Arbuscular mycorrhizal symbiosis induces strigolactone biosynthesis under drought and improves drought tolerance in lettuce and tomato.
Arbuscular mycorrhizal (AM) symbiosis alleviates drought stress in plants. However, the intimate mechanisms involved, as well as its effect on the production of signalling molecules associated with the host plant-AM fungus interaction remains largely unknown. In the present work, the effects of drought on lettuce and tomato plant performance and hormone levels were investigated in non-AM and AM plants. Three different water regimes were applied, and their effects were analysed over time. AM plants showed an improved growth rate and efficiency of photosystem II than non-AM plants under drought from very early stages of plant colonization. The levels of the phytohormone abscisic acid, as well as the expression of the corresponding marker genes, were influenced by drought stress in non-AM and AM plants. The levels of strigolactones and the expression of corresponding marker genes were affected by both AM symbiosis and drought. The results suggest that AM symbiosis alleviates drought stress by altering the hormonal profiles and affecting plant physiology in the host plant. In addition, a correlation between AM root colonization, strigolactone levels and drought severity is shown, suggesting that under these unfavourable conditions, plants might increase strigolactone production in order to promote symbiosis establishment to cope with the stress.


Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux.
Parkinson's disease (PD) is characterized by accumulation of alpha-synuclein (alpha-syn) and degeneration of neuronal populations in cortical and subcortical regions. Mitochondrial dysfunction has been considered a potential unifying factor in the pathogenesis of the disease. Mutations in genes linked to familial forms of PD, including SNCA encoding alpha-syn and Pten-induced putative kinase 1 (PINK1), have been shown to disrupt mitochondrial activity. We investigated the mechanisms through which mutant Pink1 might disrupt mitochondrial function in neuronal cells with alpha-syn accumulation. For this purpose, a neuronal cell model of PD was infected with virally-delivered Pink1, and was analyzed for cell survival, mitochondrial activity and calcium flux. Mitochondrial morphology was analyzed by confocal and electron microscopy. These studies showed that mutant (W437X) but not wildtype Pink1 exacerbated the alterations in mitochondrial function promoted by mutant (A53T) alpha-syn. This effect was associated with increased intracellular calcium levels. Co-expression of both mutant Pink1 and alpha-syn led to alterations in mitochondrial structure and neurite outgrowth that were partially ameliorated by treatment with cyclosporine A, and completely restored by treatment with the mitochondrial calcium influx blocker Ruthenium Red, but not with other cellular calcium flux blockers. Our data suggest a role for mitochondrial calcium influx in the mechanisms of mitochondrial and neuronal dysfunction in PD. Moreover, these studies support an important function for Pink1 in regulating mitochondrial activity under stress conditions.


Rapid identification of synthetic colorants in food samples by using indium oxide nanoparticle-functionalized porous polymer monolith coupled with HPLC-MS/MS.
A synthetic protocol for the preparation of an indium oxide nanoparticle-functionalized poly(methacrylic acid-glycidyl methacrylate-ethylene dimethacrylate-ethanediamine) monolithic column is reported. Various techniques, including scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermal gravimetric analysis-derivative thermogravimetric analysis were employed to characterize the synthesized monolith. The modified monolithic column was coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for determining synthetic colorants in various food samples. Under optimized conditions, good linearity was obtained for all the targets with squared regression coefficients greater than 0.9982. The limits of detection (S/N = 3) for 12 synthetic colorants were in the range of 0.012-2.97 μg kg(-1). The intra-day and inter-day relative standard deviations, ranging from 2.7% to 8.5%, were within the acceptable range. The developed method was successfully applied to the determination of synthetic colorants in food samples (candy, milk, jelly, jam, canned food, juice, and carbonated drink). Target recoveries at different spiked levels ranged from 73.5% to 112.1% with relative standard deviations of less than 10.3%.


Process Mining of Incoming Patients with Sepsis.
Data mining is a technique for analyzing large amounts of data, in various formats, often called Big Data, in order to gain knowledge about it. The healthcare industry is the next Big Data area of interest as its large variability in patients, their health status and their records which can include image scans, graphical test results, and hand-written physician notes, has been untapped for analysis. In addition to data mining, there is a newer analysis method called process mining. Process mining is similar to data mining in that large data files are reviewed and analyzed, but in this case, event logs specific to a particular process or series of processes, are analyzed. Process mining allows one to understand the initial baseline, determine any bottlenecks or resource constraints, and evaluate a recently implemented change. Process mining was conducted on a hospital event log of patients entering the emergency room with sepsis, to better understand this newer analysis method, to highlight the information discovered, and to determine its role with data mining. Not only did the analysis of the event logs provide process mapping and process analysis, but it also highlighted areas in the clinical operations in need of further investigation, including a possible relationship with patient re-admission and their release method. In addition, the data mining method of creating a histogram, of the process data, was applied, allowing data mining and process mining to be utilized complimentary.


Self assembly of magnetic nanoparticles at silicon surfaces.
Neutron reflectometry was used to study the assembly of magnetite nanoparticles in a water-based ferrofluid close to a silicon surface. Under three conditions, static, under shear and with a magnetic field, the depth profile is extracted. The particles have an average diameter of 11 nm and a volume density of 5% in a D2O-H2O mixture. They are surrounded by a 4 nm thick bilayer of carboxylic acid for steric repulsion. The reflectivity data were fitted to a model using a least square routine based on the Parratt formalism. From the scattering length density depth profiles the following behavior is concluded: the fits indicate that excess carboxylic acid covers the silicon surface and almost eliminates the water in the densely packed wetting layer that forms close to the silicon surface. Under constant shear the wetting layer persists but a depletion layer forms between the wetting layer and the moving ferrofluid. Once the flow is stopped, the wetting layer becomes more pronounced with dense packing and is accompanied by a looser packed second layer. In the case of an applied magnetic field the prolate particles experience a torque and align with their long axes along the silicon surface which leads to a higher particle density.


The molecular evolution of spiggin nesting glue in sticklebacks.
Gene duplication and subsequent divergence can lead to the evolution of new functions and lineage-specific traits. In sticklebacks, the successive duplication of a mucin gene (MUC19) into a tandemly arrayed, multigene family has enabled the production of copious amounts of 'spiggin', a secreted adhesive protein essential for nest construction. Here, we examine divergence between spiggin genes among three-spined sticklebacks (Gasterosteus aculeatus) from ancestral marine and derived freshwater populations, and propose underpinning gene duplication mechanisms. Sanger sequencing revealed substantial diversity among spiggin transcripts, including alternatively spliced variants and interchromosomal spiggin chimeric genes. Comparative analysis of the sequenced transcripts and all other spiggin genes in the public domain support the presence of three main spiggin lineages (spiggin A, spiggin B and spiggin C) with further subdivisions within spiggin B (B1, B2) and spiggin C (C1, C2). Spiggin A had diverged least from the ancestral MUC19, while the spiggin C duplicates had diversified most substantially. In silico translations of the spiggin gene open reading frames predicted that spiggins A and B are secreted as long mucin-like polymers, while spiggins C1 and C2 are secreted as short monomers, with putative antimicrobial properties. We propose that diversification of duplicated spiggin genes has facilitated local adaptation of spiggin to a range of aquatic habitats.


Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia.
Idiopathic cervical dystonia (ICD) is the most common form of adult-onset focal dystonia. Previously, disagreement existed about whether ICD was a psychiatric illness, but the disorder is now viewed as a neurological illness and large clinical series have clarified the clinical features of the disease. At the time of diagnosis, extracervical dystonia is found in approximately 20% of patients, and there may be a concomitant head or hand tremor. Importantly, adult-onset ICD does not become generalized, although there may be segmental spread and pain may increase independently of the dystonia. While 10-20% of patients may experience remission, nearly all patients relapse within 5 years and are left with persistent disease. The aetiology of ICD is unknown, but there has been much progress in clarifying the genetic abnormality in families with inherited adult-onset cervical dystonia; linkage to chromosome 18p has been demonstrated in one family, and the DYT1 locus has been excluded in two other families. Painful trauma may be involved in the pathogenesis of ICD. Painful stimuli are received and processed by the basal ganglia, and the synaptic changes provoked by pain may lead to the abnormal physiology underlying dystonia. Consistent with this idea are experiments which demonstrate that altered sensory input leads to plasticity of the motor cortex, and those that explore the 'tonic vibration reflex' in patients with dystonia. Another theory suggests that a primary vestibular abnormality is responsible for ICD. Botulinum toxin is the most effective treatment for ICD. Roughly 75% of patients improve, and a response is generally seen within the first week. However, many questions remain regarding the optimal technique of administration. The development of neutralizing antibodies occurs in at least 5-10% of patients, and appears to be related both to dosage and to the interval between treatments. Side-effects are generally mild and result from the action of the toxin in the periphery. If the response to botulinum toxin is not adequate, anticholinergics, benzodiazepines, baclofen and other medications are used as adjunctive therapy. Surgical therapies are available for the treatment of ICD but are reserved for patients refractory to conservative measures.


Multi-model comparison of the economic and energy implications for China and India in an international climate regime.
This paper presents a modeling comparison on how stabilization of global climate change at about 2 °C above the pre-industrial level could affect economic and energy systems development in China and India. Seven General Equilibrium (CGE) and energy system models on either the global or national scale are soft-linked and harmonized with respect to population and economic assumptions. We simulate a climate regime, based on long-term convergence of per capita carbon dioxide (CO2) emissions, starting from the emission pledges presented in the Copenhagen Accord to the United Nations Framework Convention on Climate Change and allowing full emissions trading between countries. Under the climate regime, Indian emission allowances are allowed to grow more than the Chinese allowances, due to the per capita convergence rule and the higher population growth in India. Economic and energy implications not only differ among the two countries, but also across model types. Decreased energy intensity is the most important abatement approach in the CGE models, while decreased carbon intensity is most important in the energy system models. The reduction in carbon intensity is mostly achieved through deployment of carbon capture and storage, renewable energy sources and nuclear energy. The economic impacts are generally higher in China than in India, due to higher 2010-2050 cumulative abatement in China and the fact that India can offset more of its abatement cost though international emission trading.


Humic acid interference with virus recovery by electropositive microporous filters.
The effects of humic acid on poliovirus type 1 recovery from water by Zeta Plus 60S filters were investigated. The humic acid interfered by preventing virus adsorption to the filters, and the interference increased as a function of the amount of humic acid filtered. Humic acid decreased virus adsorption when filtered before the virus, but did not elute virus which had adsorbed to the filters. The effects on virus recovery were not due to alterations in virus titer or neutralizability. The addition of AlCl3, which improved virus recovery by electronegative filters in the presence of humic acid, did not aid in overall virus recovery by the Zeta Plus filters in the presence or absence of humic acid. However, the salt and humic acid in combination improved virus adsorption and concurrently reduced virus elution efficiency. The addition of NaH2PO4 had no direct effect on virus recovery and did not alter the effect of humic acid. In an attempt to identify the components of humic acid responsible for the interference, humic materials were fractionated by size by using Sephadex gel chromatography and dialysis, and the fractions were tested for interfering activity. Interference was not associated with specific size fractions of the humic materials.


Protective effects of sesamol on systemic oxidative stress-induced cognitive impairments via regulation of Nrf2/Keap1 pathway.
Oxidative stress is considered as a pivotal culprit in neurodegenerative diseases and brain aging. The aim of present study was to investigate antioxidative and neuroprotective effects of sesamol, a phenolic lignan from sesame oil, on oxidative stress induced neuron damage and memory impairments. C57BL/6J mice were treated by intraperitoneal injections of d-galactose for 8 weeks. Sesamol treatment (0.05% w/v, in drinking water) suppressed d-galactose-induced liver damages and improved HO-1 and NQO1 mRNA levels. Behavioral tests, including Y-maze test and water maze-test, revealed that sesamol significantly improved oxidative stress-induced cognitive impairments. Meanwhile, sesamol ameliorated neuronal damage and improved BDNF level in rat hippocampus. Sesamol elevated mRNA levels and protein expressions of antioxidant enzymes HO-1 and NQO1 as well as decreased inflammatory cytokines TNF-α and IL-1β in d-galactose-treated mice serum. In addition, activity of CAT and GSH level were increased in sesamol-treated mice serum. Moreover, sesamol treatment also balanced cellular redox status, protected mitochondrial dysfunction and upregulated antioxidant enzymes by activating the Nrf2 transcriptional pathway and its nuclear translocation in H2O2-treated SH-SY5Y cells. In conclusion, these results revealed that sesamol could be a potential neuroprotective agent during aging process due to its beneficial effects on liver-brain axis.


The effects of joint damage on muscle function, proprioception and rehabilitation.
SUMMARY. The paper summarizes a series of studies investigating reduced quadriceps femoris activation and its effect on rehabilitation of patients with traumatic and arthritic knee damage. It incorporates findings from related research fields and speculates on the physiological causes of reduced voluntary activation following joint damage and its clinical implications. Arthrogenic reduction in voluntary activation is the inability to maximally activate muscles acting across damaged joints. This phenomenon may cause muscle weakness by preventing complete activation of the muscle and if prolonged may result in muscle fibre atrophy, and may possibly impede rehabilitation. In patients with anterior cruciate ligament (ACL) deficient knees the reduction in quadriceps femoris activation was related to the amount of joint damage sustained and caused some quadriceps femoris weakness. Patients with isolated ACL ruptures had a small reduction of quadriceps femoris activation that did not impede conservative rehabilitation. However, patients with ACL ruptures and associated joint damage had a large reduction in activation and responded poorly to rehabilitation. Operative stabilization of ACL-deficient limbs may increase activation and improve efficacy of rehabilitation. Quadriceps femoris activation was also reduced in patients with mild knee osteoarthritis, who responded well to rehabilitation. Following joint damage, abnormal articular afferent information may decrease alpha-motoneurone excitability, reducing voluntary quadriceps femoris activation. If joint damage is extensive the resulting large reduction in activation may prevent the threshold for stimulation of muscle hypertrophy from being reached, which impedes rehabilitation. Abnormal articular afferent information may also decrease gamma-motoneurone excitability causing proprioceptive deficits. Rehabilitation which increases alpha-motoneurone excitability may also increase gamma-motoneurone excitability, improving proprioception. Copyright 1997 Harcourt Publishers Ltd.


Pathogenic free-living amoebae.
Studies on pathogenic free-living amoebae performed in Korea were briefly reviewed. One strain of Naegleria fowleri was isolated from the sewage, and 3 strains of Acanthamoeba culbertsoni from a reservoir and the gill of fish. They were identified by morphological characteristics. Three strains among the 4 were experimentally proved pathogenic to cause primary amoebic meningoencephalitis in mice. The virulence of N. fowleri depended upon various factors such as strain, weight and sex of mice, and number of the inoculated amoebae. A. culbertsoni was found to retain cytolytic activities which were related to the pathogenicity. Also these amoebae were demonstrated to harbour the activities of acid phosphatase, peroxidase and ATPase. There is one case record of systemic Acanthamoeba infection in Korea, proved at autopsy. Cellular or humoral responses to these amoebae have been studied in vitro or in vivo. Immunization could reduce the mortality of experimentally infected mice.


Spectrum of urorectal septum malformation sequence.
Urorectal septum malformation sequence (URSMS) is a rare spectrum of malformations involving various organ systems. Here, we present eight cases of URSMS, noted in autopsy, with different degrees of complexity, seven being the complete type and one being the partial type. All cases had gastrointestinal tract malformation in the form of the imperforate anus and indeterminate genitalia. Other gastrointestinal tract anomalies were anal agenesis in two cases, anorectal agenesis in two cases, and malformed lower intestinal tract in four cases. The associated renal abnormality was noted in five cases, which were unilateral renal agenesis, dysplastic kidney, hydronephrosis, horseshoe kidney, and unilateral hypoplastic ectopic kidney. External genital malformation, present in both male and female fetuses, included a knob-like structure at perineum in female fetuses, genital fold hypoplasia and penile aplasia or hypoplasia in male fetuses. Skeletal abnormalities included two cases of sacral agenesis and one case of lumbosacral dysraphism. Other anomalies included a case with alobar holoprosencephaly, truncus arteriosus with hypoplastic lungs in one case, and three cases with abdominal wall defects. It is our attempt to delineate a spectrum of abnormalities associated with URSMS.


Phase 1 trial of allogeneic gene-modified tumor cell vaccine RCC-26/CD80/IL-2 in patients with metastatic renal cell carcinoma.
Preclinical studies showed that the allogeneic tumor cell line RCC-26 displayed natural immunogenic potential that was enhanced through expression of CD80 costimulatory molecules and secretion of interleukin-2. Here we report the study of RCC-26/CD80/IL-2 cells in a phase 1 vaccine trial of renal cell carcinoma patients with metastatic disease (mRCC). Fifteen patients of the HLA-A*0201 allotype, with at least one metastatic lesion, were included. Irradiated vaccine cells were applied in increasing doses of 2.5, 10, and 40 x 10(6) cells over 22 weeks. Primary study parameters included safety and toxicity. Sequential blood samples were analyzed by interferon-gamma enzyme-linked immunospot assays to detect tumor antigen-associated (TAA) effector cells. The vaccine was well tolerated and the designated vaccination course was completed in 9 of 15 patients. Neither vaccine-induced autoimmunity nor systemic side effects were observed. Delayed-type hypersensitivity skin reactions were detected in 11 of 12 evaluated patients and were particularly strong in patients with prolonged survival. In parallel, vaccine-induced immune responses against vaccine or overexpressed TAA were detected in 9 of 12 evaluated patients. No tumor regressions occurred according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria; however, median time to progression was 5.3 months and median survival was 15.6 months, indicating substantial disease stabilization. We conclude that vaccine use was safe and feasible in mRCC. Clinical benefits were limited in these patients with advanced disease; however, immune monitoring revealed vaccine-induced responses against multiple TAAs in the majority of study participants. These results suggest that this vaccine could be useful in combination therapies and/or minimal residual disease.


Correlation of radiovisuographic analysis of interdental and interradicular bone loss in furcation involvement of mandibular first molars: A retrospective study.
The presence of furcation involvement represents a formidable problem in the treatment of periodontal disease. Advances in radiographic analysis such as radiovisuographic (RVG) aid in the early diagnosis and treatment planning, which is critical for long-term success. The present investigation aims to correlate the interdental and interradicular bone loss in chronic periodontitis patients so as to explore the potential of interdental bone loss as a rough approximate screening tool for early furcation diagnosis in mandibular first molar. RVG radiographs with furcation radiolucency in mandibular first molars were selected. The morphometric measurements of mesial, distal interdental bone loss, and interradicular bone loss in mandibular first molars were recorded using RVG. The correlation between mesial and distal interdental bone loss and interradicular bone loss was analyzed. In this retrospective investigation, it was observed that distal interdental bone loss was not significantly different when compared with mesial interdental bone loss. The interradicular bone loss was significantly different when compared with mesial interdental bone loss, whereas on analysis between distal interdental bone loss and interradicular bone loss was also found to be statistically significant. Interdental bone loss was found to be associated with progressive bone destruction in furcation area which suggests that early detection of interdental bone loss can be helpful in predicting future interradicular bone loss.


Observation of Two New Excited Ξ_{b}^{0} States Decaying to Λ_{b}^{0}K^{-}π^{+}.
Two narrow resonant states are observed in the Λ_{b}^{0}K^{-}π^{+} mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb^{-1}. The minimal quark content of the Λ_{b}^{0}K^{-}π^{+} system indicates that these are excited Ξ_{b}^{0} baryons. The masses of the Ξ_{b}(6327)^{0} and Ξ_{b}(6333)^{0} states are m[Ξ_{b}(6327)^{0}]=6327.28_{-0.21}^{+0.23}±0.12±0.24 and m[Ξ_{b}(6333)^{0}]=6332.69_{-0.18}^{+0.17}±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41_{-0.27}^{+0.26}±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λ_{b}^{0} mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξ_{b}(6327)^{0}]<2.20(2.56) and Γ[Ξ_{b}(6333)^{0}]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξ_{b}^{0} resonances.


Inhibition of ethanol-producing yeast and bacteria by degradation products produced during pre-treatment of biomass.
An overview of the different inhibitors formed by pre-treatment of lignocellulosic materials and their inhibition of ethanol production in yeast and bacteria is given. Different high temperature physical pre-treatment methods are available to render the carbohydrates in lignocellulose accessible for ethanol fermentation. The resulting hydrolyzsates contain substances inhibitory to fermentation-depending on both the raw material (biomass) and the pre-treatment applied. An overview of the inhibitory effect on ethanol production by yeast and bacteria is presented. Apart from furans formed by sugar degradation, phenol monomers from lignin degradation are important co-factors in hydrolysate inhibition, and inhibitory effects of these aromatic compounds on different ethanol producing microorganisms is reviewed. The furans and phenols generally inhibited growth and ethanol production rate (Q(EtOH)) but not the ethanol yields (Y(EtOH)) in Saccharomyces cerevisiae. Within the same phenol functional group (aldehyde, ketone, and acid) the inhibition of volumetric ethanol productivity was found to depend on the amount of methoxyl substituents and hence hydrophobicity (log P). Many pentose-utilizing strains Escherichia coli, Pichia stipititis, and Zymomonas mobilis produce ethanol in concentrated hemicellulose liquors but detoxification by overliming is needed. Thermoanaerobacter mathranii A3M3 can grow on pentoses and produce ethanol in hydrolysate without any need for detoxification.


Robotic-assisted placement of a hepatic artery infusion catheter for regional chemotherapy.
Hepatic arterial infusion chemotherapy can be of value to patients with metastatic liver disease from colorectal cancer. Arterial infusion therapy requires surgical placement of a catheter into the gastroduodenal artery connected to a subcutaneous infusion pump or port, a procedure involving major abdominal surgery. Placement of chemotherapy infusion catheters by conventional laparoscopic techniques has been described, but is a technically challenging procedure. The purpose of this report is to introduce a new, minimally invasive approach for hepatic artery catheter placement using the DaVinci robotic system with the potential to minimize surgical trauma, pain, and hospital stay, and to render this minimal access procedure more feasible and widely applicable.


Electrophysiological Evidence for Alternative Motor Networks in REM Sleep Behavior Disorder.
Patients with Parkinson's disease (PD) and REM sleep behavior disorder (RBD) show mostly unimpaired motor behavior during REM sleep, which contrasts strongly to coexistent nocturnal bradykinesia. The reason for this sudden amelioration of motor control in REM sleep is unknown, however. We set out to determine whether movements during REM sleep are processed by different motor networks than movements in the waking state. We recorded local field potentials in the subthalamic nucleus (STN) and scalp EEG (modified 10/20 montage) during sleep in humans with PD and RBD. Time-locked event-related β band oscillations were calculated during movements in REM sleep compared with movements in the waking state and during NREM sleep. Spectral analysis of STN local field potentials revealed elevated β power during REM sleep compared with NREM sleep and β power in REM sleep reached levels similar as in the waking state. Event-related analysis showed time-locked β desynchronization during WAKE movements. In contrast, we found significantly elevated β activity before and during movements in REM sleep and NREM sleep. Corticosubthalamic coherence was reduced during REM and NREM movements. We conclude that sleep-related movements are not processed by the same corticobasal ganglia network as movements in the waking state. Therefore, the well-known seemingly normal motor performance during RBD in PD patients might be generated by activating alternative motor networks for movement initiation. These findings support the hypothesis that pathological movement-inhibiting basal ganglia networks in PD patients are bypassed during sleep. This study provides evidence that nocturnal movements during REM sleep in Parkinson's disease (PD) patients are not processed by the same corticobasal ganglia network as movements in the waking state. This implicates the existence of an alternative motor network that does not depend directly on the availability of l-Dopa in the basal ganglia. These findings further indicate that some PD patients are able to perform movements in the dopamine depleted state, possibly by bypassing the pathological basal ganglia network. The existence and direct activation of such alternative motor networks might finally have potential therapeutic effects for PD patients.


Bromodeoxyuridine and deoxyribonucleic acid bivariate analysis in human renal cell carcinoma. Does flow cytometric determination predict malignant potential or prognosis of patients with renal cell carcinoma?
Sixty-one renal cell carcinomas were analyzed by simultaneous flow cytometric bivariate measurements of deoxyribonucleic acid (DNA) and bromodeoxyuridine. Bromodeoxyuridine in vitro labeling was performed by sample incubation with bromodeoxyuridine under hyperbaric oxygen. DNA ploidy status statistically correlated only with the presence or absence of distant metastasis. When the mean bromodeoxyuridine labeling index (LI) was accordingly compared with each histologic feature, architecturally solid, grade 3, high-stage (beyond pT3a) tumor, and the presence of distant metastasis showed significantly higher LI. When LI were compared with DNA ploidy, diploid tumors showed a 6.3% +/- 4.9% LI, whereas aneuploid tumors exhibited a 7.6% +/- 5.4% LI. The difference was not statistically significant. Five patients with a mean survival time of 10.2 +/- 4.1 months who had a mean LI of 11.5% +/- 7.7% died, whereas 56 patients with a mean LI of 6.7% +/- 4.8% survived. The difference was significant (P less than 0.05). However, the results did not necessarily correlate with the histologic features of the malignant potential or with the prognosis in individual patients. These data indicate that flow cytometric DNA/bromodeoxyuridine bivariate analysis remains inconsistent for predicting the malignant potential or prognosis of renal cell carcinoma.


Horizontal gene transfer from a flowering plant to the insular pine Pinus canariensis (Chr. Sm. Ex DC in Buch).
Horizontal gene transfer (HGT) is viewed as very common in the plant mitochondrial (mt) genome, but, to date, only one case of HGT has been found in gymnosperms. Here we report a new case of HGT, in which a mt nad5-1 fragment was transferred from an angiosperm to Pinus canariensis. Quantitative assay and sequence analyses showed that the foreign nad5-1 is located in the mt genome of P. canariensis and is nonfunctional. An extensive survey in the genus Pinus revealed that the angiosperm-derived nad5-1 is restricted to P. canariensis and present across the species' range. Molecular dating based on chloroplast DNA suggested that the HGT event occurred in the late Miocene after P. canariensis split from its closest relatives, and that the foreign copy became fixed in P. canariensis owing to drift during its colonization of the Canary Islands. The mechanism of this HGT is unclear but it was probably achieved through either direct cell-cell contact or external vectors. Our discovery provides evidence for an important role of HGT in plant mt genome evolution.


A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma.
Gene-directed enzyme prodrug therapy (GDEPT) has been investigated as a means of cancer treatment without affecting normal tissues. This system is based on the delivery of a suicide gene, a gene encoding an enzyme which is able to convert its substrate from non-toxic prodrug to cytotoxin. In this experiment, we have developed a targeted suicide gene therapeutic system that is completely contained within tumor-tropic cells and have tested this system for melanoma therapy in a preclinical model. First, we established double stable RAW264.7 monocyte/macrophage-like cells (Mo/Ma) containing a Tet-On® Advanced system for intracellular carboxylesterase (InCE) expression. Second, we loaded a prodrug into the delivery cells, double stable Mo/Ma. Third, we activated the enzyme system to convert the prodrug, irinotecan, to the cytotoxin, SN-38. Our double stable Mo/Ma homed to the lung melanomas after 1 day and successfully delivered the prodrug-activating enzyme/prodrug package to the tumors. We observed that our system significantly reduced tumor weights and numbers as targeted tumor therapy after activation of the InCE. Therefore, we propose that this system may be a useful targeted melanoma therapy system for pulmonary metastatic tumors with minimal side effects, particularly if it is combined with other treatments.


The effect of moisture absorption on the physical properties of polyurethane shape memory polymer foams.
The effect of moisture absorption on the glass transition temperature (T(g)) and stress/strain behavior of network polyurethane shape memory polymer (SMP) foams has been investigated. With our ultimate goal of engineering polyurethane SMP foams for use in blood contacting environments, we have investigated the effects of moisture exposure on the physical properties of polyurethane foams. To our best knowledge, this study is the first to investigate the effects of moisture absorption at varying humidity levels (non-immersion and immersion) on the physical properties of polyurethane SMP foams. The SMP foams were exposed to differing humidity levels for varying lengths of time, and they exhibited a maximum water uptake of 8.0% (by mass) after exposure to 100% relative humidity for 96 h. Differential scanning calorimetry results demonstrated that water absorption significantly decreased the T(g) of the foam, with a maximum water uptake shifting the T(g) from 67 °C to 5 °C. Samples that were immersed in water for 96 h and immediately subjected to tensile testing exhibited 100% increases in failure strains and 500% decreases in failure stresses; however, in all cases of time and humidity exposure, the plasticization effect was reversible upon placing moisture-saturated samples in 40% humidity environments for 24 h.


Predicting Therapy Success and Costs for Personalized Treatment Recommendations Using Baseline Characteristics: Data-Driven Analysis.
Different treatment alternatives exist for psychological disorders. Both clinical and cost effectiveness of treatment are crucial aspects for policy makers, therapists, and patients and thus play major roles for healthcare decision-making. At the start of an intervention, it is often not clear which specific individuals benefit most from a particular intervention alternative or how costs will be distributed on an individual patient level. This study aimed at predicting the individual outcome and costs for patients before the start of an internet-based intervention. Based on these predictions, individualized treatment recommendations can be provided. Thus, we expand the discussion of personalized treatment recommendation. Outcomes and costs were predicted based on baseline data of 350 patients from a two-arm randomized controlled trial that compared treatment as usual and blended therapy for depressive disorders. For this purpose, we evaluated various machine learning techniques, compared the predictive accuracy of these techniques, and revealed features that contributed most to the prediction performance. We then combined these predictions and utilized an incremental cost-effectiveness ratio in order to derive individual treatment recommendations before the start of treatment. Predicting clinical outcomes and costs is a challenging task that comes with high uncertainty when only utilizing baseline information. However, we were able to generate predictions that were more accurate than a predefined reference measure in the shape of mean outcome and cost values. Questionnaires that include anxiety or depression items and questions regarding the mobility of individuals and their energy levels contributed to the prediction performance. We then described how patients can be individually allocated to the most appropriate treatment type. For an incremental cost-effectiveness threshold of 25,000 €/quality-adjusted life year, we demonstrated that our recommendations would have led to slightly worse outcomes (1.98%), but with decreased cost (5.42%). Our results indicate that it was feasible to provide personalized treatment recommendations at baseline and thus allocate patients to the most beneficial treatment type. This could potentially lead to improved decision-making, better outcomes for individuals, and reduced health care costs.


BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD.
Recently, treatment with bromodomain and extraterminal protein antagonist (BA) such as JQ1 has been shown to inhibit growth and induce apoptosis of human acute myelogenous leukemia (AML) cells, including those expressing FLT3-ITD. Here, we demonstrate that cotreatment with JQ1 and the FLT3 tyrosine kinase inhibitor (TKI) ponatinib or AC220 synergistically induce apoptosis of cultured and primary CD34(+) human AML blast progenitor cells (BPC) expressing FLT3-ITD. Concomitantly, as compared with each agent alone, cotreatment with JQ1 and the FLT3-TKI caused greater attenuation of c-MYC, BCL2, and CDK4/6. Simultaneously, cotreatment with JQ1 and the FLT3-TKI increased the levels of p21, BIM, and cleaved PARP, as well as mediated marked attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels in AML BPCs. Conversely, cotreatment with JQ1 and FLT3-TKI was significantly less active against CD34(+) normal bone marrow progenitor cells. Knockdown of BRD4 by short hairpin RNA also sensitized AML cells to FLT3-TKI. JQ1 treatment induced apoptosis of mouse Ba/F3 cells ectopically expressing FLT3-ITD with or without FLT3-TKI-resistant mutations F691L and D835V. Compared with the parental human AML FLT3-ITD-expressing MOLM13, MOLM13-TKIR cells resistant to AC220 were markedly more sensitive to JQ1-induced apoptosis. Furthermore, cotreatment with JQ1 and the pan-histone deacetylase inhibitor (HDI) panobinostat synergistically induced apoptosis of FLT3-TKI-resistant MOLM13-TKIR and MV4-11-TKIR cells. Collectively, these findings support the rationale for determining the in vivo activity of combined therapy with BA and FLT3-TKI against human AML cells expressing FLT3-ITD or with BA and HDI against AML cells resistant to FLT3-TKI.


The temporal spectrum of adult mosquito population fluctuations: conceptual and modeling implications.
An improved understanding of mosquito population dynamics under natural environmental forcing requires adequate field observations spanning the full range of temporal scales over which mosquito abundance fluctuates in natural conditions. Here we analyze a 9-year daily time series of uninterrupted observations of adult mosquito abundance for multiple mosquito species in North Carolina to identify characteristic scales of temporal variability, the processes generating them, and the representativeness of observations at different sampling resolutions. We focus in particular on Aedes vexans and Culiseta melanura and, using a combination of spectral analysis and modeling, we find significant population fluctuations with characteristic periodicity between 2 days and several years. Population dynamical modelling suggests that the observed fast fluctuations scales (2 days-weeks) are importantly affected by a varying mosquito activity in response to rapid changes in meteorological conditions, a process neglected in most representations of mosquito population dynamics. We further suggest that the range of time scales over which adult mosquito population variability takes place can be divided into three main parts. At small time scales (indicatively 2 days-1 month) observed population fluctuations are mainly driven by behavioral responses to rapid changes in weather conditions. At intermediate scales (1 to several month) environmentally-forced fluctuations in generation times, mortality rates, and density dependence determine the population characteristic response times. At longer scales (annual to multi-annual) mosquito populations follow seasonal and inter-annual environmental changes. We conclude that observations of adult mosquito populations should be based on a sub-weekly sampling frequency and that predictive models of mosquito abundance must include behavioral dynamics to separate the effects of a varying mosquito activity from actual changes in the abundance of the underlying population.


Pseudogene accumulation in the evolutionary histories of Salmonella enterica serovars Paratyphi A and Typhi.
Of the > 2000 serovars of Salmonella enterica subspecies I, most cause self-limiting gastrointestinal disease in a wide range of mammalian hosts. However, S. enterica serovars Typhi and Paratyphi A are restricted to the human host and cause the similar systemic diseases typhoid and paratyphoid fever. Genome sequence similarity between Paratyphi A and Typhi has been attributed to convergent evolution via relatively recent recombination of a quarter of their genomes. The accumulation of pseudogenes is a key feature of these and other host-adapted pathogens, and overlapping pseudogene complements are evident in Paratyphi A and Typhi. We report the 4.5 Mbp genome of a clinical isolate of Paratyphi A, strain AKU_12601, completely sequenced using capillary techniques and subsequently checked using Illumina/Solexa resequencing. Comparison with the published genome of Paratyphi A ATCC9150 revealed the two are collinear and highly similar, with 188 single nucleotide polymorphisms and 39 insertions/deletions. A comparative analysis of pseudogene complements of these and two finished Typhi genomes (CT18, Ty2) identified several pseudogenes that had been overlooked in prior genome annotations of one or both serovars, and identified 66 pseudogenes shared between serovars. By determining whether each shared and serovar-specific pseudogene had been recombined between Paratyphi A and Typhi, we found evidence that most pseudogenes have accumulated after the recombination between serovars. We also divided pseudogenes into relative-time groups: ancestral pseudogenes inherited from a common ancestor, pseudogenes recombined between serovars which likely arose between initial divergence and later recombination, serovar-specific pseudogenes arising after recombination but prior to the last evolutionary bottlenecks in each population, and more recent strain-specific pseudogenes. Recombination and pseudogene-formation have been important mechanisms of genetic convergence between Paratyphi A and Typhi, with most pseudogenes arising independently after extensive recombination between the serovars. The recombination events, along with divergence of and within each serovar, provide a relative time scale for pseudogene-forming mutations, affording rare insights into the progression of functional gene loss associated with host adaptation in Salmonella.


Evolution in caves: Darwin's 'wrecks of ancient life' in the molecular era.
Cave animals have historically attracted the attention of evolutionary biologists because of their bizarre 'regressive' characters and convergent evolution. However, understanding of their biogeographic and evolutionary history, including mechanisms of speciation, has remained elusive. In the last decade, molecular data have been obtained for subterranean taxa and their surface relatives, which have allowed some of the classical debates on the evolution of cave fauna to be revisited. Here, we review some of the major studies, focusing on the contribution of phylogeography in the following areas: biogeographic history and the relative roles of dispersal and vicariance, colonization history, cryptic species diversity and modes of speciation of cave animals. We further consider the limitations of current research and prospects for the future. Phylogeographic studies have confirmed that cave species are often cryptic, with highly restricted distributions, but have also shown that their divergence and potential speciation may occur despite the presence of gene flow from surface populations. Significantly, phylogeographic studies have provided evidence for speciation and adaptive evolution within the confines of cave environments, questioning the assumption that cave species evolved directly from surface ancestors. Recent technical developments involving 'next generation' DNA sequencing and theoretical developments in coalescent and population modelling are likely to revolutionize the field further, particularly in the study of speciation and the genetic basis of adaptation and convergent evolution within subterranean habitats. In summary, phylogeographic studies have provided an unprecedented insight into the evolution of these unique fauna, and the future of the field should be inspiring and data rich.


Clinical importance of thrombocytopenia in patients with acute coronary syndromes: a systematic review and meta-analysis.
Thrombocytopenia (TP) is common in hospitalized patients. In the context of acute coronary syndromes (ACS), TP has been linked to adverse clinical outcomes. We present a systematic review and meta-analysis of the evidence on the clinical importance of preexisting and in-hospital acquired TP in the context of ACS. Specifically, we address (a) the prevalence and associated factors with TP in the context of ACS; and (b) the association between TP and all-cause mortality, major adverse cardiovascular events (MACEs), and major bleeding. We conducted systematic literature searches in MEDLINE and Web of Science. For the meta-analysis, we fit linear mixed models with a random study-specific intercept for the aggregate outcomes. A total of 16 studies and 190 915 patients were included in this study. Of these patients, 8.8% ± 1.2% presented with preexisting TP while 5.8% ± 1.0% developed TP after hospital admission. Preexisting TP was not statistically significantly associated with adverse outcomes. Acquired TP was associated with greater risk of all-cause mortality (risk difference [RD]: 4.3%; 95% confidence interval [CI]: 2-6%; p = 0.04), MACE (RD: 8.5%; 95% CI: 1-16.0%; p = 0.037), and major bleeding (RD: 11.9%; 95% CI: 5-19%; p = 0.005). In conclusion, TP is a prevalent condition in patients admitted for an ACS and identifies a high-risk patient population more likely to experience ischemic and bleeding complications, as well as higher mortality.


Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner.
Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.


Gene expression profiling of colorectal mucinous adenocarcinomas.
Although mucinous adenocarcinomas represent 6% to 19% of all colorectal adenocarcinomas, little is known about the genome-wide alterations associated with this malignancy. We have sought to characterize both the gene expression profiles of mucinous adenocarcinomas and their clinicopathologic features. Tumors from 171 patients with primary colorectal cancer were profiled using the Affymetrix HG-U133Plus 2.0 GeneChip with characterization of clinicopathologic data. Gene ontology software was used to identify altered biologic pathways. Twenty (11.7%) mucinous adenocarcinomas and 151 (89.3%) nonmucinous adenocarcinomas were identified. Mucinous adenocarcinomas were more likely to be diagnosed with lymph node (LN) metastases (75% vs 51%, P = .04) and at a more advanced stage (85% vs 54%, P = .006) but long-term survival (5-y survival 58.9% vs 58.7%, P = NS) was similar. Mucinous adenocarcinomas displayed 182 upregulated and 135 downregulated genes. The most upregulated genes included those involved in cellular differentiation and mucin metabolism (eg, AQP3 + 4.6, MUC5AC +4.2, MUC2 + 2.8). Altered biologic pathways included those associated with mucin substrate metabolism (P = .002 and .02), amino acid metabolism (P = .02), and the mitogen-activated protein kinase cascade (P = .02). Using gene expression profiling of mucinous adenocarcinomas, we have identified the differential upregulation of genes involved in differentiation and mucin metabolism, as well as specific biologic pathways. These findings suggest that mucinous adenocarcinomas represent a genetically distinct variant of colorectal adencarcinoma and have implications for the development of targeted therapies.


The influence of anatomical noise on optimal beam quality in mammography.
Beam-quality optimization in digital mammography traditionally considers detection of a target obscured by quantum noise in a homogeneous background. This does not correspond well to the clinical imaging task because real mammographic images contain a complex superposition of anatomical structures, resulting in anatomical noise that may dominate over quantum noise. The purpose of this paper is to assess the influence on optimal beam quality in mammography when anatomical noise is taken into account. The detectability of microcalcifications and masses was quantified using a theoretical ideal-observer model that included quantum noise as well as anatomical noise and a simplified model of a photon-counting mammography system. The outcome was experimentally verified using two types of simulated tissue phantoms. The theoretical model showed that the detectability of tumors and microcalcifications behaves differently with respect to beam quality and dose. The results for small microcalcifications were similar to what traditional optimization methods yield, which is to be expected because quantum noise dominates over anatomical noise at high spatial frequencies. For larger tumors, however, low-frequency anatomical noise was the limiting factor. Because anatomical structure noise has similar energy dependence as tumor contrast, the optimal x-ray energy was found to be higher and the useful energy region was wider than traditional methods suggest. A simplified scalar model was able to capture this behavior using a fitted noise mixing parameter. The phantom measurements confirmed these theoretical results. It was shown that since quantum noise constitutes only a small fraction of the noise, the dose could be reduced substantially without sacrificing tumor detectability. Furthermore, when anatomical noise is included, the tube voltage can be increased well beyond what is conventionally considered optimal and used clinically, without loss of image quality. However, no such conclusions can be drawn for the more complex mammographic imaging task as a whole.


Major histocompatibility complex variation in the Arabian oryx.
In the 1960s, the Arabian oryx was one of the most endangered species in the world, extinct in the wild and surviving in only a few captive herds. The present day population of over 2000 descends from a small number of founders and may have restricted genetic variation for important adaptive genes. We have examined the amount of genetic variation for a class II gene in the major histocompatibility complex thought to be the most important genetic basis for pathogen resistance in vertebrates. We found three very divergent alleles, which on average, differed by 24 nucleotides and 15 amino acids in the 236-bp fragment we examined. Using single-strand conformation polymorphism, we found that in a sample of 57 animals, the alleles were in Hardy-Weinberg proportions, although one allele was found only in four heterozygous individuals. The average heterozygosity for the 22 amino acid positions involved in antigen binding was 0.165, three times as high as that for the 56 amino acids not involved with antigen binding. Because the three alleles have such divergent sequences, it is likely that they may recognize peptides from quite different pathogens. As a result, maintenance of these variants should be considered as a goal in the captive breeding program of the Arabian oryx.


Streptococcus pneumoniae Eradicates Preformed Staphylococcus aureus Biofilms through a Mechanism Requiring Physical Contact.
Staphylococcus aureus (Sau) strains are a main cause of disease, including nosocomial infections which have been linked to the production of biofilms and the propagation of antibiotic resistance strains such as methicillin-resistant Staphylococcus aureus (MRSA). A previous study found that Streptococcus pneumoniae (Spn) strains kill planktonic cultures of Sau strains. In this work, we have further evaluated in detail the eradication of Sau biofilms and investigated ultrastructural interactions of the biofilmicidal effect. Spn strain D39, which produces the competence stimulating peptide 1 (CSP1), reduced Sau biofilms within 8 h of inoculation, while TIGR4, producing CSP2, eradicated Sau biofilms and planktonic cells within 4 h. Differences were not attributed to pherotypes as other Spn strains producing different pheromones eradicated Sau within 4 h. Experiments using Transwell devices, which physically separated both species growing in the same well, demonstrated that direct contact between Spn and Sau was required to efficiently eradicate Sau biofilms and biofilm-released planktonic cells. Physical contact-mediated killing of Sau was not related to production of hydrogen peroxide as an isogenic TIGR4ΔspxB mutant eradicated Sau bacteria within 4 h. Confocal micrographs confirmed eradication of Sau biofilms by TIGR4 and allowed us to visualize ultrastructural point of contacts between Sau and Spn. A time-course study further demonstrated spatial colocalization of Spn chains and Sau tetrads as early as 30 min post-inoculation (Pearson's coefficient >0.72). Finally, precolonized biofilms produced by Sau strain Newman, or MRSA strain USA300, were eradicated by mid-log phase cultures of washed TIGR4 bacteria within 2 h post-inoculation. In conclusion, Spn strains rapidly eradicate pre-colonized Sau aureus biofilms, including those formed by MRSA strains, by a mechanism(s) requiring bacterium-bacterium contact, but independent from the production of hydrogen peroxide.


Subsets of tumors responsive to cisplatin or carboplatin combinations in patients with carcinoma of unknown primary site. A Hellenic Cooperative Oncology Group Study.
In this retrospective analysis 48 patients with metastatic undifferentiated carcinoma, adenocarcinoma and epidermoid carcinoma of unknown origin were studied. The purpose of this analysis was to evaluate both the response rate and the toxicity of combination chemotherapy containing cisplatin or carboplatin, and to attempt to identify certain clinical subsets of patients sensitive to these drugs. Four patients were not evaluable and 13 (29.5%), eight of the 34 treated with regimens containing cisplatin and 5/14 with carboplatin-based chemotherapy, responded to treatment. Six of the 23 with undifferentiated tumours, 4/17 with adenocarcinomas and 3/8 with epidermoid cancers responded to chemotherapy. Four of 6 women with adenocarcinoma of the peritoneal cavity, 5/11 with undifferentiated carcinomas with midline distribution and 3/5 with epidermoid carcinomas of the cervical nodes responded. Seven patients achieved complete and six partial remissions. The mean duration of response was nine months; a number of patients enjoyed prolonged and/or durable remissions. Toxicity was tolerable. We conclude that: (a) both cisplatin and carboplatin are active agents in this syndrome with one-third of the evaluable patients responding, and (b) there may be chemosensitive subgroups, such as patients with peritoneal adenocarcinomatosis, undifferentiated carcinoma with midline distribution and metastatic epidermoid carcinoma of the neck nodes. The effectiveness of carboplatin in these patients and the responsiveness of metastatic epidermoid carcinoma of unknown origin have not been adequately dealt with in the literature.


Navigating through incontinence: A qualitative systematic review and meta-aggregation of the experiences of family caregivers.
Community dwelling older adults who are care dependent are highly affected by incontinence, resulting in substantial informal caregiver burden. Understanding the experiences of these caregivers is needed to develop supportive programs that reduce caregiver burden and rates of institutionalization for care recipients. This systematic review aimed to critically appraise and synthesize the qualitative literature on the perceptions, experiences, and consequences of informal caregivers managing incontinence in community dwelling older adults. A qualitative evidence synthesis using meta-aggregation. CINAHL, Embase, Ovid Medline, PsycInfo, Scopus, and ProQuest Dissertations and Theses. A comprehensive search was conducted to identify qualitative studies of all designs, published in English from January 1970 to November 2020, reporting on the experiences of unpaid adult family members or friends providing care at home to an adult aged 60 or older with urinary and/or fecal incontinence. Screening, data extraction, and quality appraisal were conducted independently by two reviewers, with disagreements resolved by consensus with all team members. Joanna Briggs Institute (JBI) processes were used to assess study quality, and the dependability and credibility of both study findings and synthesized findings. All articles included met predetermined criteria. Database searches yielded 1165 references, of which 117 full-text documents were screened. Seven articles of moderate to high methodological quality met eligibility criteria and were included. Studies occurred in nine countries with 134 participants who were mostly female spouses of the care recipient. From these eligible studies, 49 findings were extracted with 35 equivocal or credible findings eligible for meta-aggregation. Findings were synthesized into the following four categories: 1) emotional responses, 2) physical, financial, and social consequences, 3) family roles and caregiver support, and 4) management and coping strategies. Informal caregivers experience many physical, psychosocial, and financial challenges in caring for an older family member with incontinence. Educational and supportive programs for managing incontinence should be multi-component and tailored to meet the individual needs of informal caregivers. Future research should incorporate strategies to cope with emotional responses and offer practical strategies for managing incontinence. CRD42017069185.


Complete plastid genome sequences of three Rosids (Castanea, Prunus, Theobroma): evidence for at least two independent transfers of rpl22 to the nucleus.
Functional gene transfer from the plastid to the nucleus is rare among land plants despite evidence that DNA transfer to the nucleus is relatively frequent. During the course of sequencing plastid genomes from representative species from three rosid genera (Castanea, Prunus, Theobroma) and ongoing projects focusing on the Fagaceae and Passifloraceae, we identified putative losses of rpl22 in these two angiosperm families. We further characterized rpl22 from three species of Passiflora and one species of Quercus and identified sequences that likely represent pseudogenes. In Castanea and Quercus, both members of the Fagaceae, we identified a nuclear copy of rpl22, which consisted of two exons separated by an intron. Exon 1 encodes a transit peptide that likely targets the protein product back to the plastid and exon 2 encodes rpl22. We performed phylogenetic analyses of 97 taxa, including 93 angiosperms and four gymnosperm outgroups using alignments of 81 plastid genes to examine the phylogenetic distribution of rpl22 loss and transfer to the nucleus. Our results indicate that within rosids there have been independent transfers of rpl22 to the nucleus in Fabaceae and Fagaceae and a putative third transfer in Passiflora. The high level of sequence divergence between the transit peptides in Fabaceae and Fagaceae strongly suggest that these represent independent transfers. Furthermore, Blast searches did not identify the "donor" genes of the transit peptides, suggesting a de novo origin. We also performed phylogenetic analyses of rpl22 for 87 angiosperms and four gymnosperms, including nuclear-encoded copies for five species of Fabaceae and Fagaceae. The resulting trees indicated that the transfer of rpl22 to the nucleus does not predate the origin of angiosperms as suggested in an earlier study. Using previously published angiosperm divergence time estimates, we suggest that these transfers occurred approximately 56-58, 34-37, and 26-27 Ma for the Fabaceae, Fagaceae, and Passifloraceae, respectively.


The discordant histology of grafted fat: a systematic review of the literature.
All combinations of harvesting, processing, and injection have been attempted to maximize fat graft take following transplantation. Two theories behind fat transplantation have been proposed: cell survival and host replacement. Although the cell survival theory states that fat cells survive and undergo neovascularization following transfer, host replacement theory predicts adipocyte necrosis and replacement of cells by host tissues. Whether or not transferred fat survives, proliferates, or is replaced by fibrous tissue is relevant for the investment of future resources into this thriving field of research. A literature search of the MEDLINE and Cochrane databases was performed for studies focusing on the histology of grafted fat after transplantation up to December of 2013. Histologic examinations of grafted fat were reviewed and compared in humans and animals. Sixty-six articles met inclusion criteria, and eight of them were human studies. There was widespread diversity in the method of fat harvest and transfer among the studies, and the date of examination after transfer. Many studies reported the presence of viable adipocytes, although an extensive amount of fibrosis and inflammatory infiltration was also seen, depending on the period of examination. Free fat grafts show a variable response following transplantation, with significant disagreement in the reported evidence. Although neovascularization and preservation of adipocyte architecture appear possible, other fat grafts are completely replaced by necrotic ghost cells and fibrotic ingrowth. Adipocyte survival likely contributes to volume maintenance, but fibrosis may also play a role.


Enantiopure, supramolecular helices containing three-dimensional tetranuclear lanthanide(III) arrays: synthesis, structure, properties, and solvent-driven trinuclear/tetranuclear interconversion.
The enantiomerically pure pinene-bipyridine-based receptor, (-) or (+) L(-), diastereoselectively self-assembles in dry acetonitrile in the presence of Ln(III) ions (Ln = La, Pr, Nd, Sm, Eu, Gd, and Tb) to give a C3-symmetrical, pyramidal architecture with the general formula [Ln4(L)9(mu3-OH)](ClO4)2) (abbreviated as tetra-Ln4L9). Three metal centers shape the base: an equilateral triangle surrounded by two sets of helically wrapping ligands with opposite configurations. This part of the structure is very similar to the species [Ln3(L)6(mu3-OH)(H2O)3](ClO4)2) (recently reported by us and abbreviated as tris-LnL2) formed by the ligand and the Ln(III) ions when the reactions are performed in methanol. The tetranuclear structure is completed by a capping, helical unit LnL3 whose chirality is also predetermined by the chirality of the ligand. A complete characterization of these isostructural, chiral compounds was performed in solid state (X-ray, IR) and in solution (ES-MS, NMR, CD, UV-vis and emission spectroscopies). The sign and the intensity of the CD bands in the region of the pi pi* transitions of the bipyridine (absolute Delta epsilon values at 327 nm are about 280 M(-1) x cm(-1)) are highly influenced by the helicity of the capping fragment LnL3. The photophysical properties (lifetime, quantum yield) of the visible (Eu and Tb complexes) and NIR (Nd complex) emitters indicate a good energy transfer between the ligands and the metal centers. The two related superstructures tetra-Ln4L9 and tris-LnL2 can be interconverted in acetonitrile, the switching process depending on the amount of water present in the solvent, the size of the Ln(III) ion, and the concentration. The weak chiral recognition capabilities of the self-assembly leading to the formation of tetra-Ln4L9 either by direct synthesis from a racemic mixture of the ligand and Ln(III) ions or by the conversion of a tris-Ln[(+/-)-L]2 racemate were likewise demonstrated.


Grape seed proanthocyanidin supplementation reduces adipocyte size and increases adipocyte number in obese rats.
White adipose tissue (WAT) expands through hypertrophy (increased adipocyte size) and/or hyperplasia (increased adipocyte number). Hypertrophy has been associated with insulin resistance and dyslipidemia independently of body composition and fat distribution. In contrast, hyperplasia protects against metabolic alterations. Proanthocyanidins, which are the most abundant flavonoids in the human diet, improve metabolic disturbances associated with diet-induced obesity without reducing body weight or adiposity. The aim of this study was to determine whether grape seed proanthocyanidin extract (GSPE) can modulate WAT expandability. Because GSPE also contains gallic acid, we also studied the capacity of gallic acid to remodel WAT. Male Wistar rats were fed a standard chow diet (n=6) or a cafeteria diet (CAF) for 11 weeks. After 8 weeks, the CAF-fed animals were supplemented with 25 mg GSPE/kg body weight (n=6), 7 mg gallic acid/kg body weight (n=6) or the vehicle (n=6) for 3 weeks. Histological analyses were performed in the retroperitoneal (rWAT) and inguinal (iWAT) WAT to determine adipocyte size and number. Specific markers for adipogenesis and WAT functionality were analysed in rWAT using quantitative RT-PCR. GSPE or gallic acid supplementation did not reduce weight gain or reverse and adiposity. However, GSPE reduced adipocyte size significantly in rWAT and moderately in iWAT and tripled the adipocyte number in rWAT. Gallic acid slightly reduced adipocyte size in rWAT and iWAT and doubled the adipocyte number in both WATs. In accordance with this adipogenic activity, Pref-1 and PPARγ tended to be overexpressed in rWAT of rats supplemented with GSPE. Moreover, GSPE supplementation increased Plin1 and Fabp4 expression and restored adiponectin expression completely, indicating a better functionality of visceral WAT. GSPE supplementation has anti-hypertrophic and hyperplasic activities in rats with established obesity, mainly in visceral WAT inducing a healthier expansion of WAT to match the surplus energy provided by the cafeteria diet.


Myricetin inhibits matrix metalloproteinase 2 protein expression and enzyme activity in colorectal carcinoma cells.
Colorectal carcinoma is a leading cause of human mortality due to its high metastatic ability. Because the activation of matrix metalloproteinases (MMP) is a key factor in the metastatic process, agents with the ability to inhibit MMP activity have potential in the treatment of colorectal carcinoma. In the present study, among 36 flavonoids examined, myricetin was found to be the most potent inhibitor of MMP-2 enzyme activity in COLO 205 cells (IC50 = 7.82 micromol/L). Myricetin inhibition of MMP-2 enzyme activity was also found in the human colorectal carcinoma cell lines COLO 320HSR, COLO 320DM, HT 29, and COLO 205-X (IC50 = 11.18, 11.56, 13.25, and 23.51 micromol/L, respectively). In contrast, no inhibitory effect of MMP-2 protein expression or enzyme activity was observed in myricitrin (myricetin-3-rhamnoside)-treated cells. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated COLO 205 cells, an increase in MMP-2 protein expression and enzyme activity, as well as of protein kinase C (PKC) alpha protein translocation, extracellular signal-regulated kinase (ERK) 1/2 protein phosphorylation, and c-Jun protein expression was observed. ERK inhibitor (PD98059) and PKC inhibitors (GF-109203X and H-7), but not p38 inhibitor (SB203580) or c-jun-NH2-kinase inhibitor (SP600125), significantly inhibited TPA-induced MMP-2 protein expression, with reduced ERK phosphorylation and c-Jun protein expression. Addition of myricetin but not myricitrin suppressed TPA-induced MMP-2 protein expression in COLO 205 cells by blocking the TPA-induced events, including translocation of PKCalpha from cytosol to membrane, phosphorylation of ERK1/2 protein, and induction of c-Jun protein expression. Addition of PD98059 or GF-109203X significantly enhanced the inhibitory effect of myricetin on MMP-2 enzyme activity induced by TPA. Furthermore, myricetin, but not myricitrin, suppressed TPA-induced invasion of COLO 205 cells in an in vitro invasion assay using Engelbreth-Holm-Swarm sarcoma tumor extract Matrigel-coated Transwells. Results of the present study indicate that myricetin significantly blocked both endogenous and TPA-induced MMP-2 enzyme activity by inhibiting its protein expression and enzyme activity. The blockade involved suppression of PKC translocation, ERK phosphorylation, and c-Jun protein expression.


Revised nomenclature for avian telencephalon and some related brainstem nuclei.
The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is based on flawed assumptions of homology to mammals. In particular, the outdated terminology implies that most of the avian telencephalon is a hypertrophied basal ganglia, when it is now clear that most of the avian telencephalon is neurochemically, hodologically, and functionally comparable to the mammalian neocortex, claustrum, and pallial amygdala (all of which derive from the pallial sector of the developing telencephalon). Recognizing that this promotes misunderstanding of the functional organization of avian brains and their evolutionary relationship to mammalian brains, avian brain specialists began discussions to rectify this problem, culminating in the Avian Brain Nomenclature Forum held at Duke University in July 2002, which approved a new terminology for avian telencephalon and some allied brainstem cell groups. Details of this new terminology are presented here, as is a rationale for each name change and evidence for any homologies implied by the new names. Revisions for the brainstem focused on vocal control, catecholaminergic, cholinergic, and basal ganglia-related nuclei. For example, the Forum recognized that the hypoglossal nucleus had been incorrectly identified as the nucleus intermedius in the Karten and Hodos (1967) pigeon brain atlas, and what was identified as the hypoglossal nucleus in that atlas should instead be called the supraspinal nucleus. The locus ceruleus of this and other avian atlases was noted to consist of a caudal noradrenergic part homologous to the mammalian locus coeruleus and a rostral region corresponding to the mammalian A8 dopaminergic cell group. The midbrain dopaminergic cell group in birds known as the nucleus tegmenti pedunculopontinus pars compacta was recognized as homologous to the mammalian substantia nigra pars compacta and was renamed accordingly; a group of gamma-aminobutyric acid (GABA)ergic neurons at the lateral edge of this region was identified as homologous to the mammalian substantia nigra pars reticulata and was also renamed accordingly. A field of cholinergic neurons in the rostral avian hindbrain was named the nucleus pedunculopontinus tegmenti, whereas the anterior nucleus of the ansa lenticularis in the avian diencephalon was renamed the subthalamic nucleus, both for their evident mammalian homologues. For the basal (i.e., subpallial) telencephalon, the actual parts of the basal ganglia were given names reflecting their now evident homologues. For example, the lobus parolfactorius and paleostriatum augmentatum were acknowledged to make up the dorsal subdivision of the striatal part of the basal ganglia and were renamed as the medial and lateral striatum. The paleostriatum primitivum was recognized as homologous to the mammalian globus pallidus and renamed as such. Additionally, the rostroventral part of what was called the lobus parolfactorius was acknowledged as comparable to the mammalian nucleus accumbens, which, together with the olfactory tubercle, was noted to be part of the ventral striatum in birds. A ventral pallidum, a basal cholinergic cell group, and medial and lateral bed nuclei of the stria terminalis were also recognized. The dorsal (i.e., pallial) telencephalic regions that had been erroneously named to reflect presumed homology to striatal parts of mammalian basal ganglia were renamed as part of the pallium, using prefixes that retain most established abbreviations, to maintain continuity with the outdated nomenclature. We concluded, however, that one-to-one (i.e., discrete) homologies with mammals are still uncertain for most of the telencephalic pallium in birds and thus the new pallial terminology is largely devoid of assumptions of one-to-one homologies with mammals. The sectors of the hyperstriatum composing the Wulst (i.e., the hyperstriatum accessorium intermedium, and dorsale), the hyperstriatum ventrale, the neostriatum, and the archistriatum have been renamed (respectively) the hyperpallium (hypertrophied pallium), the mesopallium (middle pallium), the nidopallium (nest pallium), and the arcopallium (arched pallium). The posterior part of the archistriatum has been renamed the posterior pallial amygdala, the nucleus taeniae recognized as part of the avian amygdala, and a region inferior to the posterior paleostriatum primitivum included as a subpallial part of the avian amygdala. The names of some of the laminae and fiber tracts were also changed to reflect current understanding of the location of pallial and subpallial sectors of the avian telencephalon. Notably, the lamina medularis dorsalis has been renamed the pallial-subpallial lamina. We urge all to use this new terminology, because we believe it will promote better communication among neuroscientists. Further information is available at http://avianbrain.org


Protein Adsorption Patterns and Analysis on IV Nanoemulsions-The Key Factor Determining the Organ Distribution.
Intravenous nanoemulsions have been on the market for parenteral nutrition since the 1950s; meanwhile, they have also been used successfully for IV drug delivery. To be well tolerable, the emulsions should avoid uptake by the MPS cells of the body; for drug delivery, they should be target-specific. The organ distribution is determined by the proteins adsorbing them after injection from the blood (protein adsorption pattern), typically analyzed by two-dimensional polyacrylamide gel electrophoresis, 2-D PAGE. The article reviews the 2-D PAGE method, the analytical problems to be faced and the knowledge available on how the composition of emulsions affects the protein adsorption patterns, e.g., the composition of the oil phase, stabilizer layer and drug incorporation into the interface or oil core. Data were re-evaluated and compared, and the implications for the in vivo distribution are discussed. Major results are that the interfacial composition of the stabilizer layer is the main determining factor and that this composition can be modulated by simple processes. Drug incorporation affects the pattern depending on the localization of the drug (oil core versus interface). The data situation regarding in vivo effects is very limited; mainly, it has to be referred to in the in vivo data of polymeric nanoparticles. As a conclusion, determination of the protein adsorption patterns can accelerate IV nanoemulsion formulation development regarding optimized organ distribution and related pharmacokinetics.


Are interstitial cells of Cajal involved in mechanical stress-induced gene expression and impairment of smooth muscle contractility in bowel obstruction?
The network of interstitial cells of Cajal (ICC) is altered in obstructive bowel disorders (OBD). However, whether alteration in ICC network is a cause or consequence of OBD remains unknown. This study tested the hypothesis that mechanical dilation in obstruction disrupts the ICC network and that ICC do not mediate mechanotranscription of COX-2 and impairment of smooth muscle contractility in obstruction. Medical-grade silicon bands were wrapped around the distal colon to induce partial obstruction in wild-type and ICC deficient (W/W(v)) mice. In wild-type mice, colon obstruction led to time-dependent alterations of the ICC network in the proximal colon segment. Although unaffected on days 1 and 3, the ICC density decreased markedly and the network was disrupted on day 7 of obstruction. COX-2 expression increased, and circular muscle contractility decreased significantly in the segment proximal to obstruction. In W/W(v) control mice, COX-2 mRNA level was 4.0 (±1.1)-fold higher (n=4) and circular muscle contractility was lower than in wild-type control mice. Obstruction further increased COX-2 mRNA level in W/W(v) mice to 7.2 (±1.0)-fold vs. W/W(v) controls [28.8 (±4.1)-fold vs. wild-type controls] on day 3. Obstruction further suppressed smooth muscle contractility in W/W(v) mice. However, daily administration of COX-2 inhibitor NS-398 significantly improved muscle contractility in both W/W(v) sham and obstruction mice. Lumen dilation disrupts the ICC network. ICC deficiency has limited effect on stretch-induced expression of COX-2 and suppression of smooth muscle contractility in obstruction. Rather, stretch-induced COX-2 plays a critical role in motility dysfunction in partial colon obstruction.


Motor-Imagery EEG-Based BCIs in Wheelchair Movement and Control: A Systematic Literature Review.
The pandemic emergency of the coronavirus disease 2019 (COVID-19) shed light on the need for innovative aids, devices, and assistive technologies to enable people with severe disabilities to live their daily lives. EEG-based Brain-Computer Interfaces (BCIs) can lead individuals with significant health challenges to improve their independence, facilitate participation in activities, thus enhancing overall well-being and preventing impairments. This systematic review provides state-of-the-art applications of EEG-based BCIs, particularly those using motor-imagery (MI) data, to wheelchair control and movement. It presents a thorough examination of the different studies conducted since 2010, focusing on the algorithm analysis, features extraction, features selection, and classification techniques used as well as on wheelchair components and performance evaluation. The results provided in this paper could highlight the limitations of current biomedical instrumentations applied to people with severe disabilities and bring focus to innovative research topics.


The use of Nanotrap particles for biodefense and emerging infectious disease diagnostics.
Detection of early infectious disease may be challenging due to the low copy number of organisms present. To overcome this limitation and rapidly measure low concentrations of the pathogen, we developed a novel technology: Nanotrap particles, which are designed to capture, concentrate, and protect biomarkers from complex biofluids. Nanotrap particles are thermoresponsive hydrogels that are capable of antigen capture through the coupling of affinity baits to the particles. Here, we describe recent findings demonstrating that Nanotrap particles are able to capture live infectious virus, viral RNA, and viral proteins. Capture is possible even in complex mixtures such as serum and allows the concentration and protection of these analytes, providing increased performance of downstream assays. The Nanotrap particles are a versatile sample preparation technology that has far reaching implications for biomarker discovery and diagnostic assays.


Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain.
Excessive erythrocytosis results in severely increased blood viscosity that may compromise the vascular endothelium. Using our transgenic mouse model of excessive erythrocytosis we previously showed that despite altered brain endothelial cell morphology and an activated vasculature, brain vascular integrity was largely maintained up to 4-5 months of age. We now present data showing that persistent long-term damage of the vascular wall during the later stages of adulthood (9-12 months) results in a chronic detrimental inflammatory phenotype and increased vessel permeability that likely contributes to the reduced life span of our erythropoietin overexpressing transgenic mouse. In aged transgenic animals inflammatory cells were detected in brain tissue and elevated RNA and protein levels of inflammatory markers such as IL-6 and TNFα were observed in both brain tissue and blood plasma. Additionally, increased expression of p53 and other pro-apoptotic markers, as well as decreased Bcl-xL expression in the brain vasculature, indicated ongoing cell death within the vascular compartment. Finally, abnormally elevated vascular permeability in all organs was detected in correlation with decreased expression of the tight junction protein occludin and the adherens junction protein β-catenin in brain. Thus chronic erythrocytosis results in sustained activation of inflammatory pathways, vascular dysfunction and blood-brain barrier disruption.


Evolution of a Catalytic Mechanism.
The means by which superfamilies of specialized enzymes arise by gene duplication and functional divergence are poorly understood. The escape from adaptive conflict hypothesis, which posits multiple copies of a gene encoding a primitive inefficient and highly promiscuous generalist ancestor, receives support from experiments showing that resurrected ancestral enzymes are indeed more substrate-promiscuous than their modern descendants. Here, we provide evidence in support of an alternative model, the innovation-amplification-divergence hypothesis, which posits a single-copied ancestor as efficient and specific as any modern enzyme. We argue that the catalytic mechanisms of plant esterases and descendent acetone cyanohydrin lyases are incompatible with each other (e.g., the reactive substrate carbonyl must bind in opposite orientations in the active site). We then show that resurrected ancestral plant esterases are as catalytically specific as modern esterases, that the ancestor of modern acetone cyanohydrin lyases was itself only very weakly promiscuous, and that improvements in lyase activity came at the expense of esterase activity. These observations support the innovation-amplification-divergence hypothesis, in which an ancestor gains a weak promiscuous activity that is improved by selection at the expense of the ancestral activity, and not the escape from adaptive conflict in which an inefficient generalist ancestral enzyme steadily loses promiscuity throughout the transition to a highly active specialized modern enzyme.


Transitions in bacterial communities along the 2000 km salinity gradient of the Baltic Sea.
Salinity is a major factor controlling the distribution of biota in aquatic systems, and most aquatic multicellular organisms are either adapted to life in saltwater or freshwater conditions. Consequently, the saltwater-freshwater mixing zones in coastal or estuarine areas are characterized by limited faunal and floral diversity. Although changes in diversity and decline in species richness in brackish waters is well documented in aquatic ecology, it is unknown to what extent this applies to bacterial communities. Here, we report a first detailed bacterial inventory from vertical profiles of 60 sampling stations distributed along the salinity gradient of the Baltic Sea, one of world's largest brackish water environments, generated using 454 pyrosequencing of partial (400 bp) 16S rRNA genes. Within the salinity gradient, bacterial community composition altered at broad and finer-scale phylogenetic levels. Analogous to faunal communities within brackish conditions, we identified a bacterial brackish water community comprising a diverse combination of freshwater and marine groups, along with populations unique to this environment. As water residence times in the Baltic Sea exceed 3 years, the observed bacterial community cannot be the result of mixing of fresh water and saltwater, but our study represents the first detailed description of an autochthonous brackish microbiome. In contrast to the decline in the diversity of multicellular organisms, reduced bacterial diversity at brackish conditions could not be established. It is possible that the rapid adaptation rate of bacteria has enabled a variety of lineages to fill what for higher organisms remains a challenging and relatively unoccupied ecological niche.


Impact of the FindMyApps program on people with mild cognitive impairment or dementia and their caregivers; an exploratory pilot randomised controlled trial.
FindMyApps is a web-based selection-tool and errorless learning training program to help people with mild dementia/Mild Cognitive Impairment (MCI) and caregivers find user-friendly apps. In preparation of a definitive trial, the impact and feasibility of the FindMyApps intervention on self-management and engagement in meaningful activities, including social participation, was explored. An exploratory pilot randomised controlled trial (trial registration approval number: NL7210) with pre/post measurements was conducted with community-dwelling people with mild dementia/MCI and their caregivers (n = 59) in the Netherlands. Dyads in the experimental group (n = 28) received training to use the tablet and FindMyApps, and the errorless learning method was taught to their caregivers. Control group dyads (n = 31) received a tablet (without FindMyApps), instructions on tablet-use and links to dementia-friendly apps. Validated instruments were used to assess person with dementia's self-management, meaningful activities and social participation, caregiver's sense of competence and both their quality of life. No statistical significant group differences on the outcomes were found. Small to moderate effect-sizes in favour of the FindMyApps group were found for self-management and social participation. Caregivers tended to have more positive care experiences. Subgroup analyses showed that people older than 70 benefitted more from FindMyApps regarding self-management and higher educated people benefitted more regarding social participation. FindMyApps is feasible for the target group and may have potential to improve self-management and social participation. For a future definitive effectiveness trial a larger sample size is recommended, as well as taking into account the possible impact of education and age.IMPLICATIONS FOR REHABILITATIONThe FindMyApps program is feasible for people with dementia/MCI and may have potential to improve their self-management and social participation.Informal caregivers may develop a more positive care experience when utilizing FindMyApps to find suitable apps for self-management and social participation for the person with dementia/MCI.


An initial-fit comparison of two generic hearing aid prescriptive methods (NAL-NL2 and CAM2) to individuals having mild to moderately severe high-frequency hearing loss.
Johnson and Dillon (2011) provided a model-based comparison of current generic hearing aid prescriptive methods for adults with hearing loss based on the attributes of speech intelligibility, loudness, and bandwidth. This study compared the National Acoustic Laboratories-Non-linear 2 (NAL-NL2) and Cambridge Method for Loudness Equalization 2-High-Frequency (CAM2) prescriptive methods using adult participants with less high-frequency hearing loss than Johnson and Dillon (2011). Of study interest was quantification of prescribed audibility, speech intelligibility, and loudness. The preferences of participants for either NAL-NL2 or CAM2 and preferred deviations from prescribed settings are also reported. Using a single-blind, counter-balanced, randomized design, preference judgments for the prescriptive methods with regard to sound quality of speech and music stimuli were obtained. Preferred gain adjustments from the prescription within the 4-10 kHz frequency range were also obtained from each participant. Speech intelligibility and loudness model calculations were completed on the prescribed and adjusted amplification. Fourteen male Veterans, whose average age was 65 yr and whose hearing sensitivity averaged normal to borderline normal through 1000 Hz sloping to a moderately severe sensorineural loss, served as participants. Following a brief listening time (~10 min), typical of an initial fitting visit, the participants made paired comparison of sound quality between the NAL-NL2 and CAM2 prescriptive settings. Participants were also asked to modify each prescription in the range of 4-10 kHz using an overall gain control and make subsequent comparisons of sound quality preference between prescriptive and adjusted settings. Participant preferences were examined with respect to quantitative analysis of loudness modeling, speech intelligibility modeling, and measured high-frequency bandwidth audibility. Consistent with the lack of difference in predicted speech intelligibility between the two prescriptions, sound quality preferences on the basis of clarity were split across participants while some participants did not have a discernable preference. Considering sound quality judgments of pleasantness, the majority of participants preferred the sound quality of the NAL-NL2 (8 of 14) prescription instead of the CAM2 prescription (2 of 14). Four of the 14 participants showed no preference on the basis of pleasantness for either prescription. Individual subject preferences were supported by loudness modeling that indicated NAL-NL2 was the softer of the two prescriptions and CAM2 was the louder. CAM2 did provide more audibility to the higher frequencies (5-8 kHz) than NAL-NL2. Participants turned the 4-10 kHz gain recommendation of CAM2 lower, on average, by a significant amount of 4 dB when making adjustments while no significant adjustment was made to the initial NAL-NL2 recommendation. NAL-NL2 prescribed gains were more often preferred at the initial fitting by the majority of participating veterans. For those patients with preference for a louder fitting than NAL-NL2, CAM2 is a good alternative. When the participant adjustment from the prescription between 4 and 10 kHz exceeded 4 dB from either NAL-NL2 (2 of 14) or CAM2 (11 of 14), the participants demonstrated a later preference for that adjustment 69% of the time. These findings are viewed as limited evidence that some individuals may have a preference for high-frequency gain that differs from the starting prescription.


The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells.
The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β2-adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during ADT and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and neuroendocrine genes. ADRB2 overexpression induced a neuroendocrine-like morphology in both androgen receptor (AR)-positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and neuroendocrine genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence. IMPLICATIONS: This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC.


Genetic structure of Neisseria meningitidis populations in relation to serogroup, serotype, and outer membrane protein pattern.
The genetic structure of populations of Neisseria meningitidis was examined by an analysis of electrophoretically demonstrable allelic variation at 15 genes encoding enzymes in 650 isolates of eight serogroups (A, B, C, W135, X, Y, Z, and 29E) and 38 nonserogroupable isolates. A total of 331 distinctive multilocus genotypes (electrophoretic types, ETs) was identified, among which mean genetic diversity per locus (H = 0.547) was greater than in Escherichia coli and other bacterial species thus far studied. The intercontinental distribution of some ETs and the recovery of organisms of identical genotype over periods of many years strongly suggest that the genetic structure of N. meningitidis is basically clonal as a consequence of low rates of recombination of chromosomal genes. Variation among strains in serogroup, serotype, and the electrophoretic pattern of the major outer membrane proteins has little relationship to the complex structure of populations revealed by enzyme electrophoresis, which involves 14 major lineages of clones diverging from one another at genetic distances greater than 0.50. Genetic diversity among ETs of isolates of the same serogroup was, on average, 84% of that in the total sample. Clones of serogroup A were unusual in being genotypically less heterogeneous than those of other serogroups and in forming a single phylogenetic group. Isolates of the same serotype or outer membrane protein pattern were also highly heterogeneous; on average, 87 and 97%, respectively, of the total species diversity was represented by ETs of the same serotype or outer membrane protein.