Vitamin D and the brain: key questions for future research

Over the last decade a convergent body of evidence has emerged from epidemiology, animal experiments and clinical trials which links low vitamin D status with a range of adverse neuropsychiatric outcomes. This research demonstrates that the timing of exposure to low vitamin D influences the nature of brain phenotypes, as exposures during gestation versus adulthood result in different phenotypes. With respect to early life exposures, there is robust evidence from rodent experiments indicating that transient developmental vitamin D (DVD) deficiency is associated with changes in brain structure, neurochemistry, gene and protein expression and behavior. In particular, DVD deficiency is associated with alterations in the dopaminergic neurotransmitter systems. In contrast, recently published animal experiments indicate that adult vitamin D (AVD) deficiency is associated with more subtle neurochemical and behavioral phenotypes. This paper explores key issues that need to be addressed in future research. There is a need to define the timing and duration of the ‘critical window’ during which low vitamin D status is associated with differential and adverse brain outcomes. We discuss the role for ‘two-hit hypotheses’, which propose that adult vitamin D deficiency leaves the brain more vulnerable to secondary adverse exposures, and thus may exacerbate disease progression. Finally, we explore the evidence implicating a role for vitamin D in rapid, non-genomic mechanisms that may involve L-type calcium channels and brain functio

Audio-visual End-to-end Multi-channel Speech Separation, Dereverberation and Recognition

Accurate recognition of cocktail party speech containing overlapping speakers, noise and reverberation remains a highly challenging task to date. Motivated by the invariance of visual modality to acoustic signal corruption, an audio-visual multi-channel speech separation, dereverberation and recognition approach featuring a full incorporation of visual information into all system components is proposed in this paper. The efficacy of the video input is consistently demonstrated in mask-based MVDR speech separation, DNN-WPE or spectral mapping (SpecM) based speech dereverberation front-end and Conformer ASR back-end. Audio-visual integrated front-end architectures performing speech separation and dereverberation in a pipelined or joint fashion via mask-based WPD are investigated. The error cost mismatch between the speech enhancement front-end and ASR back-end components is minimized by end-to-end jointly fine-tuning using either the ASR cost function alone, or its interpolation with the speech enhancement loss. Experiments were conducted on the mixture overlapped and reverberant speech data constructed using simulation or replay of the Oxford LRS2 dataset. The proposed audio-visual multi-channel speech separation, dereverberation and recognition systems consistently outperformed the comparable audio-only baseline by 9.1% and 6.2% absolute (41.7% and 36.0% relative) word error rate (WER) reductions. Consistent speech enhancement improvements were also obtained on PESQ, STOI and SRMR scores.Comment: IEEE/ACM Transactions on Audio, Speech, and Language Processin

Exploring Self-supervised Pre-trained ASR Models For Dysarthric and Elderly Speech Recognition

Automatic recognition of disordered and elderly speech remains a highly challenging task to date due to the difficulty in collecting such data in large quantities. This paper explores a series of approaches to integrate domain adapted SSL pre-trained models into TDNN and Conformer ASR systems for dysarthric and elderly speech recognition: a) input feature fusion between standard acoustic frontends and domain adapted wav2vec2.0 speech representations; b) frame-level joint decoding of TDNN systems separately trained using standard acoustic features alone and with additional wav2vec2.0 features; and c) multi-pass decoding involving the TDNN/Conformer system outputs to be rescored using domain adapted wav2vec2.0 models. In addition, domain adapted wav2vec2.0 representations are utilized in acoustic-to-articulatory (A2A) inversion to construct multi-modal dysarthric and elderly speech recognition systems. Experiments conducted on the UASpeech dysarthric and DementiaBank Pitt elderly speech corpora suggest TDNN and Conformer ASR systems integrated domain adapted wav2vec2.0 models consistently outperform the standalone wav2vec2.0 models by statistically significant WER reductions of 8.22% and 3.43% absolute (26.71% and 15.88% relative) on the two tasks respectively. The lowest published WERs of 22.56% (52.53% on very low intelligibility, 39.09% on unseen words) and 18.17% are obtained on the UASpeech test set of 16 dysarthric speakers, and the DementiaBank Pitt test set respectively.Comment: accepted by ICASSP 202

Understanding and optimising the transfection of lipopolyplexes formulated in saline: the effects of peptide and serum

Lipopolyplexes (LPDs) are of considerable interest for use as gene delivery vehicles. Here LPDs have been prepared from cationic vesicles (composed of a 1 : 1 molar ratio of DOTMA with the neutral helper lipid, DOPE), singly branched cationic peptides and plasmid DNA. All peptides contained a linker sequence (cleaved by endosomal furin) attached to a targeting sequence selected to bind human airway epithelial cells and mediate gene delivery. The current study investigates the effects of novel Arg-containing cationic peptide sequences on the biophysical and transfection properties of LPDs. Mixed His/Arg cationic peptides were of particular interest, as these sequences have not been previously used in LPD formulations. Lengthening the number of cationic residues in a homopolymer from 6 to 12 in each branch reduced transfection using LPDs, most likely due to increased DNA compaction hindering the release of pDNA within the target cell. Furthermore, LPDs containing mixed Arg-containing peptides, particularly an alternating Arg/His sequence exhibited an increase in transfection, probably because of their optimal ability to complex and subsequently release pDNA. To confer stability in serum, LPDs were prepared in 0.12 M sodium chloride solution (as opposed to the more commonly used water) yielding multilamellar LPDs with very high levels of size reproducibility and DNA protection, especially when compared to the (unilamellar) LPDs formed in water. Significantly for the clinical applications of the LPDs, those prepared in the presence of sodium chloride retained high levels of transfection in the presence of media supplemented with fetal bovine serum. This work therefore represents a significant advance for the optimisation of LPD formulation for gene delivery, under physiologically relevant conditions, in vivo

Two-pass Decoding and Cross-adaptation Based System Combination of End-to-end Conformer and Hybrid TDNN ASR Systems

Fundamental modelling differences between hybrid and end-to-end (E2E) automatic speech recognition (ASR) systems create large diversity and complementarity among them. This paper investigates multi-pass rescoring and cross adaptation based system combination approaches for hybrid TDNN and Conformer E2E ASR systems. In multi-pass rescoring, state-of-the-art hybrid LF-MMI trained CNN-TDNN system featuring speed perturbation, SpecAugment and Bayesian learning hidden unit contributions (LHUC) speaker adaptation was used to produce initial N-best outputs before being rescored by the speaker adapted Conformer system using a 2-way cross system score interpolation. In cross adaptation, the hybrid CNN-TDNN system was adapted to the 1-best output of the Conformer system or vice versa. Experiments on the 300-hour Switchboard corpus suggest that the combined systems derived using either of the two system combination approaches outperformed the individual systems. The best combined system obtained using multi-pass rescoring produced statistically significant word error rate (WER) reductions of 2.5% to 3.9% absolute (22.5% to 28.9% relative) over the stand alone Conformer system on the NIST Hub5'00, Rt03 and Rt02 evaluation data.Comment: It' s accepted to ISCA 202

Flow cytometric fluorescence lifetime analysis of DNA binding fluorochromes

Most flow cytometry (FCM) applications monitor fluorescence intensity to quantitate the various cellular parameters; however, the fluorescence emission also contains information relative to the fluorescence lifetime. Recent developments in FCM (Pinsky et al., 1993; Steinkamp & Crissman, 1993; Steinkamp et al., 1993), provide for the measurement of fluorescence lifetime which is also commonly referred to as fluorescence decay, or the time interval in which a fluorochrome remains in the excited state. Many unbound fluorochromes have characteristic lifetime values that are determined by their molecular structure; however, when the probe becomes bound, the lifetime value is influenced by a number of factors that affect the probe interaction with a target molecule. Monitoring the changes in the lifetime of the probe yields information relating to the molecular conformation, the functional state or activity of the molecular target. In addition, the lifetime values can be used as signatures to resolve the emissions of multiple fluorochrome labels with overlapping emission spectra that cannot be resolved by conventional FCM methodology. Such strategies can increase the number of fluorochrome combinations used in a flow cytometer with a single excitation source. Our studies demonstrate various applications of lifetime measurements for the analysis of the binding of different fluorochromes to DNA in single cells. Data presented in this session will show the utility of lifetime measurements for monitoring changes in chromatin structure associated with cell cycle progression, cellular differentiation, or DNA damage, such as induced during apoptosis. Several studies show that dyes with specificity for nucleic acids display different lifetime values when bound to DNA or to dsRNA. The Phase Sensitive Flow Cytometer is a multiparameter instrument, capable of performing lifetime measurements in conjunction with all the conventional FCM measurements. Future modifications of this instrumentation will provide the capability for simultaneously measuring multiple lifetimes, thereby significantly enhancing the subcellular resolution of the multiple complexes of fluorescent compounds, such as chemotherapeutic agents, in single cells (Sailer et al., 1997b)

The zinc cluster protein Sut1 contributes to filamentation in Saccharomyces cerevisiae

Copyright © 2013, American Society for Microbiology. All Rights ReservedSut1 is a transcriptional regulator of the Zn(II)(2)Cys(6) family in the budding yeast Saccharomyces cerevisiae. The only function that has been attributed to Sut1 is sterol uptake under anaerobic conditions. Here, we show that Sut1 is also expressed in the presence of oxygen, and we identify a novel function for Sut1. SUT1 overexpression blocks filamentous growth, a response to nutrient limitation, in both haploid and diploid cells. This inhibition by Sut1 is independent of its function in sterol uptake. Sut1 downregulates the expression of GAT2, HAP4, MGA1, MSN4, NCE102, PRR2, RHO3, and RHO5. Several of these Sut1 targets (GAT2, HAP4, MGA1, RHO3, and RHO5) are essential for filamentation in haploids and/or diploids. Furthermore, the expression of the Sut1 target genes, with the exception of MGA1, is induced during filamentous growth. We also show that SUT1 expression is autoregulated and inhibited by Ste12, a key transcriptional regulator of filamentation. We propose that Sut1 partially represses the expression of GAT2, HAP4, MGA1, MSN4, NCE102, PRR2, RHO3, and RHO5 when nutrients are plentiful. Filamentation-inducing conditions relieve this repression by Sut1, and the increased expression of Sut1 targets triggers filamentous growth.The project was supported by Deutsche Forschungsgemeinschaft grant HO 2098/

(E)-4-[(4-Bromo­benzyl­idene)amino]phenol

In the title compound, C13H10BrNO, the dihedral angle between the benzene rings is 35.20 (8)°. In the crystal, mol­ecules are linked by O—H⋯N hydrogen bonds, forming a zigzag chain along the a axis. A weak C—H⋯π inter­action is observed between the chains