Comparison between Slow Freezing and Vitrification for Human Ovarian Tissue Cryopreservation and Xenotransplantation.
Two methods for the cryopreservation of human ovarian tissue were compared using a xenotransplantation model to establish a safe and effective cryopreservation method. Ovarian tissues were obtained from women who underwent benign ovarian surgery in the gynecology research unit of a university hospital. The tissues were transplanted into 112 ovariectomized female severe combined immunodeficient mice 4 weeks after slow freezing or vitrification cryopreservation. Tissues were retrieved 4 weeks later. Primordial follicular counts decreased after cryopreservation and xenotransplantation, and were significantly higher in the slow freezing group than in the vitrification group (p < 0.001). Immunohistochemistry and TUNEL assay showed that the Ki-67 and CD31 markers of follicular proliferation and angiogenesis were higher in the slow freezing group (p < 0.001 and p = 0.006, respectively) and DNA damage was greater in the vitrification group (p < 0.001). Western blotting showed that vitrification increased cellular apoptosis. Anti-Müllerian hormone expression was low in transplanted samples subjected to both cryopreservation techniques. Electron microscopy revealed primordial follicle deformation in the vitrification group. Slow freezing for ovarian tissue cryopreservation is superior to vitrification in terms of follicle survival and growth after xenotransplantation. These results will be useful for fertility preservation in female cancer patients.


Duration of effect by injection volume and facial subregion for a volumizing hyaluronic acid filler in treating midface volume deficit.
Juvéderm Voluma XC (VYC-20L) is approved in the United States for correction of age-related volume loss in the midface region in adults. To characterize the effects of VYC-20L in 3 midface subregions based on injection volumes. In this single-blind controlled trial, subjects with midface volume deficit received VYC-20L in ≥1 of 3 facial subregions (zygomaticomalar, anteromedial cheek, and submalar), with touch-up treatment available 30 days later. Responders achieved ≥1-point improvement on the Mid-Face Volume Deficit Scale (MFVDS), analyzed by facial subregion and stratified by injection volume quartiles. Subject satisfaction and safety were assessed. The treatment arm comprised 235 subjects aged 35 to 65 years. Month 6 MFVDS responder rates were 75.5% for zygomaticomalar, 83.2% for anteromedial cheek, and 76.9% for submalar subregions. Higher responder rates were observed with increasing injection volume quartiles for each subregion. Similar median injection volumes (≈2.0 mL total) of VYC-20L provided correction durations of 15 to 24 months: 24 months for anteromedial cheek, 19 months for zygomaticomalar, and 15 months for submalar subregions. Subject satisfaction was high across injection volume quartiles. No unanticipated treatment-site adverse reactions occurred. VYC-20L is effective at restoring midface volume, with high subject satisfaction and an acceptable safety profile.


Pulsed laser deposition of ITO/AZO transparent contact layers for GaN LED applications.
In this study, indium-tin oxide (ITO)/Al-doped zinc oxide (AZO) composite films were fabricated by pulsed laser deposition and used as transparent contact layers (TCLs) in GaN-based blue light emitting diodes (LEDs). The ITO/AZO TCLs were composed of the thin ITO (50 nm) films and AZO films with various thicknesses from 200 to 1000 nm. Conventional LED with ITO (200 nm) TCL prepared by E-beam evaporation was fabricated and characterized for comparison. From the transmittance spectra, the ITO/AZO films exhibited high transparency above 90% at wavelength of 465 nm. The sheet resistance of ITO/AZO TCL decreased as the AZO thickness increased, which could be attributed to the increase in a carrier concentration, leading to a decrease in the forward bias of LED. The LEDs with ITO/AZO composite TCLs showed better light extraction as compared to LED with ITO TCL in compliance with simulation. When an injection current of 20 mA was applied, the output power for LEDs fabricated with ITO/AZO TCLs had 45%, 63%, and 71% enhancement as compared with those fabricated using ITO (200 nm) TCL for the AZO thicknesses of 200, 460, and 1000 nm, respectively.


EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.
Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.


Photosensitive liquid crystals with nanoparticulate internal structure.
Stabilization of thermodynamic relaxation of photoinduced cis isomers of azobenzene liquid-crystal molecules is observed in nanoparticulate networks. The phenomenon permits bistability of the phase state (anisotropic and isotropic) of the material and reversible all-optical switching between those states, resulting in strong changes in the light-scattering properties of the material. Recording of complex optical structures with high spatial resolution with the aid of laser beams of different wavelengths is demonstrated.


A method for deriving leading causes of death.
A standard list for ranking leading causes of death worldwide does not exist. WHO headquarters, regional offices and Member States all use different lists that have varying levels of detail. We sought to derive a standard list to enable countries to identify their leading causes of death and to permit comparison between countries. Our aim is to share the criteria and methodology we used to bring some order to the construction of such a list, to provide a consistent procedure that can be used by others, and to give researchers and data owners an opportunity to utilize the list at national and subnational levels. Results were primarily data-driven. Data from individual countries representing different regions of the world were extracted from the WHO Mortality Database. Supplementary information from WHO estimates on mortality was used for regions where data were scarce. In addition, a set of criteria was used to group the candidate causes and to determine other causes that should be included on the list. A ranking list of the leading causes of death that contains broad cause groupings (such as "all cancers", "all heart diseases" or "all accidents") is not effective and does not identify the leading individual causes within these broad groupings; thus it does not allow policy-makers to generate appropriate health advocacy and cost-effective interventions. Similarly, defining candidate causal groups too narrowly or including diseases that have a low frequency does not meet these objectives. For international comparisons, we recommend that countries use this list; it is based on extensive evidence and the application of public health disease-prevention criteria. It is not driven by political or financial motives. This list may be adapted for national statistical purposes.


Neural dynamics of motion perception: direction fields, apertures, and resonant grouping.
A neural network model of global motion segmentation by visual cortex is described. Called the motion boundary contour system (BCS), the model clarifies how ambiguous local movements on a complex moving shape are actively reorganized into a coherent global motion signal. Unlike many previous researchers, we analyze how a coherent motion signal is imparted to all regions of a moving figure, not only to regions at which unambiguous motion signals exist. The model hereby suggests a solution to the global aperture problem. The motion BCS describes how preprocessing of motion signals by a motion oriented contrast (MOC) filter is joined to long-range cooperative grouping mechanisms in a motion cooperative-competitive (MOCC) loop to control phenomena such as motion capture. The motion BCS is computed in parallel with the static BCS of Grossberg and Mingolla (1985a, 1985b, 1987). Homologous properties of the motion BCS and the static BCS, specialized to process motion directions and static orientations, respectively, support a unified explanation of many data about static form perception and motion form perception that have heretofore been unexplained or treated separately. Predictions about microscopic computational differences of the parallel cortical streams V1-->MT and V1-->V2-->MT are made--notably, the magnocellular thick stripe and parvocellular interstripe streams. It is shown how the motion BCS can compute motion directions that may be synthesized from multiple orientations with opposite directions of contrast. Interactions of model simple cells, complex cells, hyper-complex cells, and bipole cells are described, with special emphasis given to new functional roles in direction disambiguation for endstopping at multiple processing stages and to the dynamic interplay of spatially short-range and long-range interactions.


Modified condylotomy versus conventional conservative treatment in painful reciprocal clicking--a preliminary prospective study in eight patients.
Modified condylotomy may be relevant in severe painful reciprocal clicking of the temporomandibular joint (TMJ) where conservative treatment is insufficient. The effect of the modified condylotomy was analyzed and compared with conventional nonsurgical treatment in a randomized pilot study of eight patients, 19-44 years of age, with severe painful reciprocal clicking. Before and after treatment, assessments were performed by subjective reports, clinical recordings, and blinded evaluations of radiography and magnetic resonance imaging (MRI). Based on the clinical evaluations before treatment, all conditions were disc displacements with reduction and arthralgia (Research diagnostic criteria for temporomandibular disorders), but based on MRI, one patient had disc displacement without reduction and another had normal disc position. The treatment effect was significantly better and the disorders were significantly more reduced with condylotomy than with conventional nonsurgical treatment (P < 0.05, Mann-Whitney U test). In the surgical group, the clicking and locking had disappeared, the pain during function was significantly reduced (P < 0.05, Friedman ANOVA), and in two patients the disc position was normalized. The clicking still persisted in the nonsurgical patients and the disc position was unchanged. Our conclusion is that modified condylotomy is a promising option to reduce symptoms and signs in severe painful reciprocal clicking.


Neuronal circadian clock protein oscillations are similar in behaviourally rhythmic forager honeybees and in arrhythmic nurses.
Internal clocks driving rhythms of about a day (circadian) are ubiquitous in animals, allowing them to anticipate environmental changes. Genetic or environmental disturbances to circadian clocks or the rhythms they produce are commonly associated with illness, compromised performance or reduced survival. Nevertheless, some animals including Arctic mammals, open sea fish and social insects such as honeybees are active around-the-clock with no apparent ill effects. The mechanisms allowing this remarkable natural plasticity are unknown. We generated and validated a new and specific antibody against the clock protein PERIOD of the honeybee Apis mellifera (amPER) and used it to characterize the circadian network in the honeybee brain. We found many similarities to Drosophila melanogaster and other insects, suggesting common anatomical organization principles in the insect clock that have not been appreciated before. Time course analyses revealed strong daily oscillations in amPER levels in foragers, which show circadian rhythms, and also in nurses that do not, although the latter have attenuated oscillations in brain mRNA clock gene levels. The oscillations in nurses show that activity can be uncoupled from the circadian network and support the hypothesis that a ticking circadian clock is essential even in around-the-clock active animals in a constant physical environment.


Within-family dyadic patterns of parental monitoring and adolescent information management.
In line with increasing calls for within-family analyses of monitoring processes, this study examined profiles of (combined) adolescent information management strategies and parent knowledge-gathering strategies among 174 families with middle adolescents (Mage = 15.7 years; 164 mother-teen and 112 father-teen dyads). Three mother-adolescent profiles (open, intrusive, indirect) and two father-adolescent profiles (reserved, covert) emerged, with voluntary disclosure and snooping particularly differentiating profiles and fathers reporting gaining more knowledge from others. Profile membership was associated with adjustment and relationship quality both concurrently and over one year, controlling for prior levels. For mother-teen dyads, open communicators reported less behavioral control over time, intrusive communicators reported more negative interactions concurrently and greater depression and less maternal knowledge over time, and indirect communicators reported more problem behavior over time. For father-teen dyads, covert communicators reported more problem behavior concurrently and more negative interactions over time. Profile membership in mother-teen and father-teen dyads was not significantly associated. Results confirm the importance of disclosure and the problematic nature of snooping, while highlighting diverse ways that monitoring processes play out within families. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Chemical intervention of influenza virus mRNA nuclear export.
Influenza A viruses are human pathogens with limited therapeutic options. Therefore, it is crucial to devise strategies for the identification of new classes of antiviral medications. The influenza A virus genome is constituted of 8 RNA segments. Two of these viral RNAs are transcribed into mRNAs that are alternatively spliced. The M1 mRNA encodes the M1 protein but is also alternatively spliced to yield the M2 mRNA during infection. M1 to M2 mRNA splicing occurs at nuclear speckles, and M1 and M2 mRNAs are exported to the cytoplasm for translation. M1 and M2 proteins are critical for viral trafficking, assembly, and budding. Here we show that gene knockout of the cellular protein NS1-BP, a constituent of the M mRNA speckle-export pathway and a binding partner of the virulence factor NS1 protein, inhibits M mRNA nuclear export without altering bulk cellular mRNA export, providing an avenue to preferentially target influenza virus. We performed a high-content, image-based chemical screen using single-molecule RNA-FISH to label viral M mRNAs followed by multistep quantitative approaches to assess cellular mRNA and cell toxicity. We identified inhibitors of viral mRNA biogenesis and nuclear export that exhibited no significant activity towards bulk cellular mRNA at non-cytotoxic concentrations. Among the hits is a small molecule that preferentially inhibits nuclear export of a subset of viral and cellular mRNAs without altering bulk cellular mRNA export. These findings underscore specific nuclear export requirements for viral mRNAs and phenocopy down-regulation of the mRNA export factor UAP56. This RNA export inhibitor impaired replication of diverse influenza A virus strains at non-toxic concentrations. Thus, this screening strategy yielded compounds that alone or in combination may serve as leads to new ways of treating influenza virus infection and are novel tools for studying viral RNA trafficking in the nucleus.


A reproducibility study for a fluoride assay in bone.
Osteosarcoma is a rare malignancy of largely unknown etiology. Although there is no consistent evidence for an association between fluoridation and cancer, some concerns remain about osteosarcoma. As part of the design of a collaborative study, bone samples were collected to allow for an evaluation of the association between osteosarcoma risk and individual fluoride exposure measured by levels of fluoride in bone. In this report, we provide the results of pilot experiments to consider issues that arose during the study design and to assess the reliability of the bone assays. Correlations of fluoride levels between normal bone near the affected area and iliac crest bone were strong and positive. The day-to-day laboratory analysis of fluoride in human and deer jaw bone yielded acceptable average coefficients of variation below 10% and an overall estimate of 5%. The intraclass correlation (ICC) is of particular importance to epidemiologists because it indicates the effect of measurement error on study results. Here, the estimated ICC is 0.86, and the estimated downward bias is only 14%. Hence, the ICC is strong enough so that the estimates of the relative risk will suffer little attenuation from lab measurements.


Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism.
The human host comprises a range of specific niche environments. In order to successfully persist, pathogens such as Aspergillus fumigatus must adapt to these environments. One key example of in-host adaptation is the development of resistance to azole antifungals. Azole resistance in A. fumigatus is increasingly reported worldwide and the most commonly reported mechanisms are cyp51A mediated. Using a unique series of A. fumigatus isolates, obtained from a patient suffering from persistent and recurrent invasive aspergillosis over 2 years, this study aimed to gain insight into the genetic basis of in-host adaptation. Single nucleotide polymorphisms (SNPs) unique to a single isolate in this series, which had developed multi-azole resistance in-host, were identified. Two nonsense SNPs were recreated using CRISPR-Cas9; these were 213* in svf1 and 167* in uncharacterised gene AFUA_7G01960. Phenotypic analyses including antifungal susceptibility testing, mycelial growth rate assessment, lipidomics analysis and statin susceptibility testing were performed to associate genotypes to phenotypes. This revealed a role for svf1 in A. fumigatus oxidative stress sensitivity. In contrast, recapitulation of 167* in AFUA_7G01960 resulted in increased itraconazole resistance. Comprehensive lipidomics analysis revealed decreased ergosterol levels in strains containing this SNP, providing insight to the observed itraconazole resistance. Decreases in ergosterol levels were reflected in increased resistance to lovastatin and nystatin. Importantly, this study has identified a SNP in an uncharacterised gene playing a role in azole resistance via a non-cyp51A mediated resistance mechanism. This mechanism is of clinical importance, as this SNP was identified in a clinical isolate, which acquired azole resistance in-host.


The effect of prostacyclin on the gastric mucosa in portal-hypertensive rats.
This study investigates the effect of prostacyclin, which is thought to be involved in the hemodynamic circulation, on the gastric mucosa of rats with portal hypertension. Various gastric functions were evaluated in portal vein ligated rats after the intraperitoneal administration of either a placebo or prostacyclin for 7 days. The gastric mucosal damage induced by the instillation of 90% ethanol was significantly greater in the prostacyclin-treated group than in placebo-treated group. The portal pressure was similar in both groups. There was no significant difference between the two groups in plasma concentration of 6-keto-PGF1a (a stable metabolite of prostacyclin), whereas the mucosal content of 6-keto-PGF1a was significantly higher in the prostacyclin-treated group than in the placebo-treated group. Prostacyclin pretreatment significantly increased the gastric mucosal blood flow, estimated by laser-Doppler flowmetry, and the hemoglobin content of the gastric mucosa, measured by reflectance spectrophotometry, whereas the oxygen content remained unchanged. We speculate that the increased gastric mucosal perfusion induced by a high content of prostacyclin in the portal hypertensive gastric mucosa may play a role in the pathogenesis of ethanol-induced gastric mucosal damage.


First Report of the Root-Knot Nematode Meloidogyne artiellia in Belgium.
In 2011, second-stage juveniles (J2) of an unknown root-knot nematode (Meloidogyne spp.) were detected during a routine survey for root-knot nematodes on arable land in Harveng, Belgium, after a crop of wheat. Most of the loamy soil samples (36 out of 42) contained J2 of the common root-knot nematode M. naasi Franklin, 1965 (1), while 15 of these also contained the unknown species, albeit in lower densities (22 J2/100 ml vs. 157 J2/100 ml soil). After detailed morphological observation of the unknown J2, they were until further notice identified as Meloidogyne artiellia Franklin, 1961 (2), the British root-knot nematode. To confirm the identification, a pure culture of M. artiellia was established by adding nematode suspensions to pots planted with kale (Brassica oleracea var. laciniata), a non-host for M. naasi (3). After 2 months, Meloidogyne spp. females, males, and J2 were isolated from galled kale roots. Morphological characteristics (n = 25) from the perineal pattern (rounded with fine striae, lateral area with coarse ridges, angular dorsal arch) and stylet knobs (small, ovoid, and backwardly sloping) for the females, the head shape (set off with distinct head cap) and stylet knobs (small, ovoid and backwardly sloping) for the males, the hemizonid position (anterior, adjacent to S to E pore), tail shape (conical), and short tail length (18 to 27 μm) for the J2, fit with previous observed populations of M. artiellia (3). Young egg-laying females were used for isozyme electrophoresis, and showed typical malate dehydrogenase (N1b) and esterase (M2-VF1) patterns (3). Additionally, DNA was extracted from single juveniles by incubating them in a lysis buffer (200 mM NaCl, 200 mM Tris-HCl (pH 8), 1% β-mercaptoethanol and 800 μg/ml Proteinase K) during 1.5 h at 65°C and 5 min at 99°C in a thermocycler. One microliter of crude DNA extract was used for PCR. ITS-rDNA sequencing (GenBank Accession Numbers JX393299 and JX393300) confirmed the identity, showing a 98 to 100% homology with other M. artiellia sequences (AY150368 and AF248478). To our knowledge, this is the first report of the root-knot nematode, M. artiellia, in Belgium. This nematode has been reported from the Mediterranean area, where it causes damage on chickpea and wheat (4), as well as from the U.K. Its finding in Harveng, close to the French border, suggests a more extensive geographical distribution. References: (1) M. T. Franklin. Nematologica 11:79, 1965. (2) M. T. Franklin et al. Suppl.:85, 1961. (3) G. Karssen. Pages 93-97 in: The Plant-Parasitic Nematode Genus Meloidogyne Göldi, 1892 (Tylenchida) in Europe, Brill Leiden, The Netherlands, 2002. (4) M. Di Vito and N. Greco. Revue Nématol. 11:223, 1988.


Effects of the electromagnetic field of mobile telephones on hearing.
The widespread use of mobile telephones has given rise to concern about the potential influences of electromagnetic fields (EMFs) on human health. Anatomically, the ear is in close proximity to the mobile telephone during use. Hearing loss due to mobile telephone use has not been described in the medical literature; however, if there is a subtle cochlear involvement, it might be detected by means of changes in evoked otoacoustic emissions (OAEs). Thirty volunteers with normal hearing were exposed to mobile telephone EMFs for 10 min and evoked OAEs were measured before and after exposure. No measurable change in evoked OAEs was detected and none of the subjects reported a deterioration in hearing level. To the best of our knowledge, this is the first study on the effects of EMFs emitted by mobile telephones on hearing. It was concluded that a 10-min exposure to the EMF emitted from a mobile telephone had no effect on hearing, at least at outer ear, middle ear and cochlear levels.


Lipid deposition on hydrogel contact lenses: how history can help us today.
The tear film is a complex fluid that is precisely maintained and which is essential to the health of the ocular surface. One of the major components of the tear film is lipid, which is produced by the meibomian glands and serves many important functions on the ocular surface. It is estimated that there are more than 45 individual lipids within the tear film, which vary greatly in their structure and properties. The composition of the lipid within the tear film has an enormous influence on the stability of the tear film, with a subsequent impact on the occurrence of dry eye and the ultimate success of contact lens wear. The purpose of this review article is to describe the composition of the tear film lipids and their interaction with contact lens materials, with a particular emphasis on how the chemistry of novel silicone hydrogel materials has resulted in clinicians needing to understand the deposition of lipids onto contact lenses and how they may best manage this complication.


Differences in human antagonistic ankle dorsiflexor coactivation between legs; can they explain the moment deficit in the weaker plantarflexor leg?
The present study examined the hypothesis that the antagonistic ankle dorsiflexor coactivation level during maximum isometric voluntary plantarflexion (MVC) is a function of ankle angle. Six male subjects generated plantarflexion and dorsiflexion MVC trials at ankle angles of -15 deg (dorsiflexed direction), 0 deg (neutral position), +15 deg (plantarflexed direction) and +30 deg having the knee flexed at an angle of 90 deg. In all contractions surface EMG measurements were taken from tibialis anterior and soleus which were considered representative muscles of all dorsiflexors and plantarflexors, respectively. Antagonistic dorsiflexor coactivation was expressed as normalized EMG and moment. Calculations of the antagonistic dorsiflexor moment were based on the tibialis anterior EMG-dorsiflexor moment relationship from contractions at 50, 40, 30, 20 and 10 % of the dorsiflexion MVC moment. In both legs dorsiflexor coactivation level followed an open U-shaped pattern as a function of ankle angle. Differences of 9 and 14 % (P < 0.05) were found in the measured net plantarflexion MVC moment between legs at ankle angles of -15 and +30 deg, respectively. No difference (P > 0.05) was found in the calf circumference between legs. Differences were found in the antagonistic dorsiflexor coactivation between legs at ankle angles of -15 and +30 deg. In the weaker leg the antagonistic EMG measurements were higher by 100 and 45 % (P < 0.01) and the estimated antagonistic moments were higher by 70 and 43 % (P < 0.01) compared with the weaker leg at -15 and +30 deg, respectively. This finding was associated with a decreased range of motion (ROM) in the weaker leg (14 %, P < 0.01), such that no difference (P > 0.05) was found in dorsiflexor antagonistic coactivation between legs at end-range ankle angles. The findings of the study (i) have to be taken into consideration when estimating musculoskeletal loads in the lower extremity, (ii) imply that stretching training can result in a stronger plantarflexion at end-range ankle angles through inhibition of the dorsiflexors, and (iii) imply a neural drive inadequacy during a plantarflexion MVC at end-range angles.


Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials.
The conditions responsible for the associative properties of long-term potentiation (LTP) were examined in the CA1 region of the hippocampal slice preparation. Intracellularly recorded EPSPs resulting from single-volley stimulation at low frequency (0.15-0.1 Hz) in the stratum radiatum or oriens were paired with depolarizing current pulses (50-100 msec) injected through the recording microelectrode. It is shown that these EPSPs, when paired with pulses of sufficient magnitude, become potentiated. This potentiation generally reached a peak after 20-30 pairing events and could outlast the conditioning period by more than 1 hr. It was specific to the paired input, was blocked by 2-amino-5-phosphonovalerate (APV) and was largely blocked by prior homosynaptic tetanization (and vice versa). In experiments performed with picrotoxin (PTX) in the bath, EPSPs were potentiated using 2-4 nA current pulses, with somewhat higher values in normal solution. The effective current pulses, in both normal and PTX solution, produced a repetitive spike discharge of 7-11 spikes (per 100 msec), and within this range, higher frequencies were associated with larger potentiations. However, since similar degrees of EPSP potentiation were observed following blockade of spike activity by intracellular QX-314, spike activity was not the primary conditioning factor. For the potentiation to appear, the EPSP had to occur together with the current pulse or precede it by less than about 100 msec. No potentiation was observed when the EPSP immediately succeeded the pulse. The results suggest that the cooperativity aspect of LTP is related to a need for sufficient postsynaptic depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification of a laccase from Ganoderma lucidum CBS 229.93 having potential for enhancing cellulase catalyzed lignocellulose degradation.
Based on a differential pre-screening of 44 white-rot fungi on a lignocellulose-supplemented minimal medium, four basidiomycetes were selected for further study: Ganoderma lucidum, Polyporus brumalis, Polyporus ciliatus and Trametes versicolor. Only G. lucidum was able to grow vividly on malt extract or minimal media supplemented with alkali lignin. When grown on malt extract or minimal medium supplemented with lignocellulose (sugar cane bagasse), the crude G. lucidum protein extract exhibited high laccase activity, ∼3U/mL toward syringaldazine. This activity was 13-17 fold higher than the corresponding activities of the crude protein extracts of P. brumalis, P. ciliatus and T. versicolor. Native PAGE electrophoresis of the crude G. lucidum extract confirmed the presence of an active laccase. The G. lucidum laccase had a molecular weight of ∼62.5kDa, and a Km value of 0.107mM (determined on ABTS). A partial amino acid sequence analysis of four short de novo sequenced peptides, defined after trypsin digest analysis using MALDI-TOF MS/MS analysis, revealed 64-100% homology to sequences in related laccases in the UniProt database, but also indicated that certain sequence stretches had low homology. Addition of the laccase-rich G. lucidum broth to lignocellulosic biomass (pretreated sugar cane bagasse) together with a state-of-the-art cellulase enzyme preparation (Cellic™CTec1) produced significantly increased cellulolytic yields, which were also better than those obtained with a T. versicolor laccase addition, indicating that the laccase from G. lucidum has unique properties that may be momentous in lignocellulosic biomass conversion.


X-ray microscopy studies of protein adsorption on a phase segregated polystyrene/polymethylmethacrylate surface. 2. Effect of pH on site preference.
X-ray photoemission electron microscopy (XPEEM) using synchrotron radiation illumination has been used to study the adsorption of human serum albumin (HSA) onto a phase segregated polystyrene/polymethylmethacrylate (PS/PMMA) blend surface from solutions of five different pH values. The absolute coverage of albumin on each of three chemically distinct components of the surface, PS domains, PMMA domains, and the interface between the domains, was determined from a quantitative analysis of C 1s image sequences. At all pH values, the preferred adsorption site is the interface. At neutral pH (7.0), albumin showed a slight preference for PS regions relative to PMMA. At strongly acidic pH (2.0) and strongly basic pH (10.0), similar amounts of albumin adsorb on the PS and PMMA regions. However, at pH 4.0, the amount of albumin adsorbed on PMMA domains is approximately 1.6 times greater than that on PS domains, while at pH 8.6 the amount of albumin adsorbed on PMMA is one-half that adsorbed on PS domains. The pH dependence of the site preference is rationalized in terms of the known changes of albumin conformation with pH [Peters, T., Jr. All About Albumin: Biochemistry, Genetics, and Medical Applications; Academic Press: New York, 1995]. We infer from our results that the site preference of albumin adsorption on PS/PMMA blends is related mainly to changes in hydrophobic interactions, which are driven by pH-dependent electrostatic effects, that is, changes to the protein surface structure as the charge on the protein changes. The results provide insight into changes in the secondary structure of albumin in acid and basic media.


Does Racial Bias Affect NCI-Funded PIs' Willingness to Mentor Prospective Graduate Students?
Audit studies suggest that racial discrimination disadvantages black individuals in educational/professional advancement. We hypothesized that prospective black male doctoral students would experience greater disparity in responses when seeking access to National Cancer Institute (NCI)-funded principal investigators (PI) compared with prospective white males. Primary aim was to explore response and acceptance rates for black versus white men seeking cancer research mentorship. Identical e-mails were sent to 1,028 randomly selected PIs affiliated with 65 NCI-designated cancer centers from "Lamar Washington" (black; n = 515) or "Brad Anderson" (white; n = 513). Primary outcomes: (i) responses within one week; and (ii) type of response. We used logistic regression to examine effects of condition (black/white) on primary outcomes. Approximately 48.3% and 50.0% of the sample responded to "Lamar" and "Brad," respectively. For responders, 40.9% and 43.7% and "agreed" to meet with Lamar and Brad, respectively. This design did not detect bias by PIs against black prospective male students. Cancer Res; 78(17); 4809-11. ©2018 AACR.


[Sexuality of women living with HIV/AIDS in São Paulo].
The social and cultural setting which increases female vulnerability to HIV does not disappear when women living with HIV/AIDS discover that they are infected. Following diagnosis, new challenges arise in their emotional lives, an issue which has received little attention in the literature. This study interviewed 1068 women living with HIV/AIDS using a questionnaire consisting of both open and closed questions, aimed at describing aspects of their sexual and reproductive lives and how they perceive counseling at Reference Centers in two cities in the State of São Paulo, where they have access to free antiretroviral therapy. Of the women with stable sexual partners, 63% used condoms in all their sexual relations, or three times the national average; 43% of the partners were HIV-negative and 14% had unknown serological status; 73% of the women had children and 15% were considering becoming pregnant. Knowledge on mother-to-child transmission was less than expected, and the interviewees complained of limited space and receptiveness for discussing sexuality, especially with regard to their childbearing wishes. Counseling on sexuality should be a continuing process and requires interdisciplinary training for the professional team working in health care services, with an emphasis on sexual and reproductive rights.


Synthesis, optical resolution, absolute configuration, and osteogenic activity of cis-pterocarpans.
A convenient synthesis of natural and synthetic pterocarpans was achieved in three steps. Optical resolution of the respective enantiomers was accomplished by analytical and semi-preparative HPLC on a chiral stationary phase. For medicarpin and its synthetic derivative 9-demethoxymedicarpin, the absolute configuration was confirmed by a combination of experimental LC-ECD coupling and quantum-chemical ECD calculations. (-)-Medicarpin and (-)-9-demethoxymedicarpin are both 6aR,11aR-configured, and consequently the corresponding enantiomers, (+)-medicarpin and (+)-9-demethoxymedicarpin, possess the 6aS,11aS-configuration. A comparative mechanism study for osteogenic (bone forming) activity of medicarpin (racemic versus enantiomerically pure material) revealed that (+)-(6aS,11aS)-medicarpin (6a) significantly increased the bone morphogenetic protein-2 (BMP2) expression and the level of the bone-specific transcription factor Runx-2 mRNA, while the effect was opposite for the other enantiomer, (-)-(6aR,11aR)-medicarpin (6a), and for the racemate, (±)-medicarpin, the combined effect of both the enantiomers on transcription levels was observed.


Acclimation of photosynthetic temperature optima of temperate and boreal tree species in response to experimental forest warming.
Rising temperatures caused by climate change could negatively alter plant ecosystems if temperatures exceed optimal temperatures for carbon gain. Such changes may threaten temperature-sensitive species, causing local extinctions and range migrations. This study examined the optimal temperature of net photosynthesis (Topt ) of two boreal and four temperate deciduous tree species grown in the field in northern Minnesota, United States under two contrasting temperature regimes. We hypothesized that Topt would be higher in temperate than co-occurring boreal species, with temperate species exhibiting greater plasticity in Topt , resulting in better acclimation to elevated temperatures. The chamberless experiment, located at two sites in both open and understory conditions, continuously warmed plants and soils during three growing seasons. Results show a modest, but significant shift in Topt of 1.1 ± 0.21 °C on average for plants subjected to a mean 2.9 ± 0.01 °C warming during midday hours in summer, and shifts with warming were unrelated to species native ranges. The 1.1 °C shift in Topt with 2.9 °C warming might be interpreted as suggesting limited capacity to shift temperature response functions to better match changes in temperature. However, Topt of warmed plants was as well-matched with prior midday temperatures as Topt of plants in the ambient treatment, and Topt in both treatments was at a level where realized photosynthesis was within 90-95% of maximum. These results suggest that seedlings of all species were close to optimizing photosynthetic temperature responses, and equally so in both temperature treatments. Our study suggests that temperate and boreal species have considerable capacity to match their photosynthetic temperature response functions to prevailing growing season temperatures that occur today and to those that will likely occur in the coming decades under climate change.


Principles of tunneled cuffed catheter placement.
Tunneled cuffed catheters provide reliable and instant long-term intravenous access for a large variety of therapeutic purposes, including chemotherapy, parenteral nutrition, and apheresis. The most frequent application is for patients with renal failure as an access device for hemodialysis. In this capacity, the rate of catheter use has remained stable in the United States, despite the promotion of arteriovenous fistulas and arteriovenous grafts. The latter 2 procedures achieve superior longevity and much higher cost-efficiency. Tunneled catheters, however, serve as bridging devices during maturation of newly placed arteriovenous fistulas or as the final option in patients in whom fistulas and grafts have failed. High-quality vascular access is a hallmark of interventional radiology, and its significance for patient care and for our specialty cannot be overestimated. Familiarity with basic concepts of the device and procedural techniques are crucial to achieve successful long-term venous access. The following article demonstrates key concepts of tunneled venous catheter placement by means of dialysis, inasmuch as dialysis catheters represent the most commonly placed tunneled central venous catheters. The principles of placement and techniques utilized, however, are applicable to devices that are used for chemotherapy or parenteral nutrition, such as the Hickman, Broviac, Groshong, or tunneled peripherally inserted central catheters.


Effects of leptin and neuropeptide Y (NPY) on hormones release in female rats.
The aim of this study was to investigate the influence of NMMA on the mechanism of leptin and NPY action in in vivo and in vitro on pituitary hormone release by female rats in diestrus. In vivo experiments based on four-day ip injections of: 1) murine recombinant leptin (mrLep); 2) human NPY; 3) saline; 4) NMMA (50 microg) was applied prior to administration of mrLep; 5) NMMA (50 microg) was applied prior to administration of NPY; 6) NMMA (50 microg); 7) NMMA (350 microg) was applied prior to administration of mrLep; 8) NMMA (350 microg). The blood samples for LH and FSH were collected after decapitation of animals on the fifth day of study. In vitro experiments studied the effects of these peptides on LH release from pituitary cell culture. In vivo: Leptin+ NMMA (50 microg) stimulated LH. NPY+ NMMA (50 microg) increased LH. NMMA (350 microg) stimulated FSH release. In vitro: The stimulatory effect of leptin on LH release in vitro was observed after 120 min of incubation, but after 60 mins of incubation the inhibitory effect of leptin on LH release was increased by NMMA. Leptin +NMMA (vs NMMA) decreased LH release with highest statistical significance. NPY 10 nM 60 min after incubation decreased LH release. There was no effect of NMMA on LH release. In vivo results show, that NO probably mediates in leptin action on LH release. Moreover, effects of leptin on LH release from cultured pituitary cells are dependent on time of incubation. NPY decreased LH release in vitro.


X-ray diffraction from membrane protein nanocrystals.
Membrane proteins constitute > 30% of the proteins in an average cell, and yet the number of currently known structures of unique membrane proteins is < 300. To develop new concepts for membrane protein structure determination, we have explored the serial nanocrystallography method, in which fully hydrated protein nanocrystals are delivered to an x-ray beam within a liquid jet at room temperature. As a model system, we have collected x-ray powder diffraction data from the integral membrane protein Photosystem I, which consists of 36 subunits and 381 cofactors. Data were collected from crystals ranging in size from 100 nm to 2 μm. The results demonstrate that there are membrane protein crystals that contain < 100 unit cells (200 total molecules) and that 3D crystals of membrane proteins, which contain < 200 molecules, may be suitable for structural investigation. Serial nanocrystallography overcomes the problem of x-ray damage, which is currently one of the major limitations for x-ray structure determination of small crystals. By combining serial nanocrystallography with x-ray free-electron laser sources in the future, it may be possible to produce molecular-resolution electron-density maps using membrane protein crystals that contain only a few hundred or thousand unit cells.


Automated estimation of collagen fibre dispersion in the dermis and its contribution to the anisotropic behaviour of skin.
Collagen fibres play an important role in the mechanical behaviour of many soft tissues. Modelling of such tissues now often incorporates a collagen fibre distribution. However, the availability of accurate structural data has so far lagged behind the progress of anisotropic constitutive modelling. Here, an automated process is developed to identify the orientation of collagen fibres using inexpensive and relatively simple techniques. The method uses established histological techniques and an algorithm implemented in the MATLAB image processing toolbox. It takes an average of 15 s to evaluate one image, compared to several hours if assessed visually. The technique was applied to histological sections of human skin with different Langer line orientations and a definite correlation between the orientation of Langer lines and the preferred orientation of collagen fibres in the dermis (p < 0.001, R(2) = 0.95) was observed. The structural parameters of the Gasser-Ogden-Holzapfel (GOH) model were all successfully evaluated. The mean dispersion factor for the dermis was κ = 0.1404±0.0028. The constitutive parameters μ, k(1) and k(2) were evaluated through physically-based, least squares curve-fitting of experimental test data. The values found for μ, k(1) and k(2) were 0.2014 MPa, 243.6 and 0.1327, respectively. Finally, the above model was implemented in ABAQUS/Standard and a finite element (FE) computation was performed of uniaxial extension tests on human skin. It is expected that the results of this study will assist those wishing to model skin, and that the algorithm described will be of benefit to those who wish to evaluate the collagen dispersion of other soft tissues.


Academy of Nutrition and Dietetics: Standards of Practice and Standards of Professional Performance for Registered Dietitian Nutritionists (Competent, Proficient, and Expert) in Public Health and Community Nutrition.
The need and demand for population-level disease prevention has increased, especially with the passage of the Affordable Care Act, a worldwide increase in obesity and chronic disease, and a global emphasis on preventative health care that includes behavioral, environmental, and policy interventions. In response to these evolving needs, the Public Health and Community Nutrition Dietetic Practice Group, with guidance from the Academy of Nutrition and Dietetics Quality Management Committee, has developed Standards of Practice and Standards of Professional Performance as tools for registered dietitian nutritionists (RDNs) currently in practice or interested in working in public health and community nutrition, to assess their current skill levels and to identify areas for professional development. The Standards of Practice address the four steps of the Nutrition Care Process for community and public health RDNs, which are assessment, diagnosis, intervention, and evaluation/monitoring. The Standards of Professional Performance consist of the following six domains of professional performance for community and public health RDNs: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Within each standard, specific indicators provide measurable action statements that illustrate the ways in which RDNs can address client and population nutrition and health. The indicators describe three skill levels (competent, proficient, and expert) for RDNs. These tools highlight the unique scope of expertise that RDNs provide to the field of public health and community nutrition.


Design considerations for a high power, ultrabroadband optical parametric chirped-pulse amplifier.
A conceptual design of a high power, ultrabroadband optical parametric chirped-pulse amplifier (OPCPA) was carried out comparing nonlinear crystals (LBO and BBO) for 810 nm centered, sub-7.0 fs pulses with energies above 1 mJ. These amplifiers are only possible with a parallel development of kilowatt-level OPCPA-pump amplifiers. It is therefore important to know good strategies to use the available OPCPA-pump energy efficiently. Numerical simulations, including self- and cross-phase modulation, were used to investigate the critical parameters to achieve sufficient spectral and spatial quality. At high output powers, thermal absorption in the nonlinear crystals starts to degrade the output beam quality. Strategies to minimize thermal effects and limits to the maximum average power are discussed.


Preparation for oxidative stress under hypoxia and metabolic depression: Revisiting the proposal two decades later.
Organisms that tolerate wide variations in oxygen availability, especially to hypoxia, usually face harsh environmental conditions during their lives. Such conditions include, for example, lack of food and/or water, low or high temperatures, and reduced oxygen availability. In contrast to an expected strong suppression of protein synthesis, a great number of these animals present increased levels of antioxidant defenses during oxygen deprivation. These observations have puzzled researchers for more than 20 years. Initially, two predominant ideas seemed to be irreconcilable: on one hand, hypoxia would decrease reactive oxygen species (ROS) production, while on the other the induction of antioxidant enzymes would require the overproduction of ROS. This induction of antioxidant enzymes during hypoxia was viewed as a way to prepare animals for oxidative damage that may happen ultimately during reoxygenation. The term "preparation for oxidative stress" (POS) was coined in 1998 based on such premise. However, there are many cases of increased oxidative damage in several hypoxia-tolerant organisms under hypoxia. In addition, over the years, the idea of an assured decrease in ROS formation under hypoxia was challenged. Instead, several findings indicate that the production of ROS actually increases in response to hypoxia. Recently, it became possible to provide a comprehensive explanation for the induction of antioxidant enzymes under hypoxia. The supporting evidence and the limitations of the POS idea are extensively explored in this review as we discuss results from research on estivation and situations of low oxygen stress, such as hypoxia, freezing exposure, severe dehydration, and air exposure of water-breathing animals. We propose that, under some level of oxygen deprivation, ROS are overproduced and induce changes leading to hypoxic biochemical responses. These responses would occur mainly through the activation of specific transcription factors (FoxO, Nrf2, HIF-1, NF-κB, and p53) and post translational mechanisms, both mechanisms leading to enhanced antioxidant defenses. Moreover, reactive nitrogen species are candidate modulators of ROS generation in this scenario. We conclude by drawing out the future perspectives in this field of research, and how advances in the knowledge of the mechanisms involved in the POS strategy will offer new and innovative study scenarios of biological and physiological cellular responses to environmental stress.


Rapid generation of endogenously driven transcriptional reporters in cells through CRISPR/Cas9.
CRISPR/Cas9 technologies have been employed for genome editing to achieve gene knockouts and knock-ins in somatic cells. Similarly, certain endogenous genes have been tagged with fluorescent proteins. Often, the detection of tagged proteins requires high expression and sophisticated tools such as confocal microscopy and flow cytometry. Therefore, a simple, sensitive and robust transcriptional reporter system driven by endogenous promoter for studies into transcriptional regulation is desirable. We report a CRISPR/Cas9-based methodology for rapidly integrating a firefly luciferase gene in somatic cells under the control of endogenous promoter, using the TGFβ-responsive gene PAI-1. Our strategy employed a polycistronic cassette containing a non-fused GFP protein to ensure the detection of transgene delivery and rapid isolation of positive clones. We demonstrate that firefly luciferase cDNA can be efficiently delivered downstream of the promoter of the TGFβ-responsive gene PAI-1. Using chemical and genetic regulators of TGFβ signalling, we show that it mimics the transcriptional regulation of endogenous PAI-1 expression. Our unique approach has the potential to expedite studies on transcription of any gene in the context of its native chromatin landscape in somatic cells, allowing for robust high-throughput chemical and genetic screens.


Postprandial variations in fibrinolytic activity in middle-aged men are modulated by plasminogen activator inhibitor I 4G-675/5G genotype but not by the fat content of a meal.
Decreased fibrinolytic activity is associated with an increased risk of ischemic heart disease and elevated plasma triacylglycerol concentrations. The goal was to determine whether plasminogen activator inhibitor 1 (PAI-1) and fibrinolytic activities are influenced by 1) dietary fat intake from a test meal and 2) the PAI-1 4G allele. A parallel randomized controlled trial was used to compare the effect on fibrinolytic activity, measured as dilute clot lysis time, of high-oleate or high-palmitate test meals (both containing 50 g fat; both n = 18) with that of a low-fat test meal (15 g fat; n = 15) in men aged > 52 y. In a second study, postprandial changes in PAI-1 activity were measured in 32 men in response to a high-oleate meal containing 50 g fat. The results from both studies were analyzed according to PAI-1 4G-675/5G genotype. Fasting dilute clot lysis time was positively associated with body mass index (r = 0.326, P = 0.02) and was shortened postprandially (P < 0.00001) independent of the fat content of the meal. Fasting PAI-1 activity was higher in those carrying the 4G allele and was correlated with fasting plasma triacylglycerol concentrations (r = 0.48, P = 0.008) and factor VII coagulant activity (r = 0.46, P = 0.012) after adjustments for age, body mass index, and genotype. Plasma PAI-1 activity decreased significantly after a meal but was not associated with postprandial changes in plasma triacylglycerols after a high-fat meal. The postprandial increase in plasma triacylglycerols was higher in subjects carrying the 4G allele. Fibrinolytic activity is not lower after meals rich in palmitate or oleate than after a low-fat meal.


How Do Women Interpret the NHS Information Leaflet about Cervical Cancer Screening?
Background. Organized screening programs often rely on written materials to inform the public. In the United Kingdom, women invited for cervical cancer screening receive a leaflet from the National Health Service (NHS) to support screening decisions. However, information about screening may be too complex for people to understand, potentially hindering informed decision making. Objectives. We aimed to identify women's difficulties in interpreting the leaflet used in England and negative and positive responses to the leaflet. Methods. We used a sequential mixed-methods design involving 2 steps: cognitive think-aloud interviews (n = 20), followed by an England-wide survey (n = 602). Data were collected between June 2017 and December 2018, and participants included women aged 25 to 64 y with varying sociodemographics. Results. Interview results revealed misunderstandings concerning screening results, benefits, and additional tests and treatment, although participants tended to react positively to numerical information. Participants were often unfamiliar with the potential harms associated with screening (i.e., screening risks), key aspects of human papillomavirus, and complex terms (e.g., dyskaryosis). Survey results indicated that interpretation difficulties were common (M correct items = 12.5 of 23). Lower understanding was associated with lower educational level (β's >0.15, P's <0.001), lower numeracy scores (β = 0.36, P < 0.001), and nonwhite ethnicity (β = 0.10, P = 0.007). The leaflet was evaluated positively overall. Conclusions. Despite previous user testing of the leaflet, key information may be too complex for some recipients. As a consequence, they may struggle to make informed decisions about screening participation based on the information provided. We discuss implications for the improvement of communications about screening and decision support.


An iterative model of diffuse illumination from bidirectional photometric data.
This paper presents a methodology for including the photometric raw data sets into the diffuse illumination design process. The method is based on computing the luminance distribution on the outgoing side of diffusing elements from measured bidirectional scattering distribution functions (BSDFs). The model is limited to specimens that create rotationally symmetric scattering distribution. The calculation procedure includes the linear superposition and the correcting feedback. As an application example, the method is verified by a commercially available diffusing sheet illuminated by a 32-inch backlighting module. Close agreement (correlation coefficient = 98.6%) with the experimental measurement confirmed the validity of the proposed procedure.


Cognitive-affective neural plasticity following active-controlled mindfulness intervention.
Mindfulness meditation is a set of attention-based, regulatory, and self-inquiry training regimes. Although the impact of mindfulness training (MT) on self-regulation is well established, the neural mechanisms supporting such plasticity are poorly understood. MT is thought to act through interoceptive salience and attentional control mechanisms, but until now conflicting evidence from behavioral and neural measures renders difficult distinguishing their respective roles. To resolve this question we conducted a fully randomized 6 week longitudinal trial of MT, explicitly controlling for cognitive and treatment effects with an active-control group. We measured behavioral metacognition and whole-brain blood oxygenation level-dependent (BOLD) signals using functional MRI during an affective Stroop task before and after intervention in healthy human subjects. Although both groups improved significantly on a response-inhibition task, only the MT group showed reduced affective Stroop conflict. Moreover, the MT group displayed greater dorsolateral prefrontal cortex responses during executive processing, consistent with increased recruitment of top-down mechanisms to resolve conflict. In contrast, we did not observe overall group-by-time interactions on negative affect-related reaction times or BOLD responses. However, only participants with the greatest amount of MT practice showed improvements in response inhibition and increased recruitment of dorsal anterior cingulate cortex, medial prefrontal cortex, and right anterior insula during negative valence processing. Our findings highlight the importance of active control in MT research, indicate unique neural mechanisms for progressive stages of mindfulness training, and suggest that optimal application of MT may differ depending on context, contrary to a one-size-fits-all approach.


Influence of the photoperiod on redox regulation and stress responses in Arabidopsis thaliana L. (Heynh.) plants under long- and short-day conditions.
Arabidopsis thaliana L. (Heynh.) plants were grown in low light (150 micromol photons m(-2) s(-1) and 20 degrees C) either in short days (7.5 h photoperiod) or long days (16 h photoperiod), and then transferred into high light and low temperature (350-800 micromol photons m(-2) s(-1) at 12 degrees C). Plants grown in short days responded with a rapid increase in NADP-malate dehydrogenase (EC 184.108.40.206) activation state. However, persisting overreduction revealed a new level of regulation of the malate valve. Activity measurements and Northern-blot analyses indicated that NADP-malate dehydrogenase transcript and protein levels increased within a few hours. Using macroarrays, additional changes in gene expression were identified. Transcript levels for several enzymes of glutathione metabolism and of some photosynthetic genes increased. The cellular glutathione level increased, but its redox state remained unchanged. A different situation was observed in plants grown in long-day conditions. Neither NADP-malate dehydrogenase nor glutathione content changed, but the expression of several antioxidative enzymes increased strongly. We conclude that the endogenous systems that measure day length interact with redox regulation, and override the interpretation of the signals, i.e. they redirect redox-mediated acclimation signals to allow for more efficient light usage and redox poising in short days to systems for the prevention of oxidative damages when grown under long-day conditions.


Experimental study of antiangiogenic and photodynamic therapies combination for treatment of peritoneal carcinomatosis: preliminary results.
To create adequate orthotopic model of peritoneal carcinomatosis in rats using a transplantable rat tumor M-1 sarcoma, to assess the early tumor response after intraperitoneal photodynamic and/or antiangiogenic therapy for peritoneal carcinomatosis. In 14-18 days after intraperitoneal inoculation, eighteen tumor-bearing animals were divided into three groups and undergone intraperitoneal photodynamic therapy and/or antiangiogenic therapy. Assessment of the tumor posttreatment changes was performed using a method of vital staining with Evans blue, MRI-monitoring and morphologic investigation. Percentage of necrosis in disseminated tumors of animals undergone combination therapy significantly higher then after each of the methods alone and achieved 89.46% vs 41.47% after antiangiogenic therapy and 69.73% after photodynamic therapy. Contrast-enhanced MRI showed entirely necrotic tumor nodes in rats undergone the combination therapy. Morphologic study confirmed that tumor response after combination therapy was characterized by maximal spread of necrotic and inflammatory changes in tumor. Preliminary results demonstrate enhance of the treatment outcome after combination of antiangiogenic and intraperitoneal photodynamic therapies for peritoneal carcinomatosis in rats.


An analysis using DNA microarray of the time course of gene expression during syncytialization of a human placental cell line (BeWo).
Placental trophoblast syncytialization is a unique biological process. We have studied the time course of this process using DNA microarray in a cell model of syncytialization (the cytotrophoblast cell line BeWo following increased intracellular cAMP by forskolin). Total RNA was extracted from BeWo cells and labelled-cRNA target was then hybridized to a specific oligonucleotide probe set containing probes to over 12?000 human transcripts. Detectable levels of signal were found on average for 44 per cent of the total number of genes assayed. The correlation coefficient for the level of expression of independent replicates was #10878;0.99. The mRNA expression profile of specific genes analysed by microarray correlated quantitatively well with that analysed by reverse transcription-polymerase chain reaction and with protein secretion. In the absence of forskolin there are relatively few changes in gene expression (reaching a threshold of two fold); in the presence of forskolin there are a substantial number of changes. By clustering the patterns of altered gene expression at least ten groups could be extracted. Seven of these clusters involved increased gene expression and three decreased expression. Each cluster has been categorized by gene ontology (confining the analysis to genes with 'known' function). Among the genes with increased expression following forskolin treatment were many required for cellular communication (such as placental specific peptide hormones) and metabolism (such as cholesterol side chain cleavage enzyme). Several genes known to be involved in cell adhesion and fusion have markedly changed expression levels very early following forskolin exposure, thus preceding morphological fusion of BeWo cells. Further analysis of this data and expression profiling in general will be able to contribute to understanding the functional basis for the formation of the placental syncytiotrophoblast.


Prolonged health worker strikes in Kenya- perspectives and experiences of frontline health managers and local communities in Kilifi County.
While health worker strikes are experienced globally, the effects can be worst in countries with infrastructural and resource challenges, weak institutional arrangements, underdeveloped organizational ethics codes, and unaffordable alternative options for the poor. In Kenya, there have been a series of public health worker strikes in the post devolution period. We explored the perceptions and experiences of frontline health managers and community members of the 2017 prolonged health workers' strikes. We employed an embedded research approach in one county in the Kenyan Coast. We collected in-depth qualitative data through informal observations, reflective meetings, individual and group interviews and document reviews (n = 5), and analysed the data using a thematic approach. Individual interviews were held with frontline health managers (n = 26), and group interviews with community representatives (4 health facility committee member groups, and 4 broader community representative groups). Interviews were held during and immediately after the nurses' strike. In the face of major health facility and service closures and disruptions, frontline health managers enacted a range of strategies to keep key services open, but many strategies were piecemeal, inconsistent and difficult to sustain. Interviewees reported huge negative health and financial strike impacts on local communities, and especially the poor. There is limited evidence of improved health system preparedness to cope with any future strikes. Strikes cannot be seen in isolation of the prevailing policy and health systems context. The 2017 prolonged strikes highlight the underlying and longer-term frustration amongst public sector health workers in Kenya. The health system exhibited properties of complex adaptive systems that are interdependent and interactive. Reactive responses within the public system and the use of private healthcare led to limited continued activity through the strike, but were not sufficient to confer resilience to the shock of the prolonged strikes. To minimise the negative effects of strikes when they occur, careful monitoring and advanced planning is needed. Planning should aim to ensure that emergency and other essential services are maintained, threats between staff are minimized, health worker demands are reasonable, and that governments respect and honor agreements.


What Affects the Demand for Long-Term Care Insurance? A Study of Middle-Aged and Older Adults in Hong Kong.
Despite the potential of private insurance in financing long-term care (LTC), its coverage remains rather limited. This study is built on a comprehensive framework to examine the demand for LTC insurance in Hong Kong, a rapidly aging Asian society. A telephone survey was conducted in 2016 to collect data that formed a sample of 1,474 middle-aged and older adults. Multivariate analysis reveals more nuanced characteristics of Hong Kong middle-aged and older adults who tend to show a demand for LTC insurance, including: (a) being younger, better educated, relatively high status, and financially literate; (b) living with children but reluctant to be a burden on the family; (c) being in a better financial situation and able to afford premiums; and (d) anticipation of LTC needs and dependence, and a preference for formal care. This study offers preliminary evidence to understand the demand structure of the LTC insurance market in an Asian society.


Factors contributing to frequent use of psychiatric inpatient services by schizophrenia patients.
Although present findings about frequent users of psychiatric inpatient services vary from study to study, some potentially important predictors of frequent use were extracted. The purpose of this study was to examine the potentially contributory factors of frequent use of psychiatric inpatient services by schizophrenia patients and to test the influence single factors have in an overall model. A total of 307 schizophrenia patients were interviewed five times with intervals of 6 months. Data were collected about service receipt and health care costs, strength of primary diagnosis and comorbidities, as well as about patients' needs for care and satisfaction with care. Patients with three or more psychiatric admissions within a 30-month period were defined as frequent users. According to this criterion, 12% of the study population were frequent users. Compared with ordinary users, these patients accounted for significantly higher costs in hospital- and community-based care. Important predictors for frequent use of psychiatric inpatient services were the number of previous hospitalizations and current scores of psychopathology. In addition, a longitudinal analysis showed the importance of social factors for the use of psychiatric inpatient care. Therefore, a number of the frequent users' multiple admissions could also be caused by social problems. The mental health system should, thus, provide well-directed community-based resources, which give frequent users support to solve their social problems.


Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis.
Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1β and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1β, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.


Prostitution, disability and prohibition.
Criminalisation of prostitution, and minority rights for disabled persons, are important contemporary political issues. The article examines their intersection by analysing the conditions and arguments for making a legal exception for disabled persons to a general prohibition against purchasing sexual services. It explores the badness of prostitution, focusing on and discussing the argument that prostitution harms prostitutes, considers forms of regulation and the arguments for and against with emphasis on a liberty-based objection to prohibition, and finally presents and analyses three arguments for a legal exception, based on sexual rights, beneficence, and luck egalitarianism, respectively. It concludes that although the general case for and against criminalisation is complicated there is a good case for a legal exception.


The influence of the choice of preemptive analgesia on long-term postsurgical pain after tibial plateau leveling osteotomy in dogs.
To evaluate the prevalence of chronic postsurgical pain (CPSP) after tibial plateau leveling osteotomy (TPLO) in dogs and to determine the influence of preemptive locoregional analgesia on CPSP. Retrospective study. One hundred twenty client-owned dogs. Medical records of dogs that underwent TPLO between 2012 and 2016 were reviewed for demographic information and type of preemptive analgesia. Owners were contacted to retrospectively assess the quality of life of their dogs by using the Helsinki Chronic Pain Index (HCPI) before and 6 months after surgery and at the time of questioning. An HCPI score > 12 was considered indicative of CPSP. Medical records were reviewed for demographic information and type of preemptive analgesia. A cumulative logit model was used to assess correlation of type of perioperative analgesia, HCPI, and demographic data. The HCPI score was consistent with CPSP in 41 of 101 dogs with long-term follow-up (2.9 ± 1.5 years after surgery). Chronic postsurgical pain was documented in 11 of 32 and 13 of 28 dogs that received a spinal or epidural injection, respectively, or in 28 of 80 and 25 of 67 dogs with sciatic-femoral block at 6 months or with long-term follow-up after TPLO, respectively (P > .05). A negative correlation was found between HCPI and both weight and age 6 months after surgery. Only weight remained negatively correlated 2.9 years after surgery. Forty-one percent of dogs that were evaluated exhibited HCPI values compatible with CPSP long-term after TPLO, regardless of the type of preemptive analgesia. Increased body weight was a negative prognostic factor for CPSP development. Additional studies are required to evaluate CPSP development after TPLO.


Pharmaceutical and biomedical applications of affinity chromatography: recent trends and developments.
Affinity chromatography is a separation technique that has become increasingly important in work with biological samples and pharmaceutical agents. This method is based on the use of a biologically related agent as a stationary phase to selectively retain analytes or to study biological interactions. This review discusses the basic principles behind affinity chromatography and examines recent developments that have occurred in the use of this method for biomedical and pharmaceutical analysis. Techniques based on traditional affinity supports are discussed, but an emphasis is placed on methods in which affinity columns are used as part of HPLC systems or in combination with other analytical methods. General formats for affinity chromatography that are considered include step elution schemes, weak affinity chromatography, affinity extraction and affinity depletion. Specific separation techniques that are examined include lectin affinity chromatography, boronate affinity chromatography, immunoaffinity chromatography, and immobilized metal ion affinity chromatography. Approaches for the study of biological interactions by affinity chromatography are also presented, such as the measurement of equilibrium constants, rate constants, or competition and displacement effects. In addition, related developments in the use of immobilized enzyme reactors, molecularly imprinted polymers, dye ligands and aptamers are briefly considered.


Sexual molestation of men by women.
The belief that it is impossible for males to respond sexually when subjected to sexual molestation by women is contradicted. Previous research indicating that male sex response can occur in a variety of emotional states, including anger and terror, are corroborated. Eleven cases of male sexual molestation by females are classified and described. A post-trauma reaction occurs in which sexual function and psychological state are affected. The men were all personally interviewed. Recognition of this phenomenon should lead to increased identification of male victims as well as to better medical, psychological, and legal services for them.


Novel mutations in reverse transcriptase of human immunodeficiency virus type 1 reduce susceptibility to foscarnet in laboratory and clinical isolates.
Foscarnet (phosphonoformic acid) is a pyrophosphate analog that inhibits the replication of human immunodeficiency virus type 1 (HIV-1) in vitro and in patients with AIDS. HIV-1 resistance to foscarnet has not been reported despite long-term foscarnet therapy of AIDS patients with cytomegalovirus disease. We therefore attempted to select foscarnet-resistant HIV-1 in vitro by serial endpoint passage of virus in 400 microM foscarnet. After 13 cycles of passage in MT-2 cells, virus exhibiting > or = 8.5-fold foscarnet resistance was isolated. The reverse transcriptase (RT) from resistant virions exhibited a similar level of foscarnet resistance in enzyme inhibition assays (approximately 10-fold resistance). Foscarnet-resistant virus showed increased susceptibility to 3'-azido-3'-deoxythymidine (90-fold) and to the HIV-1-specific RT inhibitors TIBO R82150 (30-fold) and nevirapine (20-fold). DNA sequence analysis of RT clones from resistant virus revealed the coexistence of two mutations in all clones: Gln-161 to Leu (CAA to CTA) and His-208 to Tyr (CAT to TAT). Sequence analysis of six clinical HIV-1 isolates showing reduced susceptibility to foscarnet revealed the Tyr-208 mutation in two, the Leu-161 mutation in one, and a Trp-88-to-Ser or -Gly mutation in four isolates. Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that the Leu-161, Ser-88, and Tyr-208 mutations reduced HIV-1 susceptibility to foscarnet 10.5-, 4.3-, and 2.4-fold, respectively, in MT-2 cells. In the crystal structure of HIV-1 RT, the Gln-161 residue lies in the alpha E helix beneath the putative deoxynucleoside triphosphate (dNTP) binding site. The Gln-161-to-Leu mutation may affect the structure of the dNTP binding site and its affinity for foscarnet. The location of the Trp-88 residue in the Beta5a strand of HIV-1 RT suggest that the Ser-88 mutation affects template-primer binding, as do several mutations that affect RT susceptibility to nucleoside analogs.


Occurrence of adventitious sprouting in short-lived monocarpic herbs: a field study of 22 weedy species.
Adventitious sprouting from the hypocotyle and roots in monocarpic herbs has been confirmed in previous experimental studies as a means to avoid bud limitation after severe injury in annual and biennial plants. Data regarding the role of adventitious sprouting in natural populations, however, were lacking. The aim of the present study was to assess whether adventitious sprouting occurs in natural populations and how it is affected by plant size, plant injury, plant cover and environmental characteristics. Data were sampled from 14 037 individual plants from 389 populations belonging to 22 annual and biennial species. Growth parameters were measured in individual plants, species composition and plant cover in communities were evaluated, and environmental characteristics were estimated using Ellenberg indicator values. It was confirmed that adventitious sprouting occurs in natural populations of all but five species examined. Adventitious sprouting was positively affected by plant size and plant injury. Environmental factors including availability of soil nitrogen were not shown to affect adventitious sprouting. Annual and biennial plants did not differ in sprouting, but upright annuals had a lower number of and longer adventitious shoots than prostrate annuals. Adventitious bud formation is used to overcome meristem limitation when stem parts are lost due to injury, and thus resprouting in short-lived monocarps should not be overlooked.


Transplantation of Immortalized CD34+ and CD34- Adipose-Derived Stem Cells Improve Cardiac Function and Mitigate Systemic Pro-Inflammatory Responses.
Adipose-derived stem cells (ADSCs) have the potential to differentiate into various cell lineages and they are easily obtainable from patients, which makes them a promising candidate for cell therapy. However, a drawback is their limited life span during in vitro culture. Therefore, hTERT-immortalized CD34+ and CD34- mouse ADSC lines (mADSCshTERT) tagged with GFP were established. We evaluated the proliferation capacity, multi-differentiation potential, and secretory profiles of CD34+ and CD34- mADSCshTERT in vitro, as well as their effects on cardiac function and systemic inflammation following transplantation into a rat model of acute myocardial infarction (AMI) to assess whether these cells could be used as a novel cell source for regeneration therapy in the cardiovascular field. CD34+ and CD34- mADSCshTERT demonstrated phenotypic characteristics and multi-differentiation potentials similar to those of primary mADSCs. CD34+ mADSCshTERT exhibited a higher proliferation ability compared to CD34- mADSCshTERT, whereas CD34- mADSCshTERT showed a higher osteogenic differentiation potential compared to CD34+ mADSCshTERT. Primary mADSCs, CD34+, and CD34- mADSCshTERT primarily secreted EGF, TGF-β1, IGF-1, IGF-2, MCP-1, and HGFR. CD34+ mADSCshTERT had higher secretion of VEGF and SDF-1 compared to CD34- mADSCshTERT. IL-6 secretion was severely reduced in both CD34+ and CD34- mADSCshTERT compared to primary mADSCs. Transplantation of CD34+ and CD34- mADSCshTERT significantly improved the left ventricular ejection fraction and reduced infarct size compared to AMI-induced rats after 28 days. At 28 days after transplantation, engraftment of CD34+ and CD34- mADSCshTERT was confirmed by positive Y chromosome staining, and differentiation of CD34+ and CD34- mADSCshTERT into endothelial cells was found in the infarcted myocardium. Significant decreases were observed in circulating IL-6 levels in CD34+ and CD34- mADSCshTERT groups compared to the AMI-induced control group. Transplantation of CD34- mADSCshTERT significantly reduced circulating MCP-1 levels compared to the AMI control and CD34+ mADSCshTERT groups. GFP-tagged CD34+ and CD34- mADSCshTERT are valuable resources for cell differentiation studies in vitro as well as for regeneration therapy in vivo.


The ambiguous role of alcohol in economic and social development.
An increased and industrialized alcohol supply in a developing society is usually assumed to have positive effects on economic development, although it may be recognized that the effects on public health and order will be negative. There has been little attention to the potential for negative effects on the economic side. This paper directs attention to such factors as unemployment for cottage producers (often female heads of household) and reduced industrial employment as highly-automated "turnkey" brewers are installed. On the other hand, changes in the mode of production of alcoholic beverages may have little impact on the much larger work-force involved in serving or selling alcohol in retail trade. The net contribution of an increased and industrialized alcohol supply in terms of economic development is unclear, but industrialization and development bring with them increased demands for attention and sobriety, e.g. in motorized traffic and on the production line, which increased drinking may undercut. Decisions by international development agencies on investment in alcohol production and distribution should take account of both the positive and negative impacts on economic development as well as on public health. In line with this, the World Bank has recently decided to invest in alcohol industry projects only when there is a strong positive development impact and the project is "consistent with public health issues and social policy concerns".


Optically Transparent Thermally Insulating Silica Aerogels for Solar Thermal Insulation.
Rooftop solar thermal collectors have the potential to meet residential heating demands if deployed efficiently at low solar irradiance (i.e., 1 sun). The efficiency of solar thermal collectors depends on their ability to absorb incoming solar energy and minimize thermal losses. Most techniques utilize a vacuum gap between the solar absorber and the surroundings to eliminate conduction and convection losses, in combination with surface coatings to minimize reradiation losses. Here, we present an alternative approach that operates at atmospheric pressure with simple, black, absorbing surfaces. Silica based aerogels coated on black surfaces have the potential to act as simple and inexpensive solar thermal collectors because of their high transmission to solar radiation and low transmission to thermal radiation. To demonstrate their heat-trapping properties, we fabricated tetramethyl orthosilicate-based silica aerogels. A hydrophilic aerogel with a thickness of 1 cm exhibited a solar-averaged transmission of 76% and thermally averaged transmission of ≈1% (at 100 °C). To minimize unwanted solar absorption by O-H groups, we functionalized the aerogel to be hydrophobic, resulting in a solar-averaged transmission of 88%. To provide a deeper understanding of the link between aerogel properties and overall efficiency, we developed a coupled radiative-conductive heat transfer model and used it to predict solar thermal performance. Instantaneous solar thermal efficiencies approaching 55% at 1 sun and 80 °C were predicted. This study sheds light on the applicability of silica aerogels on black coatings for solar thermal collectors and offers design priorities for next-generation solar thermal aerogels.


The current treatment landscape: other fungal diseases (cryptococcosis, fusariosis and mucormycosis).
Compared with major invasive mycoses such as aspergillosis and candidiasis, the antifungal stewardship management strategies of other fungal diseases have different opportunities and considerations. Cryptococcosis, fusariosis and mucormycosis are globally prevalent invasive fungal diseases (IFDs), but are not currently included in antifungal prophylaxis guidelines for immunocompromised hosts. Since the implementation of biomarkers as part of diagnostic screening strategies, the concept of pre-emptive antifungal therapy has emerged for these IFDs. Management of cryptococcosis, the most common IFD worldwide, generally utilizes a pre-emptive or therapeutic strategy that does not involve prophylaxis or empirical antifungal treatment strategies. Antifungal stewardship outcomes for cryptococcosis may vary according to the availability of local resources. Invasive fusariosis, the second-most common form of non-Aspergillus mould infection among haematological malignancy patients, can be managed with pre-emptive (or diagnostic-driven) approaches based on the monitoring of serum galactomannan (GM) antigen in increased-risk populations. The success of antimicrobial stewardship programmes in decreasing the burden of invasive fusariosis in selected patient populations depends on the development and implementation of rapid diagnostic strategies for early and appropriate administration of therapy. Mucormycosis may emerge as a breakthrough IFD in haematology or solid organ transplant recipients receiving antifungals that lack activity against Mucorales. The concept of pre-emptive antifungal therapy has thus arisen for mucormycosis in the haematology setting because of the recent availability of circulating Mucorales DNA measurement. These examples demonstrate the challenges of implementing antifungal stewardship programmes in areas with limited resources, as well as in IFDs that are difficult to diagnose and treat.


Relationship between sodium and potassium intake and blood pressure in a sample of overweight adults.
The aim of this study was to examine the relationship between sodium and potassium intakes and blood pressure (BP) in a clinical sample. Secondary analysis of baseline data from 328 participants (mean age: 43.6 ± 8 y, mean body mass index [BMI]: 32.4 ± 4.2 kg/m2, mean systolic BP [SBP]/diastolic BP [DBP]: 124.9 ± 14.5/73.3 ± 9.9 mm Hg) of the 12-mo HealthTrack randomized controlled weight loss trial was conducted. Resting BP and 24-h urine sodium and potassium were measured. Dietary intake was evaluated with 4-d food records and self-reported diet histories. Urinary sodium was positively correlated (Spearman's rho) with SBP (r = 0.176; P = 0.001) and DBP (r = 0.150; P = 0.003). The ratio of sodium to potassium was positively correlated with SBP (r = 0.1; P = 0.035). Urinary sodium (F [4,323] = 20.381; P < 0.0005; adjusted R2 = 0.231) and sodium-to-potassium ratio (F[4,323] = 25.008; P < 0.0005; adjusted R2 = 0.227) significantly predicted SBP after controlling for age, sex, BMI, and hypertension medication use. Dietary sodium and potassium significantly predicted urinary sodium (B = 0.33, t = 4.032, P < 0.01) and potassium (B = 0.67, t = 8.537, P < 0.01) excretion, respectively, after adjustment for energy and BMI. Median dietary sodium intake was 3197 mg/d and median dietary potassium intake was 2886 mg/d. Cereal-based products and dishes were the major contributors (22%) to total sodium intake. In the present study, a high dietary sodium intake and high sodium-to-potassium ratio predicted high SBP. This suggests a need to focus dietary advice on reduction of sources of sodium and increasing sources of potassium in weight loss interventions to improve BP control.


NTP Toxicology and Carcinogenesis Studies of Commercial Grade 2,4 (80%)- and 2,6 (20%)- Toluene Diisocyanate (CAS No. 26471-62-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Toluene diisocyanate (TDI) is commercially produced as an approximate 80:20 mixture of the 2,4- and 2,6-isomers. In 1980, 580,000 pounds of this chemical were produced in the United States, primarily for use in the manufacture of flexible polyurethane foams. These foam elastomers are found in furniture and automobile cushions, carpet underlays, pillow filling, mattresses, insulation, shoes, purses, and toys. TDI is also used to produce polyurethane coatings for lacquers and wood finishes. Groups of 50 female F344/N rats and 50 B6C3F1 mice were administered commercial grade toluene diisocyanate (80% 2,4- and 20% 2,6-) in corn oil by gavage at doses of 60 or 120 mg/kg body weight, 5 days per week for 105 or 106 weeks. Groups of 50 male F344/N rats received 30 or 60 mg/kg and groups of 50 male B6C3F1 mice received 120 or 240 mg/kg on the same schedule. Dosage analyses of toluene diisocyanate indicated that the chemical had reacted in the corn oil vehicle, resulting in actual gavage concentrations 77% to 90% of theoretical values. Groups of 50 rats and 50 mice of each sex received corn oil only and served as vehicle controls. Survival in all groups of dosed rats in the 2-year studies were shorter (P</=0.005) than that of the controls; depressions of the mean body weight gain relative to controls were greater than 10% in all dosed rat groups throughout most of the study. A dose-dependent pattern of cumulative toxicity began at 70 weeks and culminated in excessive mortality, indicating the estimated tolerated dose had been exceeded for rats. Acute bronchopneumonia occurred at increased incidences in groups of dosed male and female rats (males: control, 2/50; low dose, 6/50; high dose, 14/50; females: 1/50, 10/50, 25/49). Subcutaneous tissue fibromas or fibrosarcomas (combined) in male rats occurred with a positive trend (P<0.01; 3/50, 6/50, 12/50). The incidence in the high dose group was higher than that in the controls (P</=0.01). The same tumor comparisons were significant (P<0.001) in female rats by the life table analysis. Mammary gland fibroadenomas in female rats occurred with a positive trend (P<0.001), and the incidences in low and high dose groups were significantly higher than that in controls (P</=0.01). Pancreatic acinar cell adenomas in male rats occurred with a positive trend (P<0.05; 1/47, 3/47, 7/49). The incidence in the high dose group was higher than that in the controls (P<0.05). The incidences of pancreatic islet cell adenomas in female rats were higher by the incidental tumor test (P</=0.01) in low dose (6/49) and high dose (2/47) groups than in controls (0/50). An islet cell carcinoma was also observed in a low dose female rat. The incidences of female rats with neoplastic nodules in the liver occurred with a positive trend (P<0.05; 3/50, 8/50, 8/48), and the incidence in the high dose group was higher (P<0.05) than that in the controls. Survival of high dose male mice in the 2-year study was significantly shorter than that of the controls (P<0.001). During the second year of the study, mean body weight gains of high dose male mice were less than those of the controls. Cytomegaly of kidney tubular epithelium was found in 45/48 (94%) low dose male mice and 41/50 (82%) high dose male mice but not in any of the controls. Hemangiomas or hemangiosarcomas (combined) of the circulatory system in female mice occurred with a positive trend (P</=0.01; control, 0/50; low dose, 1/50; high dose, 5/50). The incidence in the high dose group was significantly higher than that in the controls (P<0.05). Hepatocellular adenomas in female mice occurred with a positive trend (P</=0.001; 2/50, 3/50, 12/50), and the incidence in the high dose group was higher than that in the controls (P<0.01). Toluene diisocyanate was mutagenic in Salmonella typhimurium strains TA98 and TA100 in the presence (but not the absence) of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9; it was not mutagenic in strains TA 1535 or 1537. An audit of the experimental data for these 2-year toxicological and carcinogenicity An audit of the experimental data for these 2-year toxicological and carcinogenicity studies on commercial grade 2,4- and 2,6-toluene diisocyanate was conducted. There were no data discrepancies that influenced the final interpretations. Under the conditions of these gavage studies, commercial grade toluene diisocyanate in corn oil was carcinogenic for F344/N rats, causing subcutaneous fibromas and fibrosarcomas (combined) in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in females. Toluene diisocyanate was not carcinogenic for male B6C3F1 mice. TDI was carcinogenic for female B6C3F1 mice, causing hemangiomas or hemangiosarcomas (combined), as well as hepatocellular adenomas. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Negative Female Mice: Positive Synonym: TDI


Reward-Based Improvements in Motor Control Are Driven by Multiple Error-Reducing Mechanisms.
Reward has a remarkable ability to invigorate motor behavior, enabling individuals to select and execute actions with greater precision and speed. However, if reward is to be exploited in applied settings, such as rehabilitation, a thorough understanding of its underlying mechanisms is required. In a series of experiments, we first demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Specifically, reward promoted the selection of the correct action in the presence of distractors, while also improving execution through increased speed and maintenance of accuracy. These results led to a shift in the speed-accuracy functions for both selection and execution. In addition, punishment had a similar impact on action selection and execution, although it enhanced execution performance across all trials within a block, that is, its impact was noncontingent to trial value. Although the reward-driven enhancement of movement execution has been proposed to occur through enhanced feedback control, an untested possibility is that it is also driven by increased arm stiffness, an energy-consuming process that enhances limb stability. Computational analysis revealed that reward led to both an increase in feedback correction in the middle of the movement and a reduction in motor noise near the target. In line with our hypothesis, we provide novel evidence that this noise reduction is driven by a reward-dependent increase in arm stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate motor performance without compromising accuracy.SIGNIFICANCE STATEMENT While reward is well-known for enhancing motor performance, how the nervous system generates these improvements is unclear. Despite recent work indicating that reward leads to enhanced feedback control, an untested possibility is that it also increases arm stiffness. We demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Furthermore, we show that punishment has a similar positive impact on performance. Importantly, by combining computational and biomechanical approaches, we show that reward leads to both improved feedback correction and an increase in stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate performance without compromising accuracy. This work suggests that stiffness control plays a vital, and underappreciated, role in the reward-based imporvemenets in motor control.