Starch synthesis in transgenic potato tubers with increased 3-phosphoglyceric acid content as a consequence of increased 6-phosphofructokinase activity.
The aim of this work was to test the hypothesis that changes in cytosolic 3-phosphoglyceric acid (3-PGA) content can regulate the rate of starch synthesis in potato (Solanum tuberosum L.) tubers. The amount of 3-PGA was increased by expressing bacterial phosphofructokinase (PFK; EC 184.108.40.206) in transgenic potato tubers. The resultant 3-fold increase in PFK activity was accompanied by an increase in metabolites downstream of PFK, including a 3-fold increase in 3-PGA. There was also a decrease in metabolites upstream of PFK, most notably of glucose-6-phosphate. The increase in 3-PGA did not affect the amount of starch that accumulated in developing tubers, nor its rate of synthesis in tuber discs cut from developing tubers. This suggests that changes in cytosolic 3-PGA may not affect the rate of starch synthesis under all circumstances. We propose that in this case, a decrease in glucose-6-phosphate (which is transported into the amyloplast as a substrate for starch synthesis) may be sufficient to counteract the effect of increased 3-PGA.


Efficient implementation of the pair atomic resolution of the identity approximation for exact exchange for hybrid and range- separated density functionals.
An efficient new molecular orbital (MO) basis algorithm is reported implementing the pair atomic resolution of the identity approximation (PARI) to evaluate the exact exchange contribution (K) to self-consistent field methods, such as hybrid and range-separated hybrid density functionals. The PARI approximation, in which atomic orbital (AO) basis function pairs are expanded using auxiliary basis functions centered only on their two respective atoms, was recently investigated by Merlot et al. [J. Comput. Chem. 2013, 34, 1486]. Our algorithm is significantly faster than quartic scaling RI-K, with an asymptotic exchange speedup for hybrid functionals of (1 + X/N), where N and X are the AO and auxiliary basis dimensions. The asymptotic speedup is 2 + 2X/N for range separated hybrids such as CAM-B3LYP, ωB97X-D, and ωB97X-V which include short- and long-range exact exchange. The observed speedup for exchange in ωB97X-V for a C68 graphene fragment in the cc-pVTZ basis is 3.4 relative to RI-K. Like conventional RI-K, our method greatly outperforms conventional integral evaluation in large basis sets; a speedup of 19 is obtained in the cc-pVQZ basis on a C54 graphene fragment. Negligible loss of accuracy relative to exact integral evaluation is demonstrated on databases of bonded and nonbonded interactions. We also demonstrate both analytically and numerically that the PARI-K approximation is variationally stable.


Creating a culture of safety within operative neurosurgery: the design and implementation of a perioperative safety video.
Surgical and medical errors result from failures in communication and handoffs as well as lack of standardization in clinical protocols and safety practices. Checklists, simulation training, and teamwork training have been shown to decrease adverse patient events and increase the safety culture of surgical teams. The goal of this project was to simplify and standardize perioperative patient safety practices and team communication processes within operative neurosurgery through the creation of an educational safety video targeted at a neurosurgical provider audience. A multidisciplinary group consisting of neurosurgeons, anesthesiologists, nurses, neuromonitoring specialists, quality champions, and a professional video production company met over several months in an iterative process to 1) determine the overall objectives of the video, 2) decide on the content and format of the video, 3) modify the proposed content and format based on stakeholder feedback, and 4) record the video and complete final revisions during postproduction. The video was launched within the authors' institution in July 2012 in conjunction with ongoing research projects to study the effects of the video on 1) multidisciplinary providers' knowledge of perioperative safety practices, 2) provider safety attitudes and safety culture in the operating room, and 3) provider behavior in performing predetermined elements of the preoperative timeout and postoperative debrief. The neurosurgical perioperative safety video can serve as a national model for how quality champions can drive changes in safety culture and provider behavior among multidisciplinary perioperative patient care teams. Ongoing research is being performed to assess the impact of the video on provider knowledge, behavior, and safety attitudes and culture.


Measurement of methyl axis orientations in invisible, excited states of proteins by relaxation dispersion NMR spectroscopy.
Few detailed studies of transiently populated conformations of biological molecules have emerged despite the fact that such states are often important to processes such as protein folding, enzyme catalysis, molecular recognition and binding. A major limitation has been the lack of experimental tools to study these often invisible, short-lived conformers. Recent advances in relaxation dispersion NMR spectroscopy are changing this paradigm with the potential to generate high resolution structural information which is necessary for a rigorous characterization of these states. In this study, we present an experimental method for establishing the relative orientations of methyl groups in invisible, excited states of proteins by measuring methyl (1)H-(13)C residual dipolar couplings (RDCs). In our approach, four two-dimensional spectra are acquired at a pair of static magnetic fields. Each spectrum contains one of the four isolated multiplet components of a coupled methyl carbon, whose signal intensities, modulated by the pulsing frequency of a Carr-Purcell-Meiboom-Gill (CPMG) element, are sensitive to both chemical shift and RDC differences between exchanging states. In addition, data sets from a CPMG experiment which monitors the decay of in-phase methyl (13)C magnetization are recorded, that are sensitive only to the differences in chemical shifts between the states. Using our methodology, RDC values obtained from an invisible state in an exchanging system are shown to be in good agreement with the corresponding values measured under conditions where the invisible state is stabilized to become the highly populated ground state. The approach allows the measurement of anisotropic restraints at methyl positions in excited states and complements previously developed experiments focusing on the protein backbone.


Management of acute coronary syndromes from a gender perspective.
Acute Coronary Syndromes are the most frequent manifestations of coronary heart disease (CHD). Gender differences in treatment intensity, including differences in level of care, have been reported. Also differences in benefit from certain treatments, especially invasive treatment, have been discussed. Finally, differences in outcome between men and women have been proposed. Results have been inconsistent, partly depending on if and how adjustment for differences in background characteristics has been made.


Transcellular progression of infection threads in Medicago truncatula roots is associated with locally confined cell wall modifications.
The root nodule symbiosis with its global impact on nitrogen fertilization of soils is characterized by an intracellular colonization of legume roots by rhizobia. Although the symbionts are initially taken up by morphologically adapted root hairs, rhizobia persistently progress within a membrane-confined infection thread through several root cortical and later nodular cell layers. Throughout this transcellular passaging, rhizobia have to repeatedly pass host plasma membranes and cell walls. Here, we investigated this essential process and describe the concerted action of one of the symbiosis-specific pectin methyl esterases (SyPME1) and the nodulation pectate lyase (NPL) at the infection thread and transcellular passage sites. Their coordinated function mediates spatially confined pectin alterations in the cell-cell interface that result in the establishment of an apoplastic compartment where bacteria are temporarily released into and taken up from the subjacent cell. This process allows successful intracellular progression of infection threads through the entire root cortical tissue.


Mortality of emergency abdominal surgery in high-, middle- and low-income countries.
Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1·6 per cent at 24 h (high 1·1 per cent, middle 1·9 per cent, low 3·4 per cent; P < 0·001), increasing to 5·4 per cent by 30 days (high 4·5 per cent, middle 6·0 per cent, low 8·6 per cent; P < 0·001). Of the 578 patients who died, 404 (69·9 per cent) did so between 24 h and 30 days following surgery (high 74·2 per cent, middle 68·8 per cent, low 60·5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2·78, 95 per cent c.i. 1·84 to 4·20) and low-income (OR 2·97, 1·84 to 4·81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. NCT02179112 (http://www.clinicaltrials.gov).


Quantifying the vestibulo-ocular reflex with video-oculography: nature and frequency of artifacts.
Video-oculography devices are now used to quantify the vestibulo-ocular reflex (VOR) at the bedside using the head impulse test (HIT). Little is known about the impact of disruptive phenomena (e.g. corrective saccades, nystagmus, fixation losses, eye-blink artifacts) on quantitative VOR assessment in acute vertigo. This study systematically characterized the frequency, nature, and impact of artifacts on HIT VOR measures. From a prospective study of 26 patients with acute vestibular syndrome (16 vestibular neuritis, 10 stroke), we classified findings using a structured coding manual. Of 1,358 individual HIT traces, 72% had abnormal disruptive saccades, 44% had at least one artifact, and 42% were uninterpretable. Physicians using quantitative recording devices to measure head impulse VOR responses for clinical diagnosis should be aware of the potential impact of disruptive eye movements and measurement artifacts.


A Prospective Study of Bacteriological Etiology in Hospitalized Acute Exacerbation of COPD Patients: Relationship with Lung Function and Respiratory Failure.
Bacterial infections are the major cause of acute exacerbation of COPD (AE-COPD). The relationship between lung functions and respiratory failure (arterial blood gas parameters) with the etiology of AE-COPD has not been clearly understood. We conducted this study to determine the bacterial profile in AE-COPD and to identify the associated risk factors and drug sensitivity pattern. Seventy-two patients hospitalized for AE-COPD were prospectively evaluated. Quantitative sputum culture, blood gas analysis, and drug sensitivity testing were performed at the time of admission, and pulmonary function testing was performed 6 weeks after discharge as per standard guidelines. Bacterial pathogens were isolated in 34 (47.22%) cases. Pathogens isolated were Pseudomonas aeruginosa (38.23%), Klebsiella pneumoniae (29.41%), Staphylococcus aureus (23.53%), Streptococcus pneumoniae (5.88%), and Acinetobacter spp. (2.94%). Isolation of bacterial pathogen was observed in patients with advancing age (p=0.02), frequent exacerbations (p<0.001), systemic steroid use (p=0.005), and deranged lung function (p=0.02). Binary logistic regression analysis revealed that higher partial pressure of carbon dioxide (PaCO2) was independently associated with isolation of K. pneumoniae (p=0.025) and P. aeruginosa (p=0.001). Additional independent factors that favor isolation of K. pneumoniae were age >55 years (p=0.017) and systemic steroid use (p=0.017). Antibiotic sensitivity testing showed that ciprofloxacin and piperacillin/tazobactum were effective in 27/34 (79.41%) of isolates followed by gentamycin in 26/34 (76%). Hypercapnic respiratory failure is an independent risk factor for isolation of K. pneumoniae and P. aeruginosa in addition to advanced age and systemic steroid use. These findings may be an important adjunct in deciding the initial antibiotic therapy.


Stabilization of a long-armed fiber-optic single-photon interferometer.
We report on single-photon interference experiments in a Michelson-type interferometer built with two 6-km-long fiber spools, as well as on the active stabilization of the interferometer. A weak coherent light signal was (de-) multiplexed with a strong reference light using wavelength-division multiplexing technique, and real-time feedback control technique was applied for the reference light to actively stabilize the phase fluctuation in the long-armed fiber interferometer. The stabilized interferometer showed phase stability of 0.06 rad, which corresponds to an optical path length fluctuation of 15 nm between the 6-km-long interfering arms. The raw visibility obtained without subtracting noise counts in the single-photon interference experiment was more than 98% for stabilized conditions.


Intercircuit control via rhythmic regulation of projection neuron activity.
Synaptic feedback from rhythmically active neuronal circuits commonly causes their descending inputs to exhibit the rhythmic activity pattern generated by that circuit. In most cases, however, the function of this rhythmic feedback is unknown. In fact, generally these inputs can still activate the target circuit when driven in a tonic activity pattern. We are using the crab stomatogastric nervous system (STNS) to test the hypothesis that the neuronal circuit-mediated rhythmic activity pattern in projection neurons contributes to intercircuit regulation. The crab STNS contains an identified projection neuron, modulatory commissural neuron 1 (MCN1), whose tonic stimulation activates and modulates the gastric mill (chewing) and pyloric (filtering of chewed food) motor circuits in the stomatogastric ganglion (STG). During tonic stimulation of MCN1, the pyloric circuit regulates both gastric mill cycle frequency and gastropyloric coordination via a direct synapse onto a gastric mill neuron in the STG. However, when MCN1 is spontaneously active, it has a pyloric-timed activity pattern attributable to synaptic input from the pyloric circuit. This pyloric-timed activity in MCN1 provides the pyloric circuit with a second pathway for regulating the gastric mill rhythm. At these times, the direct STG synapse from the pyloric circuit to the gastric mill circuit is not necessary for pyloric regulation of the gastric mill rhythm. However, in the intact system, these two pathways play complementary roles in this intercircuit regulation. Thus, one role for rhythmicity in modulatory projection neurons is to enable them to mediate the interactions between distinct but related neuronal circuits.


[Analysis of phthalates in aromatic and deodorant aerosol products and evaluation of exposure risk].
We established an analytical method for the detection of seven phthalates, dimethyl phthalate, diethyl phthalate (DEP), benzyl butyl phthalate, di-i-butyl phthalate, dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), and di-n-octhyl phthalate, using an ultra high performance liquid chromatograph equipped with a photodiode array detector. This method is quick, with minimal contamination, and was applied to the analysis of aromatic and deodorant aerosol products. Phthalates were detected in 15 of 52 samples purchased from 1999 to 2012 in Yokohama. Three types of phthalate (DEP, DBP, DEHP) were detected, and their concentrations ranged from 0.0085-0.23% DEP in nine samples, 0.012-0.045% DBP in four samples, and 0.012-0.033% DEHP in four samples. No other phthalate esters were detected. Furthermore, we estimated phthalate exposure via breathing in commonly used aromatic and deodorant aerosol products, then evaluated the associated risk. The estimated levels of phthalate exposure were lower than the tolerated daily limit, but the results indicated that aromatic and deodorant aerosol products could be a significant source of phthalate exposure.


Axons pull on the brain, but tension does not drive cortical folding.
During human brain development, the cerebral cortex undergoes substantial folding, leading to its characteristic highly convoluted form. Folding is necessary to accommodate the expansion of the cerebral cortex; abnormal cortical folding is linked to various neurological disorders, including schizophrenia, epilepsy, autism, and mental retardation. Although this process requires mechanical forces, the specific force-generating mechanisms that drive folding remain unclear. The two most widely accepted hypotheses are as follows: (1) Folding is caused by differential growth of the cortex and (2) folding is caused by mechanical tension generated in axons. Direct evidence supporting either theory, however, is lacking. Here we show that axons are indeed under considerable tension in the developing ferret brain, but the patterns of tissue stress are not consistent with a causal role for axonal tension. In particular, microdissection assays reveal that significant tension exists along axons aligned circumferentially in subcortical white matter tracts, as well as those aligned radially inside developing gyri (outward folds). Contrary to previous speculation, however, axonal tension is not directed across developing gyri, suggesting that axon tension does not drive folding. On the other hand, using computational (finite element) models, we show that differential cortical growth accompanied by remodeling of the subplate leads to outward folds and stress fields that are consistent with our microdissection experiments, supporting a mechanism involving differential growth. Local perturbations, such as temporal differences in the initiation of cortical growth, can ensure consistent folding patterns. This study shows that a combination of experimental and computational mechanics can be used to evaluate competing hypotheses of morphogenesis, and illuminate the biomechanics of cortical folding.


Experimental and theoretical investigation of resonances in low-energy NO-H2 collisions.
The experimental characterization of scattering resonances in low energy collisions has proven to be a stringent test for quantum chemistry calculations. Previous measurements on the NO-H2 system at energies down to 10 cm-1 challenged the most sophisticated calculations of potential energy surfaces available. In this report, we continue these investigations by measuring the scattering behavior of the NO-H2 system in the previously unexplored 0.4 cm-1-10 cm-1 region for the parity changing de-excitation channel of NO. We study state-specific inelastic collisions with both para- and ortho-H2 in a crossed molecular beam experiment involving Stark deceleration and velocity map imaging. We are able to resolve resonance features in the measured integral and differential cross sections. Results are compared to predictions from two previously available potential energy surfaces, and we are able to clearly discriminate between the two potentials. We furthermore identify the partial wave contributions to these resonances and investigate the nature of the differences between collisions with para- and ortho-H2. Additionally, we tune the energy spreads in the experiment to our advantage to probe scattering behavior at energies beyond our mean experimental limit.


Diet and exercise for weight loss: a review of current issues.
Obesity is a fast growing epidemic that is primarily due to environmental influences. Nutrition and exercise represent modifiable factors with a major impact on energy balance. Despite considerable research, there remains continued debate regarding the energy content and the optimal macronutrient distribution for promoting healthy and effective weight loss. Low-fat diets have been advised for many years to reduce obesity. However, their effectiveness has been recently challenged, partly because the prevalence of obesity continues to rise despite reductions in fat intake. There are also concerns regarding the methodology of clinical trials showing benefits of fat reduction on weight loss. Although often viewed as a fad diet, very low-carbohydrate (ketogenic) diets are very popular and several recent clinical trials indicate they are more effective at promoting short-term weight loss and improving characteristics of the metabolic syndrome than low-fat diets. However, there is a need to obtain long-term safety and efficacy data. Clearly, weight loss can be achieved with a variety of diet interventions but the effects on other health-related aspects also need to be considered and studied in more detail. Exercise can have positive effects on weight loss, weight control and overall general health, although debate exists concerning the most effective mode, duration and intensity of exercise required to achieve these effects. Importantly, any effective weight control treatment must consider a life-long plan or there will likely be weight regain. Perhaps the most challenging, but rewarding, question that faces researchers is how to predict individual responses to diet and exercise interventions.


Pediatric emergencies in office practices: prevalence and office preparedness.
Because of a nationally apparent increased interest in emergency medical services for children and the need for a greater understanding of the relationship between office pediatric and emergency department care of children, a questionnaire was mailed to practitioners to (1) describe office physician involvement with emergent conditions, and (2) evaluate physician office preparedness for pediatric emergencies. Responses were received from 280 pediatricians and family practitioners, including information regarding the availability of equipment and medication, physician training, and practice characteristics. Of the responding physicians, 62% reported that they assessed in their offices more than one child each week who required hospitalization or urgent treatment. A preparedness score was developed and multiple regression analysis was used to investigate the relationship between this score and physician and practice characteristics. The mean overall preparedness score was 53.7 of a possible 156 (range 5 to 136, SD = 31.3). Characteristics related to this score were type of practice and advanced cardiac life support certification. Large multispecialty practices and practices with physicians trained in advanced cardiac life support tended to have better preparedness scores. Family practitioners tended to have more complete stock of medications than pediatricians. The data presented suggested that critically ill children who enter the medical system via the office setting may have a better than even chance of finding the office unprepared to treat the emergency: in fewer than one third of the offices in which it was reported that at least one patient was seen weekly with asthma, anaphylaxis, sickle cell vasoocclusive crisis, status epilepticus, and sepsis were they fully equipped to treat emergencies related to these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)


The frontline antibiotic vancomycin induces a zinc starvation response in bacteria by binding to Zn(II).
Vancomycin is a front-line antibiotic used for the treatment of nosocomial infections, particularly those caused by methicillin-resistant Staphylococcus aureus. Despite its clinical importance the global effects of vancomycin exposure on bacterial physiology are poorly understood. In a previous transcriptomic analysis we identified a number of Zur regulon genes which were highly but transiently up-regulated by vancomycin in Streptomyces coelicolor. Here, we show that vancomycin also induces similar zinc homeostasis systems in a range of other bacteria and demonstrate that vancomycin binds to Zn(II) in vitro. This implies that vancomycin treatment sequesters zinc from bacterial cells thereby triggering a Zur-dependent zinc starvation response. The Kd value of the binding between vancomycin and Zn(II) was calculated using a novel fluorometric assay, and NMR was used to identify the binding site. These findings highlight a new biologically relevant aspect of the chemical property of vancomycin as a zinc chelator.


Measurement of Azimuthal Asymmetries in Inclusive Charged Dipion Production in e^{+}e^{-} Annihilations at sqrt[s]=3.65 GeV.
We present a measurement of the azimuthal asymmetries of two charged pions in the inclusive process e^{+}e^{-}→ππX, based on a data set of 62 pb^{-1} at the center-of-mass energy of 3.65 GeV collected with the BESIII detector. These asymmetries can be attributed to the Collins fragmentation function. We observe a nonzero asymmetry, which increases with increasing pion momentum. As our energy scale is close to that of the existing semi-inclusive deep inelastic scattering experimental data, the measured asymmetries are important inputs for the global analysis of extracting the quark transversity distribution inside the nucleon and are valuable to explore the energy evolution of the spin-dependent fragmentation function.


What do patients do with access to their medical records?
We sought to study the phenomenon of patients having access to their own medical records in order to determine the impact on them and on their relationship with their health care providers. We created the Patient Clinical Information System (PatCIS) to interface with the clinical data repository at New York Presbyterian Hospital to allow patients to add to and review their medical data. We also provided educational resources and automated advice programs. We provided access to the system to thirteen subjects over a nineteen-month period and reviewed their activities in the system's usage log. We also collected data via questionnaire and telephone interview. We found that patients varied in their use of the system, from once a month or less to one or more times per day. All patients primarily used the system to review laboratory results. Both they and their physicians believed that use of the system enhanced the patients' understanding of their conditions and improved their communication with their physicians. There were no adverse events encountered during the study.


Exploring drivers for safe male circumcision: Experiences with health education and understanding of partial HIV protection among newly circumcised men in Wakiso, Uganda.
About 2.5 million men have voluntarily been circumcised since Uganda started implementing the WHO recommendation to scale up safe male circumcision to reduce HIV transmission. This study sought to understand what influences men's circumcision decisions, their experiences with health education at health facilities and their knowledge of partial HIV risk reduction in Wakiso district. Data were collected in May and June 2015 at five public health facilities in Wakiso District. Twenty-five in-depth interviews were held with adult safe male circumcision clients. Data were analysed using thematic network analysis. Safe male circumcision decisions were mainly influenced by sexual partners, a perceived need to reduce the risk of HIV/STIs, community pressure and other benefits like hygiene. Sexual partners directly requested men to circumcise or indirectly influenced them in varied ways. Health education at facilities mainly focused on the surgical procedure, circumcision benefits especially HIV risk reduction, wound care and time to resumption of sex, with less focus on post-circumcision sexual behaviour. Five men reported no health education. All men reported that circumcision only reduces and does not eliminate HIV risk, and could mention ways it protects, although some extended the benefit to direct protection for women and prevention of other STIs. Five men thought social marketing messages were 'misleading' and feared risk compensation within the community. Participants reported positive community perception about safe male circumcision campaigns, influencing men to seek services and enabling female partners to impact this decision-making process. However, there seemed to be gaps in safe male circumcision health education, although all participants correctly understood that circumcision offers only partial protection from HIV. Standard health education procedures, if followed at health facilities offering safe male circumcision, would ensure all clients are well informed, especially about post-circumcision sexual behaviour that is key to prevention of risk compensation.


Detection of antibiotics synthetized in microfluidic picolitre-droplets by various actinobacteria.
The natural bacterial diversity is regarded as a treasure trove for natural products. However, accessing complex cell mixtures derived from environmental samples in standardized high-throughput screenings is challenging. Here, we present a droplet-based microfluidic platform for ultrahigh-throughput screenings able to directly harness the diversity of entire microbial communities. This platform combines extensive cultivation protocols in aqueous droplets starting from single cells or spores with modular detection methods for produced antimicrobial compounds. After long-term incubation for bacterial cell propagation and metabolite production, we implemented a setup for mass spectrometric analysis relying on direct electrospray ionization and injection of single droplets. Even in the presence of dense biomass we show robust detection of streptomycin on the single droplet level. Furthermore, we developed an ultrahigh-throughput screening based on a functional whole-cell assay by picoinjecting reporter cells into droplets. Depending on the survival of reporter cells, droplets were selected for the isolation of producing bacteria, which we demonstrated for a microbial soil community. The established ultrahigh-throughput screening for producers of antibiotics in miniaturized bioreactors in which diverse cell mixtures can be screened on the single cell level is a promising approach to find novel antimicrobial scaffolds.


Molecularly imprinted polymers for solid-phase extraction of 1-methyladenosine from human urine.
A highly selective molecularly imprinted polymer (MIP) for 1-methyladenosine (1-MA), an urinary modified nucleoside used as cancer marker, was prepared and its use as solid-phase extraction (SPE) sorbent material was demonstrated. The MIP was prepared by a very simple procedure using methacrylic acid as functional monomer and a mixture acetonitrile/water (4/1, v/v) as porogen, overcoming in this way the problems usually related to the imprinting of biological polar compounds. The MIP was tested in batch experiments in order to evaluate its binding properties and then used as SPE sorbent for the selective clean-up and pre-concentration of 1-MA. The extraction protocol was successfully applied to the direct extraction of 1-MA from spiked human urine indicating that the MIP allowed 1-MA to be pre-concentrated while simultaneously interfering compounds were removed from the matrix.


Primary Care Practices' Abilities And Challenges In Using Electronic Health Record Data For Quality Improvement.
Federal value-based payment programs require primary care practices to conduct quality improvement activities, informed by the electronic reports on clinical quality measures that their electronic health records (EHRs) generate. To determine whether EHRs produce reports adequate to the task, we examined survey responses from 1,492 practices across twelve states, supplemented with qualitative data. Meaningful-use participation, which requires the use of a federally certified EHR, was associated with the ability to generate reports-but the reports did not necessarily support quality improvement initiatives. Practices reported numerous challenges in generating adequate reports, such as difficulty manipulating and aligning measurement time frames with quality improvement needs, lack of functionality for generating reports on electronic clinical quality measures at different levels, discordance between clinical guidelines and measures available in reports, questionable data quality, and vendors that were unreceptive to changing EHR configuration beyond federal requirements. The current state of EHR measurement functionality may be insufficient to support federal initiatives that tie payment to clinical quality measures.


Association between diet quality with concurrent vision and hearing impairment in older adults.
Published literature shows that individual nutrients could influence the risk of developing vision and hearing loss. There is, however, a lack of population-based data on the relationship between overall patterns of food intake and the presence of concurrent vision and hearing impairment. We aimed to assess the associations between diet quality with the prevalence and 5-year incidence of dual sensory impairment (DSI). Cross-sectional and 5-year longitudinal analyses. Blue Mountains, Sydney, Australia. 2443 participants aged ≥50 from baseline were examined and followed over 5 years. Dietary data were collected using a semi-quantitative food frequency questionnaire. A modified version of the Healthy Eating Index for Australians was developed to determine total diet score (TDS). Visual impairment was defined as visual acuity less than 20/40 (better eye), and hearing impairment as average pure-tone air conduction threshold greater than 25 dB HL (500-4000 Hz, better ear). After adjusting for age, sex, education, noise exposure, current smoking, and type 2 diabetes, participants in the lowest compared to the highest quintile of TDS had a 2-fold increased likelihood of having prevalent DSI, odds ratio, OR, 2.62 (95% confidence intervals, CI, 1.08-6.36), P-trend=0.04. Significant associations were not observed between TDS and the prevalence of having a single sensory impairment (vision or hearing loss). Baseline TDS was not significantly associated with the 5-year incidence of DSI. Adherence to dietary guidelines was associated with a reduced likelihood of having DSI in cross-sectional, but not in longitudinal analyses. Further studies with adequate power are warranted to assess the prospective relationship between diet quality and DSI.


'Speedy action over goal orientation': cognitive impulsivity in male forensic patients with dyslexia.
Previous neuropsychiatric studies suggest a relationship between reading disability and cognitive impulsivity. This relationship is not entirely explained by the high comorbidity between reading disability and attention deficit hyperactivity disorder (ADHD), as children with a co-occurrence of these disorders tend to be more impulsive than those with ADHD only. Other research has demonstrated that poor verbal skill (irrespective of the presence of dyslexia) deficits in executive functions and impulsivity are important risk factors for criminal behaviour. The present study bridges these two research traditions by examining whether patients undergoing forensic psychiatric investigation who also have dyslexia, have a cognitive style characterized by impulsivity. Male forensic patients (mean age 27 years, range 16-35) with (n = 9) and without (n = 13) dyslexia were evaluated on the computerized EuroCog test battery. The findings suggest that patients with dyslexia tend to use a cognitive impulsive style and suggest a more direct link between dyslexia and cognitive impulsivity that is not mediated by the presence of ADHD. In order to identify treatment needs and tailor treatment accordingly, forensic patients should be assessed with respect to poor verbal skill, dyslexia and impulsivity.


Harnessing the potential of machine learning and artificial intelligence for dementia research.
Progress in dementia research has been limited, with substantial gaps in our knowledge of targets for prevention, mechanisms for disease progression, and disease-modifying treatments. The growing availability of multimodal data sets opens possibilities for the application of machine learning and artificial intelligence (AI) to help answer key questions in the field. We provide an overview of the state of the science, highlighting current challenges and opportunities for utilisation of AI approaches to move the field forward in the areas of genetics, experimental medicine, drug discovery and trials optimisation, imaging, and prevention. Machine learning methods can enhance results of genetic studies, help determine biological effects and facilitate the identification of drug targets based on genetic and transcriptomic information. The use of unsupervised learning for understanding disease mechanisms for drug discovery is promising, while analysis of multimodal data sets to characterise and quantify disease severity and subtype are also beginning to contribute to optimisation of clinical trial recruitment. Data-driven experimental medicine is needed to analyse data across modalities and develop novel algorithms to translate insights from animal models to human disease biology. AI methods in neuroimaging outperform traditional approaches for diagnostic classification, and although challenges around validation and translation remain, there is optimism for their meaningful integration to clinical practice in the near future. AI-based models can also clarify our understanding of the causality and commonality of dementia risk factors, informing and improving risk prediction models along with the development of preventative interventions. The complexity and heterogeneity of dementia requires an alternative approach beyond traditional design and analytical approaches. Although not yet widely used in dementia research, machine learning and AI have the potential to unlock current challenges and advance precision dementia medicine.


Exposure to second hand smoke and its correlates in Northern State of India.
Second-hand smoke (SHS) has enormous adverse health impacts with grave health implications for the next generation. Section 4 of Indian legislation, Cigarettes and Other Tobacco Products Act, prohibits smoking at public places, thus protecting people from SHS. The objective of present study was to assess the exposure to SHS at home and working areas in Punjab, India. The present cross-sectional study was conducted from December 2015 to March 2016. A three-stage sampling technique was used for collecting data from three randomly selected districts representing three major regions of Punjab, India. A sample size of 510 individuals was divided equally into an urban and rural area with proportionate sampling on the basis of subsets of age groups and gender. The questionnaire based on tobacco questions for the survey, a subset of key questions from global adult tobacco survey was used. At home, the odds of exposure to SHS exposure was higher (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 0.6-7.3) in urban area, females, low educational status, and nongovernment employee as compared to their counterparts. At workplace, (OR = 3.9 and 95% CI = 1.11-14.3) SHS exposure was higher in rural area, among males, primary and middle education and nongovernment or self-employed occupation. SHS exposure was low in Punjab, India especially in females as compared to other states of the country. The socio-economic disadvantaged groups and people with low education were more likely to experience exposure to SHS at workplace, which should be targeted to reduce tobacco consumption.


Computerized restoration of nonhomogeneous deformation of a fossil cranium based on bilateral symmetry.
We developed a computerized method of correcting plastic deformation of a fossil skull, based on bilateral symmetry with respect to the midsagittal plane, and applied this method to reconstruction of a fossilized Proconsul heseloni cranium (KNM-RU-7290A). A three-dimensional (3D) model of the fossil was generated using consecutive cross-sectional images retrieved from computed tomography. 3D coordinates of anatomical landmarks that should be located on the midsagittal plane and pairs of landmarks that should be symmetrical with respect to this plane were acquired. These landmarks were then repositioned so that geometrical constraints were satisfied, while translated distances of landmarks were minimized. We adopted a thin-plate spline function to mathematically describe the 3D nonlinear volumetric transformation between acquired and repositioned landmarks. Using this function, the entire fossil shape was transformed, and the effect of reversing the deformation could be visualized. The results indicated that the proposed method was effective in eliminating nonhomogeneous deformation of the fossil skull. The antemortem appearance of the skull cannot be completely restored by this method alone, due to methodological limitations. However, the presented method has a role as an adjunct in complementing conventional restoration techniques on account of its objective nature.


Role of Unc51.1 and its binding partners in CNS axon outgrowth.
Previous studies showed that the serine/threonine kinase Unc51.1 is one of the earliest genes in neuronal differentiation and is required for granule cell axon formation. To examine the mechanism of Unc51.1 regulation of axon extension, we have identified two direct binding partners. The first, SynGAP, a negative regulator of Ras, is expressed within axons and growth cones of developing granule cells. Overexpression of SynGAP blocks neurite outgrowth by a mechanism that involves Ras-like GTPase cascade. The second binding partner is a PDZ domain-containing scaffolding protein, Syntenin, that binds Rab5 GTPase, the activity of which is attenuated by SynGAP. Thus, our results demonstrate that the Unc51.1-containing protein complex governs axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.


Patiromer: The First Potassium Binder Approved in Over 50 Years.
For over 50 years, there have been limited options for the management of hyperkalemia, especially among patients with chronic kidney disease (CKD), diabetic nephropathy, hypertension, and heart failure, who were receiving concomitant renin-angiotensin-aldosterone system (RAAS) inhibitor therapy. Hyperkalemia is a potential, life-threatening electrolyte abnormality that frequently challenges clinicians from maximizing the mortality benefit and organ-protective properties of RAAS inhibitors especially in CKD and heart failure populations. Patiromer is a novel nonabsorbed, cation-exchange polymer that binds and exchanges potassium for calcium, predominantly in the gastrointestinal tract. It has demonstrated potassium-lowering effects in normo- or hyperkalemic patients on concomitant RAAS inhibitors with heart failure, diabetic nephropathy, and CKD, in the PEARL-HF, AMETHYST-DN, and OPAL-HK studies, respectively. Across all studies, it appears to be generally effective and well tolerated, with adverse events predominantly gastrointestinal in nature. Additional investigational studies are needed to explore its use for an extended duration of treatment and in larger patient populations, as well as exploring drug-drug interactions. Overall, patiromer demonstrates a promising role in the chronic management of hyperkalemia that will allow optimization of RAAS inhibitor therapy, thus delaying progression of CKD and improving the mortality benefit in heart failure patients.


Astaxanthin from Haematococcus pluvialis Prevents Oxidative Stress on Human Endothelial Cells without Toxicity.
Astaxanthin, a powerful antioxidant, is a good candidate for the prevention of intracellular oxidative stress. The aim of the study was to compare the antioxidant activity of astaxanthin present in two natural extracts from Haematococcus pluvialis, a microalgae strain, with that of synthetic astaxanthin. Natural extracts were obtained either by solvent or supercritical extraction methods. UV, HPLC-DAD and (HPLC-(atmospheric pressure chemical ionization (APCI)+)/ion trap-MS) characterizations of both natural extracts showed similar compositions of carotenoids, but different percentages in free astaxanthin and its ester derivatives. The Trolox equivalent antioxidant capacity (TEAC) assay showed that natural extracts containing esters displayed stronger antioxidant activities than free astaxanthin. Their antioxidant capacities to inhibit intracellular oxidative stress were then evaluated on HUVEC cells. The intracellular antioxidant activity in natural extracts was approximately 90-times higher than synthetic astaxanthin (5 µM). No modification, neither in the morphology nor in the viability, of vascular human cells was observed by in vitro biocompatibility study up to 10 µM astaxanthin concentrations. Therefore, these results revealed the therapeutic potential of the natural extracts in vascular human cell protection against oxidative stress without toxicity, which could be exploited in prevention and/or treatment of cardiovascular diseases.


Modified uterine allotransplantation and immunosuppression procedure in the sheep model.
To develop an orthotopic, allogeneic, uterine transplantation technique and an effective immunosuppressive protocol in the sheep model. In this pilot study, 10 sexually mature ewes were subjected to laparotomy and total abdominal hysterectomy with oophorectomy to procure uterus allografts. The cold ischemic time was 60 min. End-to-end vascular anastomosis was performed using continuous, non-interlocking sutures. Complete tissue reperfusion was achieved in all animals within 30 s after the vascular re-anastomosis, without any evidence of arterial or venous thrombosis. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil and methylprednisolone tablets. Graft viability was assessed by transrectal ultrasonography and second-look laparotomy at 2 and 4 weeks, respectively. Viable uterine tissue and vascular patency were observed on transrectal ultrasonography and second-look laparotomy. Histological analysis of the graft tissue (performed in one ewe) revealed normal tissue architecture with a very subtle inflammatory reaction but no edema or stasis. We have developed a modified procedure that allowed us to successfully perform orthotopic, allogeneic, uterine transplantation in sheep, whose uterine and vascular anatomy (apart from the bicornuate uterus) is similar to the human anatomy, making the ovine model excellent for human uterine transplant research.


Dissecting the complete lipoprotein biogenesis pathway in Streptomyces scabies.
Following translocation, bacterial lipoproteins are lipidated by lipoprotein diacylglycerol transferase (Lgt) and cleaved of their signal peptides by lipoprotein signal peptidase (Lsp). In Gram-negative bacteria and mycobacteria, lipoproteins are further lipidated by lipoprotein N-acyl transferase (Lnt), to give triacylated lipoproteins. Streptomyces are unusual amongst Gram-positive bacteria because they export large numbers of lipoproteins via the twin arginine protein transport (Tat) pathway. Furthermore, some Streptomyces species encode two Lgt homologues and all Streptomyces species encode two homologues of Lnt. Here we characterize lipoprotein biogenesis in the plant pathogen Streptomyces scabies and report that lgt and lsp mutants are defective in growth and development while only moderately affected in virulence. Lipoproteins are lost from the membrane in an S. scabies lgt mutant but restored by expression of Streptomyces coelicolor lgt1 or lgt2 confirming that both encode functional Lgt enzymes. Furthermore, lipoproteins are N-acylated in Streptomyces with efficient N-acylation dependent on Lnt1 and Lnt2. However, deletion of lnt1 and lnt2 has no effect on growth, development or virulence. We thus present a detailed study of lipoprotein biogenesis in Streptomyces, the first study of Lnt function in a monoderm bacterium and the first study of bacterial lipoproteins as virulence factors in a plant pathogen.


Variability in interpretive performance at screening mammography and radiologists' characteristics associated with accuracy.
To identify radiologists' characteristics associated with interpretive performance in screening mammography. The study was approved by institutional review boards of University of Washington (Seattle, Wash) and institutions at seven Breast Cancer Surveillance Consortium sites, informed consent was obtained, and procedures were HIPAA compliant. Radiologists who interpreted mammograms in seven U.S. regions completed a self-administered mailed survey; information on demographics, practice type, and experience in and perceptions of general radiology and breast imaging was collected. Survey data were linked to data on screening mammograms the radiologists interpreted between January 1, 1998, and December 31, 2005, and included patient risk factors, Breast Imaging Reporting and Data System assessment, and follow-up breast cancer data. The survey was returned by 71% (257 of 364) of radiologists; in 56% (205 of 364) of the eligible radiologists, complete data on screening mammograms during the study period were provided; these data were used in the final analysis. An evaluation of whether the radiologists' characteristics were associated with recall rate, false-positive rate, sensitivity, or positive predictive value of recall (PPV(1)) of the screening examinations was performed with logistic regression models that were adjusted for patients' characteristics and radiologist-specific random effects. Study radiologists interpreted 1 036 155 screening mammograms; 4961 breast cancers were detected. Median percentages and interquartile ranges, respectively, were as follows: recall rate, 9.3% and 6.3%-13.2%; false-positive rate, 8.9% and 5.9%-12.8%; sensitivity, 83.8% and 74.5%-92.3%; and PPV(1), 4.0% and 2.6%-5.9%. Wide variability in sensitivity was noted, even among radiologists with similar false-positive rates. In adjusted regression models, female radiologists or fellowship-trained radiologists had significantly higher recall and false-positive rates (P < .05, all). Fellowship training in breast imaging was the only characteristic significantly associated with improved sensitivity (odds ratio, 2.32; 95% confidence interval: 1.42, 3.80; P < .001) and the overall accuracy parameter (odds ratio, 1.61; 95% confidence interval: 1.05, 2.45; P = .028). Fellowship training in breast imaging may lead to improved cancer detection, but it is associated with higher false-positive rates.


An evaluation of an anticoagulant clinic.
Patient comprehension of the risks of anticoagulation, tablet recognition skills and knowledge of complications of warfarin therapy were evaluated in 160 patients attending the anticoagulant clinic in a central Dublin teaching hospital group. Potential complications from over- and under- dosage with warfarin were unknown to 119 (74%) and 97 (60%) patients respectively. 1, 3 and 5 mg tablets could not be identified by 40 (25%), 55 (34%) and 60 (37%) patients respectively. The current prescribed dose could not be recollected by 31 (19%) patients. Haemorrhagic complications occurred in 23 (14%) subjects over one year, four of whom required hospital admission and two blood transfusions. No thromboembolic episodes were noted. This study reveals a widespread lack of understanding of anticoagulation and its potential complications in patients receiving warfarin therapy and has led to a critical reappraisal of patient education, patterns of referral and supervision of such individuals in our clinic.


Brazilian propolis ethanol extract and its component kaempferol induce myeloid-derived suppressor cells from macrophages of mice in vivo and in vitro.
Brazilian green propolis is produced by mixing secretions from Africanized honey bees with exudate, mainly from Baccharis dracunculifolia. Brazilian propolis is especially rich in flavonoids and cinammic acid derivatives, and it has been widely used in folk medicine owing to its anti-inflammatory, anti-viral, tumoricidal, and analgesic effects. Moreover, it is applied to prevent metabolic disorders, such as type 2 diabetes and arteriosclerosis. Previously, we demonstrated that propolis ethanol extract ameliorated type 2 diabetes in a mouse model through the resolution of adipose tissue inflammation. The aims of this study were to identify the immunosuppressive cells directly elicited by propolis extract and to evaluate the flavonoids that induce such cells. Ethanol extract of Brazilian propolis (PEE; 100 mg/kg i.p., twice a week) was injected into lean or high fat-fed obese C57BL/6 mice or C57BL/6 ob/ob mice for one month. Subsequently, immune cells in visceral adipose tissue and the peritoneal cavity were monitored using FACS analysis. Isolated macrophages and the macrophage-like cell line J774.1 were treated with PEE and its constituent components, and the expression of immune suppressive myeloid markers were evaluated. Finally, we injected one of the identified compounds, kaempferol, into C57BL/6 mice and performed FACS analysis on the adipose tissue. Intraperitoneal treatment of PEE induces CD11b+, Gr-1+ myeloid-derived suppressor cells (MDSCs) in visceral adipose tissue and the peritoneal cavity of lean and obese mice. PEE directly stimulates cultured M1 macrophages to transdifferentiate into MDSCs. Among twelve compounds isolated from PEE, kaempferol has an exclusive effect on MDSCs induction in vitro. Accordingly, intraperitoneal injection of kaempferol causes accumulation of MDSCs in the visceral adipose tissue of mice. Brazilian PEE and its compound kaempferol strongly induce MDSCs in visceral adipose tissue at a relatively early phase of inflammation. Given the strong anti-inflammatory action of MDSCs, the induction of MDSCs by PEE and kaempferol is expected to be useful for anti-diabetic and anti-inflammatory therapies.


ChloroP, a neural network-based method for predicting chloroplast transit peptides and their cleavage sites.
We present a neural network based method (ChloroP) for identifying chloroplast transit peptides and their cleavage sites. Using cross-validation, 88% of the sequences in our homology reduced training set were correctly classified as transit peptides or nontransit peptides. This performance level is well above that of the publicly available chloroplast localization predictor PSORT. Cleavage sites are predicted using a scoring matrix derived by an automatic motif-finding algorithm. Approximately 60% of the known cleavage sites in our sequence collection were predicted to within +/-2 residues from the cleavage sites given in SWISS-PROT. An analysis of 715 Arabidopsis thaliana sequences from SWISS-PROT suggests that the ChloroP method should be useful for the identification of putative transit peptides in genome-wide sequence data. The ChloroP predictor is available as a web-server at http://www.cbs.dtu.dk/services/ChloroP/.


alphaB-crystallin protects retinal tissue during Staphylococcus aureus-induced endophthalmitis.
Bacterial infections of the eye highlight a dilemma that is central to all immune-privileged sites. On the one hand, immune privilege limits inflammation to prevent bystander destruction of normal tissue and loss of vision. On the other hand, bacterial infections require a robust inflammatory response for rapid clearance of the pathogen. We demonstrate that the retina handles this dilemma, in part, by activation of a protective heat shock protein. During Staphylococcus aureus-induced endophthalmitis, the small heat shock protein alphaB-crystallin is upregulated in the retina and prevents apoptosis during immune clearance of the bacteria. In the absence of alphaB-crystallin, mice display increased retinal apoptosis and retinal damage. We found that S. aureus produces a protease capable of cleaving alphaB-crystallin to a form that coincides with increased retinal apoptosis and tissue destruction. We conclude that alphaB-crystallin is important in protecting sensitive retinal tissue during destructive inflammation that occurs during bacterial endophthalmitis.


Note on estimates of the inbreeding coefficient through study of pedigrees and isonymous marriages.
Crow and Mange (1965) developed a method to estimate the inbreeding coefficient (F) through an ingenious surname analysis. Such formulations assume a regularity of transmission of surnames, monophyletism, and random occurrence of consanguineous marriages. Accordingly, the ratio of isonymous partners to F of the offspring is equal to 4. Nevertheless, genealogy analyses show that the consanguineous marriages do not necessarily occur regularly. Therefore the isonymy analysis gives a misestimation of the inbreeding coefficient, depending on the prevailing form of nonrandomness. We suggest a small correction to the formulation in situations when pedigree information is available. The weighted mean of the ratio of isonymous partners to F of the known consanguineous marriages is suggested as a way to improve the formulas. The technique was applied to a northeastern Brazilian sample, and the results agree well with those of bioassays and therefore provide an apparently more realistic estimate of the inbreeding coefficient by isonymy.


Investigation of association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism frequency and plasma PAI-1 enzyme activity in patients with acute stroke.
This study was carried out to determine if there is any association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism and plasma PAI-1 enzyme activity in acute stroke patients. In this study, 333 genomic DNAs (from 253 acute stroke patients and 80 healthy subjects) were analyzed. Genomic DNAs were prepared from peripheral blood using a saline method. These DNAs were amplified by PCR method using primers specific for 4G and 5G alleles. PCR products were separated by 2% agarose gel electrophoresis and visualized by a charge coupled device (CCD) camera. PAI-1 enzyme activities were measured by ELISA method. The results were evaluated statistically with Student's t-test, chi(2)-test, one-way analysis of variance, and stepwise regression analysis. In this study, frequency of PAI-1 gene 4G5G genotype was found to be low both in patients and controls. PAI-1 enzyme activities were significantly increased in acute stroke patients compared to controls. Although PAI-1 gene 4G5G genotype frequencies were low, the patients carrying this allele had highest plasma PAI-1 enzyme activity; likewise, although PAI-1 gene 4G4G genotype frequencies were high, the patients carrying this allele had lowest plasma PAI-1 enzyme activities. Homocysteine levels had a positive effect of 65% on plasma PAI-1 enzyme activities. Consequently, in this study, we may assert that PAI-1 gene, 4G4G and 5G5G genotypes, PAI-1 activity, and homocysteine level determination are significant criteria for identifying patients who are likely to develop stroke; on the other hand, a direct relation does not exist between gene polymorphism and enzyme activity.


Kinetic properties of a voltage-dependent junctional conductance.
We have proposed that the gap junctions between amphibian blastomeres are comprised of voltage-sensitive channels. The kinetic properties of the junctional conductance are here studied under voltage clamp. When the transjunctional voltage is stepped to a new voltage of the same polarity, the junctional conductance changes as a single exponential to a steady-state level. The time constant of the conductance change is determined by the existing transjunctional voltage and is independent of the previous voltage. For each voltage polarity, the relations between voltage, time constant, and steady-state conductance are well modeled by a reversible two-state reaction scheme in which the calculated rate constants for the transitions between the states are exponential functions of voltage. The calculated rate constant for the transition to the low-conductance state is approximately twice as voltage dependent as that for the transition to the high-conductance state. When the transjunctional voltage polarity is reversed, the junctional conductance undergoes a transient recovery. The polarity reversal data are well modeled by a reaction scheme in which the junctional channel has two gates, each with opposite voltage sensitivity, and in which an open gate may close only if the gate in series with it is open. A simple explanation for this contingent gating is a mechanism in which each gate senses only the local voltage drop within the channel.


Spatial errors made by infants: inadequate spatial cues or evidence of egocentrism?
Nine month old infants search correctly for an object which they have seen hidden in one position, but cease to do so after they have been moved to the opposite side of the display, searching instead at a position which is apparently defined egocentrically from their experience before movement. This error can be explained on the one hand in terms of response dependence or egocentrism, or on the other hand as due to a lack of adequate spatial cues to allocentric position. In order to distinguish between these hypotheses, 64 nine month old infants were presented with a hidden object problem in which the two alternative positions had covers of different colours. The results show that infants could search correctly for an object in one location although they saw the problem from different sides. This result combines with those of other conditions to indicate that cover colour provides an adequate spatial cue, allowing the infant to specify position allocentrically, provided the correct cover maintains a stable position.


The effect of acute administration of an angiotensin converting enzyme inhibitor, captopril (SQ 14,225), on experimentally induced thirsts in rats.
In order to assess the role of angiotensin in the genesis of certain types of thirst, rats were administered the angiotensin converting enzyme inhibitor, captopril, in an attempt to block the increased water intake induced either by water deprivation or by i.p. administration of hypertonic saline. Water deprivation for 24 hr resulted in an increased water intake. Acute administration of 50 mg of captopril per kg i.p. at 45 or 60, but not at 15 or 30, min before return of water to the dehydrated rats significantly attenuated the drinking response. Rats administered 1% b.wt. i.p. of 0.25, 0.50, 0.75 or 1.00 M NaCl solution increased proportionately their water intake. Acute administration of 35 mg of captopril per kg b. wt. i.p. 15 min before loading with NaCl solution at any of the above concentrations had no effect on the increased thirst induced. These findings suggest that hypertonic saline-induced thirst is not mediated by angiotensin II receptors while water deprivation-induced thirst may involve both osmoreceptors and angiotensin II receptors.


Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.
A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.


Environmental Conditions, Preseason Fitness Levels, and Game Workload: Analysis of a Female NCAA DI National Championship Soccer Season.
Benjamin, CL, Hosokawa, Y, Curtis, RM, Schaefer, DA, Bergin, RT, Abegg, MR, and Casa, DJ. Environmental conditions, preseason fitness levels, and game workload: Analysis of a female NCAA DI National Championship Soccer Season. J Strength Cond Res 34(4): 988-994, 2020-The purpose of this study was to determine the independent and combined moderating effect of aerobic fitness and environmental conditions on physical workloads during collegiate female soccer matches. Nineteen National Collegiate Athletic Association female soccer athletes were included in this study (mean ± SD: age, 20.6 ± 1.4 years; height, 169 ± 6.1 cm; body mass 64.7 ± 5.3 kg). Maximal oxygen consumption (V[Combining Dot Above]O2max) was estimated from the yo-yo intermittent recovery test before preseason training and wet-bulb globe temperature (WBGT) was recorded onsite for home matches and at the nearest weather station for away matches. Relative distance (TD), relative high-speed running distance (%HSD), and relative high metabolic load (%HML) performance were collected during each match using a global positioning system unit (Viper Pod; STATSports, Chicago, IL). Statistically significant differences were observed in TD between LOW WBGT and MOD WBGT (mean difference [MD] = 7.08 m·min; effect size [ES] = 0.54; p < 0.001), in %HSD between LOW WBGT and MOD WBGT (MD = 1.97%; ES = 0.64; p = 0.01) and between LOW WBGT and HIGH WBGT (MD = 2.71%; ES = 1.01; p < 0.001), and in %HML between LOW WBGT and MOD WBGT (MD = 1.24%; ES = 0.56; p < 0.001) and between LOW WBGT and HIGH WBGT (MD = 1.55%; ES = 0.78; p = 0.01). There was a significant interaction between WBGT and V[Combining Dot Above]O2max for %HSD (p = 0.03). These findings demonstrate that physical performance metrics were affected by increased WBGT. In addition, aerobic fitness seemed to moderate the effect of increasing WBGT on %HSD, meaning maximizing aerobic capacity is important for optimizing running performance in the heat. Coaches and sports medicine staff could alter training time and session length based on environmental conditions as well as potentially use aggressive cooling strategies to mitigate the imposed heat stress and decrements in physical performance.


Response rates in postal surveys of healthcare professionals between 1996 and 2005: an observational study.
Postal surveys are a frequently used method of data collection in health services research. Low response rates increase the potential for bias and threaten study validity. The objectives of this study were to estimate current response rates, to assess whether response rates are falling, to explore factors that might enhance response rates and to examine the potential for non-response bias in surveys mailed to healthcare professionals. A random sample of postal or electronic surveys of healthcare workers (1996-2005) was identified from Medline, Embase or Psycinfo databases or Biomed Central. Outcome measures were survey response rate and non response analysis. Multilevel, multivariable logistic regression examined the relationship between response rate and publication type, healthcare profession, country and number of survey participants, questionnaire length and use of reminders. The analysis included 350 studies. Average response rate in doctors was 57.5% (95%CI: 55.2% to 59.8%) and significantly lower than the estimate for the prior 10 year period. Response rates were higher when reminders were sent (adjusted OR 1.3; 95%CI 1.1-1.6) but only half the studies did this. Response rates were also higher in studies with fewer than 1000 participants and in countries other than US, Canada, Australia and New Zealand. They were not significantly affected by publication type or healthcare profession (p > 0.05). Only 17% of studies attempted assessment of possible non-response bias. Response rates to postal surveys of healthcare professionals are low and probably declining, almost certainly leading to unknown levels of bias. To improve the informativeness of postal survey findings, researchers should routinely consider the use of reminders and assess potential for non-response bias.


Understanding MCP-MOD dose finding as a method based on linear regression.
MCP-MOD is a testing and model selection approach for clinical dose finding studies. During testing, contrasts of dose group means are derived from candidate dose response models. A multiple-comparison procedure is applied that controls the alpha level for the family of null hypotheses associated with the contrasts. Provided at least one contrast is significant, a corresponding set of "good" candidate models is identified. The model generating the most significant contrast is typically selected. There have been numerous publications on the method. It was endorsed by the European Medicines Agency. The MCP-MOD procedure can be alternatively represented as a method based on simple linear regression, where "simple" refers to the inclusion of an intercept and a single predictor variable, which is a transformation of dose. It is shown that the contrasts are equal to least squares linear regression slope estimates after a rescaling of the predictor variables. The test for each contrast is the usual t statistic for a null slope parameter, except that a variance estimate with fewer degrees of freedom is used in the standard error. Selecting the model corresponding to the most significant contrast P value is equivalent to selecting the predictor variable yielding the smallest residual sum of squares. This criteria orders the models like a common goodness-of-fit test, but it does not assure a good fit. Common inferential methods applied to the selected model are subject to distortions that are often present following data-based model selection.


The surface chemistry of NO(x) on mackinawite (FeS) surfaces: a DFT-D2 study.
We present density functional theory calculations with a correction for the long-range interactions (DFT-D2) of the bulk and surfaces of mackinawite (FeS), and subsequent adsorption and dissociation of NO(x) gases (nitrogen monoxide (NO) and nitrogen dioxide (NO2)). Our results show that these environmentally important molecules interact very weakly with the energetically most stable (001) surface, but adsorb relatively strongly onto the FeS(011), (100) and (111) surfaces, preferentially at Fe sites via charge donation from these surface species. The NOx species exhibit a variety of adsorption geometries, with the most favourable for NO being the monodentate Fe-NO configuration, whereas NO2 is calculated to form a bidentate Fe-NOO-Fe configuration. From our calculated thermochemical energy and activation energy barriers for the direct dissociation of NO and NO2 on the FeS surfaces, we show that NO prefers molecular adsorption, while dissociative adsorption, i.e. NO2 (ads) → [NO(ads) + O(ads)] is preferred over molecular adsorption for NO2 onto the mackinawite surfaces. However, the calculated high activation barriers for the further dissociation of the second N-O bond to produce either [N(ads) and 2O(ads)] or [N(ads) and O2(ads)] suggest that complete dissociation of NO2 is unlikely to occur on the mackinawite surfaces.


Relation between muscular strength and cardiorespiratory fitness in people with thoracic-level paraplegia.
To determine the relation between muscular strength, aerobic power (V O2 peak), submaximal blood lactate accumulation, and endurance performance in people with thoracic-level paraplegia. Participants performed tests of isokinetic strength, a graded exercise test, and 2 endurance performance tests. A Latin square counterbalanced design was used to determine the order of testing. Research laboratory in a university setting. Ten adult male volunteers with thoracic-level paraplegia. Not applicable. The relations between strength, V O2 peak, submaximal blood lactate accumulation, and endurance were determined by correlation analysis. Shoulder flexion strength correlated with V O2 peak and power output at V O2 peak. Shoulder strength accounted for 68.4% of the variation in performance time. Greater isokinetic elbow flexion and extension strength was associated with higher V O2 and power output at a blood lactate concentration of 4 mmol/L (flexion) and with a greater power output at V O2 peak (extension). These findings suggest that in this population, greater muscular strength is associated with greater aerobic power and endurance. Greater muscular strength could exert a positive influence on exercise performance by enabling higher levels of cardiorespiratory stress as the result of reduced or delayed local muscle fatigue.


Human neural stem cells induce functional myelination in mice with severe dysmyelination.
Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.


Two-way chemical signaling in Agrobacterium-plant interactions.
The discovery in 1977 that Agrobacterium species can transfer a discrete segment of oncogenic DNA (T-DNA) to the genome of host plant cells has stimulated an intense interest in the molecular biology underlying these plant-microbe associations. This attention in turn has resulted in a series of insights about the biology of these organisms that continue to accumulate at an ever-increasing rate. This excitement was due in part to the notion that this unprecedented interkingdom DNA transfer could be exploited to create transgenic plants containing foreign genes of scientific or commercial importance. In the course of these discoveries, Agrobacterium became one of the best available models for studying the molecular interactions between bacteria and higher organisms. One extensively studied aspect of this association concerns the exchange of chemical signals between Agrobacterium spp. and host plants. Agrobacterium spp. can recognize no fewer than five classes of low-molecular-weight compounds released from plants, and other classes probably await discovery. The most widely studied of these are phenolic compounds, which stimulate the transcription of the genes needed for infection. Other compounds include specific monosaccharides and acidic environments which potentiate vir gene induction, acidic polysaccharides which induce one or more chromosomal genes, and a family of compounds called opines which are released from tumorous plant cells to the bacteria as nutrient sources. Agrobacterium spp. in return release a variety of chemical compounds to plants. The best understood is the transferred DNA itself, which contains genes that in various ways upset the balance of phytohormones, ultimately causing neoplastic cell proliferation. In addition to transferring DNA, some Agrobacterium strains directly secrete phytohormones. Finally, at least some strains release a pectinase, which degrades a component of plant cell walls.


Antibiofilm activity of Dendrophthoe falcata against different bacterial pathogens.
Dendrophthoe falcata is a hemiparasitic plant commonly used for ailments such as ulcers, asthma, impotence, paralysis, skin diseases, menstrual troubles, pulmonary tuberculosis, and wounds. In this context, the validations of the traditional claim that the leaf extract of D. falcata possesses antibiofilm and anti-quorum sensing activity against different bacterial pathogens were assessed. The bacterial biofilms were quantified by crystal violet staining. Among the 17 bacterial pathogens screened, the methanolic fraction of the leaf extract clearly demonstrated antibiofilm activity for Proteus mirabilis, Vibrio vulnificus, Aeromonas hydrophila, Shigella sonnei, Chromobacterium violaceum ATCC 12472, Vibrio parahaemolyticus, Vibrio harveyi, Vibrio alginolyticus, Vibrio cholerae, and Proteus vulgaris. At biofilm inhibitory concentrations, biofilm formation was reduced by up to 70-90 %. Furthermore, the potential quorum-sensing activity of the leaf extract was tested by agar well diffusion using Chromobacterium violaceum (ATCC 12472 & CV O26) reporter strains. The inhibition of violacein production may be due to direct or indirect interference on QS by active constituents or the interactive effect of different phytocompounds present in the extracts. This is the first report on antibiofilm and QS activity of D. falcata leaf extracts, signifying the scope for development of complementary medicine for biofilm-associated infections.


C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocyte-derived cytokines.
Differential chemokine production by colonic epithelial cells is thought to contribute to the characteristic increased infiltration of selected population of leukocytes cells in inflammatory bowel disease. We have previously demonstrated that IL-13 enhances IL-1alpha-induced IL-8 secretion by the colonic epithelial cell line HT-29. We have now explored the C-C chemokine expression and modulation in this system. The combination of TNF-alpha and IFN-gamma was the minimal stimulation required for regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein (MCP-1) mRNA expression and secretion by HT-29 cells. The same stimulation induced a stronger IL-8 mRNA expression and secretion. Pretreatment with IL-13 or IL-4, reduced significantly the RANTES, and MCP-1, but not IL-8 mRNA expression and secretion. In contrast, IL-10 had no effect on either MCP-1, or RANTES, or IL-8 generation. Pretreatment of HT-29 cells with wortmannin suggested that the IL-13-induced inhibition of C-C chemokine expression is via activation of a wortmannin-sensitive phosphatidylinositol 3-kinase. These data demonstrate that colonic epithelial cell chemokine production can be differentially regulated by T cell-derived cytokines and suggest an interplay between epithelial cells and T lymphocytes potentially important in the intestinal inflammation.


Hepatitis C virus is a weak inducer of interferon alpha in plasmacytoid dendritic cells in comparison with influenza and human herpesvirus type-1.
Plasmacytoid dendritic cells (pDCs) are responsible for the production of type I IFN during viral infection. Viral elimination by IFN-alpha-based therapy in more than 50% of patients chronically infected with hepatitis C virus (HCV) suggests a possible impairment of production of endogenous IFN-alpha by pDCs in infected individuals. In this study, we investigated the impact of HCV on pDC function. We show that exposure of pDCs to patient serum- and cell culture-derived HCV resulted in production of IFN-alpha by pDCs isolated from some donors, although this production was significantly lower than that induced by influenza and human herpesvirus type 1 (HHV-1). Using specific inhibitors we demonstrate that endocytosis and endosomal acidification were required for IFN-alpha production by pDCs in response to cell culture-derived HCV. HCV and noninfectious HCV-like particles inhibited pDC-associated production of IFN-alpha stimulated with Toll-like receptor 9 (TLR9) agonists (CpG-A or HHV-1) but not that of IFN-alpha stimulated with TLR7 agonists (resiquimod or influenza virus). The blockade of TLR9-mediated production of IFN-alpha, effective only when pDCs were exposed to virus prior to or shortly after CpG-A stimulation, was already detectable at the IFN-alpha transcription level 2 h after stimulation with CpG-A and correlated with down-regulation of the transcription factor IRF7 expression and of TLR9 expression. In conclusion, rapidly and early occurring particle-host cell protein interaction during particle internalization and endocytosis followed by blockade of TLR9 function could result in less efficient sensing of HCV RNA by TLR7, with impaired production of IFN-alpha. This finding is important for our understanding of HCV-DC interaction and immunopathogenesis of HCV infection.


Human apoE isoforms differentially regulate brain amyloid-β peptide clearance.
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.


Current approaches to the diagnosis of herpes genitalis.
The current methods of diagnosing and treating herpes genitalis in clinics for sexually transmitted diseases in England and Wales are reported. Virus cultures were used as a diagnostic test in some or all patients in nearly two-thirds of clinics. Darkground examinations were performed on all or selected patients in most clinics, but fewer than half the clinics performed them on three or more separate occasions. In over 80% of clinics attempts were made to see some or all contacts of patients with herpes. The treatments prescribed varied, the commonest being saline washes, idoxuridine, and oral antibiotics. Serological tests were repeated after the disappearance of the lesions in 90% of clinics, while in 60% of clinics women with herpes genitalis were advised to have cytological examination at regular intervals in future. The importance of excluding syphilis in patients presenting with genital ulceration, the most appropriate treatments for herpes, and the possible association between the disease and cervical carcinoma are discussed.


XE991 and Linopirdine Are State-Dependent Inhibitors for Kv7/KCNQ Channels that Favor Activated Single Subunits.
M-channel inhibitors, especially XE991, are being used increasingly in animal experiments; however, insufficient characterization of XE991 at times confounds the interpretation of results when using this compound. Here, we demonstrate that XE991 and linopirdine are state-dependent inhibitors that favor the activated-subunit of neuronal Kv7/KCNQ channels. We performed patch-clamp experiments on homomeric Kv7.2 or heteromeric Kv7.2/3 channels expressed in Chinese hamster ovary cells to characterize XE991 and linopirdine. Neither inhibitor was efficacious around the resting membrane potential of cells in physiologic conditions. Inhibition of Kv7.2 and Kv7.2/3 channels by XE991 was closely related with channel activation. When the voltage dependence of activation was left-shifted by retigabine or right-shifted by the mutation, Kv7.2(R214D), the shift in half-activation voltage proportionally coincided with the shift in the half-effective potential for XE991 inhibition. Inhibition kinetics during XE991 wash-in was facilitated at depolarized potentials. Ten-minute washout of XE991 resulted in ∼30% current recovery, most of which was attributed to surface transport of Kv7.2 channels. Linopirdine also exhibited similar inhibition characteristics, with the exception of near- complete current recovery after washout at depolarized potentials. Inhibition kinetics of both XE991 and linopirdine was not as sensitive to changes in voltage as would be predicted by open- channel inhibition. Instead, they were well explained by binding to a single activated subunit. The characteristics of XE991 and linopirdine should be taken into account when these M-channel inhibitors are used in experiments.


Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family.
Non-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members. Family members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton™ System. Validation of identified variants was performed with Sanger sequencing. The linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders. DNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.


An Exploration of Family Caregiver Experiences of Burden and Coping While Caring for People with Mental Disorders in Saudi Arabia-A Qualitative Study.
Family caregivers of people with mental disorders face a number of burdens and stressors, such as associative stigma and burnout. These burdens are often a result of their caring role coupled with insufficient support or ineffective coping strategies, which can affect their quality of life and biopsychosocial integrity that, in turn, may affect the care they provide. This study aimed to explore the experiences of family caregivers of people with mental disorders, through examining the burdens that they face and the coping strategies that they use. Using a descriptive qualitative approach, 13 semi-structured interviews were conducted with members of the Saudi public, recruited through popular social media platforms and analyzed using thematic analysis. Five main themes were constructed from the data: Type of care, Challenges, Coping and support, Perceptions of public awareness, and Messages to others. The findings emphasize the different types of burdens that caregivers experience, and their needs that require a range of responses such as educational training on effective coping strategies, and psychological support in the form of counseling or group therapy. This study highlights the voice of caregivers and their message to the public, in order to correct the misconceptions surrounding mental disorders and those associated with them.


Building the crops of tomorrow: advantages of symbiont-based approaches to improving abiotic stress tolerance.
The exponential growth in world population is feeding a steadily increasing global need for arable farmland, a resource that is already in high demand. This trend has led to increased farming on subprime arid and semi-arid lands, where limited availability of water and a host of environmental stresses often severely reduce crop productivity. The conventional approach to mitigating the abiotic stresses associated with arid climes is to breed for stress-tolerant cultivars, a time and labor intensive venture that often neglects the complex ecological context of the soil environment in which the crop is grown. In recent years, studies have attempted to identify microbial symbionts capable of conferring the same stress-tolerance to their plant hosts, and new developments in genomic technologies have greatly facilitated such research. Here, we highlight many of the advantages of these symbiont-based approaches and argue in favor of the broader recognition of crop species as ecological niches for a diverse community of microorganisms that function in concert with their plant hosts and each other to thrive under fluctuating environmental conditions.


Would universal antenatal screening for HIV infection be cost-effective in a setting of very low prevalence? Modelling the data for Australia.
The economics of universal antenatal human immunodeficiency virus (HIV) screening should be explored if mother-to-child transmission of HIV occurs, the health-service infrastructure for universal screening exists, and optimal risk-reducing treatments can be supplied. We evaluated a hypothetical cohort of the antenatal population of Australia during 2001-2002, to examine whether universal antenatal HIV screening is cost-effective in this setting. A quasi-societal perspective was adopted, secondary data sources were used, and sensitivity analyses were undertaken. Costs and benefits incurred in the future were discounted to their present value. The intervention would be cost-effective if the prevalence of undiagnosed HIV in the currently unscreened Australian antenatal population was >or=0.004372%. We predict 6.95 new diagnoses of HIV, 1.73 infections avoided, and 46.97 discounted-life-years gained. Applying favorable and unfavorable values for key variables suggests that the prevalence at which the intervention would be cost-effective is 0.0016%-0.0106%. Universal antenatal HIV screening would be cost-effective at a very low prevalence and would generate net benefits under many scenarios; accurate statistics on the true prevalence of HIV in the currently unscreened antenatal population are required.


Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers.
Expression of several members of the Bcl-2 family proteins was investigated by means of both immunohistochemical analysis in 30 invasive ductal adenocarcinomas and 23 intraductal papillary-mucinous tumors (IPMTs) and immunoblot analysis in 6 cancer tissues and 7 pancreatic cancer cell lines. We found that Bcl-2 was expressed in 23%, Bax in 53%, Bcl-X in 90%, and Mcl-1 in 90% of the invasive ductal adenocarcinomas. In intraductal papillary-mucinous adenocarcinomas, the expression rate of Bax was 44% and those of Bcl-XL and Mcl-1 were 88%; these values were higher than those for intraductal papillary-mucinous adenomas. Immunoblot analysis identified Bcl-XL as the predominant form of the Bcl-X protein in both pancreatic cancer tissues and cell lines, and demonstrated that both Bcl-XL and Mcl-1 protein levels were uniformly high in all cell lines. These results suggest that an imbalance between antiapoptosis proteins (such as Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (such as Bax and Bcl-Xs) is involved in the distinctive biologic features of adenocarcinomas of the pancreas. Furthermore, predominantly high expressions of Bcl-XL and Mcl-1 in intraductal papillary-mucinous adenocarcinomas might be involved in the carcinogenesis in IPMT of the pancreas.


Exposure to sodium molybdate results in mild oxidative stress in Drosophila melanogaster.
The study was conducted to assess the redox status of Drosophila flies upon oral intake of insulin-mimetic salt, sodium molybdate (Na2MoO4). Oxidative stress parameters and activities of antioxidant and associated enzymes were analyzed in two-day-old D. melanogaster insects after exposure of larvae and newly eclosed adults to three molybdate levels (0.025, 0.5, or 10 mM) in the food. Molybdate increased content of low molecular mass thiols and activities of catalase, superoxide dismutase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase in males. The activities of these enzymes were not affected in females. Males exposed to molybdate demonstrated lower carbonyl protein levels than the control cohort, whereas females at the same conditions had higher carbonyl protein content and catalase activity than ones in the control cohort. The exposure to 10 mM sodium molybdate decreased the content of protein thiols in adult flies of both sexes. Sodium molybdate did not affect the activities of NADP-dependent malate dehydrogenase and thioredoxin reductase in males or NADP-dependent isocitrate dehydrogenase in either sex at any concentration. Enhanced antioxidant capacity in upon Drosophila flies low molybdate levels in the food suggests that molybdate can be potentially useful for the treatment of certain pathologies associated with oxidative stress.


Regularized Partial Least Squares with an Application to NMR Spectroscopy.
High-dimensional data common in genomics, proteomics, and chemometrics often contains complicated correlation structures. Recently, partial least squares (PLS) and Sparse PLS methods have gained attention in these areas as dimension reduction techniques in the context of supervised data analysis. We introduce a framework for Regularized PLS by solving a relaxation of the SIMPLS optimization problem with penalties on the PLS loadings vectors. Our approach enjoys many advantages including flexibility, general penalties, easy interpretation of results, and fast computation in high-dimensional settings. We also outline extensions of our methods leading to novel methods for non-negative PLS and generalized PLS, an adoption of PLS for structured data. We demonstrate the utility of our methods through simulations and a case study on proton Nuclear Magnetic Resonance (NMR) spectroscopy data.