Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance.
Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia (SCA27). In addition, mice lacking Fgf14 (Fgf14(-/-)) exhibit an ataxia phenotype resembling SCA27, accompanied by marked changes in the excitability of cerebellar granule and Purkinje neurons. It is not known, however, whether these phenotypes result from defects in neuronal development or if they reflect a physiological requirement for iFGF14 in the adult cerebellum. Here, we demonstrate that the acute and selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without measurably affecting the expression or localization of voltage-gated Na(+) (Nav) channels at Purkinje neuron axon initial segments. The selective shRNA-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance. Repetitive firing can be restored in Fgf14-targeted shRNA-expressing Purkinje neurons, as well as in Fgf14(-/-) Purkinje neurons, by prior membrane hyperpolarization, suggesting that the iFGF14-mediated regulation of the excitability of mature Purkinje neurons depends on membrane potential. Further experiments revealed that the loss of iFGF14 results in a marked hyperpolarizing shift in the voltage dependence of steady-state inactivation of the Nav currents in adult Purkinje neurons. We also show here that expressing iFGF14 selectively in adult Fgf14(-/-) Purkinje neurons rescues spontaneous firing and improves motor performance. Together, these results demonstrate that iFGF14 is required for spontaneous and evoked action potential firing in adult Purkinje neurons, thereby controlling the output of these cells and the regulation of motor coordination and balance.


Decreased expression of B cell related genes in leukocytes of women with Parkinson's disease.
Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.


Tuning hexagonal NaYbF4 nanocrystals down to sub-10 nm for enhanced photon upconversion.
Enhancing upconversion emission is critical for small-sized lanthanide doped upconversion nanocrystals. A promising way is increasing the doping concentration of excitation energy absorbers, the Yb3+ sensitizer. However, it is still a challenge to obtain small-sized hexagonal NaLnF4 (Ln: lanthanide) upconversion nanocrystals with a high Yb3+ concentration due to the fast growth of NaYbF4 crystals, which hinders their applications particularly in biology. We here demonstrate a highly repeatable and controllable method for tuning the size of hexagonal NaYbF4 nanocrystals, down to ∼7 nm, without the assistance of additional impurity doping. By monitoring the reaction process, we found that ultrasmall hexagonal NaYbF4 nanocrystals were formed through an in situ transformation of their cubic counterparts. We observed an enhanced upconversion emission of NaYbF4:Tm nanocrystals when compared to that of NaYbF4:Y/Tm nanocrystals with less Yb3+ doping. After coating a thin layer of a NaYF4 shell on NaYbF4:Tm nanocrystals, a ∼100 times upconversion emission enhancement with over 800 times stronger emission in the ultraviolet and blue ranges was observed. This versatile method, together with the strong upconversion emission of the as-prepared ultrasmall nanocrystals, should facilitate the future applications of upconversion nanocrystals.


Temporal Coding of Visual Space.
Establishing a representation of space is a major goal of sensory systems. Spatial information, however, is not always explicit in the incoming sensory signals. In most modalities it needs to be actively extracted from cues embedded in the temporal flow of receptor activation. Vision, on the other hand, starts with a sophisticated optical imaging system that explicitly preserves spatial information on the retina. This may lead to the assumption that vision is predominantly a spatial process: all that is needed is to transmit the retinal image to the cortex, like uploading a digital photograph, to establish a spatial map of the world. However, this deceptively simple analogy is inconsistent with theoretical models and experiments that study visual processing in the context of normal motor behavior. We argue here that, as with other senses, vision relies heavily on temporal strategies and temporal neural codes to extract and represent spatial information.


Pyloric Stenosis: National Trends in the Incidence Rate and Resource Use in the United States From 2012 to 2016.
Infantile hypertrophic pyloric stenosis (IHPS) is the most common reason for abdominal surgery in infants; however, national-level data on incidence rate and resource use are lacking. We aimed to examine the national trends in hospitalizations for IHPS and resource use in its management in the United States from 2012 to 2016. We performed a retrospective serial cross-sectional study using data from the National Inpatient Sample, the largest health care database in the United States. We included infants aged ≤1 year assigned an International Classification of Diseases, Ninth Revision, or International Classification of Diseases, 10th Revision, code for IHPS who underwent pyloromyotomy or pyloroplasty. We examined the temporal trends in the incidence rate (cases per 1000 live births) according to sex, insurance status, geographic region, and race. We examined resource use using length of stay (LOS) and hospital costs. Linear regression was used for trend analysis. Between 2012 and 2016, there were 32 450 cases of IHPS and 20 808 149 live births (incidence rate of 1.56 per 1000). Characteristics of the study population were 82.7% male, 53% white, and 63.3% on Medicaid, and a majority were born in large (64%), urban teaching hospitals (90%). The incidence of IHPS varied with race, sex, socioeconomic status, and geographic region. In multivariable regression analysis, the incidence rate of IHPS decreased from 1.76 to 1.57 per 1000 (adjusted odds ratio 0.93; 95% confidence interval 0.92-0.93). The median cost of care was $6078.30, whereas the median LOS was 2 days, and these remained stable during the period. The incidence rate of IHPS decreased significantly between 2012 and 2016, whereas LOS and hospital costs remained stable. The reasons for the decline in the IHPS incidence rate may be multifactorial.


Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.
Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.


Synchronization and fluctuations: Coupling a finite number of stochastic units.
It is well established that ensembles of globally coupled stochastic oscillators may exhibit a nonequilibrium phase transition to synchronization in the thermodynamic limit (infinite number of elements). In fact, since the early work of Kuramoto, mean-field theory has been used to analyze this transition. In contrast, work that directly deals with finite arrays is relatively scarce in the context of synchronization. And yet it is worth noting that finite-number effects should be seriously taken into account since, in general, the limits N→∞ (where N is the number of units) and t→∞ (where t is time) do not commute. Mean-field theory implements the particular choice first N→∞ and then t→∞. Here we analyze an ensemble of three-state coupled stochastic units, which has been widely studied in the thermodynamic limit. We formally address the finite-N problem by deducing a Fokker-Planck equation that describes the system. We compute the steady-state solution of this Fokker-Planck equation (that is, finite N but t→∞). We use this steady state to analyze the synchronic properties of the system in the framework of the different order parameters that have been proposed in the literature to study nonequilibrium transitions.


Development of the human coagulation system in the full-term infant.
The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St Joseph's Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 weeks' gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high-molecular weight kininogen. Factor XIII subunits A and S, von Willebrand factor, and the inhibitors antithrombin III, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C, and protein S were measured immunologically. Plasminogen, prekallikrein, and heparin cofactor II were measured by using chromogenic substrates. The large number of infants studied at each time point allowed us to determine the following: the range of normal for each test at five time points in the postnatal period; that coagulation tests vary with the postnatal age of the infant; that different coagulation factors show different postnatal patterns of maturation; and that near-adult values are achieved for most components by 6 months of life. In summary, this large cohort of infants studied consecutively in the postnatal period allowed us to determine the normal development of the human coagulation system in the full-term infant.


Automated leukocyte processing by microfluidic deterministic lateral displacement.
We previously developed a Deterministic Lateral Displacement (DLD) microfluidic method in silicon to separate cells of various sizes from blood (Davis et al., Proc Natl Acad Sci 2006;103:14779-14784; Huang et al., Science 2004;304:987-990). Here, we present the reduction-to-practice of this technology with a commercially produced, high precision plastic microfluidic chip-based device designed for automated preparation of human leukocytes (white blood cells; WBCs) for flow cytometry, without centrifugation or manual handling of samples. After a human blood sample was incubated with fluorochrome-conjugated monoclonal antibodies (mAbs), the mixture was input to a DLD microfluidic chip (microchip) where it was driven through a micropost array designed to deflect WBCs via DLD on the basis of cell size from the Input flow stream into a buffer stream, thus separating WBCs and any larger cells from smaller cells and particles and washing them simultaneously. We developed a microfluidic cell processing protocol that recovered 88% (average) of input WBCs and removed 99.985% (average) of Input erythrocytes (red blood cells) and >99% of unbound mAb in 18 min (average). Flow cytometric evaluation of the microchip Product, with no further processing, lysis or centrifugation, revealed excellent forward and side light scattering and fluorescence characteristics of immunolabeled WBCs. These results indicate that cost-effective plastic DLD microchips can speed and automate leukocyte processing for high quality flow cytometry analysis, and suggest their utility for multiple other research and clinical applications involving enrichment or depletion of common or rare cell types from blood or tissue samples. © 2016 International Society for Advancement of Cytometry.


Oxidative Stress Induced Damage to Paternal Genome and Impact of Meditation and Yoga - Can it Reduce Incidence of Childhood Cancer?
Background: Sperm DNA damage is underlying aetiology of poor implantation and pregnancy rates but also affects health of offspring and may also result in denovo mutations in germ line and post fertilization. This may result in complex diseases, polygenic disorders and childhood cancers. Childhood cancer like retinoblastoma (RB) is more prevalent in developing countries and the incidence of RB has increased more than three fold in India in the last decade. Recent studies have documented increased incidence of cancers in children born to fathers who consume alcohol in excess and tobacco or who were conceived by assisted conception. The aetiology of childhood cancer and increased disease burden in these children is lin ked to oxidative stress (OS) and oxidative DNA damage( ODD) in sperm of their fathers. Though several antioxidants are in use to combat oxidative stress, the effect of majority of these formulations on DNA is not known. Yoga and meditation cause significant decline in OS and ODD and aid in regulating OS levels such that reactive oxygen speues meditated signal transduction, gene expression and several other physiological functions are not disrupted. Thus, this study aimed to analyze sperm ODD as a possible etiological factor in childhood cancer and role of simple life style interventions like yoga and meditation in significantly decreasing seminal oxidative stress and oxidative DNA damage and thereby decreasing incidence of childhood cancers. Materials and Methods: A total of 131 fathers of children with RB (non-familial sporadic heritable) and 50 controls (fathers of healthy children) were recruited at a tertiary center in India. Sperm parameters as per WHO 2010 guidelines and reactive oxygen species (ROS), DNA fragmentation index (DFI), 8-hydroxy-2'-deoxy guanosine (8-OHdG) and telomere length were estimated at day 0, and after 3 and 6 months of intervention. We also examined the compliance with yoga and meditation practice and smoking status at each follow-up. Results: The seminal mean ROS levels (p<0.05), sperm DFI (p<0.001), 8-OHdG (p<0.01) levels were significantly higher in fathers of children with RB, as compared to controls and the relative mean telomere length in the sperm was shorter. Levels of ROS were significantly reduced in tobacco users (p<0.05) as well as in alcoholics (p<0.05) after intervention. DFI reduced significantly (p<0.05) after 6 months of yoga and meditation practice in all groups. The levels of oxidative DNA damage marker 8-OHdG were reduced significantly after 3 months (p<0.05) and 6 months (p<0.05) of practice. Conclusions: Our results suggest that OS and ODD DNA may contribute to the development of childhood cancer. This may be due to accumulation of oxidized mutagenic base 8OHdG , and elevated MDA levels which results in MDA dimers which are also mutagenic, aberrant methylation pattern, altered gene expression which affect cell proliferation and survival through activation of transcription factors. Increased mt DNA mutations and aberrant repair of mt and nuclear DNA due to highly truncatred DNA repair mechanisms all contribute to sperm genome hypermutability and persistant oxidative DNA damage. Oxidative stress is also associated with genome wide hypomethylation, telomere shortening and mitochondrial dysfunction leading to genome hypermutability and instability. To the best of our knowledge, this is the first study to report decline in OS and ODD and improvement in sperm DNA integrity following adoption of meditation and yoga based life style modification.This may reduce disease burden in next generation and reduce incidence of childhood cancers.


The organization of the transcriptional network in specific neuronal classes.
Genome-wide expression profiling has aided the understanding of the molecular basis of neuronal diversity, but achieving broad functional insight remains a considerable challenge. Here, we perform the first systems-level analysis of microarray data from single neuronal populations using weighted gene co-expression network analysis to examine how neuronal transcriptome organization relates to neuronal function and diversity. We systematically validate network predictions using published proteomic and genomic data. Several network modules of co-expressed genes correspond to interneuron development programs, in which the hub genes are known to be critical for interneuron specification. Other co-expression modules relate to fundamental cellular functions, such as energy production, firing rate, trafficking, and synapses, suggesting that fundamental aspects of neuronal diversity are produced by quantitative variation in basic metabolic processes. We identify two transcriptionally distinct mitochondrial modules and demonstrate that one corresponds to mitochondria enriched in neuronal processes and synapses, whereas the other represents a population restricted to the soma. Finally, we show that galectin-1 is a new interneuron marker, and we validate network predictions in vivo using Rgs4 and Dlx1/2 knockout mice. These analyses provide a basis for understanding how specific aspects of neuronal phenotypic diversity are organized at the transcriptional level.


A surprisingly large RNase P RNA in Candida glabrata.
We have found an extremely large ribonuclease P (RNase P) RNA (RPR1) in the human pathogen Candida glabrata and verified that this molecule is expressed and present in the active enzyme complex of this hemiascomycete yeast. A structural alignment of the C. glabrata sequence with 36 other hemiascomycete RNase P RNAs (abbreviated as P RNAs) allows us to characterize the types of insertions. In addition, 15 P RNA sequences were newly characterized by searching in the recently sequenced genomes Candida albicans, C. glabrata, Debaryomyces hansenii, Eremothecium gossypii, Kluyveromyces lactis, Kluyveromyces waltii, Naumovia castellii, Saccharomyces kudriavzevii, Saccharomyces mikatae, and Yarrowia lipolytica; and by PCR amplification for other Candida species (Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida stellatoidea, and Candida tropicalis). The phylogenetic comparative analysis identifies a hemiascomycete secondary structure consensus that presents a conserved core in all species with variable insertions or deletions. The most significant variability is found in C. glabrata P RNA in which three insertions exceeding in total 700 nt are present in the Specificity domain. This P RNA is more than twice the length of any other homologous P RNAs known in the three domains of life and is eight times the size of the smallest. RNase P RNA, therefore, represents one of the most diversified noncoding RNAs in terms of size variation and structural diversity.


Household Clustering of Escherichia coli Sequence Type 131 Clinical and Fecal Isolates According to Whole Genome Sequence Analysis.
Background. Within-household sharing of strains from the resistance-associated H30R1 and H30Rx subclones of Escherichia coli sequence type 131 (ST131) has been inferred based on conventional typing data, but it has been assessed minimally using whole genome sequence (WGS) analysis. Methods. Thirty-three clinical and fecal isolates of ST131-H30R1 and ST131-H30Rx, from 20 humans and pets in 6 households, underwent WGS analysis for comparison with 52 published ST131 genomes. Phylogenetic relationships were inferred using a bootstrapped maximum likelihood tree based on core genome sequence polymorphisms. Accessory traits were compared between phylogenetically similar isolates. Results. In the WGS-based phylogeny, isolates clustered strictly by household, in clades that were distributed widely across the phylogeny, interspersed between H30R1 and H30Rx comparison genomes. For only 1 household did the core genome phylogeny place epidemiologically unlinked isolates together with household isolates, but even there multiple differences in accessory genome content clearly differentiated these 2 groups. The core genome phylogeny supported within-household strain sharing, fecal-urethral urinary tract infection pathogenesis (with the entire household potentially providing the fecal reservoir), and instances of host-specific microevolution. In 1 instance, the household's index strain persisted for 6 years before causing a new infection in a different household member. Conclusions. Within-household sharing of E coli ST131 strains was confirmed extensively at the genome level, as was long-term colonization and repeated infections due to an ST131-H30Rx strain. Future efforts toward surveillance and decolonization may need to address not just the affected patient but also other human and animal household members.


Vertical and horizontal distribution of Desmophyllum dianthus in Comau Fjord, Chile: a cold-water coral thriving at low pH.
Cold-water corals provide an important habitat for a rich fauna along the continental margins and slopes. Although these azooxanthellate corals are considered particularly sensitive to ocean acidification, their responses to natural variations in pH and aragonite saturation are largely unknown due to the difficulty of studying their ecology in deep waters. Previous SCUBA investigations have shown an exceptionally shallow population of the cold-water coral Desmophyllum dianthus in near-surface waters of Comau Fjord, a stratified 480 m deep basin in northern Chilean Patagonia with suboxic deep waters. Here, we use a remotely operated vehicle to quantitatively investigate the distribution of D. dianthus and its physico-chemical drivers in so far uncharted naturally acidified waters. Remarkably, D. dianthus was ubiquitous throughout the fjord, but particularly abundant between 20 and 280 m depth in a pH range of 8.4 to 7.4. The persistence of individuals in aragonite-undersaturated waters suggests that present-day D. dianthus in Comau Fjord may show pre-acclimation or pre-adaptation to conditions of ocean acidification predicted to reach over 70% of the known deep-sea coral locations by the end of the century.


The Effect of Starting a New Residency Program on the Quality of Care Measures at a Community Hospital: A 2-Year Follow-Up.
Introducing graduate medical education to a non-teaching hospital has been a challenging issue due to its perceived possible negative impact on quality and cost of care. To assess the impact of starting a new Internal Medicine (IM) residency program on the quality of care measures in a Graduate Medical Education (GME) naïve community hospital. In a retrospective longitudinal study, we compared quality of care parameters (mortality rate, 30-day readmission rate, length of stay, case mix index and severity level) for a hospitalist group ten months before (September 2015-June 2016) and two consecutive years (July 2016-June 2018) after the implementation of an IM residency program at a community hospital. We compared the aggregated data from 1,295 patients before starting the residency program to 2,532 and 3,061 patients, in two consecutive academic years after initiating an IM residency. For the hospitalist group that became the teaching group, the mortality rate decreased significantly from 10 months pre- and the two post-residency periods (2%, 1% and 0.2%, p-value < 0.01), while the mortality rate among non-teaching hospitalist group patients at the same hospital remained unchanged over the same time period (p = 0.70). Length of stay decreased significantly from 10-months pre-residency to 1-year post-residency (6.23 and 5.31, p-value = 0.01). Furthermore, there were no other significant differences between the groups in terms of 30-day readmission rate, complications in care and average cost per case. Starting a new residency program in a non-teaching hospital improves mortality rate without significantly affecting other quality measures.


Sources of carbon dioxide in penguin air sacs.
CO2 tensions in the caudal air sacs of birds cannot be quantitatively predicted by current models of avian respiration, mainly because the contribution of neopulmonic parabronchial gas exchange has not been determined. To overcome this problem we studied penguins that have purely paleopulmonic lungs. Three penguins were anesthetized, intubated, and ventilated at a constant respiratory rate and different tidal volumes (VT). PO2 and PCO2 were measured in arterial blood and end-expired, mixed-expired, interclavicular air sac, and caudal thoracic air sac gas. Interclavicular air sac and end-expired gas had similar compositions. Caudal thoracic air sac gas was intermediate in composition to end-expired and inspired gas, and its PCO2 was 1.5-3.5 times greater than the value predicted from reinhaled dead space. This difference between measured and predicted caudal thoracic air sac PCO2 increased with VT but showed no relationship to changes in dead space-to-VT ratio. The difference is not explained by stratification or diffusive gas exchange across air sac walls. The results can be explained by postulating that inspired gas passes over exchange surfaces on its path to caudal air sacs. This is unexpected in the purely paleopulmonic lungs of penguins and suggests that airflow may not be caudocranial in all paleopulmonic parabronchi.


Alternative trans-splicing of Caenorhabditis elegans sma-9/schnurri generates a short transcript that provides tissue-specific function in BMP signaling.
Transcription cofactors related to Drosophila Schnurri facilitate the transcriptional programs regulated by BMP signaling in C. elegans, Drosophila, Xenopus, and mouse. In different systems, Schnurri homologs have been shown to act as either agonists or antagonists of Smad function, and as either positive or negative regulators of transcription. How Schnurri proteins achieve this diversity of activities is not clear. The C. elegans sma-9/schnurri locus undergoes alternative splicing, including an unusual trans-splicing event that could generate two non-overlapping shorter transcripts. We demonstrate here that the shorter transcripts are expressed in vivo. Furthermore, we find that one of the short transcripts plays a tissue-specific role in sma-9 function, contributing to the patterning of male-specific sensory rays, but not to the regulation of body size. Based on previous results, we suggest that this transcript encodes a C-terminal SMA-9 isoform that may provide transcriptional activation activity, while full length isoforms may mediate transcriptional repression and/or activation in a context-dependent manner. The alternative trans-splicing of sma-9 may contribute to the diversity of functions necessary to mediate tissue-specific outputs of BMP signaling.


MIG-10 functions with ABI-1 to mediate the UNC-6 and SLT-1 axon guidance signaling pathways.
Extracellular guidance cues steer axons towards their targets by eliciting morphological changes in the growth cone. A key part of this process is the asymmetric recruitment of the cytoplasmic scaffolding protein MIG-10 (lamellipodin). MIG-10 is thought to asymmetrically promote outgrowth by inducing actin polymerization. However, the mechanism that links MIG-10 to actin polymerization is not known. We have identified the actin regulatory protein ABI-1 as a partner for MIG-10 that can mediate its outgrowth-promoting activity. The SH3 domain of ABI-1 binds to MIG-10, and loss of function of either of these proteins causes similar axon guidance defects. Like MIG-10, ABI-1 functions in both the attractive UNC-6 (netrin) pathway and the repulsive SLT-1 (slit) pathway. Dosage sensitive genetic interactions indicate that MIG-10 functions with ABI-1 and WVE-1 to mediate axon guidance. Epistasis analysis reveals that ABI-1 and WVE-1 function downstream of MIG-10 to mediate its outgrowth-promoting activity. Moreover, experiments with cultured mammalian cells suggest that the interaction between MIG-10 and ABI-1 mediates a conserved mechanism that promotes formation of lamellipodia. Together, these observations suggest that MIG-10 interacts with ABI-1 and WVE-1 to mediate the UNC-6 and SLT-1 guidance pathways.


Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs.
The relationship between market pricing of new anticancer drugs and the magnitude of clinical benefit caused by them has not been reported. Randomized clinical trials (RCTs) that evaluated approved new agents for solid tumors by the U.S. Food and Drug administration since the year 2000 were assessed. Hazard ratios (HRs) and 95% CIs were extracted for time-to-event end points described for each RCT. HRs were pooled for three groups: agents directed against a specific molecular target, for which the target population is selected by a biomarker (group A); less specific biologic targeted agents (group B); and chemotherapeutic agents (group C). Monthly market prices of these different drugs were compared. For overall survival (OS), the pooled HR was 0.69 (95% CI, 0.59 to 0.81) for group A (six drugs, six trials); it was 0.78 (95% CI, 0.74 to 0.83) for group B (seven drugs, 14 trials); and it was 0.84 (95% CI, 0.79 to 0.90) for group C (eight drugs, 12 trials). For progression-free survival (PFS), the pooled HR was 0.42 (95% CI, 0.36 to 0.49) for group A (six drugs, seven trials); it was 0.57 (95% CI, 0.51 to 0.64) for group B (seven drugs, 14 trials); and it was 0.75 (95% CI, 0.66 to 0.85) for group C (six drugs, 10 trials). Tests for heterogeneity between subgroups were highly significant for PFS (P < .001) and OS (P = .02). The median monthly prices for standard doses of drugs were $5375 for group A, $5644 for group B, and $6584 for group C (P = .87). New agents with specific molecular targets are clinically the most beneficial, but their monthly market prices are not significantly different from those of other anticancer agents.


Ccq1-Tpz1TPP1 interaction facilitates telomerase and SHREC association with telomeres in fission yeast.
Evolutionarily conserved shelterin complex is essential for telomere maintenance in the fission yeast Schizosaccharomyces pombe. Elimination of the fission yeast shelterin subunit Ccq1 causes progressive loss of telomeres due to the inability to recruit telomerase, activates the DNA damage checkpoint, and loses heterochromatin at telomere/subtelomere regions due to reduced recruitment of the heterochromatin regulator complex Snf2/histone deacetylase-containing repressor complex (SHREC). The shelterin subunit Tpz1(TPP1) directly interacts with Ccq1 through conserved C-terminal residues in Tpz1(TPP1), and tpz1 mutants that fail to interact with Ccq1 show telomere shortening, checkpoint activation, and loss of heterochromatin. While we have previously concluded that Ccq1-Tpz1(TPP1) interaction contributes to Ccq1 accumulation and telomerase recruitment based on analysis of tpz1 mutants that fail to interact with Ccq1, another study reported that loss of Ccq1-Tpz1(TPP1) interaction does not affect accumulation of Ccq1 or telomerase. Furthermore, it remained unclear whether loss of Ccq1-Tpz1(TPP1) interaction affects SHREC accumulation at telomeres. To resolve these issues, we identified and characterized a series of ccq1 mutations that disrupt Ccq1-Tpz1(TPP1) interaction. Characterization of these ccq1 mutants established that Ccq1-Tpz1(TPP1) interaction contributes to optimal binding of the Ccq1-SHREC complex, and is critical for Rad3(ATR)/Tel1(ATM)-dependent Ccq1 Thr93 phosphorylation and telomerase recruitment.


CryoET structures of immature HIV Gag reveal six-helix bundle.
Gag is the HIV structural precursor protein which is cleaved by viral protease to produce mature infectious viruses. Gag is a polyprotein composed of MA (matrix), CA (capsid), SP1, NC (nucleocapsid), SP2 and p6 domains. SP1, together with the last eight residues of CA, have been hypothesized to form a six-helix bundle responsible for the higher-order multimerization of Gag necessary for HIV particle assembly. However, the structure of the complete six-helix bundle has been elusive. Here, we determined the structures of both Gag in vitro assemblies and Gag viral-like particles (VLPs) to 4.2 Å and 4.5 Å resolutions using cryo-electron tomography and subtomogram averaging by emClarity. A single amino acid mutation (T8I) in SP1 stabilizes the six-helix bundle, allowing to discern the entire CA-SP1 helix connecting to the NC domain. These structures provide a blueprint for future development of small molecule inhibitors that can lock SP1 in a stable helical conformation, interfere with virus maturation, and thus block HIV-1 infection.


Hyperuniform disordered terahertz quantum cascade laser.
Laser cavities have been realized in various different photonic systems. One of the forefront research fields regards the investigation of the physics of amplifying random optical media. The random laser is a fascinating concept because, further to the fundamental research investigating light transport into complex media, it allows us to obtain non-conventional spectral distribution and angular beam emission patterns not achievable with conventional approaches. Even more intriguing is the possibility to engineer a priori the optical properties of a disordered distribution in an amplifying medium. We demonstrate here the realization of a terahertz quantum cascade laser in an isotropic hyperuniform disordered distribution exhibiting unique features, such as the presence of a photonic band gap, low threshold current density, unconventional angular emission and optical bistability.


Intraguild predation and native lady beetle decline.
Coccinellid communities across North America have experienced significant changes in recent decades, with declines in several native species reported. One potential mechanism for these declines is interference competition via intraguild predation; specifically, increased predation of native coccinellid eggs and larvae following the introduction of exotic coccinellids. Our previous studies have shown that agricultural fields in Michigan support a higher diversity and abundance of exotic coccinellids than similar fields in Iowa, and that the landscape surrounding agricultural fields across the north central U.S. influences the abundance and activity of coccinellid species. The goal of this study was to quantify the amount of egg predation experienced by a native coccinellid within Michigan and Iowa soybean fields and explore the influence of local and large-scale landscape structure. Using the native lady beetle Coleomegilla maculata as a model, we found that sentinel egg masses were subject to intense predation within both Michigan and Iowa soybean fields, with 60.7% of egg masses attacked and 43.0% of available eggs consumed within 48 h. In Michigan, the exotic coccinellids Coccinella septempunctata and Harmonia axyridis were the most abundant predators found in soybean fields whereas in Iowa, native species including C. maculata, Hippodamia parenthesis and the soft-winged flower beetle Collops nigriceps dominated the predator community. Predator abundance was greater in soybean fields within diverse landscapes, yet variation in predator numbers did not influence the intensity of egg predation observed. In contrast, the strongest predictor of native coccinellid egg predation was the composition of edge habitats bordering specific fields. Field sites surrounded by semi-natural habitats including forests, restored prairies, old fields, and pasturelands experienced greater egg predation than fields surrounded by other croplands. This study shows that intraguild predation by both native and exotic predators may contribute to native coccinellid decline, and that landscape structure interacts with local predator communities to shape the specific outcomes of predator-predator interactions.


Functional analysis of GS28, an intra-Golgi SNARE, in Caenorhabditis elegans.
Intra-Golgi retrograde transport is assumed to maintain Golgi function by recycling Golgi-resident proteins to younger cisternae in the progression of entire Golgi stack from cis to trans. GS28 (Golgi SNARE of 28 kDa, also known as GOS28) is a Golgi-localized SNARE protein and has been implicated in intra-Golgi retrograde transport. However, the in vivo functions of GS28, and consequently, the roles of the intra-Golgi retrograde transport in animal development are largely unknown. In this study, we generated deletion mutants of Caenorhabditis elegans GS28 and performed a synthetic lethal RNAi screen using GS28 mutants. We found that another Golgi-localized SNARE, Ykt6, functions cooperatively with GS28 in embryonic development. During post-embryonic development, GS28 mutants exhibited reduced seam cell numbers and a missing ray phenotype under Ykt6 knockdown conditions, suggesting that cell proliferation and/or differentiation of stem cell-like seam cells are impaired in GS28- and Ykt6-depleted worms. We also demonstrated that GS28 and Ykt6 act redundantly for the proper expression of Golgi-resident proteins in adult intestinal cells. This study reveals the in vivo importance of the Golgi-localized SNAREs GS28 and Ykt6.


A Study of Publicly Available Resources Addressing Legal Data-Sharing Barriers: Systematic Assessment.
United States data protection laws vary depending on the data type and its context. Data projects involving social determinants of health often concern different data protection laws, making them difficult to navigate. We systematically aggregated and assessed useful online resources to help navigate the data-sharing landscape. We included publicly available resources that discussed legal data-sharing issues with some health relevance and published between 2010 and 2019. We conducted an iterative search with a common string pattern using a general-purpose search engine that targeted 24 different sectors identified by Data Across Sectors for Health. We scored each online resource for its depth of legal and data-sharing discussions and value for addressing legal barriers. Out of 3710 total search hits, 2721 unique URLs were reviewed for scope, 322 received full-text review, and 154 were selected for final coding. Legal agreements, consent, and agency guidance were the most widely covered legal topics, with HIPAA (The Health Insurance Portability and Accountability Act), Family Educational Rights and Privacy Act (FERPA), Title 42 of the Code of Federal Regulations Part 2 being the top 3 federal laws discussed. Clinical health care was the most prominent sector with a mention in 73 resources. This is the first systematic study of publicly available resources on legal data-sharing issues. We found existing gaps where resources covering certain laws or applications may be needed. The volume of resources we found is an indicator that real and perceived legal issues are a substantial barrier to efforts in leveraging data from different sectors to promote health.


R120G alphaB-crystallin promotes the unfolding of reduced alpha-lactalbumin and is inherently unstable.
alpha-Crystallin is the principal lens protein which, in addition to its structural role, also acts as a molecular chaperone, to prevent aggregation and precipitation of other lens proteins. One of its two subunits, alphaB-crystallin, is also expressed in many nonlenticular tissues, and a natural missense mutation, R120G, has been associated with cataract and desmin-related myopathy, a disorder of skeletal muscles [Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM, Paulin D & Fardeau M (1998) Nat Genet20, 92-95]. In the present study, real-time 1H-NMR spectroscopy showed that the ability of R120G alphaB-crystallin to stabilize the partially folded, molten globule state of alpha-lactalbumin was significantly reduced in comparison with wild-type alphaB-crystallin. The mutant showed enhanced interaction with, and promoted unfolding of, reduced alpha-lactalbumin, but showed limited chaperone activity for other target proteins. Using NMR spectroscopy, gel electrophoresis, and MS, we observed that, unlike the wild-type protein, R120G alphaB-crystallin is intrinsically unstable in solution, with unfolding of the protein over time leading to aggregation and progressive truncation from the C-terminus. Light scattering, MS, and size-exclusion chromatography data indicated that R120G alphaB-crystallin exists as a larger oligomer than wild-type alphaB-crystallin, and its size increases with time. It is likely that removal of the positive charge from R120 of alphaB-crystallin causes partial unfolding, increased exposure of hydrophobic regions, and enhances its susceptibility to proteolysis, thus reducing its solubility and promoting its aggregation and complexation with other proteins. These characteristics may explain the involvement of R120G alphaB-crystallin with human disease states.


Gene expression of the liver in response to chronic hypoxia.
Hypoxia is an important ecological, evolutionary, and biomedical stressor. While physiological acclimatization of mammals to hypoxia is well studied, the variation in gene expression that underlies acclimatization is not well studied. We acclimatized inbred mice for 32 days to hypoxic conditions that simulated altitudes of 1400, 3000, and 4500 m. We used oligonucleotide microarrays to measure changes in steady-state abundance of mRNA in the livers of these mice. Mice exposed to more severe hypoxia (simulated altitude of 4500 m) were smaller in mass and had higher hematocrit than mice exposed to less severe hypoxia. ANOVA and false discovery rate tests indicated that 580 genes were significantly differentially expressed in response to chronic hypoxia. Few of these 580 genes have previously been reported to respond to hypoxia. In contrast, many of these 580 genes belonged to same functional groups typically respond to acute hypoxia. That is, both chronic and acute hypoxia elicit changes in transcript abundance for genes involved in angiogenesis, glycolysis, lipid metabolism, carbohydrate metabolism, and protein amino acid phosphorylation, but the particular genes affected by the two types of hypoxia were mostly different. Numerous genes affecting the immune system were differentially expressed in response to chronic hypoxia, which supports recently proposed hypotheses that link immune function and hypoxia. Furthermore, our results discovered novel elevated mRNA abundance of genes involved in hematopoiesis and oxygen transport not reported previously, but consistent with extreme hematocrits found in hypoxic mice.


Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking.
Homeostasis of the endoplasmic reticulum (ER) is essential for normal cellular functions. Disturbance of this homeostasis causes ER stress and activates the Unfolded Protein Response (UPR). The Ufm1 conjugation system is a novel Ubiquitin-like (Ubl) system whose physiological target(s) and biological functions remain largely undefined. Genetic study has demonstrated that the Ufm1-activating enzyme Uba5 is indispensible for erythroid differentiation in mice, highlighting the importance of this novel system in animal development. In this report we present the evidence for involvement of RCAD/Ufl1, a putative Ufm1-specific E3 ligase, and its binding partner C53/LZAP protein in ufmylation of endogenous Ufm1 targets. Moreover, we found that the Ufm1 system was transcriptionally up-regulated by disturbance of the ER homeostasis and inhibition of vesicle trafficking. Using luciferase reporter and ChIP assays, we dissected the Ufm1 promoter and found that Ufm1 was a potential target of Xbp-1, one of crucial transcription factors in UPR. We further examined the effect of Xbp-1 deficiency on the expression of the Ufm1 components. Interestingly, the expression of Ufm1, Uba5, RCAD/Ufl1 and C53/LZAP in wild-type mouse embryonic fibroblasts (MEFs) was significantly induced by inhibition of vesicle trafficking, but the induction was negated by Xbp-1 deficiency. Finally, we found that knockdown of the Ufm1 system in U2OS cells triggered UPR and amplification of the ER network. Taken together, our study provided critical insight into the regulatory mechanism of the Ufm1 system and established a direct link between this novel Ubl system and the ER network.


Mathematical models are a powerful method to understand and control the spread of Huanglongbing.
Huanglongbing (HLB), or citrus greening, is a global citrus disease occurring in almost all citrus growing regions. It causes substantial economic burdens to individual growers, citrus industries and governments. Successful management strategies to reduce disease burden are desperately needed but with so many possible interventions and combinations thereof it is difficult to know which are worthwhile or cost-effective. We review how mathematical models have yielded useful insights into controlling disease spread for other vector-borne plant diseases, and the small number of mathematical models of HLB. We adapt a malaria model to HLB, by including temperature-dependent psyllid traits, "flushing" of trees, and economic costs, to show how models can be used to highlight the parameters that require more data collection or that should be targeted for intervention. We analyze the most common intervention strategy, insecticide spraying, to determine the most cost-effective spraying strategy. We find that fecundity and feeding rate of the vector require more experimental data collection, for wider temperatures ranges. Also, the best strategy for insecticide intervention is to spray for more days rather than pay extra for a more efficient spray. We conclude that mathematical models are able to provide useful recommendations for managing HLB spread.


Impact of genetic variants on major bleeding after percutaneous coronary intervention based on a prospective multicenter registry.
Although dual antiplatelet therapy is essential for patients who undergo percutaneous coronary interventions, the risk of bleeding remains an unsolved problem, and there is limited information on the potential relationship between genetic variants and major bleeding. We analyzed the correlations between four major single nucleotide polymorphisms (CYP2C19, ABCB1, PON1, and P2Y12 G52T polymorphisms) and clinical outcomes in 4489 patients from a prospective multicenter registry. The primary endpoint was major bleeding, defined as a Bleeding Academic Research Consortium ≥ 3 bleeding event. The allelic frequencies of ABCB1, PON1, and both individual and combined CYP2C19 variants did not differ significantly between patient groups with and without major bleeding. However, the allelic frequency of the P2Y12 variant differed significantly between the two groups. Focusing on the P2Y12 G52T variant, patients in the TT group had a significantly higher rate of major bleeding (6.4%; adjusted hazard ratio [HR] 2.51; 95% confidence interval [CI] 1.08-5.84; p = 0.033) than patients in the other groups (GG [2.9%] or GT [1.9%]). Therefore, the TT variant of the P2Y12 G52T polymorphism may be an independent predictor of major bleeding.Trial registration: NCT02707445 ( https://clinicaltrials.gov/ct2/show/NCT02707445?term=02707445&draw=2&rank=1 ).


Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway.
Inflammation plays a key role in the progression of subarachnoid hemorrhage (SAH). Here, we examined the effects of astaxanthin (ATX) on the inflammatory response and secondary damage after SAH and the underlying mechanisms of action. In vivo, a prechiasmatic cistern injection model was established in rats and mice. In addition, neuron-microglia cocultures were exposed to oxyhemoglobin to mimic SAH in vitro. Western blotting revealed that protein expression of TLR4 was markedly increased in microglia at 24 h after SAH, with consequent increases in the downstream molecules myeloid differentiation factor 88 and NF-кB. Treatment with ATX significantly inhibited the TLR4 activation, increased sirtuin 1 expression, and inhibited the subsequent inflammatory response both in vivo and in vitro. ATX also significantly decreased high-mobility group box 1 nuclear translocation and secretion in neurons, an effect that was reversed by the sirtuin 1-specific inhibitor sirtinol. ATX administered 4 h after SAH ameliorated cerebral inflammation, brain edema, and neuronal death and improved neurologic function. ATX reduced neuronal death but did not improve neurologic function in TLR4 knockout mice. These results suggest that ATX reduces the proinflammatory response and secondary brain injury after SAH, primarily by increasing sirtuin 1 levels and inhibiting the TLR4 signaling pathway.-Zhang, X., Lu, Y., Wu, Q., Dai, H., Li, W., Lv, S., Zhou, X., Zhang, X., Hang, C., Wang, J. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway.


Mitochondrial DNA polymorphisms in Gelao ethnic group residing in Southwest China.
Gelao ethnic group, an aboriginal population residing in southwest China, has undergone a long and complex evolutionary process. To investigate the genetic structure of this ancient ethnic group, mitochondrial DNA (mtDNA) polymorphisms of 102 Gelao individuals were collected and analyzed in this study. With the aid of the information extracted from control-region hypervariable segments (HVSs) I and II as well as some necessary coding-region segments, phylogenetic status of all mtDNAs under study were determined by means of classifying into various defined haplogroups. The southern-prevalent haplogroups B, R9, and M7 account for 45.1% of the gene pool, whereas northern-prevalent haplogroups A, D, G, N9, and M8 consist of 39.2%. Haplogroup distribution indicates that the Gelao bears signatures of southern populations and possesses some regional characters. In the PC map, Gelao clusters together with populations with Bai-Yue tribe origin as well as the local Han and the Miao. The results demonstrate the complexity of Gelao population and the data can well supplement the China mtDNA database.


Learning to read changes children's phonological skills: evidence from a latent variable longitudinal study of reading and nonword repetition.
Individual differences in nonword repetition are associated with language and literacy development, but few studies have considered the extent to which learning to read influences phonological skills as indexed by nonword repetition performance. We explored this question using a latent variable longitudinal design. Reading, oral language and nonword repetition were assessed in 215 children at age 6 years and one year later at age 7. Reading at 6 years predicted growth in nonword repetition between 6 and 7 years, independent of the effects of oral language skills and the autoregressive effect of nonword repetition at 6 years, but nonword repetition was not a longitudinal predictor of the growth of reading. These findings demonstrate that learning to read has a powerful effect on children's language processing systems. We consider how learning to read might influence speech processing, and discuss the implications of our findings for theoretical accounts of reading disorder.


Molecular breeding for introgression of fatty acid desaturase mutant alleles (ahFAD2A and ahFAD2B) enhances oil quality in high and low oil containing peanut genotypes.
High oleate peanuts have two marketable benefits, health benefits to consumers and extended shelf life of peanut products. Two mutant alleles present on linkage group a09 (ahFAD2A) and b09 (ahFAD2B) control composition of three major fatty acids, oleic, linoleic and palmitic acids which together determine peanut oil quality. In conventional breeding, selection for fatty acid composition is delayed to advanced generations. However by using DNA markers, breeders can reject large number of plants in early generations and therefore can optimize time and resources. Here, two approaches of molecular breeding namely marker-assisted backcrossing (MABC) and marker-assisted selection (MAS) were employed to transfer two FAD2 mutant alleles from SunOleic 95R into the genetic background of ICGV 06110, ICGV 06142 and ICGV 06420. In summary, 82 MABC and 387 MAS derived introgression lines (ILs) were developed using DNA markers with elevated oleic acid varying from 62 to 83%. Oleic acid increased by 0.5-1.1 folds, with concomitant reduction of linoleic acid by 0.4-1.0 folds and palmitic acid by 0.1-0.6 folds among ILs compared to recurrent parents. Finally, high oleate ILs, 27 with high oil (53-58%), and 28 ILs with low oil content (42-50%) were selected that may be released for cultivation upon further evaluation.


What is the optimal interval between successive home blood pressure readings using an automated oscillometric device?
To clarify whether a shorter interval between three successive home blood pressure (HBP) readings (10 s vs. 1 min) taken twice a day gives a better prediction of the average 24-h BP and better patient compliance. We enrolled 56 patients from a hypertension clinic (mean age: 60 +/- 14 years; 54% female patients). The study consisted of three clinic visits, with two 4-week periods of self-monitoring of HBP between them, and a 24-h ambulatory BP monitoring at the second visit. Using a crossover design, with order randomized, the oscillometric HBP device (HEM-5001) could be programmed to take three consecutive readings at either 10-s or 1-min intervals, each of which was done for 4 weeks. Patients were asked to measure three HBP readings in the morning and evening. All the readings were stored in the memory of the monitors. The analyses were performed using the second-third HBP readings. The average systolic BP/diastolic BP for the 10-s and 1-min intervals at home were 136.1 +/- 15.8/77.5 +/- 9.5 and 133.2 +/- 15.5/76.9 +/- 9.3 mmHg (P = 0.001/0.19 for the differences in systolic BP and diastolic BP), respectively. The 1-min BP readings were significantly closer to the average of awake ambulatory BP (131 +/- 14/79 +/- 10 mmHg) than the 10-s interval readings. There was no significant difference in patients' compliance in taking adequate numbers of readings at the different time intervals. The 1-min interval between HBP readings gave a closer agreement with the daytime average BP than the 10-s interval.


FURTHER STUDIES ON IMMUNITY IN EXPERIMENTAL CRYPTOCOCCOSIS.
Following infection with 10(3) cells of Cryptococcus neoformans, progressive multiplication occurred in all tissues for 7 to 28 days. Thereafter, most mice gained control of the infection so that 3 to 6 months after inoculation, tissues were usually sterile or contained only small numbers of cryptococci. Survivors challenged 1 to 4 months after infection with 10(3) cells lived longer than controls and had an increased survival rate. Pretreatment with bacterial endotoxin also resulted in protection against cryptococcal challenge. Endotoxin-protected animals showed no ability to limit the infection until circulating antibody could be demonstrated. Histologic studies revealed an increased cellular infiltration in the brains of specifically protected and endotoxin-protected mice 1 to 2 weeks after challenge. However, control of cryptococcal multiplication could be correlated with the presence of antibody but could not be correlated with the enhanced cellular response. Although protection against cryptococcal challenge appears to be antibody-dependent, it is unclear whether protective antibody is to be found in plasma or is tissue-bound.


Optimal Perceived Timing: Integrating Sensory Information with Dynamically Updated Expectations.
The environment has a temporal structure, and knowing when a stimulus will appear translates into increased perceptual performance. Here we investigated how the human brain exploits temporal regularity in stimulus sequences for perception. We find that the timing of stimuli that occasionally deviate from a regularly paced sequence is perceptually distorted. Stimuli presented earlier than expected are perceptually delayed, whereas stimuli presented on time and later than expected are perceptually accelerated. This result suggests that the brain regularizes slightly deviant stimuli with an asymmetry that leads to the perceptual acceleration of expected stimuli. We present a Bayesian model for the combination of dynamically-updated expectations, in the form of a priori probability of encountering future stimuli, with incoming sensory information. The asymmetries in the results are accounted for by the asymmetries in the distributions involved in the computational process.


Phylogenetic approach reveals that virus genotype largely determines HIV set-point viral load.
HIV virulence, i.e. the time of progression to AIDS, varies greatly among patients. As for other rapidly evolving pathogens of humans, it is difficult to know if this variance is controlled by the genotype of the host or that of the virus because the transmission chain is usually unknown. We apply the phylogenetic comparative approach (PCA) to estimate the heritability of a trait from one infection to the next, which indicates the control of the virus genotype over this trait. The idea is to use viral RNA sequences obtained from patients infected by HIV-1 subtype B to build a phylogeny, which approximately reflects the transmission chain. Heritability is measured statistically as the propensity for patients close in the phylogeny to exhibit similar infection trait values. The approach reveals that up to half of the variance in set-point viral load, a trait associated with virulence, can be heritable. Our estimate is significant and robust to noise in the phylogeny. We also check for the consistency of our approach by showing that a trait related to drug resistance is almost entirely heritable. Finally, we show the importance of taking into account the transmission chain when estimating correlations between infection traits. The fact that HIV virulence is, at least partially, heritable from one infection to the next has clinical and epidemiological implications. The difference between earlier studies and ours comes from the quality of our dataset and from the power of the PCA, which can be applied to large datasets and accounts for within-host evolution. The PCA opens new perspectives for approaches linking clinical data and evolutionary biology because it can be extended to study other traits or other infectious diseases.


Genetic Tracing of Cav3.2 T-Type Calcium Channel Expression in the Peripheral Nervous System.
Characterizing the distinct functions of the T-type ion channel subunits Cav3.1, 3.2 or 3.3 has proven difficult due to their highly conserved amino-acid sequences and the lack of pharmacological blockers specific for each subunit. To precisely determine the expression pattern of the Cav3.2 channel in the nervous system we generated two knock-in mouse strains that express EGFP or Cre recombinase under the control of the Cav3.2 gene promoter. We show that in the brains of these animals, the Cav3.2 channel is predominantly expressed in the dentate gyrus of the hippocampus. In the peripheral nervous system, the activation of the promoter starts at E9.5 in neural crest cells that will give rise to dorsal root ganglia (DRG) neurons, but not sympathetic neurons. As development progresses the number of DRG cells expressing the Cav3.2 channel reaches around 7% of the DRG at E16.5, and remains constant until E18.5. Characterization of sensory neuron subpopulations at E18.5 showed that EGFP+ cells are a heterogeneous population consisting mainly of TrkB+ and TrkC+ cells, while only a small percentage of DRG cells were TrkA+. Genetic tracing of the sensory nerve end-organ innervation of the skin showed that the activity of the Cav3.2 channel promoter in sensory progenitors marks many mechanoreceptor and nociceptor endings, but spares slowly adapting mechanoreceptors with endings associated with Merkel cells. Our genetic analysis reveals for the first time that progenitors that express the Cav3.2 T-type calcium channel, defines a sensory specific lineage that populates a large proportion of the DRG. Using our Cav3.2-Cre mice together with AAV viruses containing a conditional fluorescent reporter (tdTomato) we could also show that Cre expression is largely restricted to two functionally distinct sensory neuron types in the adult ganglia. Cav3.2 positive neurons innervating the skin were found to only form lanceolate endings on hair follicles and are probably identical to D-hair receptors. A second population of nociceptive sensory neurons expressing the Cav3.2 gene was found to be positive for the calcitonin-gene related peptide but these neurons are deep tissue nociceptors that do not innervate the skin.


The effect and molecular mechanism of hypoxia on proliferation and apoptosis of CD133+ renal stem cells.
Congenital hydronephrosis caused by ureteropelvic junction obstruction (UPJO) eventually leads to renal interstitial fibrosis and atrophy, after a series of pathophysiological problems. Renal repair after injury depends on renal stem cells. This study aimed to determine the expression of renal stem cell marker CD133 in children of different ages and the regulatory effect of stem cell microenvironment. Renal stem cells from children of different ages were identified and screened out by flow cytometry in the study. Children with hydronephrosis were divided into neonates, infants, preschool age, school age, and adolescents groups. A hypoxic cell model prepared with CoCl2 was developed to detect the effect of hypoxia on the proliferation and apoptosis of renal stem cells. The effect and molecular mechanism of hypoxia-inducible factor 1-alpha (HIF-1α) on the proliferation and apoptosis of renal stem cells were also explored. Both hypoxia and HIF-1α significantly promoted the proliferation of renal stem cells and inhibited cell apoptosis. HIF-1α could bind to the promoter region of proliferating cell nuclear antigen (PCNA) and PROM1 (CD133) to mediate their transcription and expression. The content of CD133+ renal stem cells was the highest in the neonatal group and it decreased with the increase of age. Taken together, this study clarified the effect of age on the content of human renal stem cells and determined the regulatory mechanism of hypoxia on renal stem cells. We expect our results to provide a research basis for the treatment and clinical application of renal stem cells.


Talin depletion reveals independence of initial cell spreading from integrin activation and traction.
Cell spreading, adhesion and remodelling of the extracellular matrix (ECM) involve bi-directional signalling and physical linkages between the ECM, integrins and the cell cytoskeleton. The actin-binding proteins talin1 and 2 link ligand-bound integrins to the actin cytoskeleton and increase the affinity of integrin for the ECM. Here we report that depletion of talin2 in talin1-null (talin1(-/-)) cells did not affect the initiation of matrix-activated spreading or Src family kinase (SFK) activation, but abolished the ECM-integrin-cytoskeleton linkage and sustained cell spreading and adhesion. Specifically, focal adhesion assembly, focal adhesion kinase (FAK) signalling and traction force generation on substrates were severely affected. The talin1 head domain restored beta1 integrin activation but only full-length talin1 restored the ECM-cytoskeleton linkage and normal cytoskeleton organization. Our results demonstrate three biochemically distinct steps in fibronectin-activated cell spreading and adhesion: (1) fibronectin-integrin binding and initiation of spreading, (2) fast cell spreading and (3) focal adhesion formation and substrate traction. We suggest that talin is not required for initial cell spreading. However, talin provides the important mechanical linkage between ligand-bound integrins and the actin cytoskeleton required to catalyse focal adhesion-dependent pathways.


Differential involvement of somatosensory and interoceptive cortices during the observation of affective touch.
Previous studies suggested that the observation of other individuals' somatosensory experiences also activates brain circuits processing one's own somatosensory experiences. However, it is unclear whether cortical regions involved with the elementary stages of touch processing are also involved in the automatic coding of the affective consequences of observed touch and to which extent they show overlapping activation for somatosensory experiences of self and others. In order to investigate these issues, in the present fMRI study, healthy participants either experienced touch or watched videos depicting other individuals' inanimate and animate/social touch experiences. Essentially, a distinction can be made between exteroceptive and interoceptive components of touch processing, involved with physical stimulus characteristics and internal feeling states, respectively. Consistent with this distinction, a specific negative modulation was found in the posterior insula by the mere visual perception of other individuals' social or affective cutaneous experiences, compared to neutral inanimate touch. On the other hand, activation in secondary somatosensory and posterior superior temporal regions, strongest for the most intense stimuli, seemed more dependent on the observed physical stimulus characteristics. In contrast to the detected vicarious activation in somatosensory regions, opposite activation patterns for the experience (positive modulation) and observation (negative modulation) of touch suggest that the posterior insula does not reflect a shared representation of self and others' experiences. Embedded in a distributed network of brain regions underpinning a sense of the bodily self, the posterior insula rather appears to differentiate between self and other conditions when affective experiences are implicated.


Glutathione and glutamate in schizophrenia: a 7T MRS study.
In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.


First Report of Pseudomonas viridiflava Causing a Bacterial Blight of Artichoke Bract Leaves.
In 2006, a disease was observed on two artichoke (Cynara scolymus L. cv. Lardati) fields in Crete, Greece, covering ~2 ha. Symptoms developed after several days of rainy and windy weather and >70% of capitula were affected, resulting in unmarketable produce. Initial symptoms were water-soaked, dark green spots on bracts with many sunken, necrotic, often elongated lesions, each with a brown-black center and surrounded by a water-soaked halo with a dark red-brown margin. Symptoms were more severe on inner bracts. Isolations from symptomatic, surface-disinfected bracts onto King's B agar medium (KB) consistently yielded yellow bacterial colonies that produced a green-blue fluorescent pigment. Ten selected artichoke isolates, all gram-negative, presented the LOPAT profile (- - + - +) and were levan negative, oxidase negative, potato rot positive, arginine dihydrolase negative, and showed tobacco hypersensitive reaction. All isolates used L-arabinose, D(-)-tartrate, and L-lactate, but not sucrose, L(+)-tartrate, or trigonelline. Results were identical to those obtained with the reference strain of Pseudomonas viridiflava NCPPB 1249 (3), and strains PV3005 and PV3006 from eggplant (1). Based on these biochemical tests, 10 isolates were identified as P. viridiflava group II members of the LOPAT determinative scheme of Lelliott (1,2). Two artichoke isolates (PV608 and PV609) were selected for molecular characterization. The identity and phylogenetic analysis were determined by multilocus sequence typing with the gyrB, rpoD, and rpoB genes (PV608 Accession Nos. JN383375, JN383363, and JQ267546; PV609 Accession Nos. JN383376, JN383364, and JQ267547). BLAST searches showed highest nucleotide sequence identity (96%) with GenBank sequences of P. viridiflava reference strains NCPPB 963 and CFBP 2107. Pathogenicity of 10 artichoke isolates and reference strains was tested twice on detached capitulum bracts of artichoke cv. Lardati, as well as 4-week-old tomato plants of cv. ACE, and Chrysanthemum indicum cv. Reagan plants. Each isolate was inoculated onto 10 bracts by placing 15 μl of bacterial suspension (5 × 106 CFU/ml) of a 48-h culture in KB broth on the surface of the bract, and pricking the bract through the drop of bacterial suspension with a sterile needle. Each isolate was also inoculated onto five tomato and five chrysanthemum plants by dipping a sterile toothpick in the appropriate bacterial culture and pricking the surface of the stem. Ten control plants were inoculated similarly with sterile, distilled water. Inoculated bracts and plants were kept in boxes lined with moist filter paper at 25 to 30°C and 80 to 100% relative humidity. Lesions developed on detached bracts within 72 h and were similar to those observed on the naturally infected plants. On tomato and chrysanthemum plants, pith necrosis and wilting symptoms were induced within 1 week of inoculation. Symptoms were not observed on control bracts and plants. Bacterial colonies were reisolated from bract lesions and stems with pith necrosis, but not from control plants, and the reisolates had the same LOPAT profile as the original isolates of P. viridiflava, thus fulfilling Koch's postulates. To our knowledge, this is the first report in the world of P. viridiflava causing a disease of artichoke bracts. References: (1) D. E. Goumas et al. Eur. J. Plant Pathol. 104:181, 1998. (2) Lelliott et al. J. Appl. Bacteriol. 29:470, 1966. (3) M. L. Saunier et al. Appl. Environ. Microbiol. 62:2360, 1996.


Comparison of Two Types of Liquid Biopsies in Patients With Hepatocellular Carcinoma Awaiting Orthotopic Liver Transplantation.
Orthotopic liver transplantation (OLT) is considered one of the few curative treatments available for early stages of hepatocellular carcinoma (HCC). It has been shown that more than 10% of transplanted individuals suffer relapse during the first year after surgery and most of them die because of the tumor. The circulating tumor cells (CTCs) are the main source of recurrences as they disseminate from a primary or metastatic tumor lesion through peripheral blood. We aimed to determine the concentration of CTCs in peripheral blood in these patients by 2 different approaches: the CellSearch and the IsoFlux systems to assess their applicability to this disease monitoring. A comparative study was conducted in 21 patients with HCC eligible for liver transplantation according to the Milan criteria, whose peripheral blood was processed by the CellSearch and the IsoFlux systems. CTCs were isolated in 1 of the 21 patients (4.7%) by the CellSearch system and in 19 of the 21 patients (90.5%) by the IsoFlux method. The comparison of both methods using Bland-Altman plot shows that there is not consistency in the determination of CTCs in our patients, finding a proportional bias between them. The results obtained by both CTCs isolation systems are not interchangeable nor transferable. The CellSearch system does not seem to be the ideal approach for studying CTCs in patients with HCC. The IsoFlux system displays greater sensitivity in the identification of CTCs and might become an important tool in patient management.


Depressive symptoms but not chronic pain have an impact on the survival of patients undergoing maintenance hemodialysis.
More than 1/3 of patients with end-stage renal disease who are in a chronic dialysis program suffer from chronic pain and depression/anxiety. The aim of the study was to determine the impacts of symptoms of depression/anxiety, chronic pain and quality of life (QoL) on 6-year patient survival. Observational study of end-stage renal disease patients on maintenance hemodialysis (n = 205) who met the inclusion criteria. Patients from three dialysis centers in Lower Silesia were asked to complete a battery of validated questionnaires: the Hospital Anxiety and Depression Scale (HADS), the 36-item Short Form Health Survey Questionnaire, the Verbal Rating Scale (VRS) and the Visual Analog Scale (VAS). Clinical and biochemical data (dialysis adequacy) were recorded. One hundred thirty from 205 enrolled hemodialysis patients (63.4%) suffered from chronic pain. Patients with pain were on maintenance dialysis for longer times and had higher levels of parathyroid hormone, more depressive symptoms and a lower QoL than those without pain. In the 6-year period, 96 (46.8%) patients died. The most common cause of death was cardiovascular disease in 44 (45.8%) patients. Highly depressed patients (HADS depression score > 8) exhibited higher mortality (< 8 vs. > 8 points; p = 0.016) independent of age, diabetes, cardiovascular disease, C-reactive protein or albumin level. Chronic pain, although common among hemodialysis patients, did not lower survival. Depressive symptoms are an important predictor for all-cause mortality in hemodialysis patients, with the relationship independent of nutritional or inflammatory status.


A roundabout way to cancer.
The Slit family of secreted proteins and their transmembrane receptor, Robo, were originally identified in the nervous system where they function as axon guidance cues and branching factors during development. Since their discovery, a great number of additional roles have been attributed to Slit/Robo signaling, including regulating the critical processes of cell proliferation and cell motility in a variety of cell and tissue types. These processes are often deregulated during cancer progression, allowing tumor cells to bypass safeguarding mechanisms in the cell and the environment in order to grow and escape to new tissues. In the past decade, it has been shown that the expression of Slit and Robo is altered in a wide variety of cancer types, identifying them as potential therapeutic targets. Further, studies have demonstrated dual roles for Slits and Robos in cancer, acting as both oncogenes and tumor suppressors. This bifunctionality is also observed in their roles as axon guidance cues in the developing nervous system, where they both attract and repel neuronal migration. The fact that this signaling axis can have opposite functions depending on the cellular circumstance make its actions challenging to define. Here, we summarize our current understanding of the dual roles that Slit/Robo signaling play in development, epithelial tumor progression, and tumor angiogenesis.


Lateral resolution enhancement of laser scanning microscopy by a higher-order radially polarized mode beam.
We demonstrate that the lateral resolution of confocal laser scanning microscopy is dramatically improved by a higher-order radially polarized (HRP) beam with six concentric rings. This beam was generated simply by inserting liquid crystal devices in front of an objective lens. An HRP beam visualized aggregated 0.17 μm beads individually and is also applicable to biological imaging. This method can extend the capability of conventional laser scanning microscopes without modification of the system, with the exception of the addition of the liquid crystal devices in the optical path.


Elder Mistreatment Among Older Chinese Americans: The Role of Family Cohesion.
Cultural values are believed to influence perceptions of and solutions to elder mistreatment (EM) perpetrated by family members. This study aimed to understand the influence of family cohesion on EM reported by community-dwelling older Chinese Americans. A mixed-method approach consisting of a quantitative survey built on focus group interviews was utilized. Focus group interviews were conducted to ensure subsequent survey questions about EM were culturally and linguistically appropriate. The revised survey questionnaires were then administered to 266 Chinese American older adults to assess estimated EM prevalence and the effects of family cohesion. Survey findings indicate that 1 in 10 reported at least one occurrence of EM in the past year. Depressed Chinese older adults (OR= 1.14) and those reporting low levels of family cohesion (OR = .82) were more likely to experience EM. Multigenerational family interventions can be designed to reduce older adults' depression levels and promote family cohesion.


Functional role for cannabinoids in respiratory stability during sleep.
Serotonin, acting in the peripheral nervous system, can exacerbate sleep-related apnea, and systemically administered serotonin antagonists reduce sleep-disordered respiration in rats and bulldogs. Because cannabinoid receptor agonists are known to inhibit the excitatory effects of serotonin on nodose ganglion cells, we examined the effects of endogenous (oleamide) and exogenous (delta9-tetrahydrocannabinol; delta9THC) cannabimimetic agents on sleep-related apnea. Sleep architecture, respiratory pattern, and apnea expression in rats were assessed by polysomnography. A repeated measures, within-subjects, fully nested crossover design was used in which each animal was recorded on exactly 12 occasions. Eleven adult male Sprague-Dawley rats were instrumented for chronic polysomnography. Animals were recorded following intraperitoneal injection of various doses of delta9THC, oleamide, and serotonin, alone and in combination. Our data show that delta9THC and oleamide each stabilized respiration during all sleep stages. With delta9THC, apnea index decreased by 42% (F=2.63; p=0.04) and 58% (F=2.68; p=0.04) in NREM and REM sleep, respectively. Oleamide produced equivalent apnea suppression. This observation suggests an important role for endocannabinoids in maintaining autonomic stability during sleep. Oleamide and delta9THC blocked serotonin-induced exacerbation of sleep apnea (p<0.05 for each), suggesting that inhibitory coupling between cannabinoids and serotonin receptors in the peripheral nervous system may act on apnea expression. This study demonstrates potent suppression of sleep-related apnea by both exogenous and endogenous cannabinoids. These findings are of relevance to the pathogenesis and pharmacological treatment of sleep-related breathing disorders.


A Novel Transdermal Protein Delivery Strategy via Electrohydrodynamic Coating of PLGA Microparticles onto Microneedles.
Transdermal delivery of biological therapeutics is emerging as a potent alternative to intravenous or subcutaneous injections. The latter possess major challenges including patient discomfort, the necessity for trained personnel, specialized sharps disposal, and risk of infection. The microneedle (MN) technology circumvents many of the abovementioned challenges, delivering biological materials directly into the skin and allowing sustained release of the active ingredient both in animal models and in humans. This study describes the use of electrohydrodynamic atomization (EHDA) to coat ovalbumin (OVA)-loaded PLGA nanoparticles onto hydrogel-forming MN arrays. The particles showed extended release of OVA over ca. 28 days. Microscopic analysis demonstrated that EHDA could generate a uniform particle coating on the MNs, with 30% coating efficiency. Furthermore, the coated MN array manifested similar mechanical characteristics and insertion properties to the uncoated system, suggesting that the coating should have no detrimental effects on the application of the MNs. The coated MNs resulted in no significant increase in anti-OVA-specific IgG titres in C57BL/6 mice in vivo as compared to the untreated mice (paired t-test, p > 0.05), indicating that the formulations are nonimmunogenic. The approach of using EHDA to coat an MN array thus appears to have potential as a novel noninvasive protein delivery strategy.


Male accessory sex organ morphogenesis is altered by loss of function of Hoxd-13.
The role of the Hox gene Hoxd-13 in postnatal morphogenesis of the male accessory sex organs was examined by correlating the distribution and temporal regulation of expression in the accessory sex organs of postnatal mice with morphologic abnormalities of Hoxd-13-deficient transgenic mice. Previous studies of Hoxd-13 expression in the perinatal period have shown a broad domain of expression in the lower genitourinary tract, with expression in both mesenchyme and epithelium; focal expression was also noted in the epithelium of the nascent ducts of the developing prostate. Quantitative RT-PCR studies of Hoxd-13 expression in the 5 day mouse confirm widespread expression in the accessory sex organs developing from both the Wolffian duct and the urogenital sinus. Expression is down-regulated with age, and a detailed time course of expression in the developing prostate shows that the level of Hoxd-13 expression correlates with morphogenetic activity in the development of the prostate ductal system. Transgenic Hoxd-13-deficient mice display multiple abnormalities in the male accessory sex organs. The most severe abnormalities were observed in organs exhibiting ductal branching during postnatal development and included diminished mesenchymal folding in the seminal vesicles, decreased size and diminished ductal branching in the ventral and dorsal prostate, and agenesis of the bulbourethral gland. We conclude that Hoxd-13 expression in the postnatal period correlates with a period of intense morphogenetic activity in accessory sex organ development and that the function of Hoxd-13 is evidenced by morphologic abnormalities in accessory sex organs of the Hoxd-13-deficient mutant.


The Adaptive Behavior of a Soccer Team: An Entropy-Based Analysis.
To optimize its performance, a competitive team, such as a soccer team, must maintain a delicate balance between organization and disorganization. On the one hand, the team should maintain organized patterns of behavior to maximize the cooperation between its members. On the other hand, the team's behavior should be disordered enough to mislead its opponent and to maintain enough degrees of freedom. In this paper, we have analyzed this dynamic in the context of soccer games and examined whether it is correlated with the team's performance. We measured the organization associated with the behavior of a soccer team through the Tsallis entropy of ball passes between the players. Analyzing data taken from the English Premier League (2015/2016), we show that the team's position at the end of the season is correlated with the team's entropy as measured with a super-additive entropy index. Moreover, the entropy score of a team significantly contributes to the prediction of the team's position at the end of the season beyond the prediction gained by the team's position at the end of the previous season.


Gender Difference in Intraocular Pressure and Incidence of Metabolic Syndrome: A Community-Based Cohort Study in Matsu, Taiwan.
Background: We aimed to assess the effect of intraocular pressure (IOP) on incident metabolic syndrome (MetS) using a longitudinal follow-up of screening cohort in contrast to most of previous studies addressing the association between both. Methods: The empirical data were derived from a community-based integrated screening program in Matsu during the period 2003 to 2010. A total of 1347 participants older than 30 years were enrolled in this study. With the enrollment of 1056 participants with MetS free at baseline, the cohort with IOP measurement in 2003 were followed up over time to identify incident MetS to elucidate the temporal sequence of both. Results: The statistically significant effect noted was that elevated IOP (≥15 mmHg vs. <15 mmHg) had 1.46-fold risk for developing incident MetS (adjusted relative ratio [aRR]: 1.46; 95% confidence interval [CI]: 1.08-1.99) for both sex combined, particularly in men (aRR: 1.66; 95% CI: 1.13-2.45) but not in women. The finding that elevated IOP occurred before the presence of high blood pressure was noted in both men and women, whereas men with elevated IOP may be concomitant with more individual components (severity) of MetS earlier than women with elevated IOP. Conclusions: Elevated IOP leading to the risk for incident or severe MetS was noted in men but not in women. Evidence on this temporal sequence revealed the possibility of showing signs of elevated IOP before the development of MetS, which indicates the necessity of monitoring IOP in routine health check-up for prevention of MetS-related chronic diseases.


The anatomy of phenotype ontologies: principles, properties and applications.
The past decade has seen an explosion in the collection of genotype data in domains as diverse as medicine, ecology, livestock and plant breeding. Along with this comes the challenge of dealing with the related phenotype data, which is not only large but also highly multidimensional. Computational analysis of phenotypes has therefore become critical for our ability to understand the biological meaning of genomic data in the biological sciences. At the heart of computational phenotype analysis are the phenotype ontologies. A large number of these ontologies have been developed across many domains, and we are now at a point where the knowledge captured in the structure of these ontologies can be used for the integration and analysis of large interrelated data sets. The Phenotype And Trait Ontology framework provides a method for formal definitions of phenotypes and associated data sets and has proved to be key to our ability to develop methods for the integration and analysis of phenotype data. Here, we describe the development and products of the ontological approach to phenotype capture, the formal content of phenotype ontologies and how their content can be used computationally.


Use of measured scatter data for the attenuation correction of single photon emission tomography without transmission scanning.
Attenuation correction is essential for reliable interpretation of emission tomography, however, the use of transmission measurements to generate attenuation maps is limited by availability of equipment and potential mismatches between the transmission and emission measurements. The authors present a first step toward a method of estimating an attenuation map from measured scatter data without a transmission scan. A scatter model has been developed that accurately predicts the distribution of photons which have been scattered once. The scatter model has been used as the basis of a maximum likelihood gradient ascent method to estimate an attenuation map from measured scatter data. In order to estimate both the attenuation map and activity distribution, iterations of the derived scatter based algorithm have been alternated with the maximum likelihood expectation maximization algorithm in a joint estimation process. For each iteration of the attenuation map estimation, the activity distribution is fixed at the values estimated during the previous activity iteration, and in each iteration of the activity distribution estimation the attenuation map is fixed at the values estimated during the previous attenuation iteration. The use of photopeak data to enhance the estimation of the attenuation map compared to the use of scatter data alone has also been considered. The algorithm derived has been used to reconstruct data simulated for an idealized two-dimensional situation and using a physical phantom. The reconstruction of idealized data demonstrated good reconstruction of both the activity distribution and attenuation map. The inclusion of information recorded in the photopeak energy window in the attenuation map estimation step demonstrated an improvement in the accuracy of the reconstruction, enabling an accurate attenuation map to be recovered. Validation of the results with physical phantom data demonstrated that different regions of attenuation could be distinguished in a real situation and produces results that represent a promising first step toward the use of scatter data to estimate the activity distribution and attenuation map from single photon emission tomography (SPECT) data without a transmission scan. The technique presented shows promise as a method of attenuation correction for SPECT data without the need for a separate transmission scan. Further work is required to further improve the method and to compensate for the assumptions used in the scatter model.


Fecal Microbiota Transplantation from Overweight or Obese Donors in Cachectic Patients with Advanced Gastroesophageal Cancer: A Randomized, Double-blind, Placebo-Controlled, Phase II Study.
Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer. In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics). Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14-1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21-1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota. FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.


Adult-born neurons immature during learning are necessary for remote memory reconsolidation in rats.
Memory reconsolidation, the process by which memories are again stabilized after being reactivated, has strengthened the idea that memory stabilization is a highly plastic process. To date, the molecular and cellular bases of reconsolidation have been extensively investigated particularly within the hippocampus. However, the role of adult neurogenesis in memory reconsolidation is unclear. Here, we combined functional imaging, retroviral and chemogenetic approaches in rats to tag and manipulate different populations of rat adult-born neurons. We find that both mature and immature adult-born neurons are activated by remote memory retrieval. However, only specific silencing of the adult-born neurons immature during learning impairs remote memory retrieval-induced reconsolidation. Hence, our findings show that adult-born neurons immature during learning are required for the maintenance and update of remote memory reconsolidation.


A depth-based head-mounted visual display to aid navigation in partially sighted individuals.
Independent navigation for blind individuals can be extremely difficult due to the inability to recognise and avoid obstacles. Assistive techniques such as white canes, guide dogs, and sensory substitution provide a degree of situational awareness by relying on touch or hearing but as yet there are no techniques that attempt to make use of any residual vision that the individual is likely to retain. Residual vision can restricted to the awareness of the orientation of a light source, and hence any information presented on a wearable display would have to limited and unambiguous. For improved situational awareness, i.e. for the detection of obstacles, displaying the size and position of nearby objects, rather than including finer surface details may be sufficient. To test whether a depth-based display could be used to navigate a small obstacle course, we built a real-time head-mounted display with a depth camera and software to detect the distance to nearby objects. Distance was represented as brightness on a low-resolution display positioned close to the eyes without the benefit focussing optics. A set of sighted participants were monitored as they learned to use this display to navigate the course. All were able to do so, and time and velocity rapidly improved with practise with no increase in the number of collisions. In a second experiment a cohort of severely sight-impaired individuals of varying aetiologies performed a search task using a similar low-resolution head-mounted display. The majority of participants were able to use the display to respond to objects in their central and peripheral fields at a similar rate to sighted controls. We conclude that the skill to use a depth-based display for obstacle avoidance can be rapidly acquired and the simplified nature of the display may appropriate for the development of an aid for sight-impaired individuals.


Transcriptional activity of the human pseudogene psi alpha globin compared with alpha globin, its functional gene counterpart.
Transcriptional analysis of the human pseudogene psi alpha globin has revealed the following features: (1) The promoter with a 23 bp deletion between the CCAAT and ATA boxes is functional both in vitro and in vivo, 3 fold and 10 fold less efficient, respectively, than alpha. (2) Both the psi alpha and alpha globin gene promoters are active in the absence of transcriptional enhancers, either a gene-encoded or viral enhancer. (3) The mutated poly(A) addition signal in psi alpha (AATGAA) appears to be completely nonfunctional. This result provides an explanation for the absence of psi alpha transcripts in human erythroid cells.