Long-Term Outcome of Proximal Gastrectomy for Upper-Third Advanced Gastric and Siewert Type II Esophagogastric Junction Cancer Compared With Total Gastrectomy: A Propensity Score-Matched Analysis.

BACKGROUND: This study aimed to investigate the oncologic long-term safety of proximal gastrectomy for upper-third advanced gastric cancer (AGC) and Siewert type II esophagogastric junction (EGJ) cancer. METHODS: The study enrolled patients who underwent proximal gastrectomy (PG) or total gastrectomy (TG) with standard lymph node (LN) dissection for pathologically proven upper-third AGC and EGJ cancers between January 2007 and December 2018. Propensity score-matching with a 1:1 ratio was performed to reduce the influence of confounding variables such as age, sex, tumor size, T stage, N stage, and tumor-node-metastasis (TNM) stage. Kaplan-Meier survival analysis was performed to analyze oncologic outcome. The prognostic factors of recurrence-free survival (RFS) were analyzed using the Cox proportional hazard analysis. RESULTS: Of the 713 enrolled patients in this study, 60 received PG and 653 received TG. Propensity score-matching yielded 60 patients for each group. The overall survival rates were 61.7 % in the PG group and 68.3 % in the TG group (p = 0.676). The RFS was 86.7 % in the PG group and 83.3 % in the TG group (p = 0.634). The PG group showed eight recurrences (1 anastomosis site, 1 paraaortic LN, 1 liver, 1 spleen, 1 lung, 1 splenic hilar LN, and 2 remnant stomachs). In the multivariate analysis, the operation method was not identified as a prognostic factor of tumor recurrence. CONCLUSION: The patients who underwent PG had a long-term oncologic outcome similar to that for the patients who underwent TG for upper-third AGC and EGJ cancer.

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes.

Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.

A Cantonese Audio-Visual Emotional Speech (CAVES) dataset.

We present a Cantonese emotional speech dataset that is suitable for use in research investigating the auditory and visual expression of emotion in tonal languages. This unique dataset consists of auditory and visual recordings of ten native speakers of Cantonese uttering 50 sentences each in the six basic emotions plus neutral (angry, happy, sad, surprise, fear, and disgust). The visual recordings have a full HD resolution of 1920 × 1080 pixels and were recorded at 50 fps. The important features of the dataset are outlined along with the factors considered when compiling the dataset. A validation study of the recorded emotion expressions was conducted in which 15 native Cantonese perceivers completed a forced-choice emotion identification task. The variability of the speakers and the sentences was examined by testing the degree of concordance between the intended and the perceived emotion. We compared these results with those of other emotion perception and evaluation studies that have tested spoken emotions in languages other than Cantonese. The dataset is freely available for research purposes.

Effect of sustained selective attention on steady-state visual evoked potentials.

Visual-spatial selective attention enhances the processing of task-relevant visual events while suppressing the processing of irrelevant ones. In this study, we employed a frequency-tagging paradigm to investigate how sustained visual-spatial attention modulates the first harmonic and second harmonic steady-state visual evoked potentials (SSVEPs). Unlike previous studies, that investigated stimulation durations of 10 s or less, we tested a 30-s period. SSVEPs were elicited by simultaneously presenting to the right and left visual hemifields two pattern reversal checkerboard stimuli modulating at 7.14 Hz and 11.11 Hz. Participants were cued to selectively attend to one visual hemifield while ignoring the other. Behavioral results indicated that participants selectively attended to the cued visual hemifield. When participants attended to the visual stimuli, there were larger second harmonic SSVEPs but no attentional modulation of first harmonics. The results are consistent with the proposal that neural populations underlying first, and second harmonics have distinct functional roles, i.e., first harmonics' mechanisms preserve stimulus properties and are resistant to attentional gain, whereas second harmonics mediate attentional modulation. This interpretation is supported by a gain control theory of selective attention.

Older adults get masked emotion priming for happy but not angry faces: evidence for a positivity effect in early perceptual processing of emotional signals.

In higher-level cognitive tasks, older compared to younger adults show a bias towards positive emotion information and away from negative information (a positivity effect). It is unclear whether this effect occurs in early perceptual processing. This issue is important for determining if the positivity effect is due to automatic rather than controlled processing. We tested this with older and younger adults on a positive/negative face emotion valence classification task using masked priming. Positive (happy) and negative (angry) face targets were preceded by masked repetition or valence primes with neutral face baselines. In Experiment 1, 30 younger and 30 older adults were tested with 50 ms primes. Younger adults showed repetition priming for both positive and negative targets. Older adults showed repetition priming for positive but not negative targets. Neither group showed valence priming. In Experiment 2, 30 older and 29 younger adults were tested with longer duration primes. Younger adults showed repetition priming for both positive and negative emotions, and no valence priming. Older adults only showed repetition and valence priming for positive targets. We proposed older adults' lack of angry face priming was due to an early attention orienting strategy favouring happy expressions at the expense of angry ones.

Demarcating the Exact Midplane of the Liver Using Indocyanine Green Near-Infrared Fluorescence Imaging During Laparoscopic Donor Hepatectomy.

Indocyanine green (ICG) near-infrared fluoroscopy has been recently implemented in pure laparoscopic donor hepatectomy (PLDH). This study aims to quantitatively evaluate the effectiveness of ICG fluoroscopy during liver midplane dissection in PLDH and to demonstrate that a single injection of ICG is adequate for both midplane dissection and bile duct division. Retrospective analysis was done with images acquired from recordings of PLDH performed without ICG (pre-ICG group) from November 2015 to May 2016 and with ICG (post-ICG group) from June 2016 to May 2017. 30 donors from the pre-ICG group were compared with 46 donors from the post-ICG group. The operation time was shorter (P = 0.002) and postoperative peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were lower (P = 0.031 and P = 0.019, respectively) in the post-ICG group than the pre-ICG group. Within the post-ICG group, the color intensity differences between the clamped versus nonclamped regions in the natural, black-and-white, and fluorescent modes were 39.7 ± 36.2, 89.6 ± 46.9, and 19.1 ± 36.8 (mean ± SD, P < 0.001), respectively. The luminosity differences were 37.2 ± 34.5, 93.8 ± 32.1, and 26.7 ± 25.7 (P < 0.001), respectively. Meanwhile, the time from when ICG was injected to when the near-infrared camera was turned on for bile duct visualization was 85.6 ± 25.8 minutes. All grafts received from the 46 donors were successfully transplanted. In conclusion, ICG fluoroscopy helps to reduce operation time and lower postoperative AST/ALT levels. ICG injection visualized with black-and-white imaging is most effective for demarcating the liver midplane during PLDH. A single intravenous injection of ICG is sufficient for midplane dissection as well as bile duct division.

Does working memory protect against auditory distraction in older adults?

BACKGROUND: Past research indicates that when younger adults are engaged in a visual working memory task, they are less distracted by novel auditory stimuli than when engaged in a visual task that does not require working memory. The current study aimed to determine whether working memory affords the same protection to older adults. METHOD: We examined behavioral and EEG responses in 16 younger and 16 older adults to distractor sounds when the listeners performed two visual tasks; one that required working memory (W1) and the other that did not (W0). Auditory distractors were presented in an oddball paradigm, participants were exposed to either standard tones (600 Hz: 80%) or various novel environmental sounds (20%). RESULTS: It was found that: 1) when presented with novel vs standard sounds, older adults had faster correct response times in the W1 visual task than in the W0 task, indicating that they were less distracted by the novel sound; there was no difference in error rates. Younger adults did not show a task effect for correct response times but made slightly more errors when a novel sound was presented in the W1 task compared to the W0 task. 2) In older adults (but not the younger adults), the amplitude of N1 was smaller in the W1 condition compared to the W0 condition. 3) The working memory manipulation had no effect on MMN amplitude in older adults. 4) For the W1 compared to W0 task, the amplitude of P3a was attenuated for the older adults but not for the younger adults. CONCLUSIONS: These results suggest that during the working memory manipulation older adults were able to engage working memory to reduce the processing of task-irrelevant sounds.

The influence of pacer-movement continuity and pattern matching on auditory-motor synchronisation.

People commonly move along with auditory rhythms in the environment. Although the processes underlying such sensorimotor synchronisation have been extensively investigated in the previous research, the properties of auditory rhythms that facilitate the synchronisation remain largely unclear. This study explored the possible benefits of a continuity matching between auditory pacers and the movement produced as well as of a spatial pattern matching that has been previously demonstrated with visual pacers. Participants synchronised either finger tapping or forearm oscillations with either discrete or continuous pacers. The pacers had either a spatial pattern (left-right panning) that matched the movement pattern produced or no spatial pattern. The accuracy and variability of synchronisation were assessed by the mean and standard deviation of the asynchronies, respectively, between participant's movement and the pacers. Results indicated that synchronisation was more accurate and less variable for discrete pacers and continuous movement (i.e., forearm oscillations). The interaction between those two factors involved a more complex relationship than a simple continuity match benefit. Although synchronisation variability increased with continuous pacers for both types of movement, this increase was smaller for continuous movement than discrete movement, suggesting that continuous movement is more beneficial only for continuous pacers. Moreover, the results revealed limited benefits of spatial pattern matching on auditory-motor synchronisation variability, which might be due to lower spatial resolution of the auditory sensory modality. Together, these findings confirm that sensorimotor synchronisation is modulated by complex relations between pacer and movement properties.

Maternal Setdb1 Is Required for Meiotic Progression and Preimplantation Development in Mouse.

Oocyte meiotic progression and maternal-to-zygote transition are accompanied by dynamic epigenetic changes. The functional significance of these changes and the key epigenetic regulators involved are largely unknown. Here we show that Setdb1, a lysine methyltransferase, controls the global level of histone H3 lysine 9 di-methyl (H3K9me2) mark in growing oocytes. Conditional deletion of Setdb1 in developing oocytes leads to meiotic arrest at the germinal vesicle and meiosis I stages, resulting in substantially fewer mature eggs. Embryos derived from these eggs exhibit severe defects in cell cycle progression, progressive delays in preimplantation development, and degeneration before reaching the blastocyst stage. Rescue experiments by expressing wild-type or inactive Setdb1 in Setdb1-deficient oocytes suggest that the catalytic activity of Setdb1 is essential for meiotic progression and early embryogenesis. Mechanistically, up-regulation of Cdc14b, a dual-specificity phosphatase that inhibits meiotic progression, greatly contributes to the meiotic arrest phenotype. Setdb1 deficiency also leads to derepression of transposons and increased DNA damage in oocytes, which likely also contribute to meiotic defects. Thus, Setdb1 is a maternal-effect gene that controls meiotic progression and is essential for early embryogenesis. Our results uncover an important link between the epigenetic machinery and the major signaling pathway governing meiotic progression.

Intelligibility of conversational and clear speech in young and older talkers as perceived by young and older listeners.

A related paper [Hazan, Tuomainen, Tu, Kim, Davis, Brungart, and Sheffield. (2018b). Hear. Res. 369, 33-41] showed that, for young adult listeners, speech produced by older adults was less intelligible than the speech of young adults but both talker groups improved the intelligibility of their speech via clear speech modifications. Here, this study was extended to include older listeners with/without presbycusis. The results showed that for older listeners, speech produced by older adults was less intelligible than the speech of young adults and scores improved in the clear speech condition. The best predictor of intelligibility was the amount of energy in the mid-frequency range of the spectrum.

PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch.

PRMT5 is the primary enzyme responsible for the deposition of the symmetric dimethylarginine in mammalian cells. In an effort to understand how PRMT5 is regulated, we identified a threonine phosphorylation site within a C-terminal tail motif, which is targeted by the Akt/serum- and glucocorticoid-inducible kinases. While investigating the function of this posttranslational modification, we serendipitously discovered that its free C-terminal tail binds PDZ domains (when unphosphorylated) and 14-3-3 proteins (when phosphorylated). In essence, a phosphorylation event within the last few residues of the C-terminal tail generates a posttranslational modification-dependent PDZ/14-3-3 interaction "switch." The C-terminal motif of PRMT5 is required for plasma membrane association, and loss of this switching capacity is not compatible with life. This signaling phenomenon was recently reported for the HPV E6 oncoprotein but has not yet been observed for mammalian proteins. To investigate the prevalence of PDZ/14-3-3 switching in signal transduction, we built a protein domain microarray that harbors PDZ domains and 14-3-3 proteins. We have used this microarray to interrogate the C-terminal tails of a small group of candidate proteins and identified ERBB4, PGHS2, and IRK1 (as well as E6 and PRMT5) as conforming to this signaling mode, suggesting that PDZ/14-3-3 switching may be a broad biological paradigm.

Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome.

Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABAA agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS.

Temporal factors in cochlea-scaled entropy and intensity-based intelligibility predictions.

Cochlea-scaled entropy (CSE) was proposed as a signal-based metric for automatic detection of speech regions most important for intelligibility, but its proposed superiority over traditional linguistic and psychoacoustical characterisations was not subsequently confirmed. This paper shows that the CSE concept is closely related to intensity and as such captures similar speech regions. However, a slight but significant advantage of a CSE over an intensity-based characterisation was observed, associated with a time difference between the two metrics, suggesting that the CSE index may capture dynamical properties of the speech signal crucial for intelligibility.

Clear speech adaptations in spontaneous speech produced by young and older adults.

The study investigated the speech adaptations by older adults (OA) with and without age-related hearing loss made to communicate effectively in challenging communicative conditions. Acoustic analyses were carried out on spontaneous speech produced during a problem-solving task (diapix) carried out by talker pairs in different listening conditions. There were 83 talkers of Southern British English. Fifty-seven talkers were OAs aged 65-84, 30 older adults with normal hearing (OANH), and 27 older adults with hearing loss (OAHL) [mean pure tone average (PTA) 0.250-4 kHz: 27.7 dB HL]. Twenty-six talkers were younger adults (YA) aged 18-26 with normal hearing. Participants were recorded while completing the diapix task with a conversational partner (YA of the same sex) when (a) both talkers heard normally (NORM), (b) the partner had a simulated hearing loss, and (c) both talkers heard babble noise. Irrespective of hearing status, there were age-related differences in some acoustic characteristics of YA and OA speech produced in NORM, most likely linked to physiological factors. In challenging conditions, while OANH talkers typically patterned with YA talkers, OAHL talkers made adaptations more consistent with an increase in vocal effort. The study suggests that even mild presbycusis in healthy OAs can affect the speech adaptations made to maintain effective communication.

A flexible and accurate method to estimate the mode and stability of spontaneous coordinated behaviors: The index-of-stability (IS) analysis.

Patterns of coordination result from the interaction between (at least) two oscillatory components. This interaction is typically understood by means of two variables: the mode that expresses the shape of the interaction, and the stability that is the robustness of the interaction in this mode. A potent method of investigating coordinated behaviors is to examine the extent to which patterns of coordination arise spontaneously. However, a prominent issue faced by researchers is that, to date, no standard methods exist to fairly assess the stability of spontaneous coordination. In the present study, we introduce a new method called the index-of-stability (IS) analysis. We developed this method from the phase-coupling (PC) analysis that has been traditionally used for examining locomotion-respiration coordinated systems. We compared the extents to which both methods estimate the stability of simulated coordinated behaviors. Computer-generated time series were used to simulate the coordination of two rhythmic components according to a selected mode m:n and a selected degree of stability. The IS analysis was superior to the PC analysis in estimating the stability of spontaneous coordinated behaviors, in three ways: First, the estimation of stability itself was found to be more accurate and more reliable with the IS analysis. Second, the IS analysis is not constrained by the limitations of the PC analysis. Third and last, the IS analysis offers more flexibility, and so can be adapted according to the user's needs.

Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome.

Down syndrome (DS), trisomy 21, is caused by increased dose of genes present on human chromosome 21 (HSA21). The gene-dose hypothesis argues that a change in the dose of individual genes or regulatory sequences on HSA21 is necessary for creating DS-related phenotypes, including cognitive impairment. We focused on a possible role for Kcnj6, the gene encoding Kir3.2 (Girk2) subunits of a G-protein-coupled inwardly-rectifying potassium channel. This gene resides on a segment of mouse Chromosome 16 that is present in one extra copy in the genome of the Ts65Dn mouse, a well-studied genetic model of DS. Kir3.2 subunit-containing potassium channels serve as effectors for a number of postsynaptic metabotropic receptors including GABAB receptors. Several studies raise the possibility that increased Kcnj6 dose contributes to synaptic and cognitive abnormalities in DS. To assess directly a role for Kcnj6 gene dose in cognitive deficits in DS, we produced Ts65Dn mice that harbor only 2 copies of Kcnj6 (Ts65Dn:Kcnj6++- mice). The reduction in Kcnj6 gene dose restored to normal the hippocampal level of Kir3.2. Long-term memory, examined in the novel object recognition test with the retention period of 24h, was improved to the level observed in the normosomic littermate control mice (2N:Kcnj6++). Significantly, both short-term and long-term potentiation (STP and LTP) was improved to control levels in the dentate gyrus (DG) of the Ts65Dn:Kcnj6++- mouse. In view of the ability of fluoxetine to suppress Kir3.2 channels, we asked if fluoxetine-treated DG slices of Ts65Dn:Kcnj6+++ mice would rescue synaptic plasticity. Fluoxetine increased STP and LTP to control levels. These results are evidence that increased Kcnj6 gene dose is necessary for synaptic and cognitive dysfunction in the Ts65Dn mouse model of DS. Strategies aimed at pharmacologically reducing channel function should be explored for enhancing cognition in DS.

Older and younger adults' identification of sentences filtered with amplitude and frequency modulations in quiet and noise.

Adding frequency modulations (FM) cues to vocoded (AM) speech aids speech recognition for younger listeners. However, this may not be true for older listeners since they have poorer FM detection thresholds. We measured FM detection thresholds of young and older adults; and in a sentence context examined whether adding FM cues to vocoded speech would assist older adults. Young and old participants were presented vocoded sentences in quiet and multitalker-babble with/without FM cues. Older adults had elevated FM detection thresholds but received the same-size FM benefit as younger adults, showing that they have the capacity to benefit from FM speech cues.

The Processing of Attended and Predicted Sounds in Time.

Neural responses to an attended event are typically enhanced relative to those from an unattended one (attention enhancement). Conversely, neural responses to a predicted event are typically reduced relative to those from an unpredicted one (prediction suppression). What remains to be established is what happens with attended and predicted events. To examine the interaction between attention and prediction, we combined two robust paradigms developed for studying attention and prediction effects on ERPs into an orthogonal design. Participants were presented with sounds in attended or unattended intervals with onsets that were either predicted by a moving visual cue or unpredicted (no cue was provided). We demonstrated an N1 enhancement effect for attended sounds and an N1 suppression effect for predicted sounds; furthermore, an interaction between these effects was found that emerged early in the N1 (50-95 msec), indicating that attention enhancement only occurred when the sound was unpredicted. This pattern of results can be explained by the precision of the predictive cue that reduces the need for attention selection in the attended and predicted condition.