CentralNet: a Multilayer Approach for Multimodal Fusion

This paper proposes a novel multimodal fusion approach, aiming to produce best possible decisions by integrating information coming from multiple media. While most of the past multimodal approaches either work by projecting the features of different modalities into the same space, or by coordinating the representations of each modality through the use of constraints, our approach borrows from both visions. More specifically, assuming each modality can be processed by a separated deep convolutional network, allowing to take decisions independently from each modality, we introduce a central network linking the modality specific networks. This central network not only provides a common feature embedding but also regularizes the modality specific networks through the use of multi-task learning. The proposed approach is validated on 4 different computer vision tasks on which it consistently improves the accuracy of existing multimodal fusion approaches

Statistical analysis of modal gating in ion channels

Ion channels regulate the concentrations of ions within cells. By stochastically opening and closing its pore, they enable or prevent ions from crossing the cell membrane. However, rather than opening with a constant probability, many ion channels switch between several different levels of activity even if the experimental conditions are unchanged. This phenomenon is known as modal gating: instead of directly adapting its activity, the channel seems to mix sojourns in active and inactive modes in order to exhibit intermediate open probabilities. Evidence is accumulating that modal gating rather than modulation of opening and closing at a faster time scale is the primary regulatory mechanism of ion channels. However, currently, no method is available for reliably calculating sojourns in different modes. In order to address this challenge, we develop a statistical framework for segmenting single-channel datasets into segments that are characteristic for particular modes. The algorithm finds the number of mode changes, detects their locations and infers the open probabilities of the modes. We apply our approach to data from the inositol-trisphosphate receptor. Based upon these results, we propose that mode changes originate from alternative conformational states of the channel protein that determine a certain level of channel activity

Schur\u27s Lemma For Coupled Reducibility And Coupled Normality

Let $\mathcal A = \{A_{ij} \}_{i, j \in \mathcal I}$, where $\mathcal I$ is an index set, be a doubly indexed family of matrices, where $A_{ij}$ is $n_i \times n_j$. For each $i \in \mathcal I$, let $\mathcal V_i$ be an $n_i$-dimensional vector space. We say $\mathcal A$ is reducible in the coupled sense if there exist subspaces, $\mathcal U_i \subseteq \mathcal V_i$, with $\mathcal U_i \neq \{0\}$ for at least one $i \in \mathcal I$, and $\mathcal U_i \neq \mathcal V_i$ for at least one $i$, such that $A_{ij} (\mathcal U_j) \subseteq \mathcal U_i$ for all $i, j$. Let $\mathcal B = \{B_{ij} \}_{i, j \in \mathcal I}$ also be a doubly indexed family of matrices, where $B_{ij}$ is $m_i \times m_j$. For each $i \in \mathcal I$, let $X_i$ be a matrix of size $n_i \times m_i$. Suppose $A_{ij} X_j = X_i B_{ij}$ for all $i, j$. We prove versions of Schur\u27s lemma for $\mathcal A, \mathcal B$ satisfying coupled irreducibility conditions. We also consider a refinement of Schur\u27s lemma for sets of normal matrices and prove corresponding versions for $\mathcal A, \mathcal B$ satisfying coupled normality and coupled irreducibility conditions

Vimentin is a novel AKT1 target mediating motility and invasion.

The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth and metabolic-related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial prometastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT-driven function. By implication, study of AKT signaling should optimally be conducted in an appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), the aggressive malignancies of mesenchymal origin, is poor, reflecting our modest ability to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving STS progression and dissemination. We examined the impact of the cancer progression-relevant AKT pathway on the mesenchymal tumor cell internal milieu. We demonstrate that AKT1 activation induces STS cell motility and invasiveness at least partially through a novel interaction with the intermediate filament vimentin (Vim). The binding of AKT (tail region) to Vim (head region) results in Vim Ser39 phosphorylation enhancing the ability of Vim to induce motility and invasion while protecting Vim from caspase-induced proteolysis. Moreover, vimentin phosphorylation was shown to enhance tumor and metastasis growth in vivo. Insights into this mesenchymal-related molecular mechanism may facilitate the development of critically lacking therapeutic options for these devastating malignancies

Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. © 2013 Gerö et al

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective.

Benzodiazepines represent the first-line treatment for the acute management of epileptic seizures and status epilepticus. The emergency use of benzodiazepines must be timely, and because most seizures occur outside of the hospital environment, there is a significant need for delivery methods that are easy for nonclinical caregivers to use and administer quickly and safely. In addition, the ideal route of administration should be reliable in terms of absorption. Rectal diazepam is the only licensed formulation in the USA, whereas rectal diazepam and buccal midazolam are currently licensed in the EU. However, the sometimes unpredictable absorption with rectal and buccal administration means they are not ideal routes. Several alternative routes are currently being explored. This is a narrative review of data about delivery methods for benzodiazepines alternative to the intravenous and oral routes for the acute treatment of seizures. Unconventional delivery options such as direct delivery to the central nervous system or inhalers are reported. Data show that intranasal diazepam or midazolam and the intramuscular auto-injector for midazolam are as effective as rectal or intravenous diazepam. Head-to-head comparisons with buccal midazolam are urgently needed. In addition, the majority of trials focused on children and adolescents, and further trials in adults are warranted

Neurophysiological Correlates of Executive Function: A Comparison of European-Canadian and Chinese-Canadian 5-Year-Old Children

This study explored the neurophysiological correlates of executive function (EF) in young children from two different cultural backgrounds. Twenty European-Canadian and 17 Chinese-Canadian 5-year-olds participated in a go/no-go task, during which high-density electroencephalographic (EEG) data were recorded. No cultural group differences were observed in children's behavioral performance on the task, but marked differences were revealed by ERP analyses, which focused on the amplitude and latency of the N2 waveform. Chinese-Canadian children showed larger (i.e., more negative) N2 amplitudes than European-Canadian children on the right side of the scalp on no-go trials, as well as on the left side of the scalp on go trials, and for all children, larger N2 amplitudes were associated with faster median reaction times. Source analyses of the N2 were consistent with the hypothesis that compared to European-Canadian children, Chinese-Canadian children showed more activation in dorsomedial, ventromedial, and (bilateral) ventrolateral prefrontal cortex. These findings reveal that EEG can provide a measure of cultural differences in neurocognitive function that is more sensitive than behavioral data alone; that Chinese-Canadian children show a pattern of hemispheric differentiation in the context of this task than that is more pronounced than that of age-matched European-Canadian children; that the asymmetrically lateralized N2 may be a reliable marker of both effortful inhibition (on the right) and effortful approach (on the left); and that the neural correlates of EF may vary across samples of healthy participants, even in children

Revisional Surgery of One Anastomosis Gastric Bypass for Severe Protein–Energy Malnutrition

Background: One anastomosis gastric bypass (OAGB) is safe and effective. Its strong malabsorptive component might cause severe protein–energy malnutrition (PEM), necessitating revisional surgery. We aimed to evaluate the safety and outcomes of OAGB revision for severe PEM. Methods: This was a single-center retrospective analysis of OAGB patients undergoing revision for severe PEM (2015–2021). Perioperative data and outcomes were retrieved. Results: Ten patients underwent revision for severe PEM. Our center’s incidence is 0.63% (9/1425 OAGB). All patients were symptomatic. Median (interquartile range) EWL and lowest albumin were 103.7% (range 57.6, 114) and 24 g/dL (range 19, 27), respectively, and 8/10 patients had significant micronutrient deficiencies. Before revision, nutritional optimization was undertaken. Median OAGB to revision interval was 18.4 months (range 15.7, 27.8). Median BPL length was 200 cm (range 177, 227). Reversal (n = 5), BPL shortening (n = 3), and conversion to Roux-en-Y gastric bypass (RYGB) (n = 2) were performed. One patient had anastomotic leak after BPL shortening. No death occurred. Median BMI and albumin increased from 22.4 kg/m2 (range 20.6, 30.3) and 35.5 g/dL (range 29.2, 41), respectively, at revision to 27.5 (range 22.2, 32.4) kg/m2 and 39.5 g/dL (range 37.2, 41.7), respectively, at follow-up (median 25.4 months, range 3.1, 45). Complete resolution occurs after conversion to RYGB or reversal to normal anatomy, but not after BPL shortening. Conclusions: Revisional surgery of OAGB for severe PEM is feasible and safe after nutritional optimization. Our results suggest that the type of revision may be an important factor for PEM resolution. Comparative studies are needed to define the role of each revisional option

Retroperitoneal liposarcomas: The experience of a tertiary Asian center

10.1186/1477-7819-9-12World Journal of Surgical Oncology9