In our natural environment, the brain needs to combine signals from multiple sensory modalities into a coherent percept. Whereas spatial attention guides perceptual decisions by prioritizing processing of signals that are task-relevant, spatial expectations encode the probability of signals over space. Previous studies have shown that behavioral effects of spatial attention generalize across sensory modalities. However, because they manipulated spatial attention as signal probability over space, these studies could not dissociate attention and expectation or assess their interaction. In two experiments, we orthogonally manipulated spatial attention (i.e., task-relevance) and expectation (i.e., signal probability) selectively in one sensory modality (i.e., primary modality) (experiment 1: audition, experiment 2: vision) and assessed their effects on primary and secondary sensory modalities in which attention and expectation were held constant. Our results show behavioral effects of spatial attention that are comparable for audition and vision as primary modalities; however, signal probabilities were learned more slowly in audition, so that spatial expectations were formed later in audition than vision. Critically, when these differences in learning between audition and vision were accounted for, both spatial attention and expectation affected responses more strongly in the primary modality in which they were manipulated and generalized to the secondary modality only in an attenuated fashion. Collectively, our results suggest that both spatial attention and expectation rely on modality-specific and multisensory mechanisms.

Natural image statistics exhibit temporal regularities of slow changes and short-term correlations and visual perception, too, is biased toward recently seen stimuli, i.e., a positive serial dependence. Some studies report strong individual differences in serial dependence in perceptual decision-making: some observers show positive serial effects, others repulsive effects, and some show no bias. To understand these contrasting results, this study separates the influences of physical stimuli per se, perceptual choices, and motor responses on serial dependence in perceptual decision making. In two experiments, human observers reported which orientation (45° or -45°, at threshold contrast) they perceived. Experiment 1, used a consistent mapping between stimulus and response buttons whereas in Experiment 2, observers did two tasks: one with a consistent stimulus-response mapping, the other with a random stimulus-response mapping (perceptual choice and motor response unrelated). Results show that the stimulus percept (not the physical stimulus per se) affected subsequent perceptual choices in an attractive way and that motor responses produced a repulsive serial effect. When the choice-response mapping was consistent (inseparable choice and response, typical of most experiments), individual differences in the overall serial effect was observed: some were positive, some repulsive, and some were bias-free. The multiple regression analysis revealed that observers' overall serial effects in the consistent choice-response mapping task could be predicted by their serial effects for choices and motor responses in the random mapping task. These individual differences likely reflect relative weightings of a positive choice bias and a repulsive motor bias.

Pupil size changes with light. For this reason, researchers studying the effect of attention, contextual processing, and arousal on the pupillary response have matched the mean luminance of their stimuli across conditions to eliminate the contribution of differences in light levels. Here, we argue that the match of mean luminance is not enough. In Experiment 1, we presented a circular sinewave grating on a gray background for 2 seconds. The area of the grating could be 3°, 6°, or 9°. The mean luminance of each grating was equal to the luminance of the gray background, such that regardless of the size of the grating there was no change in mean luminance between conditions. Participants were asked to fixate the center of the grating and passively view it. We found that in all size conditions, there was a pupil constriction starting at about 300 ms after stimulus onset, and the pupil constriction increased with the size of the grating. In Experiment 2, when a small grating was presented immediately after the presentation of a large grating (or vice versa), the pupil constriction changed accordingly. In Experiment 3, we replicated Experiment 1 but had the subjects perform an attention-demanding fixation task in one session, and passively view the stimuli in the other. We found that the main effect of task was not significant. In sum, our results show that stimulus size can modulate pupil size robustly and steadily even when the luminance is matched across the different stimuli.

In addition to canonical open reading frames (ORFs), thousands of translated small ORFs (containing less than 100 codons) have been identified in untranslated mRNA regions (UTRs) across eukaryotes. Small ORFs in 5' UTRs (upstream (u)ORFs) often repress translation of the canonical ORF within the same mRNA. However, the function of translated small ORFs in the 3' UTRs (downstream (d)ORFs) is unknown. Contrary to uORFs, we find that translation of dORFs enhances translation of their corresponding canonical ORFs. This translation stimulatory effect of dORFs depends on the number of dORFs, but not the length or peptide they encode. We propose that dORFs represent a new, strong, and universal translation regulatory mechanism in vertebrates.

CD154 plays a major role in the pathogenesis of several autoimmune and inflammatory diseases. In addition to CD40, soluble CD154 (sCD154) binds to other receptors namely αIIbβ3, αMβ2, α5β1 and αvβ3 integrins. We have previously reported that binding of sCD154 to α5β1 integrin expressed on several human T cell lines is capable of inhibiting Fas-induced cell death. In the current study, we show that such effect of the sCD154/α5β1 interaction is not restricted to the cell death response induced by Fas but could also be exhibited toward other death signals such as TRAIL and TNF- α. We also demonstrate that sCD154 is capable of inhibiting Fas-mediated death of human activated T cells, more importantly of CD4+ than CD8+ T ones. Our data also show that membrane-bound CD154 and α5β1 integrin expressed on the surface of distinct cells failed to influence cell death responses. However, when membrane-bound CD154 and α5β1 are expressed on the surface of same cell, their interaction was capable of down regulating cell death. CD154 was shown to co-localize with the α5β1 integrin on the surface of these cells. These data strongly suggest a cis-type of interaction between CD154 and α5β1 when both are expressed on the same cell surface, rather than a trans-interaction which usually implicates the ligand and its receptor each expressed on the surface of a distinct cell. Taken together, these findings add to the list of roles through which CD154 is contributing to the pathogenesis of autoimmune-inflammatory diseases, i.e. by protecting T cells from death and enhancing their survival.

Zika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in ~1-40% of cases of pregnant women infected by ZIKV, suggesting that mothers' infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses' tissues.

The Scar/WAVE complex is the principal catalyst of pseudopod and lamellipod formation. Here we show that Scar/WAVE's proline-rich domain is polyphosphorylated after the complex is activated. Blocking Scar/WAVE activation stops phosphorylation in both Dictyostelium and mammalian cells, implying that phosphorylation modulates pseudopods after they have been formed, rather than controlling whether they are initiated. Unexpectedly, phosphorylation is not promoted by chemotactic signaling but is greatly stimulated by cell:substrate adhesion and diminished when cells deadhere. Phosphorylation-deficient or phosphomimetic Scar/WAVE mutants are both normally functional and rescue the phenotype of knockout cells, demonstrating that phosphorylation is dispensable for activation and actin regulation. However, pseudopods and patches of phosphorylation-deficient Scar/WAVE last substantially longer in mutants, altering the dynamics and size of pseudopods and lamellipods and thus changing migration speed. Scar/WAVE phosphorylation does not require ERK2 in Dictyostelium or mammalian cells. However, the MAPKKK homologue SepA contributes substantially-sepA mutants have less steady-state phosphorylation, which does not increase in response to adhesion. The mutants also behave similarly to cells expressing phosphorylation-deficient Scar, with longer-lived pseudopods and patches of Scar recruitment. We conclude that pseudopod engagement with substratum is more important than extracellular signals at regulating Scar/WAVE's activity and that phosphorylation acts as a pseudopod timer by promoting Scar/WAVE turnover.

The fall armyworm (Spodoptera frugiperda) is a moth pest native to the Western Hemisphere that has recently become a global problem, invading Africa, Asia, and Australia. The species has a broad host range, long-distance migration capability, and a propensity for the generation of pesticide resistance traits that make it a formidable invasive threat and a difficult pest to control. While fall armyworm migration has been extensively studied in North America, where annual migrations of thousands of kilometers are the norm, migration patterns in South America are less understood. As a first step to address this issue we have been genetically characterizing fall armyworm populations in Ecuador, a country in the northern portion of South America that has not been extensively surveyed for this pest. These studies confirm and extend past findings indicating similarities in the fall armyworm populations from Ecuador, Trinidad-Tobago, Peru, and Bolivia that suggest substantial migratory interactions. Specifically, we found that populations throughout Ecuador are genetically homogeneous, indicating that the Andes mountain range is not a long-term barrier to fall armyworm migration. Quantification of genetic variation in an intron sequence describe patterns of similarity between fall armyworm from different locations in South America with implications for how migration might be occurring. In addition, we unexpectedly found these observations only apply to one subset of fall armyworm (the C-strain), as the other group (R-strain) was not present in Ecuador. The results suggest differences in migration behavior between fall armyworm groups in South America that appear to be related to differences in host plant preferences.

Until 2011, stockouts of family planning commodities were common in Senegalese public health facilities. Recognizing the importance of addressing this problem, the Government of Senegal implemented the Informed Push Model (IPM) supply system, which involves logisticians to collect facility-level stock turnover data once a month and provide contraceptive supplies accordingly. The aims of this paper were to evaluate the impact of IPM on contraceptive availability and on stockout duration.

Some monocotyledonous plants, including liliaceous, amaryllidaceous and iridaceous ones, produce flowers with petaloid tepals in whorls 1 and 2 organs. For explaining the molecular mechanism of two-layered petaloid tepal development, the modified ABC model has been proposed, in which B class genes are expressed in whorl 1 organs as well as in whorls 2 and 3 organs. We have previously obtained results strongly support the modified ABC model by chimeric repressor gene-silencing technology (CRES-T)-mediated suppression of B function in the liliaceous plant Tricyrtis sp. In the present study, we introduced a CRES-T construct derived from the B class gene of Tricyrtis sp. (TrihDEFa-SRDX) into Lilium sp. in order to examine the effect of suppressing B function on the floral organ identity. Flowers of transgenic plants did not open fully and had pale pink-colored tepals with decreased numbers of papillae on the adaxial side in whorls 1 and 2 compared with those of non-transgenic plants. No apparent morphological alterations were observed in whorls 3 and 4 organs. Both the amount of total anthocyanins and the expression levels of endogenous flavonoid biosynthesis-related genes (LhMYB12, LhbHLH2, LhCHS, LhF3H, LhF3'H, LhDFR and LhANS) decreased in whorls 1 and 2 organs of transgenic plants compared with non-transgenic plants. In addition, the expression levels of endogenous B class genes (LFDEF, LFGLOA and LFGLOB) decreased in transgenic plants and the level was negatively correlated with the degree of morphological alteration. Thus suppression of B function may reduce the identity of petaloid tepals in whorls 1 and 2 of transgenic Lilium sp.

Tribbles homolog 3 (TRIB3) is pseudokinase involved in intracellular regulatory processes and has been implicated in several diseases. In this article, we report that human TRIB3 promoter contains a 33-bp variable number tandem repeat (VNTR) and characterize the heterogeneity and function of this genetic element. Analysis of human populations around the world uncovered the existence of alleles ranging from 1 to 5 copies of the repeat, with 2-, 3- and 5-copy alleles being the most common but displaying considerable geographical differences in frequency. The repeated sequence overlaps a C/EBP-ATF transcriptional regulatory element and is highly conserved, but not repeated, in various mammalian species, including great apes. The repeat is however evident in Neanderthal and Denisovan genomes. Reporter plasmid experiments in human cell culture reveal that an increased copy number of the TRIB3 promoter 33-bp repeat results in increased transcriptional activity. In line with this, analysis of whole genome sequencing and RNA-Seq data from human cohorts demonstrates that the copy number of TRIB3 promoter 33-bp repeats is positively correlated with TRIB3 mRNA expression level in many tissues throughout the body. Moreover, the copy number of the TRIB3 33-bp repeat appears to be linked to known TRIB3 eQTL SNPs as well as TRIB3 SNPs reported in genetic association studies. Taken together, the results indicate that the promoter 33-bp VNTR constitutes a causal variant for TRIB3 expression variation between individuals and could underlie the results of SNP-based genetic studies.

Ticks (order: Ixodida) are a highly diverse and ecologically important group of ectoparasitic blood-feeding organisms. One such species, the seabird tick (Ixodes uriae), is widely distributed around the circumpolar regions of the northern and southern hemispheres. It has been suggested that Ix. uriae spread from the southern to the northern circumpolar region millions of years ago and has remained isolated in these regions ever since. Such a profound biographic subdivision provides a unique opportunity to determine whether viruses associated with ticks exhibit the same evolutionary patterns as their hosts. To test this, we collected Ix. uriae specimens near a Gentoo penguin (Pygoscelis papua) colony at Neko harbour, Antarctica, and from migratory birds-the Razorbill (Alca torda) and the Common murre (Uria aalge)-on Bonden island, northern Sweden. Through meta-transcriptomic next-generation sequencing we identified 16 RNA viruses, seven of which were novel. Notably, we detected the same species, Ronne virus, and two closely related species, Bonden virus and Piguzov virus, in both hemispheres indicating that there have been at least two cross-circumpolar dispersal events. Similarly, we identified viruses discovered previously in other locations several decades ago, including Gadgets Gully virus, Taggert virus and Okhotskiy virus. By identifying the same or closely related viruses in geographically disjunct sampling locations we provide evidence for virus dispersal within and between the circumpolar regions. In marked contrast, our phylogenetic analysis revealed no movement of the Ix. uriae tick hosts between the same locations. Combined, these data suggest that migratory birds are responsible for the movement of viruses at both local and global scales.

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico: (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.

Retinopathy of prematurity (ROP) is a significant morbidity in preterm babies. Multiple risk factors for severe ROP have been extensively studied, however, only a few studies have included maternal diabetes mellitus (MDM) in their assessment. ROP and diabetic retinopathy are both retinal vascular diseases in which there is leakage and/or neovascularization from damaged retinal vessels. Diabetes may affect ROP development; however, there are conflicting results on the association between MDM and ROP.

This study aims to clarify the factors associated with the gradual withdrawal from society in older adults. We defined the stages of follow-up difficulty based on four follow-up surveys on non-respondents of longitudinal mail surveys in community-dwelling older adults to examine the main factors associated with the stages of follow-up difficulty. We conducted a follow-up mail survey (FL1) with respondents of a baseline survey, and three more follow-up surveys with the non-respondents of each previous survey: simplified mail (FL2), postcard (FL3), and home visit surveys (FL4). The respondents of each follow-up survey were defined as a stage of follow-up difficulty; their characteristics concerning social participation and interaction at baseline in each stage were analyzed. The number of respondents in the FL1, FL2, FL3, and FL4 stages and non-respondents (NR) were as follows: 2,361; 462; 234; 84; and 101, respectively. Participation in hobby groups in FL2 and FL3, sports groups in FL4, and neighborhood association and social isolation in NR were significantly associated with the stage of follow-up difficulty. Based on these results, we conclude that the following factors are associated with each stage of follow-up difficulty: 1) a decline in instrumental activities of daily living in the FL2 and FL3 stages, 2) dislike for participating in physical activity such as sports in the FL4 stage, and 3) social isolation, not even belonging to a neighborhood association due to low social interaction in the NR group.

Human cytomegalovirus (HCMV) is one of the main causative agents of congenital viral infection in neonates. HCMV infection also causes serious morbidity and mortality among organ transplant patients. Glycoprotein B (gB) is a major target for HCMV neutralizing antibodies, yet the underlying neutralization mechanisms remain largely unknown. Here we report that 3-25, a gB-specific monoclonal antibody previously isolated from a healthy HCMV-positive donor, efficiently neutralized 14 HCMV strains in both ARPE-19 cells and MRC-5 cells. The core epitope of 3-25 was mapped to a highly conserved linear epitope on antigenic domain 2 (AD-2) of gB. A 1.8 Å crystal structure of 3-25 Fab in complex with the peptide epitope revealed the molecular determinants of 3-25 binding to gB at atomic resolution. Negative-staining electron microscopy (EM) 3D reconstruction of 3-25 Fab in complex with de-glycosylated postfusion gB showed that 3-25 Fab fully occupied the gB trimer at the N-terminus with flexible binding angles. Functionally, 3-25 efficiently inhibited HCMV infection at a post-attachment step by interfering with viral membrane fusion, and restricted post-infection viral spreading in ARPE-19 cells. Interestingly, bivalency was required for HCMV neutralization by AD-2 specific antibody 3-25 but not the AD-4 specific antibody LJP538. In contrast, bivalency was not required for HCMV binding by both antibodies. Taken together, our results reveal the structural basis of gB recognition by 3-25 and demonstrate that inhibition of viral membrane fusion and a requirement of bivalency may be common for gB AD-2 specific neutralizing antibody.

Diagnostic errors are prevalent and associated with increased economic burden; however, little is known about their characteristics at the national level in Japan. This study aimed to investigate clinical outcomes and indemnity payment in cases of diagnostic errors using Japan's largest database of national claims.

Generating publication ready plots to display multiple genomic tracks can pose a serious challenge. Making desirable and accurate figures requires considerable effort. This is usually done by hand or using a vector graphic software.

Differentiation of human pluripotent stem cells (hPSCs) into ectoderm provides neurons and glia useful for research, disease modeling, drug discovery, and potential cell therapies. In current protocols, hPSCs are traditionally differentiated into an obligate rostro-dorsal ectodermal fate expressing PAX6 after 6 to 12 days in vitro when protected from mesendoderm inducers. This rate-limiting step has performed a long-standing role in hindering the development of rapid differentiation protocols for ectoderm-derived cell types, as any protocol requires 6 to 10 days in vitro to simply initiate. Here, we report efficient differentiation of hPSCs into a naive early ectodermal intermediate within 24 hours using combined inhibition of bone morphogenic protein and fibroblast growth factor signaling. The induced population responds immediately to morphogen gradients to upregulate rostro-caudal neurodevelopmental landmark gene expression in a generally accelerated fashion. This method can serve as a new platform for the development of novel, rapid, and efficient protocols for the manufacture of hPSC-derived neural lineages.

Accumulating evidence suggests that adipokines, a group of hormones secreted from adipose tissue, modulate tumor growth in a complicated manner. Among diverse adipokines, adiponectin exerts potent anti-tumor activities, whereas leptin exhibits pro-tumorigenic properties. Herein, we have examined the opposing effect of adiponectin on leptin-induced growth of cancer cells and investigated the underlying mechanisms, particularly in the context of inflammasomes activation, which plays a role in the growth of cancer cells. Globular adiponectin (gAcrp) significantly suppressed leptin-induced growth of human breast (MCF-7) and hepatic (HepG2) cancer cells by modulating both cell cycle and apoptosis. To elucidate the underlying mechanisms, we examined the modulatory effects of gAcrp and leptin on inflammasomes. Herein, we showed that gAcrp substantially abolished leptin-induced inflammasomes activation, as evidenced by suppression of IL-1β maturation, caspase-1 activation, and downregulation of inflammasomes components, including NLRP3 and ASC, in both MCF-7 and HepG2 cancer cells. Interestingly, suppression of inflammasomes activation by gAcrp was almost completely restored by blockade of heme oxygenase-1 (HO-1) signaling. In addition, suppressive effects of gAcrp on ROS production and NADPH oxidase activation, both of which critically contribute to leptin-induced inflammasomes activation, disappeared by inhibition of HO-1 signaling. Moreover, gAcrp downregulated estrogen receptor-α (ER-α) expression and blocked leptin-induced ER-α activation, which also plays an important role in inflammasomes activation. Finally, the opposing effects of gAcrp on leptin-induced inflammasomes activation and tumor growth were further confirmed in MCF-7 tumor xenografts. In summary, treatment with gAcrp prevents leptin-induced cancer cell growth by modulating inflammasome activation, which is mediated, at least in part, via HO-1 induction and modulation of ER-α signaling.