Olfactory ensheathing glia express aquaporin 1.
Olfactory ensheathing glia (OEG) are distinct from other glia in their developmental origin, presence in both the peripheral and central nervous systems, and highly restricted location. OEG are present only in the olfactory lamina propria, olfactory nerve, and the outer two layers of the olfactory bulb, where they envelop bundles of olfactory sensory neuron axons in a manner distinct from myelination. Because of their unique properties and their association with the continually generated olfactory sensory neurons, OEG have attracted interest for their potential capacity to support axonal regeneration, for example, after spinal cord injury. However, study of the properties and function of OEG has been hampered by a paucity of neurochemical markers with which to identify and distinguish them definitively from other types of glia. Here we provide evidence through anatomical colocalization studies that OEG express the water channel aquaporin 1 (AQP1), both in vivo and in vitro. We propose that AQP1 expression represents an important distinguishing characteristic of OEG, which may impart unique function to these glia.


Facebook and its effects on users' empathic social skills and life satisfaction: a double-edged sword effect.
This study examines how Facebook usage affects individual's empathic social skills and life satisfaction. Following the self-presentational theory, the study explores a key component of the Internet paradox-whether Facebook suppresses or enhances users' interpersonal competence (specifically empathic social skills), given their respective personality makeup. Going further, the study assesses these events' subsequent impacts on users' psychological well-being. Analogous to a double-edged sword, Facebook activities are hypothesized to suppress the positive effect of a user's extraversion orientation on empathic social skills but lessen the negative effect of neuroticism on these skills. The study examines a sample of college-aged Facebook users (n=515), who responded to a large-scale online survey. The findings from a structural equation modeling analysis indicate that while empathic social skills are positively associated with life satisfaction, Facebook activities mainly exert suppression effects. Only upon low usage can Facebook activities lessen the negative effect of neuroticism on empathic social skills, suggesting that Facebook may appear as a less threatening platform for social interactions among neurotics. Yet, results in general suggest that undesirable effects may occur at high levels of Facebook usage whereby both extroverted and neurotic users displace real world social ties to online ones. The findings point to the complex ways in which social media usage may impact the livelihood of users.


Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes.
Skatole (3-methylindole) is a product of bacterial fermentation of tryptophan in the intestine. A significant amount of skatole can also be inhaled during cigarette smoking. Skatole is a pulmonary toxin that induces the expression of aryl hydrocarbon receptor (AhR) regulated genes, such as cytochrome P450 1A1 (CYP1A1), in human bronchial cells. The liver has a high metabolic capacity for skatole and is the first organ encountered by the absorbed skatole; however, the effect of skatole in the liver is unknown. Therefore, we investigated the impact of skatole on hepatic AhR activity and AhR-regulated gene expression. Using reporter gene assays, we showed that skatole activates AhR and that this is accompanied by an increase of CYP1A1, CYP1A2 and CYP1B1 expression in HepG2-C3 and primary human hepatocytes. Specific AhR antagonists and siRNA-mediated AhR silencing demonstrated that skatole-induced CYP1A1 expression is dependent on AhR activation. The effect of skatole was reduced by blocking intrinsic cytochrome P450 activity and indole-3-carbinole, a known skatole metabolite, was a more potent inducer than skatole. Finally, skatole could reduce TCDD-induced CYP1A1 expression, suggesting that skatole is a partial AhR agonist. In conclusion, our findings suggest that skatole and its metabolites affect liver homeostasis by modulating the AhR pathway.


Cancer Stem Cell Plasticity Drives Therapeutic Resistance.
The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.


Bridging therapy effectiveness in the treatment of hepatocellular carcinoma prior to orthotopic liver transplantation.
Orthotopic liver transplantation (OLT) is the most effective treatment for hepatocellular carcinoma (HCC) in patients with underlying cirrhosis and portal hypertension. Availability of OLT is limited by donor-organ shortages, which increase patient waiting time until OLT. A variety of bridging therapies (BT) have been used to halt tumor progression in patients on the OLT waiting list. Despite complete radiologic responses following BT, viable tumor is often present in explants. Treatment outcomes were evaluated in 50 patients who had a total of 125 BT for treatment of 93 nodules. Success of BT was assessed by radiologic response compared to histopathological examination of explanted livers. Pre-transplant treatments included: transcatheter arterial chemoembolization (TACE), alcohol ablation (ETOH), radiofrequency ablation (RFA), microwave ablation (MWA), selective internal radiation therapy (SIRT) and stereotactic body radiation therapy (SBRT). Fifty-nine (64%) nodules had a complete radiographic response to therapy; however, only 28 nodules (30%) had complete tumor necrosis (CTN) on explant examination. Ten nodules with CTN were treated with TACE alone. Seven of the 28 nodules with CTN were treated with TACE and RFA. Three of seven nodules treated with TACE and SIRT had CTN. Patients underwent a mean of 2.5 BTs. Six of 50 patients (12%) had no residual HCC in their explants. Five of those six patients (83%) had complete response (CR) on pre-transplant imaging. Although favorable radiologic responses are seen following BT, viable HCC is seen in the majority of liver explants and radiographic imaging cannot always accurately predict pathological response. This underscores the need for aggressive treatment of patients who otherwise may not be eligible for OLT.


Phase and Frequency-Dependent Effects of Transcranial Alternating Current Stimulation on Motor Cortical Excitability.
Transcranial alternating current stimulation (tACS) can entrain ongoing brain oscillations and modulate the motor system in a frequency-dependent manner. Recent animal studies have demonstrated that the phase of a sinusoidal current also has an important role in modulation of neuronal activity. However, the phase effects of tACS on the human motor system are largely unknown. Here, we systematically investigated the effects of tACS phase and frequency on the primary motor cortex (M1) by using motor evoked potentials (MEPs) with transcranial magnetic stimulation (TMS). First, we compared the phase effects (90°, 180°, 270° or 360°) of 10 and 20 Hz tACS on MEPs. The 20 Hz tACS significantly increased M1 excitability compared with the 10 Hz tACS at 90° phase only. Second, we studied the 90° phase effect on MEPs at different tACS frequencies (5, 10, 20 or 40 Hz). The 20 vs. 10 Hz difference was again observed, but the 90° phase in 5 and 40 Hz tACS did not influence M1 excitability. Third, the 90° phase effects of 10 and 20 Hz tACS were compared with sham stimulation. The 90° phase of 20 Hz tACS enhanced MEP amplitudes compared with sham stimulation, but there was no significant effect of 10 Hz tACS. Taken together, we assume that the differential 90° phase effects on 20 Hz and 10 Hz tACS can be attributed to the neural synchronization modulated by tACS. Our results further underline that phase and frequency are the important factors in the effects of tACS on M1 excitability.


Cancer statistics, 2016.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population.


Filovirus contamination of cell cultures.
The filoviruses Marburg and Ebola comprise a newly recognized family of viruses. The first filovirus to be isolated was Marburg virus in 1967. This virus was imported in shipments of African green monkeys from Uganda and infected several cell-culture technicians, with serious illness resulting. The rarity of Marburg and Ebola virus transmission, decreasing use of imported African monkeys, and quarantine efforts have presumably been responsible for the lack of additional episodes until 1989, when a new filovirus related to Ebola was isolated from quarantined monkeys in Reston, Virginia. This virus was imported on multiple occasions from a Philippine supplier of cynomolgus macaques as a consequence of an epidemic of acute infections in the foreign holding facility. While quarantine procedures prevented the use of any of these animals in research and the three human infections that occurred were asymptomatic, this episode emphasizes that these little understood viruses have considerable potential for mischief. The finding of antibodies reacting with Ebola viruses in many biomedically important Old World primates, including colonized monkeys in the U.S., emphasizes the need for more research to understand the specificity of the antibodies, spectrum of filovirus strains in nature, potential hosts, and true distribution of the family. The filoviruses grow well in primary and established cell strains and cell lines, and cytopathogenic effects may be absent or require several days to be manifest, leading to the possibility of occult contamination. The known viruses are readily detected by polyclonal and monoclonal antibody staining of cells and by electron microscopy; nucleic acid probes exist to develop more sensitive techniques if warranted.


Ultrasound-stimulated vibro-acoustic spectrography.
An ultrasound method based on radiation force is presented for imaging the acoustic response of a material to mechanical excitation. Acoustic energy was emitted from solids and tissues in response to an oscillatory radiation force produced by interfering focused beams of ultrasound. Frequency spectra of ultrasound-stimulated acoustic emission exhibited object resonances. Raster-scanning the radiation force over the object and recording the amplitude and phase of the emitted sound resulted in data from which images related to the elastic compositions of the acoustically emitting objects could be computed. Acoustic emission signals distinguished tuning-fork resonances, submillimeter glass spheres, and calcification in excised arteries and detected object motions on the order of nanometers.


Differentiation-dependent changes in the solubility of a 195-kD protein in human epidermal keratinocytes.
We have prepared a monoclonal antibody, AE11, that recognizes specifically a 195-kD protein (pI 5.4) of human keratinocytes. This antigen constitutes approximately 0.01-0.1% of total protein in keratinocytes of skin, esophagus, and cornea, and is readily detectable in these cells by immunofluorescent staining and immunoblotting. However, it is barely detectable in MCF mammary carcinoma cells and HeLa cells, and is undetectable in nonepithelial cell types. Results from serial extraction experiments have shown that this protein exists in two distinct pools: a Tris-soluble, and a Tris-insoluble but urea- or SDS-soluble one. The distribution of the 195-kD protein between these two pools appears to be differentiation-related, since relatively undifferentiated cells selected by a low-calcium medium contain primarily the soluble form, while highly differentiated cells contain mainly the insoluble form. Data from immunofluorescent staining and trypsin-sensitivity experiments suggest that the soluble form is cytoplasmic, whereas the insoluble form is submembranously located at the cell periphery of upper, differentiated cells. The insoluble, cell peripheral form of the 195-kD antigen increases progressively during epidermal differentiation; its insolubility appears to be related to the formation of disulfide-bond(s). These results indicate that the 195-kD protein, which has recently been suggested to be involved in cornified envelope formation (Simon, M., and H. Green, 1985, Cell, 36:827-834), undergoes significant changes in its solubility characteristics and intracellular location during keratinocyte maturation.


Negative Impact of Female Sex on Outcomes from Repetitive Mild Traumatic Brain Injury in hTau Mice Is Age Dependent: A Chronic Effects of Neurotrauma Consortium Study.
Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice.


Contraceptive use dynamics of Asian women in Britain.
In-depth interviews were conducted with married Asian women from Indian, Pakistani and Bangladeshi backgrounds, to investigate patterns of contraceptive use and influences on contraceptive decision making. The results show two distinctively different contraceptive 'lifecycles'. Non-professional women typically have little knowledge about contraception until after their marriage or first birth. Their patterns of contraceptive behaviour show low levels of contraceptive use until after their first birth, when condom use is most prevalent. Non-professional women are influenced by their extended family, religion and cultural expectations on their fertility and family planning decisions. Professional women show an entirely different pattern of contraceptive behaviour. They are more likely to have knowledge about contraception before marriage, use some method of contraception throughout their childbearing years (typically the pill) and cite personal, practical or economic considerations in their fertility decisions rather than religious, cultural or extended family influences.


Analysis of synthetic cannabinoids using high-resolution mass spectrometry and mass defect filtering: implications for nontargeted screening of designer drugs.
Detection of new designer drugs remains an analytical challenge because of the ability of manufacturers to rapidly substitute closely related analogs for banned substances. Traditional targeted mass spectrometry methods rely on library searches, known masses, or multiple reaction monitoring (MRM) transitions and are therefore often unable to detect or identify recently discovered or yet unreported designer drug analogs. Here, high-resolution mass spectrometry in conjunction with mass defect filtering is presented as a method for nontargeted analysis to detect both known and novel analogs of designer drugs. The technique is applied in depth to a family of designer drugs composed of indole-derived synthetic cannabinoids closely related to JWH-018, a substance recently controlled in the United States. A single mass defect filter with a 50 mDa window encompasses over 80% of all currently published structures in this family. Searching for precursor ions of common fragment ions enables detection of compounds with mass defects that fall outside the range of mass defect filter parameters. Application of a mass defect filter to fragment ions prior to precursor ion searching increases the breadth of analogs that can be detected. The combined approach defines a broad-spectrum search for related molecules.


The superior temporal sulcus differentiates communicative and noncommunicative auditory signals.
Processing the vocalizations of conspecifics is critical for adaptive social interaction. A species-specific voice-selective region has been identified in the right STS that responds more strongly to human vocal sounds compared with a variety of nonvocal sounds. However, the STS also activates in response to a wide range of signals used in communication, such as eye gaze, biological motion, and speech. These findings raise the possibility that the voice-selective region of the STS may be especially sensitive to vocal sounds that are communicative, rather than to all human vocal sounds. Using fMRI, we demonstrate that the voice-selective region of the STS responds more strongly to communicative vocal sounds (such as speech and laughter) compared with noncommunicative vocal sounds (such as coughing and sneezing). The implications of these results for understanding the role of the STS in voice processing and in disorders of social communication, such as autism spectrum disorder, are discussed.


Arrhythmia in isolated prenatal hearts after ablation of the Cav2.3 (alpha1E) subunit of voltage-gated Ca2+ channels.
A voltage-gated calcium channel containing Cav2.3e (alpha1Ee) as the ion conducting pore has recently been detected in rat heart. Functional evidence for this Ca2+ channel to be involved in the regulation of heart beating, besides L- and T-type channels, was derived from murine embryos where the gene for Cav1.2 had been ablated. The remaining "L-type like" current component was not related to recombinant splice variants of Cav1.3 containing channels. As recombinant Cav2.3 channels from rat were reported to be weakly dihydropyridine sensitive, the spontaneous activity of the prenatal hearts from Cav2.3(-|-) mice was compared to that of Cav2.3(+|+) control animals to investigate if Cav2.3 could represent such a L-type like Ca(2+) channel. The spontaneous activity of murine embryonic hearts was recorded by using a multielectrode array. Between day 9.5 p.c. to 12.5 p.c., the beating frequency of isolated embryonic hearts from Cav2.3-deficient mice did not differ significantly from control mice but the coefficient of variation within individual episodes was more than four-fold increased in Cav2.3-deficient mice indicating arrhythmia. In isolated hearts from wild type mice, arrhythmia was induced by superfusion with a solution containing 200 nM SNX-482, a blocker of some R-type voltage gated Ca2+ channels, suggesting that R-type channels containing the splice variant Cav2.3e as ion conducting pore stabilize a more regular heart beat in prenatal mice.


The impact of changing economic conditions on overweight risk among children in California from 2008 to 2012.
The recent economic recession represents an opportunity to test whether decreases in economic resources may have deleterious consequences on childhood overweight/obesity risk. We investigated the association between indicators of changing macroeconomic conditions from 2008 to 2012 and overweight/obesity risk among school-aged children in California (n=1 741 712) using longitudinal anthropometric measurements. Multivariate regression, with individual and county fixed effects, was used to examine the effects of annual county-level unemployment and foreclosure rates on risk of child overweight/obesity, overall and among subgroups (race/ethnicity, sex, county-level median household income and county-level urban/rural status). From 2008 to 2012, ∼38% of children were overweight/obese and unemployment and foreclosure rates averaged 11% and 6.9%, respectively. A 1-percentage point (pp) increase in unemployment was associated with a 1.4 pp (95% CI 1.3 to 1.5) increase in overweight/obesity risk. Therefore, a child of average weight could expect a 14% increase in their body mass index z-score in association with a 1 pp increase in unemployment during the study period. We found some differences in the magnitude of the effects for unemployment among demographic subgroups, with the largest effects observed for unemployment among American Indians and Pacific Islanders. Comparing children to themselves over time, we provide evidence that increases in county-level unemployment are associated with increased overweight/obesity risk. Given that overweight among children with lower economic resources remains a challenge for public health, these findings highlight the importance of policy-level approaches, which aim to mitigate the impact of decreased resources as economic conditions change.


Games played by rogue proteins in prion disorders and Alzheimer's disease.
The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa.


Do standard optometric measures predict binocular coordination during reading?
In reading, binocular eye movements are required for optimal visual processing and thus, in case of asthenopia or reading problems, standard orthoptic and optometric routines check individual binocular vision by a variety of tests. The present study therefore examines the predictive value of such standard measures of heterophoria, accommodative and vergence facility, AC/A-ratio, NPC and symptoms for binocular coordination parameters during read-ing. Binocular eye movements were recorded (EyeLink II) for 65 volunteers during a typical reading task and linear regression analyses related all parameters of binocular coordination to all above-mentioned optometric measures: while saccade disconjugacy was weakly pre-dicted by vergence facility (15% explained variance), vergence facility, AC/A and symp-toms scores predicted vergence drift (31%). Heterophoria, vergence facility and NPC ex-plained 31% of fixation disparity and first fixation duration showed minor relations to symp-toms (18%). In sum, we found only weak to moderate relationships, with expected, selective associations: dynamic parameter related to optometric tests addressing vergence dynamics, whereas the static parameter (fixation disparity) related mainly to heterophoria. Most sur-prisingly, symptoms were only loosely related to vergence drift and fixation duration, re-flecting associations to a dynamic aspect of binocular eye movements in reading and poten-tially non-specific, overall but slight reading deficiency. Thus, the efficiency of optometric tests to predict binocular coordination during reading was low - questioning a simple, straightforward extrapolation of such test results to an overlearned, complex task.


R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters.
CpG islands (CGIs) function as promoters for approximately 60% of human genes. Most of these elements remain protected from CpG methylation, a prevalent epigenetic modification associated with transcriptional silencing. Here, we report that methylation-resistant CGI promoters are characterized by significant strand asymmetry in the distribution of guanines and cytosines (GC skew) immediately downstream from their transcription start sites. Using innovative genomics methodologies, we show that transcription through regions of GC skew leads to the formation of long R loop structures. Furthermore, we show that GC skew and R loop formation potential is correlated with and predictive of the unmethylated state of CGIs. Finally, we provide evidence that R loop formation protects from DNMT3B1, the primary de novo DNA methyltransferase in early development. Altogether, these results suggest that protection from DNA methylation is a built-in characteristic of the DNA sequence of CGI promoters that is revealed by the cotranscriptional formation of R loop structures.


Serotonergic antagonists differentially inhibit spontaneous activity and decrease ligand binding capacity of the rat 5-hydroxytryptamine type 2C receptor in Sf9 cells.
The activities of serotonergic antagonists as inverse agonists at the rat 5-hydroxytryptamine (5-HT)2C serotonin receptor were compared with their potencies in promoting receptor "down-regulation," after expression of the recombinant receptor in the baculovirus/Sf9 insect cell system. Baculovirus expression yielded high levels of 5-HT2C receptors (up to 10(6) receptors/cell), which were functionally coupled to polyphosphoinositide turnover in Sf9 cells through a pertussis toxin-insensitive pathway. The expressed receptor exhibited spontaneous activation of inositol phosphate production, which was inhibited in a dose-dependent manner by serotonergic antagonists, consistent with inverse agonist activity. The potencies of antagonists as inverse agonists correlated with their respective binding affinities determined in competition binding studies with membrane preparations. The maximal inhibition of spontaneous activity ranged from 32% inhibition for mianserin to no effect for spiroxatrine, indicating that antagonists differ in their intrinsic inverse efficacies. Antagonist treatment of intact Sf9 cells or membranes containing the 5-HT2C receptor, followed by washout of residual drug, resulted in a decrease (up to 90%) in the number of binding sites for [3H]mesulergine and [3H]5-HT, with no change in the affinity for [3H]mesulergine. The decrease in binding was irreversible, was not due to the presence of residual antagonist, and was not observed after treatment with agonists. This effect of antagonists in membranes was dose dependent, but the rank order of potency was clearly different from that for inverse agonist activity, indicating that the two effects reflect distinct actions of antagonists at the 5-HT2C receptor. The relative abilities of antagonists to produce loss of binding showed a good correlation with their reported abilities to down-regulate 5-HT2 receptors in vivo after chronic treatment, suggesting that these actions reflect the same underlying process.


Synthesis of Thelepamide via Catalyst-Controlled 1,4-Addition of Cysteine Derivatives and Structure Revision of Thelepamide.
The first enantioselective total synthesis and structural reassignment of (-)-thelepamide, a cytotoxic tetraketide-amino acid from the marine worm Thelepus crispus, is reported. A convergent approach provides access to all thelepamide diastereomers in six steps from four simple building blocks. Key features of the synthesis include the application of Melchiorre's organocatalytic thia-Michael reaction and a sonication-assisted assembly of an unprecedented N,O-acetal-hemiacetal moiety. The corrected structure was confirmed by NMR-DFT analysis.


Prevalence, features and health impacts of eating disorders amongst First-Australian Yiramarang (adolescents) and in comparison with other Australian adolescents.
This study aimed to support previous research conducted with First-Australians (FA) by establishing the prevalence of eating disorders, and their demographic distribution and burden in adolescent First-Australians compared to other-Australians (OA). Data were used from the baseline survey of the EveryBODY Study, a longitudinal investigation of eating disorders among Australian adolescents. Of the 5068 participants included, 402 (8%) identified as FA, 4586 (90.5%) identified as OA. Diagnosis of eating disorders was based on the Diagnostic and Statistical Manual version 5. Socioeconomic status and measures of impairment were assessed using validated instruments. Body mass index was calculated based on self-reported weight and height. Statistical analyses used data weighted to the distribution of gender in adolescents in New South Wales in the 2016 Australian Census. Chi-square tests were performed to determine prevalence of eating disorders amongst FA and to compare to OA. ANOVA and logistic regression analyses where conducted to examine the moderation effect of sociodemographic status, measures of impairment and FA status on the distribution of eating disorders. The prevalence rates for eating disorder diagnoses where similar for FA and OA with the exception of Night eating Syndrome (OSFED-NES), which occurred in 7.14% (95%CI 4.81-10.49) of FA vs. 3.72% (95%CI 3.17-4.36) in OA. The greater prevalence of OSFED-NES in FA was largely explained by poorer psychosocial quality of life amongst FA. Eating disorders are common amongst First-Australian adolescents and are associated with poor psychosocial quality of life. These findings are consistent with previous research conducted with First-Australian adults. There is a need to screen for eating disorders amongst First-Australian adolescent girls and boys.


[68Ga]Ga-NODAGA-E[(cRGDyK)]2 PET and hyperpolarized [1-13C] pyruvate MRSI (hyperPET) in canine cancer patients: simultaneous imaging of angiogenesis and the Warburg effect.
Cancer has a multitude of phenotypic expressions and identifying these are important for correct diagnosis and treatment selection. Clinical molecular imaging such as positron emission tomography can access several of these hallmarks of cancer non-invasively. Recently, hyperpolarized magnetic resonance spectroscopy with [1-13C] pyruvate has shown great potential to probe metabolic pathways. Here, we investigate simultaneous dual modality clinical molecular imaging of angiogenesis and deregulated energy metabolism in canine cancer patients. Canine cancer patients (n = 11) underwent simultaneous [68Ga]Ga-NODAGA-E[(cRGDyK)]2 (RGD) PET and hyperpolarized [1-13C]pyruvate-MRSI (hyperPET). Standardized uptake values and [1-13C]lactate to total 13C ratio were quantified and compared generally and voxel-wise. Ten out of 11 patients showed clear tumor uptake of [68Ga]Ga-NODAGA-RGD at both 20 and 60 min after injection, with an average SUVmean of 1.36 ± 0.23 g/mL and 1.13 ± 0.21 g/mL, respectively. A similar pattern was seen for SUVmax values, which were 2.74 ± 0.41 g/mL and 2.37 ± 0.45 g/mL. The [1-13C]lactate generation followed patterns previously reported. We found no obvious pattern or consistent correlation between the two modalities. Voxel-wise tumor values of RGD uptake and lactate generation analysis revealed a tendency for each canine cancer patient to cluster in separated groups. We demonstrated combined imaging of [68Ga]Ga-NODAGA-RGD-PET for angiogenesis and hyperpolarized [1-13C]pyruvate-MRSI for probing energy metabolism. The results suggest that [68Ga]Ga-NODAGA-RGD-PET and [1-13C]pyruvate-MRSI may provide complementary information, indicating that hyperPET imaging of angiogenesis and energy metabolism is able to aid in cancer phenotyping, leading to improved therapy planning.


The profile of abstract rule learning in infancy: Meta-analytic and experimental evidence.
Everyone agrees that infants possess general mechanisms for learning about the world, but the existence and operation of more specialized mechanisms is controversial. One mechanism-rule learning-has been proposed as potentially specific to speech, based on findings that 7-month-olds can learn abstract repetition rules from spoken syllables (e.g. ABB patterns: wo-fe-fe, ga-tu-tu…) but not from closely matched stimuli, such as tones. Subsequent work has shown that learning of abstract patterns is not simply specific to speech. However, we still lack a parsimonious explanation to tie together the diverse, messy, and occasionally contradictory findings in that literature. We took two routes to creating a new profile of rule learning: meta-analysis of 20 prior reports on infants' learning of abstract repetition rules (including 1,318 infants in 63 experiments total), and an experiment on learning of such rules from a natural, non-speech communicative signal. These complementary approaches revealed that infants were most likely to learn abstract patterns from meaningful stimuli. We argue that the ability to detect and generalize simple patterns supports learning across domains in infancy but chiefly when the signal is meaningfully relevant to infants' experience with sounds, objects, language, and people.


Emerging and Neglected Infectious Diseases: Insights, Advances, and Challenges.
Infectious diseases are a significant burden on public health and economic stability of societies all over the world. They have for centuries been among the leading causes of death and disability and presented growing challenges to health security and human progress. The threat posed by infectious diseases is further deepened by the continued emergence of new, unrecognized, and old infectious disease epidemics of global impact. Over the past three and half decades at least 30 new infectious agents affecting humans have emerged, most of which are zoonotic and their origins have been shown to correlate significantly with socioeconomic, environmental, and ecological factors. As these factors continue to increase, putting people in increased contact with the disease causing pathogens, there is concern that infectious diseases may continue to present a formidable challenge. Constant awareness and pursuance of effective strategies for controlling infectious diseases and disease emergence thus remain crucial. This review presents current updates on emerging and neglected infectious diseases and highlights the scope, dynamics, and advances in infectious disease management with particular focus on WHO top priority emerging infectious diseases (EIDs) and neglected tropical infectious diseases.


Neurons generated in the adult brain are recruited into functional circuits.
Adult canaries, Serinus canarius, received injections of 3H-labeled thymidine, a marker of DNA synthesis. Thirty days after the last injection, intracellular potentials were recorded from neurons in the nucleus hyperstriatum ventralis pars caudalis, a vocal control nucleus in the telencephalon; these same cells were then injected with horseradish peroxidase. Of the 74 neurons labeled with horseradish peroxidase that were recovered, the nuclei of seven were radioactively labeled. Four of these seven neurons had responded to auditory stimuli. These double-labeled neurons were apparently generated during or after the 3H-labeled thymidine treatment (during adulthood) and subsequently incorporated into functional neural circuits.


Effects of preoperative intentional hemodilution on the extravasation rate of albumin and fluid.
To evaluate the effects of preoperative intentional hemodilution with 4% albumin solution on the extravasation rate of intravascular albumin and fluid in surgical patients. A prospective, randomized, clinical study. University teaching hospital. Two groups (control group [group 1] and hemodiluted group [group 2]) of 13 healthy patients were studied during a long-term (>4 hrs) surgical procedure. Autologous technetium-99m (99mTc)-labeled red blood cells and indium-oxine ((111)In)-labeled human serum albumin were injected intravenously during anesthesia at T = 0 min in the two groups for the determination of total blood volume and albumin diffusion space, respectively. In addition, body tetrapolar electrical impedance was used to assess extracellular fluid volume. In the hemodiluted group (group 2), 15 mL/kg of blood was withdrawn over 30 mins (T = 20 mins to T = 50 mins) and simultaneously replaced by an equal volume of 4% albumin solution (0.6 g/kg). The albumin diffusion space, the colloid oncotic pressure, the plasma albumin concentration and the electrical impedance were measured before (T = 10 mins) and after (T = 60, 120, and 240 mins) hemodilution. Urine was collected from T = 10 mins to T = 240 mins. The total blood volume was calculated at T = 10 mins. No differences in the initial values were found between the two groups. In group 2, hemodilution (hematocrit 30 +/- 3%) resulted in a steeper increase in the albumin diffusion space (p < .05) and a progressive decrease in the body electrical impedance (p < .05). The extravasation rate of albumin was 0.052 +/- 0.007 mL/kg/min in group 2 vs. 0.038 +/- 0.020 mL/kg/min in group 1 (p < .05). The value of calculated plasma volume at T = 0 min did not shown any difference between the two groups. This value was then lower than expected in group 2, corresponding to a loss of plasma volume of >3 mL/kg. Urine output was significantly lower in group 2 than in group 1 (0.7 +/- 0.4 vs. 1.4 +/- 1.0 mL/min, respectively; p < .05). A comparable decrease in colloid oncotic pressure and in plasma albumin concentration was observed in both groups. These results suggest that preoperative hemodilution using 4% albumin on a 1:1 volume basis for blood substitution during a prolonged surgical procedure with reduced blood losses enhances the extravasation rate of albumin and fluid to the interstitial tissues, impeding the maintenance of isovolemia. These findings support the use of a volume of infused colloid solution higher than that of withdrawn blood during preoperative hemodilution.


Human immunodeficiency virus type 1 populations in blood and semen.
Transmission of human immunodeficiency virus type 1 (HIV-1) usually results in outgrowth of viruses with macrophage-tropic phenotype and consensus non-syncytium-inducing (NSI) V3 loop sequences, despite the presence of virus with broader host range and the syncytium-inducing (SI) phenotype in the blood of many donors. We examined proviruses in contemporaneous peripheral blood mononuclear cells (PBMC) and non-spermatozoal semen mononuclear cells (NSMC) of five HIV-1-infected individuals to determine if this preferential outgrowth could be due to compartmentalization and thus preferential transmission of viruses of the NSI phenotype from the male genital tract. Phylogenetic reconstructions of approximately 700-bp sequences covering the second constant region through the fifth variable region (C2 to V5) of the viral envelope gene revealed distinct variant populations in the blood versus the semen in two patients with AIDS and in one asymptomatic individual (patient 613), whereas similar variant populations were found in both compartments in two other asymptomatic individuals. Variants with amino acids in the V3 loop that predict the SI phenotype were found in both AIDS patients and in patient 613; however, the distribution of these variants between the two compartments was not consistent. SI variants were found only in the PBMC of one AIDS patient but only in the NSMC of the other, while they were found in both compartments in patient 613. It is therefore unlikely that restriction of SI variants from the male genital tract accounts for the observed NSI transmission bias. Furthermore, no evidence for a semen-specific signature amino acid sequence was detected.


Modeling cooperative effects in halogen-bonded infinite linear chains.
Non-additivity in noncovalent interactions is an important aspect of complex systems that can lead to stronger (cooperative) interactions when three or more molecular units influence each other. The halogen bond (XB) is a highly-directional noncovalent interaction that has been found to be cooperative. Here the strength and nature of cooperativity arising in X-bonded infinite linear chains of cyanogen halides and 4-halopyridines are investigated by means of density functional theory calculations. It is found that cyanogen halide chains are highly cooperative (up to 77%), whereas pyridines are only slightly cooperative (below 21%). It is demonstrated that XB and its non-additivity can be modeled as the sum of a local term, which depends on first nearest-neighbors only, and long-range effective dipole-dipole attractions. It is shown that the local term in cyanogen halides primarily accounts for repulsive short-range screened Coulomb interactions, whereas in 4-halopyridines such a term also includes attractive contributions, which are particularly sizeable in some elongated XB conformations. This outcome reveals differences in the nature of the XBs formed in these molecular systems. Nevertheless, it is shown that both systems behave as effective point dipoles regarding cooperative effects, at any point of the XB dissociation path. As such, these results are useful contributions for the understanding and modeling of non-additive effects of noncovalent interactions.


Macroecological patterns of sexual size dimorphism in turtles of the world.
Sexual size dimorphism (SSD) is a well-documented phenomenon in both plants and animals; however, the ecological and evolutionary mechanisms that drive and maintain SSD patterns across geographic space at regional and global scales are understudied, especially for reptiles. Our goal was to examine geographic variation of turtle SSD and to explore ecological and environmental correlates using phylogenetic comparative methods. We use published body size data on 135 species from nine turtle families to examine how geographic patterns and the evolution of SSD are influenced by habitat specialization, climate (annual mean temperature and annual precipitation) and climate variability, latitude, or a combination of these predictor variables. We found that geographic variation, magnitude and direction of turtle SSD are best explained by habitat association, annual temperature variance and annual precipitation. Use of semi-aquatic and terrestrial habitats was associated with male-biased SSD, whereas use of aquatic habitat was associated with female-biased SSD. Our results also suggest that greater temperature variability is associated with female-biased SSD. In contrast, wetter climates are associated with male-biased SSD compared with arid climates that are associated with female-biased SSD. We also show support for a global latitudinal trend in SSD, with females being larger than males towards the poles, especially in the families Emydidae and Geoemydidae. Estimates of phylogenetic signal for both SSD and habitat type indicate that closely related species occupy similar habitats and exhibit similar direction and magnitude of SSD. These global patterns of SSD may arise from sex-specific reproductive behaviour, fecundity and sex-specific responses to environmental factors that differ among habitats and vary systematically across latitude. Thus, this study adds to our current understanding that while SSD can vary dramatically across and within turtle species under phylogenetic constraints, it may be driven, maintained and exaggerated by habitat type, climate and geographic location.


Prevalence of latent and overt polyautoimmunity in autoimmune thyroid disease: A systematic review and meta-analysis.
Thyroid autoimmunity is the most frequent condition involved in polyautoimmunity (PolyA). However, the frequency of latent and overt PolyA in patients with autoimmune thyroid disease (AITD) as the index condition is unknown. Therefore, the purpose of this study was to determine the prevalence of these types of PolyA in patients with AITD as the index condition. This study adhered to the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Searches through MEDLINE, Embase and LILACS were done to find articles in Spanish and English. Relevant vocabulary terms and key terms related to AITD and other autoimmune diseases were used. Two investigators independently screened the eligible studies, extracted data and assessed the quality and risk of bias. Fixed and random effect models were used accordingly. Cluster analysis was used to determine similarities among diseases in the articles included (based on Jaccard index). A total of 56 articles fulfilled the inclusion criteria. Of these, 25 were case-controls, 17 were cohorts, and 14 were cross-sectional studies. These studies included a total of 47 509 patients. Female was the predominant gender and included 38 950 patients (81.23%, 95% CI: 80.85-81.60). Graves' disease (GD) was the most common type of thyroid autoimmunity (69.16%, 95% CI: 68.23-70.07). Globally, overt PolyA was found in 13.46% of the patients with AITD. This type of PolyA was represented mainly by type 1 diabetes and autoimmune gastritis. Latent PolyA was presented in 17.45% of the patients, and anti-proinsulin, anti-parietal cells and dsDNA antibodies were the most common. HT had the highest frequency of overt PolyA in Europe (15.60%, 95% CI: 14.72-16.53), whereas latent PolyA was most common in patients with GD in Asia (21.03%, 95% CI: 17.76-24.71). Overt and latent PolyA were associated with gastrointestinal and endocrinological ADs in most of cases and clustered with rheumatological, dermatological and neurological ADs. Latent and overt PolyA are common in patients with AITD. These results provide insightful information for early diagnosis and management of concurrent ADs in patients with AITD. Aggregation of ADs in different clusters may help to define different phenotypes associated with thyroid autoimmunity that are critically relevant in clinical settings.


Momentum-dependent power law measured in an interacting quantum wire beyond the Luttinger limit.
Power laws in physics have until now always been associated with a scale invariance originating from the absence of a length scale. Recently, an emergent invariance even in the presence of a length scale has been predicted by the newly-developed nonlinear-Luttinger-liquid theory for a one-dimensional (1D) quantum fluid at finite energy and momentum, at which the particle's wavelength provides the length scale. We present experimental evidence for this new type of power law in the spectral function of interacting electrons in a quantum wire using a transport-spectroscopy technique. The observed momentum dependence of the power law in the high-energy region matches the theoretical predictions, supporting not only the 1D theory of interacting particles beyond the linear regime but also the existence of a new type of universality that emerges at finite energy and momentum.


Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: The SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study.
This study was performed to determine the short-term risk-benefit profiles of patients treated with oral anticoagulation for acute ischemic stroke or transient ischemic attack using a multicenter, prospective registry. A total of 1137 patients (645 men, 77 ± 10 years old) with acute ischemic stroke/transient ischemic attack taking warfarin (662 patients) or non-vitamin K antagonist oral anticoagulants (dabigatran in 205, rivaroxaban in 245, apixaban in 25 patients) for nonvalvular atrial fibrillation who completed a three-month follow-up survey were studied. Choice of anticoagulants was not randomized. Primary outcome measures were stroke/systemic embolism and major bleeding. Both warfarin and non-vitamin K antagonist oral anticoagulants were initiated within four days after stroke/transient ischemic attack onset in the majority of cases. Non-vitamin K antagonist oral anticoagulant users had lower ischemia- and bleeding-risk indices (CHADS2, CHA2DS2-VASc, HAS-BLED) and milder strokes than warfarin users. The three-month cumulative rate of stroke/systemic embolism was 3.06% (95% CI 1.96%-4.74%) in warfarin users and 2.84% (1.65%-4.83%) in non-vitamin K antagonist oral anticoagulant users (adjusted HR 0.96, 95% CI 0.44-2.04). The rate of major bleeding was 2.61% (1.60%-4.22%) and 1.11% (0.14%-1.08%), respectively (HR 0.63, 0.19-1.78); that for intracranial hemorrhage was marginally significantly lower in non-vitamin K antagonist oral anticoagulant users (HR 0.17, 0.01-1.15). Major bleeding did not occur in non-vitamin K antagonist oral anticoagulant users with a CHADS2 score <4 or those with a discharge modified Rankin Scale score ≤2. Stroke or systemic embolism during the initial three-month anticoagulation period after stroke/transient ischemic attack was not frequent as compared to previous findings regardless of warfarin or non-vitamin K antagonist oral anticoagulants were used. Intracranial hemorrhage was relatively uncommon in non-vitamin K antagonist oral anticoagulant users, although treatment assignment was not randomized. Early initiation of non-vitamin K antagonist oral anticoagulants during the acute stage of stroke/transient ischemic attack in real-world clinical settings seems safe in bleeding-susceptible Japanese population.


Materials Genome in Action: Identifying the Performance Limits of Physical Hydrogen Storage.
The Materials Genome is in action: the molecular codes for millions of materials have been sequenced, predictive models have been developed, and now the challenge of hydrogen storage is targeted. Renewably generated hydrogen is an attractive transportation fuel with zero carbon emissions, but its storage remains a significant challenge. Nanoporous adsorbents have shown promising physical adsorption of hydrogen approaching targeted capacities, but the scope of studies has remained limited. Here the Nanoporous Materials Genome, containing over 850 000 materials, is analyzed with a variety of computational tools to explore the limits of hydrogen storage. Optimal features that maximize net capacity at room temperature include pore sizes of around 6 Å and void fractions of 0.1, while at cryogenic temperatures pore sizes of 10 Å and void fractions of 0.5 are optimal. Our top candidates are found to be commercially attractive as "cryo-adsorbents", with promising storage capacities at 77 K and 100 bar with 30% enhancement to 40 g/L, a promising alternative to liquefaction at 20 K and compression at 700 bar.


Management of hypertensive crises.
Malignant hypertension still constitutes a medical emergency, particularly when complicated by renal failure, encephalopathy, or left ventricular failure. A shift to the right of the autoregulatory curve of cerebral blood flow (and probably of renal blood flow) is known to occur in patients with hypertension. Local cerebral edema, complicating the malignant phase, is likely to aggravate this trend. While inadequate or tardy treatment leads to encephalopathy, renal and cardiac failure, over aggressive treatment may also result in damage to brain, heart, and kidney. Recent reports of neurological damage, sometimes fatal, following aggressive hypotensive treatment suggests the need for a reappraisal of current practices. More investigation is needed to determine the effects of the various classes of antihypertensive drugs on organ perfusion, particularly of brain, heart, and kidney, in both normal and hypertensive humans. Other hypertensive crises include raised arterial pressure in association with acute dissection of the aorta and in the presence of stroke or subarachnoid hemorrhage. While there is agreement about the need for urgent hypotensive treatment in patients with aortic dissection, there is no information with which to base rational decisions in the management of high arterial pressure in the acute phase of stroke or subarachnoid hemorrhage.


Blood pressure changes in patients with chronic heart failure undergoing slow breathing training.
Slow breathing training (SBT) has been proposed as a new non-pharmacological treatment able to induce favorable effects in patients with chronic heart failure (CHF). However, no information is available regarding its effects on orthostatic blood pressure (BP) changes in these patients, an issue of practical relevance given the reported BP-lowering effect of SBT. The aim of this study is to evaluate the influence of SBT on BP and whether SBT induces orthostatic hypotension (OH) or changes in quality of life (QoL) in CHF patients. The analysis was performed as part of an ongoing crossover open trial aimed at assessing the clinical effectiveness of SBT in treated patients with CHF. The patients underwent 10-12 weeks of SBT with the RESPeRATE device and 10-12 week follow-up under usual care. Patients were randomly divided into two groups: group I began with SBT, followed by usual care; group II began with usual care, followed by SBT. Patients undergoing SBT were asked to perform each day two separate 15 min sessions of device-guided SBT at a breathing frequency of 6 breaths/min. In all patients, before the enrollment and after each study phase, clinical data collection and BP measurements in sitting, supine and standing position were performed. OH was defined as a decrease of ≥ 20 mmHg in systolic blood pressure (SBP) or ≥ 10 mmHg in diastolic blood pressure (DBP) within 3 min of standing. QoL was assessed three times at the beginning, and after each phase of the study by the Minnesota Living with Heart Failure (MLHF) questionnaire. Forty patients (two equal groups) completed the study, with the following baseline characteristics: 32 males/eight females, age 63.3 ± 13.4 years, 25 with ischemic CHF, 37 in New York Heart Association class II and three in class III, left ventricular ejection fraction 30.8 ± 6.7%, mean BP 138.7 ± 16.5/83.1 ± 11.5 mmHg, 23 with arterial hypertension and four with a history of stroke. There were no significant differences between the groups in clinical characteristics, SBP and DBP at rest, while seated and before and after standing up. OH prevalence was low and did not change during the study (10% vs 10%). No significant difference in average SBP and DBP changes secondary to body position were found when comparing the two study phases. Decrease in MLHF score was observed in group I during SBT (p = 0.002), but not in group II. Our data indicate that SBT is safe, does not affect the prevalence of OH in CHF patients and shows a non-significant tendency to improve QoL. These results should be confirmed in a larger sample of patients to support the safety of SBT and its possible benefits as a novel component of cardiorespiratory rehabilitation programs in CHF.


Signal joint formation is also impaired in DNA-dependent protein kinase catalytic subunit knockout cells.
The effort to elucidate the mechanism of V(D)J recombination has given rise to a dispute as to whether DNA-dependent protein kinase catalytic subunit (DNA-PKcs) contributes to signal joint formation (sjf). Observations reported to date are confusing. Analyses using DNA-PKcs-deficient cells could not conclude the requirement of DNA-PKcs for sjf, because sjf can be formed by end-joining activities which are diverse among cells other than those participating in V(D)J recombination. Here, we observed V(D)J recombination in DNA-PKcs knockout cells and showed that both signal and coding joint formation were clearly impaired in the cells. Subsequently, to directly demonstrate the requirement of DNA-PKcs for sjf, we introduced full-length cDNA of DNA-PKcs into the knockout cells. Furthermore, several mutant DNA-PKcs cDNA constructs designed from mutant cell lines (irs-20, V3, murine scid, and SX9) were also introduced into the cells to obtain further evidence indicating the involvement of DNA-PKcs in sjf. We found as a result that the full-length cDNA complemented the aberrant sjf and that the mutant cDNAs constructs also partially complemented it. Lastly, we looked at whether the kinase activity of DNA-PKcs is necessary for sjf and, as a result, demonstrated a close relationship between them. Our observations clearly indicate that the DNA-PKcs controls not only coding joint formation but also the sjf in V(D)J recombination through its kinase activity.


Early Childhood Education to Promote Health Equity: A Community Guide Economic Review.
A recent Community Guide systematic review found that early childhood education (ECE) programs improve educational, social, and health-related outcomes and advance health equity because many are designed to increase enrollment for high-risk children. This follow-up economic review examines how the economic benefits of center-based ECE programs compare with their costs. Kay and Pennucci from the Washington State Institute for Public Policy, whose meta-analysis formed the basis of the Community Guide effectiveness review, conducted a benefit-cost analysis of ECE programs for low-income children in Washington State. We performed an electronic database search using both effectiveness and economic key words to identify additional cost-benefit studies published through May 2015. Kay and Pennucci also provided us with national-level benefit-cost estimates for state and district and federal Head Start programs. The median benefit-to-cost ratio from 11 estimates of earnings gains, the major benefit driver for 3 types of ECE programs (ie, state and district, federal Head Start, and model programs), was 3.39:1 (interquartile interval [IQI] = 2.48-4.39). The overall median benefit-to-cost ratio from 7 estimates of total benefits, based on all benefit components including earnings gains, was 4.19:1 (IQI = 2.62-8.60), indicating that for every dollar invested in the program, there was a return of $4.19 in total benefits. ECE programs promote both equity and economic efficiency. Evidence indicates there is positive social return on investment in ECE irrespective of the type of ECE program. The adoption of a societal perspective is crucial to understand all costs and benefits of ECE programs regardless of who pays for the costs or receives the benefits.


Immunoblot analysis of proteins associated with HEMA-MMA microcapsules: human serum proteins in vitro and rat proteins following implantation.
Human serum proteins and their fragments, associated with hydroxyethyl methacrylate-methyl methacrylate (HEMA-MMA) copolymer microcapsules, were characterized using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analysis. Capsules were incubated with serum for 1 week in vitro and then dissolved in ethanol to also precipitate the adsorbed protein. The precipitate was dissolved in 2% (w/v) SDS (the 'capsule eluate') to be assayed by electrophoresis. The majority of proteins probed for in the immunoblots were detected in the capsule eluates. These included fibronectin, plasminogen, IgG, vitronectin, Factor B, Factor H, Factor I, C3, but not beta-lipoprotein, fibrinogen, HMWK, or IgM. Complement activation fragments were detected in both the immunoblots of the capsule eluates and the medium containing serum without capsules. Thus, the adsorption of these fragments, formed independent of capsule presence, may be partially or completely responsible for the complement fragments associated with capsules. The prevention of complement activation by the addition of 5.8 mM EDTA, at the beginning of the week-long incubation, resulted in fewer low-molecular-weight C3 fragments associated with capsules. Rat proteins were also detected in immunoblots of the eluate of 'free-floating' capsules from the rat peritoneal cavity following implantation for 1 day using anti-human antibodies. Detected proteins included HMWK, fibrinogen, antithrombin III, transferrin, alpha1-antitrypsin, fibronectin, albumin, alpha2-macroglobulin, vitronectin, beta2-microglobulin, Factor B and Factor I. Rat fibrinogen, IgG, and complement C3 fragments were also detected in these immunoblots, but with monoclonal antibodies against the rat proteins.


Systematic implications of brain morphology in potamotrygonidae (Chondrichthyes: Myliobatiformes).
The gross brain morphology, brain proportions, and position of cranial nerves in all four genera (Potamotrygon, Plesiotrygon, Paratrygon, and Heliotrygon) and 11 of the species of the Neotropical stingray family Potamotrygonidae were studied to provide new characters that may have a bearing on internal potamotrygonid systematics. The brain was also studied in four other stingray (Myliobatiformes) genera (Hexatrygon, Taeniura, Dasyatis, and Gymnura) to provide a more inclusive phylogenetic context for the interpretation of features of the brain in potamotrygonids. Our results indicate, based on neuroanatomical characters, that the genera Paratrygon and Heliotrygon are sister groups, as are the genera Potamotrygon and Plesiotrygon, agreeing with previous morphological and molecular phylogenetic studies. Both groups of genera share distinct conditions of the olfactory tracts, telencephalon and its central nuclei, hypophysis and infundibulum, morphology and orientation of the metencephalic corpus cerebelli, orientation of the glossopharyngeal nerve, and overall encephalic proportions. The corpus cerebelli of Paratrygon and Heliotrygon is interpreted as being more similar to the general batoid condition and, given their phylogenetic position highly nested within stingrays, is considered secondarily derived, not plesiomorphically retained. Our observations of the corpus cerebelli of stingrays, including Hexatrygon, corroborate that the general stingray pattern previously advanced by Northcutt is derived among batoids. The morphology of the brain is shown to be a useful source of phylogenetically informative characters at lower hierarchical levels, such as between genera and species, and thus, has significant potential in phylogenetic studies of elasmobranchs.


Mental health nurses' attitudes, behaviour, experience and knowledge regarding adults with a diagnosis of borderline personality disorder: systematic, integrative literature review.
To establish whether mental health nurses responses to people with borderline personality disorder are problematic and, if so, to inform solutions to support change. There is some evidence that people diagnosed with borderline personality disorder are unpopular among mental health nurses who respond to them in ways which could be counter-therapeutic. Interventions to improve nurses' attitudes have had limited success. Systematic, integrative literature review. Computerised databases were searched from inception to April 2015 for papers describing primary research focused on mental health nurses' attitudes, behaviour, experience, and knowledge regarding adults diagnosed with borderline personality disorder. Analysis of qualitative studies employed metasynthesis; analysis of quantitative studies was informed by the theory of planned behaviour. Forty studies were included. Only one used direct observation of clinical practice. Nurses' knowledge and experiences vary widely. They find the group very challenging to work with, report having many training needs, and, objectively, their attitudes are poorer than other professionals' and poorer than towards other diagnostic groups. Nurses say they need a coherent therapeutic framework to guide their practice, and their experience of caregiving seems improved where this exists. Mental health nurses' responses to people with borderline personality disorder are sometimes counter-therapeutic. As interventions to change them have had limited success there is a need for fresh thinking. Observational research to better understand the link between attitudes and clinical practice is required. Evidence-based education about borderline personality disorder is necessary, but developing nurses to lead in the design, implementation and teaching of coherent therapeutic frameworks may have greater benefits. There should be greater focus on development and implementation of a team-wide approach, with nurses as equal partners, when working with patients with borderline personality disorder.


Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1.
Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC(50) = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [(3)H]repaglinide on membranes prepared from HEK293 cells expressing wild-type (equilibrium dissociation constant [K(D)] = 0.40 nmol/l) or mutant (K(D) = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3)H]repaglinide binding to wild-type channels with IC(50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3)H]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules.


Stem kernels for RNA sequence analyses.
Several computational methods based on stochastic context-free grammars have been developed for modeling and analyzing functional RNA sequences. These grammatical methods have succeeded in modeling typical secondary structures of RNA, and are used for structural alignment of RNA sequences. However, such stochastic models cannot sufficiently discriminate member sequences of an RNA family from nonmembers and hence detect noncoding RNA regions from genome sequences. A novel kernel function, stem kernel, for the discrimination and detection of functional RNA sequences using support vector machines (SVMs) is proposed. The stem kernel is a natural extension of the string kernel, specifically the all-subsequences kernel, and is tailored to measure the similarity of two RNA sequences from the viewpoint of secondary structures. The stem kernel examines all possible common base pairs and stem structures of arbitrary lengths, including pseudoknots between two RNA sequences, and calculates the inner product of common stem structure counts. An efficient algorithm is developed to calculate the stem kernels based on dynamic programming. The stem kernels are then applied to discriminate members of an RNA family from nonmembers using SVMs. The study indicates that the discrimination ability of the stem kernel is strong compared with conventional methods. Furthermore, the potential application of the stem kernel is demonstrated by the detection of remotely homologous RNA families in terms of secondary structures. This is because the string kernel is proven to work for the remote homology detection of protein sequences. These experimental results have convinced us to apply the stem kernel in order to find novel RNA families from genome sequences.


Chlorination for low-cost household water disinfection - A critical review and status in three Latin American countries.
Chlorination has historically provided microbiologically safe drinking water in public water supplies. Likewise, chlorine has also been introduced as a low-cost disinfection method in rural and marginalized communities, both at community and household level, as well as during emergencies. Although this practice is common and well established for use as a household water treatment technology in the Global South, several challenges in effective and efficient implementation still need to be addressed. Here, we explored these issues by a literature review and narrowed them to the status of three Latin American countries (Mexico, Colombia, and Brazil). Overall, it was found that although guidance on household-based chlorination includes information on health risks and hygiene, this may not create enough incentive for the user to adapt the method satisfactorily. Physicochemical quality of the water influences chlorination efficiency and it is found that variations in quality are rarely considered when recommending chlorine doses during implementation. These are far more often based on a few measurements of turbidity, thereby not considering dissolved organic matter, or seasonal and day-to-day variations. Other factors such as user preferences, chlorine product quality and availability also represent potential barriers to the sustainable use of chlorination. For chlorination to become a sustainable household water treatment, more focus should therefore be given to local conditions prior to the intervention, as well as support and maintenance of behavioural changes during and after the intervention.


Chronic, intermittent exposure to chlorpyrifos in rats: protracted effects on axonal transport, neurotrophin receptors, cholinergic markers, and information processing.
Persistent behavioral abnormalities have been commonly associated with acute organophosphate (OP) pesticide poisoning; however, relatively little is known about the consequences of chronic OP exposures that are not associated with acute cholinergic symptoms. In this study, the behavioral and neurochemical effects of chronic, intermittent, and subthreshold exposures to the OP pesticide, chlorpyrifos (CPF), were investigated. Rats were injected with CPF s.c. (dose range, 2.5-18.0 mg/kg) every other day over the course of 30 days and then were given a 2-week CPF-free washout period. In behavioral experiments conducted during the washout period, dose-dependent decrements in a water-maze hidden platform task and a prepulse inhibition procedure were observed, without significant effects on open-field activity, Rotorod performance, grip strength, or a spontaneous novel object recognition task. After washout, levels of CPF and its metabolite 3,5,6-trichloro-2-pyridinol were minimal in plasma and brain; however, cholinesterase inhibition was still detectable. Furthermore, the 18.0 mg/kg dose of CPF was associated with (brain region-dependent) decreases in nerve growth factor receptors and cholinergic proteins including the vesicular acetylcholine transporter, the high-affinity choline transporter, and the alpha(7)-nicotinic acetylcholine receptor. These deficits were accompanied by decreases in anterograde and retrograde axonal transport measured in sciatic nerves ex vivo. Thus, low-level (intermittent) exposure to CPF has persistent effects on neurotrophin receptors and cholinergic proteins, possibly through inhibition of fast axonal transport. Such neurochemical changes may lead to deficits in information processing and cognitive function.


Increased pCO2 and temperature reveal ecotypic differences in growth and photosynthetic performance of temperate and Arctic populations of Saccharina latissima.
The Arctic population of the kelp Saccharina latissima differs from the Helgoland population in its sensitivity to changing temperature and CO 2 levels. The Arctic population does more likely benefit from the upcoming environmental scenario than its Atlantic counterpart. The previous research demonstrated that warming and ocean acidification (OA) affect the biochemical composition of Arctic (Spitsbergen; SP) and cold-temperate (Helgoland; HL) Saccharina latissima differently, suggesting ecotypic differentiation. This study analyses the responses to different partial pressures of CO2 (380, 800, and 1500 µatm pCO2) and temperature levels (SP population: 4, 10 °C; HL population: 10, 17 °C) on the photophysiology (O2 production, pigment composition, D1-protein content) and carbon assimilation [Rubisco content, carbon concentrating mechanisms (CCMs), growth rate] of both ecotypes. Elevated temperatures stimulated O2 production in both populations, and also led to an increase in pigment content and a deactivation of CCMs, as indicated by 13C isotopic discrimination of algal biomass (ε p) in the HL population, which was not observed in SP thalli. In general, pCO2 effects were less pronounced than temperature effects. High pCO2 deactivated CCMs in both populations and produced a decrease in the Rubisco content of HL thalli, while it was unaltered in SP population. As a result, the growth rate of the Arctic ecotype increased at elevated pCO2 and higher temperatures and it remained unchanged in the HL population. Ecotypic differentiation was revealed by a significantly higher O2 production rate and an increase in Chl a, Rubisco, and D1 protein content in SP thalli, but a lower growth rate, in comparison to the HL population. We conclude that both populations differ in their sensitivity to changing temperatures and OA and that the Arctic population is more likely to benefit from the upcoming environmental scenario than its Atlantic counterpart.


Efficient transfer of HTLV-1 tax gene in various primary and immortalized cells using a flap lentiviral vector.
Human T cell leukemia virus type 1 (HTLV-1) causes two major diseases: adult T-cell leukemia-lymphoma and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). In order to understand the involvement of Tax protein in HTLV-1 pathogenesis, we constructed a HIV-1 based lentiviral vector containing the central DNA flap sequence and either the green fluorescent protein (GFP) or the HTLV-1 tax genes. Using these vectors, GFP and tax genes were introduced in several primary and immortalized cells of endothelial, lymphoid, astrocytic or macrophagic origin. As assessed by GFP expression, up to 100% efficiency of transduction was obtained for all cell types tested. Tax expression was detected by Western blot and immuno-fluorescence in the transduced cells. After transduction, the Tax transcriptional activity was confirmed by the transactivation of HTLV-1 LTR-lacZ or HTLV-1 LTR-GFP reporter genes. Increased CD25 and HLA DR expression was observed in human peripheral blood lymphocytes transduced with the Tax vector. These results indicate that both pathways of Tax transactivation, CREB (viral LTR) and NF-kappa B (CD25 and HLA DR), are functional after transduction by TRIP Tax vector. Therefore, this vector provides a useful tool for investigating the role of the Tax viral protein in the pathogenesis of diseases linked to HTLV-1 infection.


NLPR3 Inflammasomes and Their Significance for Atherosclerosis.
Atherosclerosis is a serious disorder, with numerous potential complications such as cardiovascular disease, ischemic stroke, and myocardial infarction. The origin of atherosclerosis is related to chronic inflammation, lipid metabolism alterations, and oxidative stress. Inflammasomes are the cytoplasmic multiprotein complex triggering the activation of inflammatory response. NLRP3 inflammasomes have a specific activation pathway that involves numerous stimuli, including a wide range of PAMPs and DAMPs. Recent studies of atherosclerotic pathology are focused on the mitochondria that appear to be a promising target for therapeutic approach development. Mitochondria are the main source of reactive oxygen species (ROS) associated with oxidative stress. It was previously shown that NLRP3 inflammasome activation results in mitochondrial damage, but the exact mechanisms of this need to be specified. In this review, we focused on the features of NLRP3 inflammasomes and their significance for atherosclerosis, especially concerning mitochondria.


Chemoradiotherapy in the management of localized tumors of the pancreas.
In western countries, carcinoma of the pancreas remains the most lethal of the common malignancies. Even the favorable "organ-confined" tumors present a considerable challenge. The lack of anatomic barriers to local infiltration and the biological propensity for early lymphatic, perineural, and vascular invasion are nearly insurmountable obstacles to complete surgical eradication of this malignancy. Various combinations of chemotherapy and radiotherapy (RT) have been used with marginal but measurable success. Earlier trials conducted by the Gastrointestinal Tumor Study Group established roles for 5-fluorouracil chemotherapy and RT in the treatment of patients with resectable or locally advanced pancreatic cancer. More recently, computed tomography-guided conformal RT and a variety of intraoperative RT techniques have enabled more reliable sterilization of the local surgical field and escalation of doses to potentially curative levels (7000 cGy) for unresectable lesions. Chemotherapy dose intensification through the use of portable programmable pumps for protracted venous infusions and the development of active systemic agents in addition to 5-fluorouracil suggest that an effective combination chemotherapeutic regimen might soon be developed. This report reviews the current standards of practice and integrates recent developments to construct a modern algorithm for the use of chemoradiotherapy in the management of localized (nonmetastatic) pancreatic cancer. The likely directions of future investigations are also discussed.


Incident atrial fibrillation in patients with differentiated thyroid cancer: a meta-analysis.
Differentiated thyroid cancer (DTC) represents the most common form of thyroid neoplasms and is becoming increasingly prevalent. Evidence suggests a possible relationship between DTC diagnosis and subsequent atrial fibrillation (AF). If confirmed, this may present an alarming health risk (AF) in an otherwise condition with a relatively good prognosis (DTC). The aim of this systematic review and meta-analysis is to provide for the first time a pooled estimate of AF incidence in DTC patients in comparison to healthy controls. A detailed search in electronic databases, clinical trial registries and grey literature was performed to identify studies reporting the incidence of AF in DTC patients. Newcastle-Ottawa quality assessment scale was used to assess study quality. We used a random effects (RE) generalized linear mixed model (GLMM) in pooling of individual studies and also calculated a prediction interval for the estimate of a new study. Six observational studies met the eligibility criteria, which included totally 187,754 patients with DTC and 199,770 healthy controls. The median follow-up period was 4.3 to 18.8 years; the incidence rate of AF was 4.86 (95% CI, 3.29 to 7.17, I2 = 96%) cases per 1000 person-years, while the incidence rate ratio was 1.54 (95% CI, 1.44 to 1.65, I2 = 0%, 95% PI, 1.33 to 1.78).This is the first meta-analysis to confirm that patients with DTC are at a high risk for developing AF, which may be attributed to a state of iatrogenic hyperthyroidism due to long-term thyrotropin suppression therapy.


Processing of pitch and location in human auditory cortex during visual and auditory tasks.
The relationship between stimulus-dependent and task-dependent activations in human auditory cortex (AC) during pitch and location processing is not well understood. In the present functional magnetic resonance imaging study, we investigated the processing of task-irrelevant and task-relevant pitch and location during discrimination, n-back, and visual tasks. We tested three hypotheses: (1) According to prevailing auditory models, stimulus-dependent processing of pitch and location should be associated with enhanced activations in distinct areas of the anterior and posterior superior temporal gyrus (STG), respectively. (2) Based on our previous studies, task-dependent activation patterns during discrimination and n-back tasks should be similar when these tasks are performed on sounds varying in pitch or location. (3) Previous studies in humans and animals suggest that pitch and location tasks should enhance activations especially in those areas that also show activation enhancements associated with stimulus-dependent pitch and location processing, respectively. Consistent with our hypotheses, we found stimulus-dependent sensitivity to pitch and location in anterolateral STG and anterior planum temporale (PT), respectively, in line with the view that these features are processed in separate parallel pathways. Further, task-dependent activations during discrimination and n-back tasks were associated with enhanced activations in anterior/posterior STG and posterior STG/inferior parietal lobule (IPL) irrespective of stimulus features. However, direct comparisons between pitch and location tasks performed on identical sounds revealed no significant activation differences. These results suggest that activations during pitch and location tasks are not strongly affected by enhanced stimulus-dependent activations to pitch or location. We also found that activations in PT were strongly modulated by task requirements and that areas in the inferior parietal lobule (IPL) showed task-dependent activation modulations, but no systematic activations to pitch or location. Based on these results, we argue that activations during pitch and location tasks cannot be explained by enhanced stimulus-specific processing alone, but rather that activations in human AC depend in a complex manner on the requirements of the task at hand.


Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report.
To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement. A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma. Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months. This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.


Chemoradiotherapy before and after surgery for locally advanced esophageal cancer: a SEER-Medicare analysis.
The optimal combination and timing of therapy for esophageal cancer remains controversial. The Surveillance, Epidemiology, and End Results (SEER)-Medicare registry was used to assess neoadjuvant and adjuvant therapy. Patients diagnosed with nonmetastatic T3+ or N1+ esophageal adenocarcinoma (ACA) or squamous cell carcinoma (SCC) from 1995 to 2002 who underwent surgical resection within 6 months of diagnosis were studied. Medicare data defined preoperative chemoradiotherapy (preCRT), preoperative radiotherapy (preRT), postoperative CRT (postCRT), chemotherapy and surgery (CT + S), and surgery alone. Of 419 eligible patients, 126 received preCRT, 55 preRT, 40 postCRT, 29 CT + S, and 169 surgery alone. PreCRT yielded median overall survival (OS) of 37 months, greater than surgery alone (17 months, p = 0.002) and postCRT (17 months, p = 0.06). PreRT (20 months, p = 0.20), postCRT (p = 0.88), and CT + S (20 months, p = 0.42) were not associated with OS benefit versus surgery alone. For SCC, preCRT improved survival versus surgery alone (p = 0.01), with a trend for ACA (p = 0.07). ACA (22 months) had greater OS than SCC (17 months) (p = 0.03). ACA, younger age, and married status were associated with increased OS. Adjusting for these, preCRT had longer OS versus surgery alone (p = 0.02) and postCRT (p = 0.03). Chemotherapy agents and surgical approach did not affect OS. In the SEER-Medicare cohort, preCRT significantly improved survival versus surgery alone and postCRT for locally advanced esophageal cancer, particularly for SCC. PreRT, postCRT, and CT + S were not associated with longer survival.


Methylation of DNA polymerase beta by protein arginine methyltransferase 1 regulates its binding to proliferating cell nuclear antigen.
DNA polymerase beta (pol beta) is a key player in DNA base excision repair (BER). Here, we describe the complex formation of pol beta with the protein arginine methyltransferase 1 (PRMT1). PRMT1 specifically methylated pol beta in vitro and in vivo. Arginine 137 was identified in pol beta as an important target for methylation by PRMT1. Neither the polymerase nor the dRP-lyase activities of pol beta were affected by PRMT1 methylation. However, this modification abolished the interaction of pol beta with proliferating cell nuclear antigen (PCNA). Together, our results provide evidence that PRMT1 methylation of pol beta might play a regulatory role in BER by preventing the involvement of pol beta in PCNA-dependent DNA metabolic events.


Estrogen receptor splice variants as a potential source of false-positive estrogen receptor status in breast cancer diagnostics.
It is well established that only estrogen receptor (ER)-positive tumors benefit from hormonal therapies. We hypothesized that a subgroup of breast cancer patients expresses estrogen receptor α (ERα), but fails to respond to hormonal therapy due to the expression of a non-functional receptor. We analyzed a series of 2,658 ERα-positive HER2-negative breast tumors for ERα and progesterone receptor (PR) status as determined by mRNA expression and for their molecular subtypes (Luminal type vs Basal type, assessed by BluePrint™ molecular subtyping assay). In addition, we assessed the recurrence risk (low vs high) using the 70-gene MammaPrint™ signature. We found that 55 out of 2,658 (2.1 %) tumors that are ERα positive by mRNA analysis also demonstrate a Basal molecular subtype, indicating that they lack expression of estrogen-responsive genes. These ERα-positive Basal-type tumors express significantly lower levels of both ERα and PR mRNA as compared to Luminal-type tumors (P < 0.0001) and almost invariably (94.5 %) have a high-risk MammaPrint™ profile. Twelve of the MammaPrint™ genes are directly ERα responsive, indicating that MammaPrint™ assesses ERα function in breast cancer without considering ERα mRNA levels. We find a relatively high expression of the dominant negative ERα splice variant ERΔ7 in ERα-positive Basal-type tumors as compared to ERα-positive Luminal-type tumors (P < 0.0001). Expression of the dominant negative ERα variant ERΔ7 provides a rationale as to why tumors are of the Basal molecular subtype while staining ERα positive by immunohistochemistry. These tumors may lack a functional response to estrogen and consequently may not respond to hormonal therapy. Our data indicate that such patients are of MammaPrint™ high recurrence risk and might benefit from adjuvant chemotherapy.


Color selectivity of neurons in the inferior temporal cortex of the awake macaque monkey.
We tested the color selectivity of neurons in the inferior temporal (IT) cortex of two awake macaque monkeys. A color stimulus was presented at the center of the visual field while the animal performed a fixation task. The responses of single units to various colors were recorded and were plotted in a color space. The color space was based on the CIE (Commission Internationale de l'Eclairage) chromaticity diagram. Quantitative analysis of the color selectivity was performed using a standard set of colors that were evenly distributed in the color space. Sixty-five neurons recorded from eight guide tubes implanted in anterior part of IT cortex were tested quantitatively, and their color selectivity was statistically evaluated. Forty-six of them (71%) were classified as color selective. Color-selective cells responded to some colors but not to others, and we called the responsive region in the color space the "color field." The location and the size of a cell's color field were largely independent of the luminance of the stimulus. About 80% of the color-selective neurons had color fields consisting of a single responsive region that were restricted in some part of the color space, and the remaining cells had more than one responsive region within the color space. Preferred hues of the color-selective neurons differed from cell to cell. The population of cells together covered nearly all of the color space. There was a tendency for more color-selective cells to be less sensitive to white and desaturated cyans. Some of the cells with color fields that consisted of more than one responsive region were more sensitive to saturation of the stimulus than to its hue. Although previous electrophysiological studies in IT cortex emphasized the pattern selectivity of the neurons, our results suggest that color is an important factor in the role that IT cortex plays in the object recognition.


Pulsatile insulin has greater hypoglycemic effect than continuous delivery.
The relative hypoglycemic effects of pulsatile versus steadily infused insulin have been examined in six normal subjects in whom pancreatic insulin output was suppressed by somatostatin-14. Soluble insulin was infused continuously overnight on one occasion and on another occasion the same quantity was given in pulses of 2-min duration with a gap of 11 min. The mean plasma glucose concentrations were lower when pulsed insulin was given [mean for the last hour: 4.66 +/- 0.08 mmol/L (+/- SEM) versus 5.53 +/- 0.06 mmol/L (+/- SEM) for steady infusion], diverging significantly (P less than 0.05 paired t test) 7 h after the start of the study. The specific binding of 125I(A14)mono-iodo-insulin to monocytes was greater after pulsed insulin (2.9% with pulsed versus 2.4% with steadily infused insulin at tracer-only point; P less than 0.02 paired t test). Thus, intravenous insulin has greater hypoglycemic effect when pulsed, possibly mediated by greater insulin receptor binding.


Citrus CitNAC62 cooperates with CitWRKY1 to participate in citric acid degradation via up-regulation of CitAco3.
Citric acid is the predominant organic acid of citrus fruit. Degradation of citric acid occurs during fruit development, influencing fruit acidity. Associations of CitAco3 transcripts and citric acid degradation have been reported for citrus fruit. Here, transient overexpression of CitAco3 significantly reduced the citric acid content of citrus leaves and fruits. Using dual luciferase assays, it was shown that CitNAC62 and CitWRKY1 could transactivate the promoter of CitAco3. Subcellular localization results showed that CitWRKY1 was located in the nucleus and CitNAC62 was not. Yeast two-hybrid analysis and bimolecular fluorescence complementation (BiFC) assays indicated that the two differently located transcription factors could interact with each other. Furthermore, BiFC showed that the protein-protein interaction occurred only in the nucleus, indicating the potential mobility of CitNAC62 in plant cells. A synergistic effect on citrate content was observed between CitNAC62 and CitWRKY1. Transient overexpression of CitNAC62 or CitWRKY1 led to significantly lower citrate content in citrus fruit. The combined expression of CitNAC62 and CitWRKY1 resulted in lower citrate content compared with the expression of CitNAC62 or CitWRKY1 alone. The transcript abundance of CitAco3 was consistent with the citrate content. Thus, we propose that a complex of CitWRKY1 and CitNAC62 contributes to citric acid degradation in citrus fruit, potentially via modulation of CitAco3.


Following Natures Lead: On the Construction of Membrane-Inserted Toxins in Lipid Bilayer Nanodiscs.
Bacterial toxin or viral entry into the cell often requires cell surface binding and endocytosis. The endosomal acidification induces a limited unfolding/refolding and membrane insertion reaction of the soluble toxins or viral proteins into their translocation competent or membrane inserted states. At the molecular level, the specific orientation and immobilization of the pre-transitioned toxin on the cell surface is often an important prerequisite prior to cell entry. We propose that structures of some toxin membrane insertion complexes may be observed through procedures where one rationally immobilizes the soluble toxin so that potential unfolding ↔ refolding transitions that occur prior to membrane insertion orientate away from the immobilization surface in the presence of lipid micelle pre-nanodisc structures. As a specific example, the immobilized prepore form of the anthrax toxin pore translocon or protective antigen can be transitioned, inserted into a model lipid membrane (nanodiscs), and released from the immobilized support in its membrane solubilized form. This particular strategy, although unconventional, is a useful procedure for generating pure membrane-inserted toxins in nanodiscs for electron microscopy structural analysis. In addition, generating a similar immobilized platform on label-free biosensor surfaces allows one to observe the kinetics of these acid-induced membrane insertion transitions. These platforms can facilitate the rational design of inhibitors that specifically target the toxin membrane insertion transitions that occur during endosomal acidification. This approach may lead to a new class of direct anti-toxin inhibitors.


serpent, a GATA-like transcription factor gene, induces fat-cell development in Drosophila melanogaster.
The GATA-like transcription factor gene serpent is necessary for embryonic fat-cell differentiation in Drosophila (Sam, S., Leise, W. and Hoshizaki, D. K. (1996) Mech. Dev. 60, 197-205) and has been proposed to function in a cell-fate choice between fat cell and somatic gonadal precursors (Moore, L. A., Broihier, H. T., Van Doren, M. and Lehmann, R. (1998) Development 125, 837-44; Riechmann, V., Irion, U., Wilson, R., Grosskortenhaus, R. and Leptin, M. (1997) Development 124, 2915-22). Here, we report that deregulated expression of serpent in the mesoderm induces the formation of ectopic fat cells and prevents the migration and coalescence of the somatic gonadal precursors. The ectopic fat cells do not arise from hyperproliferation of the primary fat-cell clusters but they do associate with the endogenous fat cells to form a fat body that is expanded in both the dorsal/ventral and anterior/posterior axes. Misexpression of serpent also affects the differentiation of muscle cells. Few body-wall muscle precursors are specified and there is a loss of most body-wall muscle fibers. The precursors of the visceral mesoderm are also absent and concomitantly the visceral muscle is absent. We suggest that the ectopic fat cells might originate from cells that have the potential, but do not normally, differentiate into fat cells or from cells that have acquired a fat-cell fate. In light of our results, we discuss the role of serpent in fat-cell specification and in cell fate choices.