models of GBM. In order to further augment the clinical applicability of this novel therapeutic platform, we postulate that the FDA-approved compound, methimazole (MT), can be safely utilized to delay the nasal clearance and improve the ability of NSCs to penetrate the olfactory epithelium for robust in vivo brain tumor targeting and therapeutic actions. To examine the role of reversible reduction of the olfactory epithelial barrier in non-invasive intranasal delivery, we explored the unique pharmacologic effect of MT at a single dosage regimen. In our proof-of-concept studies, quantitative magnetic resonance imaging (MRI), immunocytochemistry, and survival analysis were performed on glioma-bearing mice treated with a single dose of MT prior to intranasal anti-GBM therapy using an oncolytic virus (OV)-loaded NSCs. Based on histology and in vivo imaging, we found that disrupting the olfactory epithelium with MT effectively delays clearance and allows NSCs to persist in the nasal cavity for at least 24 h. MT pretreatment amplified the migration of NSCs to the tumor. The therapeutic advantage of this enhancement was quantitatively validated by tissue analysis and MRI tracking of NSCs loaded with superparamagnetic iron oxide nanoparticles (SPIOs) in live animals. Moreover, we observed significant survival benefits in GBM-bearing mice treated with intranasal delivery of oncolytic virus-loaded NSCs following MT injection. Our work identified a novel pharmacologic strategy to accelerate the clinical application of the non-invasive NSCs-based therapeutic platform to tackle aggressive brain tumors.


[Relationship between cardiac natriuretic peptide (ANP/BNP) and fluid intake in patients with subarachnoid hemorrhage].
Several authors described elevated natriuretic peptides, atrial natriuretic peptide(ANP) and brain natriuretic peptide (BNP), in patients with subarachnoid hemorrhage(SAH), which were account for inappropriate antidiuretic hormone(SIADH) or cerebral salt wasting syndrome(CSW). Although the secretion of natriuretic peptide depends on the total blood volume, central venous pressure, and cardiac output volume, the volume of fluid intake in patients with SAH had not been taken in consideration in previous report. We here examined the relationship between fluid intake and the natriuretic peptides in two cases without cardiac failure. ANP elevated 2 or 3 days after SAH and remained in normal range for 2 weeks. BNP elevated when the volume of fluid intake was increased, and BNP did not elevate during the periods with lower fluid intake. Several authors proposed the possibility of iatrogenic factor in natriuresis after SAH and these results supported this opinion.


Impact of Traumatic Brain Injury on Dopaminergic Transmission.
Brain trauma is often associated with severe morbidity and is a major public health concern. Even when injury is mild and no obvious anatomic disruption is seen, many individuals suffer disabling neuropsychological impairments such as memory loss, mood dysfunction, substance abuse, and adjustment disorder. These changes may be related to subtle disruption of neural circuits as well as functional changes at the neurotransmitter level. In particular, there is considerable evidence that dopamine (DA) physiology in the nigrostriatal and mesocorticolimbic pathways might be impaired after traumatic brain injury (TBI). Alterations in DA levels can lead to oxidative stress and cellular dysfunction, and DA plays an important role in central nervous system inflammation. Therapeutic targeting of DA pathways may offer benefits for both neuronal survival and functional outcome after TBI. The purpose of this review is to discuss the role of DA pathology in acute TBI and the potential impact of therapies that target these systems for the treatment of TBI.


Isolation of a cDNA encoding a portion of the cyclic nucleotide phosphodiesterase of Dictyostelium discoideum.
The cyclic nucleotide phosphodiesterase (phosphodiesterase) of Dictyostelium discoideum is one of a group of developmentally regulated proteins which enable cells to aggregate by chemotaxis during the early stages of development. We report the identification and DNA sequence of a cDNA clone encoding the amino-terminal region of the phosphodiesterase. The clone, pPD-3, was selected from a cDNA library created by priming first strand synthesis using a set of oligonucleotides with sequences predicted from the amino-terminal amino acid sequence of purified phosphodiesterase. The DNA sequence of pPD-3 encodes perfectly the available phosphodiesterase amino acid sequence, and pPD-3 selects an mRNA which can be translated into material recognized by phosphodiesterase antisera. The nucleotide sequence of pPD-3 indicates there are 49 amino acids, which contain a segment possessing the characteristics of a signal peptide, that separate the amino-terminal residue identified in the purified protein from the methionine codon at which translation originates. DNA blot analysis demonstrates that the phosphodiesterase gene exists as a single copy in the nuclear genome. Analysis of RNA indicates that the phosphodiesterase transcript is 2.1 kb long, which is approximately 0.8 kb more than the minimum required to encode this protein.


Determination of bulky DNA adducts in biomonitoring of carcinogenic chemical exposures: features and comparison of current techniques.
DNA adducts resulting from carcinogenic chemicals are becoming more frequently used as a powerful biomarker to determine the extent of exposure. The available techniques for determination of bulky DNA adducts can be classified into four major groups, these being immunological assay, fluorescence techniques, chromatography/m ass spectrom etry and the (32)P-postlabelling technique. In this review, the features of current techniques and the combined applications are summarized and compared. Among the available techniques, the (32)P-postlabelling assay seems to best meet the application criteria overall. In particular, (32)P-postlabelling is the most suitable technique for the detection of bulky DNA adducts induced by unknown environmental and occupational chemicals or m ixtures.


Early television exposure and children's behavioral and social outcomes at age 30 months.
Previous research has suggested that television (TV) viewing may be associated with increased behavioral and emotional problems in children. However, there are few prospective studies targeted for its association with outcomes of children under 3 years old. The purpose of this study was to exam the association between children's early TV exposure at ages 18 and 30 months and the behavioral and emotional outcomes at age 30 months. We analyzed data collected prospectively in the Japan Children's Study. TV exposure was assessed by mothers' report at infant ages of 18 and 30 months. The outcomes were assessed using the Strengths and Difficulties Questionnaire (SDQ). Analysis of Covariance was used to estimate the effect of TV exposure on behavioral and emotional outcomes. The percentage of children who watched TV 4 hours or more per day was 29.4% at age 18 months, 24.5% at age 30 months, and 21% at both ages. Hyperactivity-inattention at age 30 months was positively associated with TV exposure at age 18 months, whereas prosocial behavior was negatively associated with hours of exposure even after adjustment. However, there were no significant differences in SDQ subscales according to daily hours of TV viewing at age 30 months. Daily TV exposure at age 18 months was associated with hyperactivity-inattention and prosocial behavior at age 30 months. However, the directly casual relation was not proved in the present study. Additional research considering the TV program content and exposure timing are needed to investigate the causal relation between TV viewing and behavioral outcome.


Current achievements, strategies, obstacles, and overcoming the challenges of the protein engineering in Pichia pastoris expression system.
Yeasts serve as exceptional hosts in the manufacturing of functional protein engineering and possess industrial or medical utilities. Considerable focus has been directed towards yeast owing to its inherent benefits and recent advancements in this particular cellular host. The Pichia pastoris expression system is widely recognized as a prominent and widely accepted instrument in molecular biology for the purpose of generating recombinant proteins. The advantages of utilizing the P. pastoris system for protein production encompass the proper folding process occurring within the endoplasmic reticulum (ER), as well as the subsequent secretion mediated by Kex2 as a signal peptidase, ultimately leading to the release of recombinant proteins into the extracellular environment of the cell. In addition, within the P. pastoris expression system, the ease of purifying recombinant protein arises from its restricted synthesis of endogenous secretory proteins. Despite its achievements, scientists often encounter persistent challenges when attempting to utilize yeast for the production of recombinant proteins. This review is dedicated to discussing the current achievements in the usage of P. pastoris as an expression host. Furthermore, it sheds light on the strategies employed in the expression system and the optimization and development of the fermentative process of this yeast. Finally, the impediments (such as identifying high expression strains, improving secretion efficiency, and decreasing hyperglycosylation) and successful resolution of certain difficulties are put forth and deliberated upon in order to assist and promote the expression of complex proteins in this prevalent recombinant host.


Active treatment rates for lung cancer in south Manchester: are we doing enough?
In an effort to improve the current lung cancer treatment outcomes in Britain, National guidelines were published followed by the introduction of National Lung Cancer Audit (LUCADA) project. LUCADA has defined active treatment as any therapeutic intervention with the aim of improving the quality or length of patients' survival irrespective of whether it is curative or palliative. From August 2003 to December 2006, all patients diagnosed to be new primary lung cancer referrals were enrolled into a prospective study. Out of the total of 433 patients the majority of patients were male (62%) and the mean age was 69 years. The histologies were small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and other cancers in 67 (15.5%), 306 (70.7%) and 11 (2.5%) patients, respectively, while 49 (11.3%) patients had no histological confirmation. Overall, the active treatment rate was 72% with 74 (18%), 158 (36%), 66 (15%) and 11 (3%) undergoing surgery, chemotherapy, radiotherapy and other methods, respectively. The active treatment rates for histologically proven SCLC, NSCLC and all lung cancers excluding SCLC were 83%, 77% and 71%, respectively, compared to the LUCADA national average of 73.5%, 66% and 56.5%, respectively. Among the NSCLC patients overall five-year survival was 27.4%. The stage specific survivals were 64.0%, 58.3%, 24.1% and 11.5%, respectively, for stages I, II, III and IV. These reassuring results show that south Manchester has good active treatment rates for lung cancer with survival outcomes comparable to other major series.


Voluntary wheel running preserves lumbar perineuronal nets, enhances motor functions and prevents hyperreflexia after spinal cord injury.
Perineuronal nets (PNN) are a promising candidate to harness neural plasticity since their activity-dependent modulation allows to either stabilize the circuits or increase plasticity. Modulation of plasticity is the basis of rehabilitation strategies to reduce maladaptive plasticity after spinal cord injuries (SCI). Hence, it is important to understand how spinal PNN are affected after SCI and rehabilitation. Thus, this work aims to describe functional and PNN changes after thoracic SCI in mice, followed by different activity-dependent therapies: enriched environment, voluntary wheel and forced treadmill running. We found that the contusion provoked thermal hyperalgesia, hyperreflexia and locomotor impairment as measured by thermal plantar test, H wave recordings and the BMS score of locomotion, respectively. In the spinal cord, SCI reduced PNN density around lumbar motoneurons. In contrast, activity-based therapies increased motoneuron activity and reversed PNN decrease. The voluntary wheel group showed full preservation of PNN which also correlated with reduced hyperreflexia and better locomotor recovery. Furthermore, both voluntary wheel and treadmill running reduced hyperalgesia, but this finding was independent of lumbar PNN levels. In the brainstem sensory nuclei, SCI did not modify PNN whereas some activity-based therapies reduced them. The results of the present study highlight the impact of SCI on decreasing PNN at caudal segments of the spinal cord and the potential of physical activity-based therapies to reverse PNN disaggregation and to improve functional recovery. As modulating plasticity is crucial for restoring damaged neural circuits, regulating PNN by activity is an encouraging target to improve the outcome after injury.


Inheritance of a stable mutation in a family with early-onset disease.
Autosomal/dominant polycystic kidney disease (ADPKD) exhibits a high inter- and intrafamilial heterogeneity partly explained by the involvement of at least 3 different genes in the disorder transmission. PKD1, the major locus, is located on chromosome 16p. The occurrence of very early-onset cases of ADPKD (sometimes in utero) in a few PKD1 families or the increased severity of the disease in successive generations raise the question of anticipation. This is a subject of controversial discussion. This report deals with the molecular analysis in families with very early-onset ADPKD. The finding of the same stable mutation with such different phenotypes rules out a dynamic mutation. The molecular basis of severe childhood PKD in typical ADPKD families remains unclear; it may include segregation of modifying genes or unidentified factors and the two-hit mechanism.


Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumours.
Somatostatin has been identified as having anti-proliferative, anti-angiogenic and pro-apoptotic actions in many tumour systems, and these effects are mediated through a family of five transmembrane G-protein coupled SRIF receptors. Ovarian cancer is the commonest gynaecological malignancy in the UK and maintenance therapy is urgently required. Native somatostatin expression and its receptors sst(1,2,3 and 5) were studied with immunohistochemistry in 63 malignant and 35 benign ovarian tumours of various histological types. Fifty-seven out of 63 (90%) of malignant and 26/35 (74%) benign tumours expressed somatostatin. Receptors sst(1,2,3 and 5) were expressed variably in epithelial, vascular and stromal compartments for both benign and malignant tumours. Somatostatin was found to correlate significantly with stromal sst(1) (P=0.008), epithelial sst(1) (P<0.001), stromal sst(2) (P=0.019), vascular sst(2) (P=0.026), epithelial sst(3) (P=0.026), stromal sst(5) (P=0.013) and vascular sst(5) (P=0.038). Increased expression of native somatostatin correlating with somatostatin receptors in malignant ovarian tumours raises the possibility that either synthetic somatostatin antagonists or receptor agonists may have therapeutic potential.


Propionibacterium acnes causes postoperative brain abscesses unassociated with foreign bodies: case reports.
Propionibacterium acnes was isolated in pure culture from brain abscesses that occurred in two patients after intracranial surgery. Although such infections are usually associated with cerebrospinal fluid shunts and other foreign bodies, these cases clearly demonstrate the pathogenicity of this anaerobic diphtheroid in the absence of such. Progression of P. acnes infection in the central nervous system can be insidious. To treat such infections adequately, therapy cannot rely upon some standard antimicrobial agents. Metronidazole, which is useful against most anaerobic organisms, is not effective against P. acnes.


Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes: a new model for the pathogenesis of microvascular dysfunction.
To test the independent contributions of vascular endothelium, sympathetic activation and inhibition, vessel distensibility, and nociceptor-mediated vasodilation in both glabrous and hairy skin circulations. We measured blood flow using laser Doppler techniques in 10 people with type 2 diabetes and 10 age- and BMI-matched healthy control subjects at the pulp of the index finger (glabrous skin) and the dorsum of the hand (hairy skin). A 5-min ischemic block of the arm was used to test vascular endothelium. Warming of the probe site to 45 degrees C tested neurogenic vasodilation in hairy skin only. Vessel distensibility was tested by gravitational pressure. Basal blood flow and reactive hyperemia did not differ between groups at either skin site. The vasodilative response to local warming (P < 0.01) and limb lowering (P < 0.05) were significantly different between groups in hairy skin but not in glabrous skin in the absence of objective measured neuropathy. Nociceptor-mediated flow correlated significantly with the warm thermal threshold (r = -0.50, P < 0.05). Endothelial-mediated blood flow correlated with systolic blood pressure (r = -0.76, P < 0.01), LDL cholesterol (r = -0.62, P < 0.001), C-peptide (r = 0.65, P < 0.05), and triglycerides (r = 0.47, P < 0.05). These data suggest that neurogenic nociceptor-mediated vasodilation is impaired in subjects with type 2 diabetes when endothelial and sympathetic function are relatively intact. Heat-induced vasodilation may be a specific test of small heat-sensitive C-fiber peripheral neurons and may be an integral part of the metabolic syndrome.


Lifestyle risk factors and corresponding levels of clinical advice and counselling in general practice.
The objective of this study was to examine prevalence rates of lifestyle risk factors in the Western Victorian Primary Health Network (WV PHN) general practice patient population and the corresponding levels of clinical advice and counselling. Analysed data from the Bettering the Evaluation and Care of Health (BEACH) program from April 2011 to March 2015 were examined, providing a comparison of three geographical areas of general practice patients: WV PHN, Victoria and Australia. Rates of clinical advice and counselling for diet and exercise provided by general practitioners (GPs) in the WV PHN network were significantly lower than Victorian and Australian rates, despite the region's higher obesity rates. Smoking rates were higher in the WV PHN compared with Australia, but there was no difference in the levels of smoking cessation advice disseminated. Across all regions, one in four patients drank alcohol at hazardous levels. GPs in rural practice require further support, encouragement and resources to provide diet and exercise advice to their patients more frequently.


Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma.
Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. To elucidate the role of ARBs and ACE-Is in HCC. We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.


Computational and experimental studies on the mechanism of formation of poly(hexahydrotriazine)s and poly(hemiaminal)s from the reactions of amines with formaldehyde.
Combined experimental and computational studies have been performed on the mechanism of formation of poly(hexahydrotriazine) and hemiaminal dynamic covalent network (PHT and HDCN) thermosetting polymers from the reactions of diamines with formaldehyde (Science 2014, 344, 732-735). Results suggest that these polymers are formed by a mechanism involving the water promoted stepwise addition of amines with formaldehyde in preference to dimerization or cyclotrimerization of imine intermediates or self-catalysis by the amine reagents. The predicted mechanism also explains experimentally observed electronic effects for hexahydrotriazine formation.


Using Intensive Longitudinal Data to Study Treatment Effects in Patients with Major Depression: A Systematic Review.
Depression is a disabling condition, causing suffering worldwide. The purpose of this paper is to review studies that have used Intensive Longitudinal Data (ILD) in research on depression treatment. Intensive longitudinal data in the form of daily diaries, experience sampling method (ESM), and ecological momentary assessment (EMA) are increasingly used in psychotherapy research to gather individualized data. A systematic search was conducted in the research databases PsycINFO, PubMed and Scopus on depression treatment assessed with ILD methods. Seven studies met inclusion criteria; two focused on the effects of cognitive therapy/cognitive behavioral therapy (CBT)/Self-System Therapy (SST); one focused on the effects of physical exercise; and four examined ESM as an add-on intervention to pharmacological treatment. ILD is useful when studying changes in complex patterns of patients' functioning, such as daily affective reactivity, empowerment, daily dose-response effects of physical activity on PA, and associations between activity and depressive symptoms. Results also showed that ESM registration in itself can help patients with major depression (MDD) to engage more in physical and social activities and to spend less time alone or resting.


Glass transition of ion-containing polymer melts in bulk and thin films.
Ion-containing polymers often are good glass formers, and the glass transition temperature is an important parameter to consider for practical applications, which prescribes the working temperature range for different mechanical and dynamic properties. In this work, we present a systematic molecular dynamics simulation study on the coupling of ionic correlations with the glass transition, based on a generic coarse-grained model of ionic polymers. The variation of the glass transition temperature is examined concerning the influence of the electrostatic interaction strength, charge fraction, and charge sequence. The interplay with the film thickness effect is also discussed. Our results reveal a few typical features about the glass transition process that are in qualitative agreement with previous studies, further highlighting the effects of counterion entropy at weak ionic correlations and physical crosslinking of ionic aggregates at strong ionic correlations. Detailed parametric dependencies are displayed, which demonstrate that introducing strong ionic correlations promotes vitrification while adopting a precise charge sequence and applying strong confinement with weak surface affinity reduce the glass transition temperature. Overall, our investigation provides an improved picture towards a comprehensive understanding of the glass transition in ion-containing polymeric systems from a molecular simulation perspective.


Assessing the Visualization-Based Decision Support System for Environmental Impact Assessments.
Even though environmental impact assessments (EIAs) have been an important tool for environmental decision-making, most EIAs are published as a mix of text and tabular data that is not easily accessible to or understandable for the public. In this paper, we present a decision support system (DSS) that supports the decision-making of stakeholders in the EIA stage. The system was designed to improve the public's understanding of stakeholders before and after a construction project by providing visualization of key environmental elements. We recruited 107 participants to test the usability of the system and examined the impacts of individual differences between the participants on their perceptions of the system, including their environmental expertise and computer self-efficacy. The results showed that the proposed system had high usability, especially for users with high computational efficacy and environment expertise. The system could thus help to improve the communication between the public and experts during public hearings and enhance the environmental literacy of the public.


Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT.
Cryopreservation of PBMC and/or overnight shipping of samples are required for many clinical trials, despite their potentially adverse effects upon immune monitoring assays such as MHC-peptide tetramer staining, cytokine flow cytometry (CFC), and ELISPOT. In this study, we compared the performance of these assays on leukapheresed PBMC shipped overnight in medium versus cryopreserved PBMC from matched donors. Using CMV pp65 peptide pool stimulation or pp65 HLA-A2 tetramer staining, there was significant correlation between shipped and cryopreserved samples for each assay (p <or= 0.001). The differences in response magnitude between cryopreserved and shipped PBMC specimens were not significant for most antigens and assays. There was significant correlation between CFC and ELISPOT assay using pp65 peptide pool stimulation, in both shipped and cryopreserved samples (p <or= 0.001). Strong correlation was observed between CFC (using HLA-A2-restricted pp65 peptide stimulation) and tetramer staining (p < 0.001). Roughly similar sensitivity and specificity were observed between the three assays and between shipped and cryopreserved samples for each assay. We conclude that all three assays show concordant results on shipped versus cryopreserved specimens, when using a peptide-based readout. The assays are also concordant with each other in pair wise comparisons using equivalent antigen systems.


Lactation accommodation in the workplace and duration of exclusive breastfeeding.
The purpose of this study was to assess current lactation accommodations in a workplace environment and to examine the association between the different dimensions of support and the duration of exclusive breastfeeding. A survey was conducted with employees of a higher-education institution and clients of an obstetric hospital in New Jersey. Factor analysis identified dimensions of workplace support. The dimensions were correlated with the duration of exclusive breastfeeding using Pearson's r correlation analysis. One hundred and thirteen working mothers participated in the study. The mean (SD) number of working hours of the participants was 34.3 (2.8) hours per week. Participants were primarily white (89.4%), older (mean age, 33.8 [6.0] years), highly educated (>82% above college graduate), and married (92%). Participants indicated that in their workplaces, breastfeeding was not common, breast pumps were not available, and on-site day care was not always an option. The analysis identified 4 dimensions of breastfeeding accommodation: break time, workplace environment, technical support, and workplace policy. Technical support (r = 0.71, P = .01) and workplace environment (r = 0.26, P = .01) were significantly associated with the duration of exclusive breastfeeding. Employers can strengthen technical support and workplace environment to encourage breastfeeding continuation in working mothers. New federal laws should consider specific guidelines for minimum requirements for functional lactation support to achieve comprehensive breastfeeding benefits.


TDP-43-mediated neuron loss in vivo requires RNA-binding activity.
Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear--a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity in vivo. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function--but not ALS/FTLD-linked mutation, mislocalization, or truncation--for TDP-43-mediated neurotoxicity in vivo.


Single liver metastasis of a follicular variant of papillary thyroid carcinoma: a rare pattern of organ spread.
Well-differentiated thyroid cancer (WDTC), including papillary, follicular, and Hurthle-cell types, is characterized by a slow course and usually remain localized to the thyroid. However, a minority of these cases develop distant metastases with the most common sites being lungs, bones, and lymph nodes. Liver metastases of WDTC are rare and are usually found along with other distant metastases sites and in a multiple or diffuse pattern of spread. The recognition of distant metastasis in WDTC has a significant impact on the treatment and prognosis. However, because of their low incidence and awareness, distant metastases are often diagnosed late. Herein, we describe a case of a 71 years old woman who during routine surveillance of a follicular variant of papillary thyroid cancer (FV-PTC), 5 years after being treated for her primary thyroid tumor, was found to have a single liver metastasis and underwent liver segmental resection. This case highlights the importance of maintaining vigilant surveillance of patients with WDTC, and illustrates the possibility of unique metastasis at unexpected sites. Further studies are needed to understand the organ tropism of some WDTC leading to distant metastases development and to better prediction of an aggressive course. WDTC patients with distant metastases have a poor prognosis with a 10-year survival of about 50%. The most common sites of distant metastases are lung, bone and lymph nodes. Liver metastases are rare in WDTC, are usually multiple or diffuse and are found along with other distant metastases sites. Single liver metastasis of WDTC is an unexpected pattern of spread, and very few cases are reported in the literature. Rare sites of distant metastases in WDTC can manifest many years after the primary tumor, stressing the importance of maintaining vigilant surveillance. More studies are needed to predict which WDTC tumors may develop a more aggressive course, allowing clinicians to individualize patient management.


GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis.
Disturbances in granulosa cell apoptosis have been implicated in the pathogenesis of human granulosa cell tumors (GCTs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cytokine that induces apoptosis in a variety of malignancies without toxic effects on benign cells. The aim of this study was to investigate the expression and functionality of the TRAIL receptors DR4 and DR5 in human GCTs. Additionally, we examined the role of GATA4, a transcription factor expressed in normal and malignant granulosa cells, in TRAIL-induced GCT apoptosis. For this purpose, a tissue microarray of 80 primary and 12 recurrent GCTs was subjected to immunohistochemistry for DR4 and DR5, and freshly isolated primary GCT cultures were utilized to evaluate the functional effects of TRAIL on GCT cells. To clarify the role of GATA4 in the regulation of TRAIL-induced apoptosis, a human GCT-derived cell line (KGN) was transduced with lentiviral vectors expressing small hairpin RNAs targeting GATA4 or transfected with adenovirus expressing either wild-type or dominant negative mutant GATA4. We found that receptors DR4 and DR5 are expressed in a vast majority of GCTs as well as in primary GCT cultures, and that TRAIL induces apoptosis in the primary GCT cultures. Moreover, we showed that overexpressing GATA4 protects GCTs from TRAIL-induced apoptosis in vitro, whereas disrupting GATA4 function induces apoptosis and potentiates the apoptotic effect of TRAIL administration. Our results demonstrate that the TRAIL pathway is functional in GCT cells, and suggest that transcription factor GATA4 may function as a survival factor in this ovarian malignancy.


Oxidation of free fatty acids in low density lipoprotein by 15-lipoxygenase stimulates nonenzymic, alpha-tocopherol-mediated peroxidation of cholesteryl esters.
15-Lipoxygenase has been implicated in the in vivo oxidation of low density lipoprotein (LDL) a process thought to be important in the origin and/or progression of human atherogenesis. We have suggested previously that oxidation of LDL's cholesteryl esters (CE) and phospholipids by soybean (SLO) or human recombinant 15-lipoxygenase (rhLO) can be ascribed largely to alpha-tocopherol (alpha-TOH)-mediated peroxidation (TMP). In this study we demonstrate that addition to LDL of unesterified linoleate (18:2), other free fatty acid (FFA) substrates, or phospholipase A2 (PLA2) significantly enhanced the accumulation of CE hydro(pero)xides (CE-O(O)H) induced by rhLO, whereas the corresponding CE and nonsubstrate FFA were without effect. The enhanced CE-O(O)H accumulation showed a dependence on the concentration of free 18:2 in LDL. In contrast, addition of 18:2 had little effect on LDL oxidation induced by aqueous peroxyl radicals or Cu2+ ions. Analyses of the regio- and stereoisomers of oxidized 18:2 in SLO-treated native LDL demonstrated that the small amounts of 18:2 associated with the lipoprotein were oxidized enzymically and within minutes, whereas cholesteryl linoleate (Ch18:2) was oxidized nonenzymically and continuously over hours. alpha-Tocopheroxyl radical (alpha-TO.) formed in LDL exposed to SLO was enhanced by addition of 18:2 or PLA2. With rhLO and 18:2-supplemented LDL, oxidation of 18:2 was entirely enzymic, whereas that of Ch18:2 was largely, though not completely, nonenzymic. The small extent of enzymic Ch18:2 oxidation increased with increasing enzyme to LDL ratios. Ascorbate and the reduced form of coenzyme Q, ubiquinol-10, which are both capable of reducing alpha-TO. and thereby preventing TMP, inhibited nonenzymic Ch18:2 oxidation induced by rhLO. Trolox and ascorbyl palmitate, which also inhibit TMP, ameliorated both enzymic and nonenzymic oxidation of LDL's lipids, whereas probucol, a radical scavenger not capable of preventing TMP, was ineffective. These results demonstrate that rhLO-induced oxidation of CE is largely nonenzymic and increases with LDL's content of FFA substrates. We propose that conditions which increase LDL's FFA content, such as the presence of lipases, increase 15-LO-induced LDL lipid peroxidation and that this process requires only an initial, transient enzymic activity.


Appropriating Information Technology Artefacts through Trial and Error: The Case of the Tablet.
The concept of appropriation is of paramount importance for the lasting use of an Information Technology (IT) artefact following its initial adoption, and therefore its success. However, quite often, users' original expectations are negatively disconfirmed, and instead of appropriating the IT artefact, they discontinue its use. In this study we examine the use of IT artefacts following negative disconfirmation and use Grounded Theory Method techniques to analyse 136 blogposts, collected between March 2011 - July 2017, to investigate how users appropriate or reject the tablet when technology falls short of users' expectations. Our findings show that users overcome negative disconfirmation through a trial and error process. In doing so, we identify that users appropriate the tablet when the attained benefits significantly outweigh the risks or sacrifices stemming out of its use. We discuss our contribution within the context of the appropriation literature, and highlight that the success of IT lies with the user's success in identifying personal use scenarios within and across diverse contexts of use.


An Automated Telephone Monitoring System to Identify Patients with Cirrhosis at Risk of Re-hospitalization.
Hospitalizations for cirrhosis are costly and associated with increased mortality. Disease management outside of clinic, such as the use of interactive voice response (IVR) calls, may identify signs to prevent hospitalization. The aim of this study was to investigate whether IVR monitoring can predict hospitalization and mortality in cirrhosis. One hundred patients with decompensated cirrhosis were enrolled in this observational study, of which 79 patients were included in the final analysis. Participants were followed until death, transplant, or last clinical follow-up (range 7-874 days). Analysis focused on potential predictors identified during the first month of IVR calls: presence of jaundice, abdominal/leg swelling, weakness, paracentesis requirement, medication changes, and weight change. The primary outcome was time to first hospital admission; secondary outcomes included hospitalization and time to death. Potential predictors with a p value <0.1 were further analyzed after adjustment for covariates (Model for End-stage Liver Disease score, serum sodium, number of medications). Twenty (25%) patients died, and 49 (62%) were hospitalized at least once. Fifty-six (70%) patients completed >80% of their IVR calls. After adjustment for covariates, weakness was associated with an increased risk of first hospitalization (HR 2.14, CI 1.13-4.05, p = 0.02) and hospitalization rate (HR 2.1, CI 1.0-4.3, p = 0.048). Weight change of ≥ five pounds (2.3 kg) in a week increased the rate of hospitalization by 2.7 (CI 1.0-7.1, p = 0.045). No variable predicted death after covariate adjustment. These results suggest IVR calls can be used to predict hospitalization in cirrhosis.