The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif.

Endocytosis of the amyloid precursor protein (APP) is critical for generation of ß-amyloid, aggregating in Alzheimer's disease. APP endocytosis depending on the intracellular NPTY motif is well investigated, whereas involvement of the YTSI (also termed BaSS) motif remains controversial. Here, we show that APP lacking the YTSI motif (ΔYTSI) displays reduced localization to early endosomes and decreased internalization rates, similar to APP ΔNPTY. Additionally, we show that the YTSI-binding protein, PAT1a interacts with the Rab5 activator RME-6, as shown by several independent assays. Interestingly, knockdown of RME-6 decreased APP endocytosis, whereas overexpression increased the same. Similarly, APP ΔNPTY endocytosis was affected by PAT1a and RME-6 overexpression, whereas APP ΔYTSI internalization remained unchanged. Moreover, we could show that RME-6 mediated increase of APP endocytosis can be diminished upon knocking down PAT1a. Together, our data identify RME-6 as a novel player in APP endocytosis, involving the YTSI-binding protein PAT1a.

The FT/FD-dependent initiation of flowering under long-day conditions in the day-neutral species Nicotiana tabacum originates from the facultative short-day ancestor Nicotiana tomentosiformis.

Photoperiod is an important external stimulus governing the precise timing of the floral transition in plants. Members of the FLOWERING LOCUS T (FT)-like clade of phosphatidylethanolamine-binding proteins induce this developmental process in numerous species by forming regulatory protein complexes with FD-like bZIP transcription factors. We identified several thus far unknown FT-like and FD-like genes in the genus Nicotiana and found that, even in the day-neutral species Nicotiana tabacum, floral initiation requires the photoperiod-dependent expression of several FT-like genes. Furthermore, floral promotion under long-day (LD) and short-day (SD) conditions is mediated by an FT-like protein (NtFT5) that originates from the genome of the paternal, facultative SD ancestor Nicotiana tomentosiformis. In contrast, its ortholog of the maternal LD ancestor Nicotiana sylvestris is not present in the genome of N. tabacum cv. SR1. Expression profiling in N. tabacum and its ancestors confirmed the relevance of these FT and FD orthologs in the context of polyploidization. We also found that floral inhibition by tobacco FT-like proteins is not restricted to SD conditions, highlighting the coincident expression of tobacco FT-like genes encoding floral activators and floral inhibitors. Multicolor bimolecular fluorescence complementation analysis revealed the preferential formation of FT/FD complexes that promote rather than inhibit flowering, which in concert with the regulation of NtFT and NtFD expression could explain how floral promotion overcomes floral repression during the floral transition in tobacco.

Monitoring Multiple Deadlines Relies on Spatial Processing in Posterior Parietal Cortex.

Proactively coordinating one's actions is an important aspect of multitasking performance due to overlapping task sequences. In this study, we used fMRI to investigate neural mechanisms underlying monitoring of multiple overlapping task sequences. We tested the hypothesis that temporal control demands in multiple-task monitoring are offloaded onto spatial processes by representing patterns of temporal deadlines in spatial terms. Results showed that increased demands on time monitoring (i.e., responding to concurrent deadlines of one to four component tasks) increasingly activated regions in the left inferior parietal lobe and the precuneus. Moreover, independent measures of spatial abilities correlated with multiple-task performance beyond the contribution of working memory. Together, these findings suggest that monitoring and coordination of temporally overlapping task timelines rely on cortical processes involved in spatial information processing. We suggest that the precuneus is involved in tracking of multiple task timelines, whereas the inferior parietal lobe constructs spatial representations of the temporal relations of these overlapping timelines. These findings are consistent with the spatial offloading hypothesis and add new insights into the neurocognitive mechanisms underlying the coordination of multiple tasks.

APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission.

The amyloid precursor protein (APP), a key player in Alzheimer's disease, belongs to the family of synaptic adhesion molecules (SAMs) due to its impact on synapse formation and synaptic plasticity. These functions are mediated by both the secreted APP ectodomain that acts as a neurotrophic factor and full-length APP forming trans-cellular dimers. Two homologs of APP exist in mammals: the APP like proteins APLP1 and APLP2, exhibiting functions that partly overlap with those of APP. Here we tested whether APLP1 and APLP2 also show features of SAMs. We found that all three family members were upregulated during postnatal development coinciding with synaptogenesis. We observed presynaptic and postsynaptic localization of all APP family members and could show that heterologous expression of APLP1 or APLP2 in non-neuronal cells induces presynaptic differentiation in contacting axons of cocultured neurons, similar to APP and other SAMs. Moreover, APP/APLPs all bind to synaptic-signaling molecules, such as MINT/X11. Furthermore, we report that aged APLP1 knock-out mice show impaired basal transmission and a reduced mEPSC frequency, likely resulting from reduced spine density. This demonstrates an essential nonredundant function of APLP1 at the synapse. Compared to APP, APLP1 exhibits increased trans-cellular binding and elevated cell-surface levels due to reduced endocytosis. In conclusion, our results establish that APLPs show typical features of SAMs and indicate that increased surface expression, as observed for APLP1, is essential for proper synapse formation in vitro and synapse maintenance in vivoSIGNIFICANCE STATEMENT According to the amyloid-cascade hypothesis, Alzheimer's disease is caused by the accumulation of Aß peptides derived from sequential cleavage of the amyloid precursor protein (APP) by ß-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Here we show that all mammalian APP family members (APP, APLP1, and APLP2) exhibit synaptogenic activity, involving trans-synaptic dimerization, similar to other synaptic cell adhesion molecules, such as Neuroligin/Neurexin. Importantly, our study revealed that the loss of APLP1, which is one of the major substrates of BACE1, causes reduced spine density in aged mice. Because some therapeutic interventions target APP processing (e.g., BACE inhibitors), those strategies may alter APP/APLP physiological function. This should be taken into account for the development of pharmaceutical treatments of Alzheimer's disease.

RETRACTED: Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish adolescents at risk of CAH.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors due to technical errors that have called into question the reliability of the data used to inform the author's conclusions. All data on cognitive and behavioral outcomes in CAH and non­CAH cases, treated or not treated with DEX prenatally, were put into a single Excel database. The authors had in total four different patient groups for each age group (5­6 y, 7­17 y and 18-35 y). The database consisted of 237 cases in total and there were multiple columns for the different outcome measures. When the behavioral data for the sub-cohort described in this paper (first trimester treated non-CAH cases and healthy population controls, age 7­17 y) were copied to another sheet and compressed/modified in preparation for statistical analysis in SPSS, an error occurred. This technological issue caused rows to shift and the data from the different groups got mixed up. In particular, the non­CAH group versus the control group were "contaminated" with cases from the wrong patient group. The authors discovered this mistake when they started to analyse the data from the other sub­groups of patients, the CAH cases and the adult cohort, which was after their original results had already been published in Hormones and Behavior in this manuscript "Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish adolescents at risk of CAH". It then became apparent that the entire data set was unreliable and needed to be re­analysed which is what has motivated the retraction of this article. The authors have recently completed this re­analysis and the results have been published here: https://www.sciencedirect.com/science/article/pii/S0018506X17300752

Body posture modulates action perception.

Recent studies have highlighted cognitive and neural similarities between planning and perceiving actions. Given that action planning involves a simulation of potential action plans that depends on the actor's body posture, we reasoned that perceiving actions may also be influenced by one's body posture. Here, we test whether and how this influence occurs by measuring behavioral and cerebral (fMRI) responses in human participants predicting goals of observed actions, while manipulating postural congruency between their own body posture and postures of the observed agents. Behaviorally, predicting action goals is facilitated when the body posture of the observer matches the posture achieved by the observed agent at the end of his action (action's goal posture). Cerebrally, this perceptual postural congruency effect modulates activity in a portion of the left intraparietal sulcus that has previously been shown to be involved in updating neural representations of one's own limb posture during action planning. This intraparietal area showed stronger responses when the goal posture of the observed action did not match the current body posture of the observer. These results add two novel elements to the notion that perceiving actions relies on the same predictive mechanism as planning actions. First, the predictions implemented by this mechanism are based on the current physical configuration of the body. Second, during both action planning and action observation, these predictions pertain to the goal state of the action.

Motor planning is facilitated by adopting an action's goal posture: an fMRI study.

Motor planning is a hierarchical process that is typically organized around an action's goal (e.g., drinking from a cup). However, the motor plan depends not only on the goal but also on the current body state. Here, we investigated how one's own body posture interacts with planning of goal-directed actions. Participants engaged in a grasp selection (GS) task while we manipulated their arm posture. They had to indicate how they would grasp a bar when transporting it from a start to goal position and orientation. We compared situations in which one's body posture was in-congruent with the start posture and/or goal posture of the planned movement. Behavioral results show that GS took longer when one's own body state was incongruent with the goal posture of the planned movement. Correspondingly, neural activity in the intraparietal sulcus (IPS) and extrastriate body area (EBA) was modulated by congruency between the body state and the action plan. IPS was sensitive to overall congruency between body posture and action plan, while the EBA was sensitive specifically to goal posture congruency. Together, our results suggest that IPS maintains an internal state of one's own body posture, while EBA contains a representation of the goal posture of the action plan.

Brain activity during visuospatial working memory in congenital adrenal hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) require life-long replacement of cortisol. Problems with cognitive function, especially working memory, have previously been identified, but the long-term effects of this disease on brain function are unknown. OBJECTIVE: We investigate brain activity during working memory in CAH compared to controls. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine individuals with CAH (17 females) and 40 healthy controls (24 females), 16-33 years, from a single research institute, underwent functional magnetic resonance imaging while doing a verbal and visuospatial working memory task. RESULTS: Individuals with CAH responded faster on the verbal task. Although we found no differences in BOLD response over the whole group, there were significant interactions with sex: CAH males had increased activity in the bilateral lateral superior occipital cortex, left supramarginal and angular gyri, left precuneus, left posterior cingulate cortex and bilateral cerebellum during decoding of the visuospatial task, while females showed decreased activity in these regions. CONCLUSIONS: Long-term cortisol imbalances do not seem to have a major impact on the functional brain responses during working memory in CAH. However, activity of the left dorsal visual stream in particular might be affected depending on sex. As the task employed may have been relatively easy, larger studies using more complex tasks are needed to further investigate this.

Intra-individual behavioural and neural signatures of audience effects and interactions in a mirror-game paradigm.

We often perform actions while observed by others, yet the behavioural and neural signatures of audience effects remain understudied. Performing actions while being observed has been shown to result in more emphasized movements in musicians and dancers, as well as during communicative actions. Here, we investigate the behavioural and neural mechanisms of observed actions in relation to individual actions in isolation and interactive joint actions. Movement kinematics and EEG were recorded in 42 participants (21 pairs) during a mirror-game paradigm, while participants produced improvised movements alone, while observed by a partner, or by synchronizing movements with the partner. Participants produced largest movements when being observed, and observed actors and dyads in interaction produced slower and less variable movements in contrast with acting alone. On a neural level, we observed increased mu suppression during interaction, as well as to a lesser extent during observed actions, relative to individual actions. Moreover, we observed increased widespread functional brain connectivity during observed actions relative to both individual and interactive actions, suggesting increased intra-individual monitoring and action-perception integration as a result of audience effects. These results suggest that observed actors take observers into account in their action plans by increasing self-monitoring; on a behavioural level, observed actions are similar to emergent interactive actions, characterized by slower and more predictable movements.

First Trimester DEX Treatment Is Not Associated with Altered Brain Activity During Working Memory Performance in Adults.

CONTEXT: Prenatal dexamethasone (DEX) treatment is sometimes used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in female fetuses with CAH. In boys and in fetuses not having CAH, there is no benefit of early DEX treatment and the risks of this therapy must be thoroughly investigated. High doses of prenatal glucocorticoid might alter the developmental trajectory of the brain into adulthood, even for CAH unaffected subjects treated with DEX for a short term during the first trimester. OBJECTIVE: The present study investigated brain activation during working memory performance in DEX-treated subjects compared with controls. DESIGN, SETTING, AND PARTICIPANTS: We tested 18 participants who were exposed to DEX during the first trimester of fetal life but did not have CAH (8 females; mean age 20.78 [standard deviation (SD), 2.67] years) and 40 control participants (24 females; mean age 20.53 [SD, 2.64]) from a single research institute. Participants underwent functional magnetic resonance imaging on a 3T scanner during a verbal and visuospatial working memory task. RESULTS: We did not observe any differences in brain activity during working memory performance. However, DEX-treated subjects responded faster during the experimental condition of the verbal WM task. CONCLUSIONS: First trimester DEX treatment did not seem to result in altered working memory-related brain activity at adult age. Our findings contribute to the risk-benefit assessment of prenatal DEX treatment in the context of CAH.

The Major Floral Promoter NtFT5 in Tobacco (Nicotiana tabacum) Is a Promising Target for Crop Improvement.

The FLOWERING LOCUS T (FT)-like gene family encodes key regulators of flower induction that affect the timing of reproduction in many angiosperm species. Agricultural research has therefore focused on such genes to improve the success of breeding programs and enhance agronomic traits. We recently identified a novel FT-like gene (NtFT5) that encodes a day-neutral floral activator in the model tobacco crop Nicotiana tabacum. However, further characterization is necessary to determine its value as a target for breeding programs. We therefore investigated the function of NtFT5 by expression analysis and mutagenesis. Expression analysis revealed that NtFT5 is transcribed in phloem companion cells, as is typical for FT-like genes. However, high levels of NtFT5 mRNA accumulated not only in the leaves but also in the stem. Loss-of-function mutants (generated using CRISPR/Cas9) were unable to switch to reproductive growth under long-day conditions, indicating that NtFT5 is an indispensable major floral activator during long-days. Backcrossing was achieved by grafting the mutant scions onto wild-type rootstock, allowing the restoration of flowering and pollination by a wild-type donor. The resulting heterozygous Ntft5- /NtFT5+ plants flowered with a mean delay of only ~2 days, demonstrating that one functional allele is sufficient for near-normal reproductive timing. However, this minor extension of the vegetative growth phase also conferred beneficial agronomic traits, including a >10% increase in vegetative leaf biomass on the main shoot and the production of more seeds. The agronomic benefits of the heterozygous plants persisted under various abiotic stress conditions, confirming that NtFT5 is a promising target for crop improvement to address the effects of climate change.

Is the extrastriate body area part of the dorsal visuomotor stream?

The extrastriate body area (EBA) processes visual information about body parts, and it is considered one among a series of category-specific perceptual modules distributed across the occipito-temporal cortex. However, recent evidence raises the possibility that EBA might also provide an interface between perception and action, linking the ventral and dorsal streams of visual information processing. Here, we assess anatomical evidence supporting this possibility. We localise EBA in individual subjects using a perceptual task and compare the characteristics of its functional and structural connectivity to those of two perceptual areas, the lateral occipital complex (LOC) and the fusiform body area (FBA), separately for each hemisphere. We apply complementary analyses of resting-state fMRI and diffusion-weighted MRI data in a group of healthy right-handed human subjects (N = 31). Functional and structural connectivity profiles indicate that EBA interacts more strongly with dorsal-stream regions compared to other portions of the occipito-temporal cortex involved in processing body parts (FBA) and object identification (LOC). These findings provide anatomical ground for a revision of the functional role of EBA. Building on a number of recent observations, we suggest that EBA contributes to planning goal-directed actions, possibly by specifying a desired postural configuration to parieto-frontal areas involved in computing movement parameters.

The Extrastriate Body Area Computes Desired Goal States during Action Planning.

How do object perception and action interact at a neural level? Here we test the hypothesis that perceptual features, processed by the ventral visuoperceptual stream, are used as priors by the dorsal visuomotor stream to specify goal-directed grasping actions. We present three main findings, which were obtained by combining time-resolved transcranial magnetic stimulation and kinematic tracking of grasp-and-rotate object manipulations, in a group of healthy human participants (N = 22). First, the extrastriate body area (EBA), in the ventral stream, provides an initial structure to motor plans, based on current and desired states of a grasped object and of the grasping hand. Second, the contributions of EBA are earlier in time than those of a caudal intraparietal region known to specify the action plan. Third, the contributions of EBA are particularly important when desired and current object configurations differ, and multiple courses of actions are possible. These findings specify the temporal and functional characteristics for a mechanism that integrates perceptual processing with motor planning.

Sex-Dimorphic Effects of Prenatal Treatment With Dexamethasone.

CONTEXT: Dexamethasone (DEX) is used to prevent virilization in female fetuses at risk of congenital adrenal hyperplasia (CAH). Given that treatment has to be started before the genotype is known, 7 out of 8 fetuses will be exposed to DEX without benefit. OBJECTIVE: To evaluate long-term cognitive effects of prenatal DEX therapy in healthy (non-CAH) DEX-treated children. DESIGN AND SETTING: Observational study with patient and control groups from a single research institute. PARTICIPANTS: Healthy (non-CAH) DEX-treated subjects (n = 34) and untreated population controls (n = 66) from Sweden, aged 7-17 years. INTERVENTION: DEX-treatment used in unborn children at risk of CAH, during first trimester of fetal life. MAIN OUTCOME MEASURES: Standardized neuropsychological tests and questionnaires were used. RESULTS: DEX treatment has widespread negative effects in girls. In Wechsler Intelligence Scales for Children-III scale subtests, we observed significant interactions between DEX and GENDER (coding, P = .044; block design, P = .013; vocabulary, P = .025) and a trend for the subtest digit span (P = .074). All interactions were driven by DEX effects in girls, but not boys, with DEX-treated females showing lower scores than female untreated controls (coding, P = .068, d = 0.66; block design, P = .021, d = 0.81; vocabulary, P = .014, d = 0.84; digit span, P = .001, d = 1.0). Likewise, DEX-treated girls tend to have poorer visual spatial working memory performance than controls (span board test forward: P = .065, d = .80). We observed no effects on long-term memory, handedness, speed of processing, nor self-perceived or parentally reported scholastic performance. CONCLUSIONS: Early prenatal DEX exposure affects cognitive functions in healthy girls, ie, children who do not benefit from the treatment. It can therefore not be considered safe to use this therapy in the context of CAH.