Deep Learning Applied to Raman Spectroscopy for the Detection of Microsatellite Instability/MMR Deficient Colorectal Cancer

Defective DNA mismatch repair is one pathogenic pathway to colorectal cancer. It is characterised by microsatellite instability which provides a molecular biomarker for its detection. Clinical guidelines for universal testing of this biomarker are not met due to resource limitations; thus, there is interest in developing novel methods for its detection. Raman spectroscopy (RS) is an analytical tool able to interrogate the molecular vibrations of a sample to provide a unique biochemical fingerprint. The resulting datasets are complex and high-dimensional, making them an ideal candidate for deep learning, though this may be limited by small sample sizes. This study investigates the potential of using RS to distinguish between normal, microsatellite stable (MSS) and microsatellite unstable (MSI-H) adenocarcinoma in human colorectal samples and whether deep learning provides any benefit to this end over traditional machine learning models. A 1D convolutional neural network (CNN) was developed to discriminate between healthy, MSI-H and MSS in human tissue and compared to a principal component analysis-linear discriminant analysis (PCA-LDA) and a support vector machine (SVM) model. A nested cross-validation strategy was used to train 30 samples, 10 from each group, with a total of 1490 Raman spectra. The CNN achieved a sensitivity and specificity of 83% and 45% compared to PCA-LDA, which achieved a sensitivity and specificity of 82% and 51%, respectively. These are competitive with existing guidelines, despite the low sample size, speaking to the molecular discriminative power of RS combined with deep learning. A number of biochemical antecedents responsible for this discrimination are also explored, with Raman peaks associated with nucleic acids and collagen being implicated

Adults' Awareness of Faces Follows Newborns' Looking Preferences

From the first days of life, humans preferentially orient towards upright faces, likely reflecting innate subcortical mechanisms. Here, we show that binocular rivalry can reveal face detection mechanisms in adults that are surprisingly similar to inborn face detection mechanism. We used continuous flash suppression (CFS), a variant of binocular rivalry, to render stimuli invisible at the beginning of each trial and measured the time upright and inverted stimuli needed to overcome such interocular suppression. Critically, specific stimulus properties previously shown to modulate looking preferences in neonates similarly modulated adults' awareness of faces presented during CFS. First, the advantage of upright faces in overcoming CFS was strongly modulated by contrast polarity and direction of illumination. Second, schematic patterns consisting of three dark blobs were suppressed for shorter durations when the arrangement of these blobs respected the face-like configuration of the eyes and the mouth, and this effect was modulated by contrast polarity. No such effects were obtained in a binocular control experiment not involving CFS, suggesting a crucial role for face-sensitive mechanisms operating outside of conscious awareness. These findings indicate that visual awareness of faces in adults is governed by perceptual mechanisms that are sensitive to similar stimulus properties as those modulating newborns' face preferences

A Genome-Wide Analysis of Promoter-Mediated Phenotypic Noise in Escherichia coli

Gene expression is subject to random perturbations that lead to fluctuations in the rate of protein production. As a consequence, for any given protein, genetically identical organisms living in a constant environment will contain different amounts of that particular protein, resulting in different phenotypes. This phenomenon is known as “phenotypic noise.” In bacterial systems, previous studies have shown that, for specific genes, both transcriptional and translational processes affect phenotypic noise. Here, we focus on how the promoter regions of genes affect noise and ask whether levels of promoter-mediated noise are correlated with genes' functional attributes, using data for over 60% of all promoters in Escherichia coli. We find that essential genes and genes with a high degree of evolutionary conservation have promoters that confer low levels of noise. We also find that the level of noise cannot be attributed to the evolutionary time that different genes have spent in the genome of E. coli. In contrast to previous results in eukaryotes, we find no association between promoter-mediated noise and gene expression plasticity. These results are consistent with the hypothesis that, in bacteria, natural selection can act to reduce gene expression noise and that some of this noise is controlled through the sequence of the promoter region alon

Comparing Biological Motion Perception in Two Distinct Human Societies

Cross cultural studies have played a pivotal role in elucidating the extent to which behavioral and mental characteristics depend on specific environmental influences. Surprisingly, little field research has been carried out on a fundamentally important perceptual ability, namely the perception of biological motion. In this report, we present details of studies carried out with the help of volunteers from the Mundurucu indigene, a group of people native to Amazonian territories in Brazil. We employed standard biological motion perception tasks inspired by over 30 years of laboratory research, in which observers attempt to decipher the walking direction of point-light (PL) humans and animals. Do our effortless skills at perceiving biological activity from PL animations, as revealed in laboratory settings, generalize to people who have never before seen representational depictions of human and animal activity? The results of our studies provide a clear answer to this important, previously unanswered question. Mundurucu observers readily perceived the coherent, global shape depicted in PL walkers, and experienced the classic inversion effects that are typically found when such stimuli are turned upside down. In addition, their performance was in accord with important recent findings in the literature, in the abundant ease with which they extracted direction information from local motion invariants alone. We conclude that the effortless, veridical perception of PL biological motion is a spontaneous and universal perceptual ability, occurring both inside and outside traditional laboratory environments

A paediatric bone index derived by automated radiogrammetry

Hand radiographs are obtained routinely to determine bone age of children. This paper presents a method that determines a Paediatric Bone Index automatically from such radiographs. The Paediatric Bone Index is designed to have minimal relative standard deviation (7.5%), and the precision is determined to be 1.42%. Introduction We present a computerised method to determine bone mass of children based on hand radiographs, including a reference database for normal Caucasian children. Methods Normal Danish subjects (1,867), of ages 7-17, and 531 normal Dutch subjects of ages 5-19 were included. Historically, three different indices of bone mass have been used in radiogrammetry all based on A = pi TW(1 - T/W), where T is the cortical thickness and W the bone width. The indices are the metacarpal index A/W-2, DXR-BMD=A/W, and Exton-Smith's index A/(WL), where L is the length of the bone. These indices are compared with new indices of the form A/((WLb)-L-a), and it is argued that the preferred index has minimal SD relative to the mean value at each bone age and sex. Finally, longitudinal series of X-rays of 20 Japanese children are used to derive the precision of the measurements. Results The preferred index is A/((WL0.33)-L-1.33), which is named the Paediatric Bone Index, PBI. It has mean relative SD 7.5% and precision 1.42%. Conclusions As part of the BoneXpert method for automated bone age determination, our method facilitates retrospective research studies involving validation of the proposed index against fracture incidence and adult bone mineral densit

The influence of spatial pattern on visual short-term memory for contrast

Several psychophysical studies of visual short-term memory (VSTM) have shown high-fidelity storage capacity for many properties of visual stimuli. On judgments of the spatial frequency of gratings, for example, discrimination performance does not decrease significantly, even for memory intervals of up to 30 s. For other properties, such as stimulus orientation and contrast, however, such “perfect storage” behavior is not found, although the reasons for this difference remain unresolved. Here, we report two experiments in which we investigated the nature of the representation of stimulus contrast in VSTM using spatially complex, two-dimensional random-noise stimuli. We addressed whether information about contrast per se is retained during the memory interval by using a test stimulus with the same spatial structure but either the same or the opposite local contrast polarity, with respect to the comparison (i.e., remembered) stimulus. We found that discrimination thresholds got steadily worse with increasing duration of the memory interval. Furthermore, performance was better when the test and comparison stimuli had the same local contrast polarity than when they were contrast-reversed. Finally, when a noise mask was introduced during the memory interval, its disruptive effect was maximal when the spatial configuration of its constituent elements was uncorrelated with those of the comparison and test stimuli. These results suggest that VSTMfor contrast is closely tied to the spatial configuration of stimuli and is not transformed into a more abstract representation

Defining the expression hierarchy of latent T-cell epitopes in Epstein-Barr virus infection with TCR-like antibodies

Epstein-Barr virus (EBV) is a gamma herpesvirus that causes a life-long latent infection in human hosts. The latent gene products LMP1, LMP2A and EBNA1 are expressed by EBV-associated tumors and peptide epitopes derived from these can be targeted by CD8 Cytotoxic T-Lymphocyte (CTL) lines. Whilst CTL-based methodologies can be utilized to infer the presence of specific latent epitopes, they do not allow a direct visualization or quantitation of these epitopes. Here, we describe the characterization of three TCR-like monoclonal antibodies (mAbs) targeting the latent epitopes LMP1[subscript 125–133], LMP2A[subscript 426–434] or EBNA1[subscript 562–570] in association with HLA-A0201. These are employed to map the expression hierarchy of endogenously generated EBV epitopes. The dominance of EBNA1[subscript 562–570] in association with HLA-A0201 was consistently observed in cell lines and EBV-associated tumor biopsies. These data highlight the discordance between MHC-epitope density and frequencies of associated CTL with implications for cell-based immunotherapies and/or vaccines for EBV-associated disease

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Sexual Health and Well-being Among Older Men and Women in England: Findings from the English Longitudinal Study of Ageing

We describe levels of sexual activity, problems with sexual functioning, and concerns about sexual health among older adults in the English Longitudinal Study of Ageing (ELSA), and associations with age, health, and partnership factors. Specifically, a total of 6,201 core ELSA participants (56 % women) aged 50 to >90 completed a comprehensive Sexual Relationships and Activities questionnaire (SRA-Q) included in ELSA Wave 6 (2012/13). The prevalence of reporting any sexual activity in the last year declined with age, with women less likely than men at all ages to report being sexually active. Poorer health was associated with lower levels of sexual activity and a higher prevalence of problems with sexual functioning, particularly among men. Difficulties most frequently reported by sexually active women related to becoming sexually aroused (32 %) and achieving orgasm (27 %), while for men it was erectile function (39 %). Sexual health concerns most commonly reported by women related to their level of sexual desire (11 %) and frequency of sexual activities (8 %). Among men it was level of sexual desire (15 %) and erectile difficulties (14 %). While the likelihood of reporting sexual health concerns tended to decrease with age in women, the opposite was seen in men. Poor sexual functioning and disagreements with a partner about initiating and/or feeling obligated to have sex were associated with greater concerns about and dissatisfaction with overall sex life. Levels of sexual activity decline with increasing age, although a sizable minority of men and women remain sexually active until the eighth and ninth decades of life. Problems with sexual functioning were relatively common, but overall levels of sexual health concerns were much lower. Sexually active men reported higher levels of concern with their sexual health and sexual dissatisfaction than women at all ages. Older peoples’ sexual health should be managed, not just in the context of their age, gender, and general health, but also within their existing sexual relationship