Vibrational spectra, principal components analysis and the horseshoe effect

Vibrational spectroscopy studies often generate datasets containing multiple spectra that are categorized into distinct groups according to similarity. Principal components analysis (PCA) is one of the most frequently used multivariate analysis methods for data reduction of vibrational spectra and visualization of potential groupings between subjects. Vibrational spectra usually display unimodal or multimodal distribution patterns of absorbance or transmittance across wavenumbers. PCA, requires that a linear relationship exists between data distributions of the objects under analysis otherwise the method is prone to a serious artifact known as the ‘horseshoe effect’. This artifact, well known in other fields of science, manifests as a serious distortion of the pattern of how objects group according to the most important principal components leading to misinterpretation of the relationships between the samples from which they are derived. In this paper, using a simulated mid-infrared spectral dataset, we investigate for the first time the potential for the PCA horseshoe effect on vibrational spectra and the why this artifact occurs. We show that when comparing large regions of contiguous wavenumbers between multiple spectra there can be a non-linear relationship between distributions of different spectra. Such non-linearity causes the horseshoe effect and we demonstrate that the degree of distortion of how spectra map on the first two components is related to the region size. We further show that reducing the size of spectra analyzed by PCA can minimize the horseshoe effect. We conclude that PCA should be used with caution in the analysis and interpretation of vibrational spectra and the application of more robust methods should be explored

Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy

Background Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. Methods Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. Results Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8–786) and from irAE onset to tocilizumab 32 days (range 1–192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1–93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3–99), at the onset of irAE 49.5 mg/L (range 0.3–251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3–18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9–18.8) and median overall survival was not reached. Conclusions Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required

Benefits and challenges of rare genetic variation in Alzheimer's disease

Purpose of Review It is well established that sporadic Alzheimer’s disease (AD) is polygenic with common and rare genetic variation alongside environmental factors contributing to disease. Here, we review our current understanding of the genetic architecture of disease, paying specific attention to rare susceptibility variants, and explore some of the limitations in rare variant detection and analysis. Recent Findings Rare variation has been shown to robustly associate with disease. These include potentially damaging and loss of function mutations that are easily modelled in silico, in vitro and in vivo, and represent potentially druggable targets. A number of risk genes, including TREM2, SORL1 and ABCA7 show multiple independent associations suggesting that they may influence disease via multiple mechanisms. With transcriptional regulation, inflammatory response and modification of protein production suggested to be of primary importance. Summary We are at the beginning of our journey of rare variant detection in AD. Whole exome sequencing has been the predominant technology of choice. While fruitful, this has introduced a number of challenges with regard to data integration. Ultimately the future of disease-associated rare variant identification lies in whole genome sequencing projects that will allow the testing of the full range of genomic variation

Age-dependent effect of APOE and polygenic component on Alzheimer's disease

Alzheimer’s disease (AD) is a devastating neurodegenerative condition with significant genetic heritability. Several genes have been implicated in the onset of AD with the apolipoprotein E (APOE) gene being the strongest single genetic risk loci. Evidence suggests that the effect of APOE alters with age during disease progression. Here, we aim to investigate the impact of APOE and other variants outside the APOE region on AD risk in younger and older participants. Using data from both the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the UK Biobank (UKBB) we computed the polygenic risk score (PRS) of each individual informed by the latest genetic study from the International Genomics of Alzheimer’s Project (IGAP). Our analysis showed that the effect of APOE on the disease risk is greater in younger participants and reduces as participant age increases. Our findings indicate the increased impact of PRS as participant age increases. Therefore, AD in older individuals can potentially be triggered by the cumulative effect of genes which are outside the APOE region

Base damage, local sequence context andTP53mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability

The mutational pattern for the TP53 tumour suppressor gene in lung tumours differs to other cancer types by having a higher frequency of G:C>T:A transversions. The aetiology of this differing mutation pattern is still unknown. Benzo[a]pyrene,diol epoxide (BPDE) is a potent cigarette smoke carcinogen that forms guanine adducts at TP53 CpG mutation hotspot sites including codons 157, 158, 245, 248 and 273. We performed molecular modelling of BPDE-adducted TP53 duplex sequences to determine the degree of local distortion caused by adducts which could influence the ability of nucleotide excision repair. We show that BPDE adducted codon 157 has greater structural distortion than other TP53 G:C>T:A hotspot sites and that sequence context more distal to adjacent bases must influence local distortion. Using TP53 trinucleotide mutation signatures for lung cancer in smokers and non-smokers we further show that codons 157 and 273 have the highest mutation probability in smokers. Combining this information with adduct structural data we predict that G:C>T:A mutations at codon 157 in lung tumours of smokers are predominantly caused by BPDE. Our results provide insight into how different DNA sequence contexts show variability in DNA distortion at mutagen adduct sites that could compromise DNA repair at well characterized cancer related mutation hotspots

Characterising the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5

The implication of complement in multiple diseases over the last twenty years has fuelled interest in developing anti‐complement drugs. To date, the focus has been on C5; blocking cleavage of C5 prevents formation of two pro‐inflammatory activities, C5a anaphylatoxin and membrane attack complex. The concept of C5 blockade to inhibit inflammation dates back thirty years to the description of BB5.1, an anti‐C5 blocking monoclonal antibody raised in C5‐deficient mice. This antibody proved an invaluable tool to demonstrate complement involvement in mouse disease models and catalysed enthusiasm for anti‐complement drug development, culminating in the anti‐human C5 monoclonal antibody ecuizumab, the most successful anti‐complement drug to date, already in the clinic for several rare diseases. Despite its key role in providing proof‐of‐concept for C5 blockade, the mechanism of BB5.1 inhibition remains poorly understood. Here we characterised BB5.1 cross‐species inhibition, C5 binding affinity and chain specificity. BB5.1 efficiently inhibited C5 in mouse serum but not in human or other rodent sera; it prevented C5 cleavage and C5a generation. BB5.1 bound the C5 α‐chain with high affinity and slow off‐rate. BB5.1 complementarity determining regions were obtained and docking algorithms used to predict the likely binding interface on mouse C5

Carcinogen-induced DNA structural distortion differences in the RAS gene isoforms; the importance of local sequence

BACKGROUND: Local sequence context is known to have an impact on the mutational pattern seen in cancer. The RAS genes and a smoking carcinogen, Benzo[a]pyrene diol epoxide (BPDE), have been utilised to explore these context effects. BPDE is known to form an adduct at the guanines in a number of RAS gene sites, KRAS codons 12, 13 and 14, NRAS codon 12, and HRAS codons 12 and 14. RESULTS: Molecular modelling techniques, along with multivariate analysis, have been utilised to determine the sequence influenced differences between BPDE-adducted RAS gene sequences as well as the local distortion caused by the adducts. CONCLUSIONS: We conclude that G:C > T:A mutations at KRAS codon 12 in the tumours of lung cancer patients (who smoke), proposed to be predominantly caused by BPDE, are due to the effect of the interaction methyl group at the C5 position of the thymine base in the KRAS sequence with the BPDE carcinogen investigated causing increased distortion. We further suggest methylated cytosine would have a similar effect, showing the importance of methylation in cancer development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13065-021-00777-8

Dementias Platform UK (DPUK) Data Portal - World-leading infrastructure facilitating innovative multi-modal research

Introduction Modern team science requires effective sharing of data and skills. The DPUK Data Portal is a collection of tools, datasets and networks that allows for epidemiologists and specialist researchers alike to access, analyse and investigate cohort and different modalities of routine data across UK and international sources. Objectives and Approach The Portal is housed on an instance of UKSeRP (UK Secure eResearch Platform), that allows customisable infrastructure to be used for multi-modal research (thus far live in genetics, imaging and clinical data) for researchers across the world using remote access technology whilst allowing governance to remain with the data provider. A central team at Swansea University is responsible for data curation and processing, and runs an access procedure for researchers to apply to use data from multiple sources to be analysed in a central analysis environment. Other modalities are similarly hosted, with input from partner sites in Cardiff and Oxford. Results DPUK facilitates data access and research on 49 cohorts, 40 UK-based and 9 international. The centralised repository model including remote access and ability to store and make available different modalities of data, from phenotypic data, to genetic and imaging data, has allowed DPUK to begin to support research of varying topics, from those studying cognitive decline and Dementia as a disease, to those maturing analytical models. By providing access to data platforms specialising in genetics, imaging and routine clinical data, as well as to specialists in disease and biology to aid with its understanding, DPUK has realised a large-scale research exercise combining major data modalities on a central platform, and allow access to such rich data across the world under an umbrella of robust governance. Conclusion/Implications Globally, cohorts are pooling data, expertise and desire to enrich their own aims in partnership with a federated research community to enable in-depth scrutiny of the biological origins of dementia and the development and evaluation of novel approach to disease prevention and cure

A proofreading mutation with an allosteric effect allows a cluster of SARS-CoV-2 viruses to rapidly evolve

The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 virus is error prone, with errors being corrected by the exonuclease (NSP14) proofreading mechanism. However, the mutagenesis and subsequent evolutionary trajectory of the virus is mediated by the delicate interplay of replicase fidelity and environmental pressures. Here, we have shown that a single, distal mutation (F60S) in NSP14 can have a profound impact upon proofreading with an increased accumulation of mutations and elevated evolutionary rate being observed. Understanding the implications of these changes is crucial, as these underlying mutational processes may have important implications for understanding the population-wide evolution of the virus. This study underscores the urgent need for continued research into the replicative mechanisms of this virus to combat its continued impact on global health, through the re-emergence of immuno-evasive variants