Improving protein succinylation sites prediction using embeddings from protein language model

Protein succinylation is an important post-translational modification (PTM) responsible for many vital metabolic activities in cells, including cellular respiration, regulation, and repair. Here, we present a novel approach that combines features from supervised word embedding with embedding from a protein language model called ProtT5-XL-UniRef50 (hereafter termed, ProtT5) in a deep learning framework to predict protein succinylation sites. To our knowledge, this is one of the first attempts to employ embedding from a pre-trained protein language model to predict protein succinylation sites. The proposed model, dubbed LMSuccSite, achieves state-of-the-art results compared to existing methods, with performance scores of 0.36, 0.79, 0.79 for MCC, sensitivity, and specificity, respectively. LMSuccSite is likely to serve as a valuable resource for exploration of succinylation and its role in cellular physiology and disease

News, intelligence and 'little lies' : rumours between the Cherokees and the British 1740-1785

Rumour and information are one of the most fundamental ways in which people engage with one another. Rumours can change the way that individuals and groups see each other and the actions that they take. Sociologists and anthropologists have long used rumour as a way to explore the experiences of their subjects. Historians of early America have, in recent years, begun to make use of rumour as a way of examining the, often hidden, world of interactions between American Indians and white Europeans. This thesis will expand upon this work by exploring the changing role of rumour within an intercultural relationship over several decades. This thesis will focus on rumour in the relationship between the Cherokee Nation and the colonists of the British Empire. It will explore the ways that rumour influenced these interactions and the impact of the rapidly changing backcountry environment of the latter eighteenth century, both on rumour and on the wider Cherokee- British relationship. This thesis will argue that rumour shifted in the course of the eighteenth century from being a diplomatic tool which could be used- either to create further panic and confusion or to calm and smooth over problems- to an uncontrollable force which would deepen and exacerbate the divisions between Cherokees and the British. Rumour played an important role in politics and society in the eighteenth century backcountry and its changing function offers a way to better understand the shifting currents of life in early America

Design and technology of DEPFET pixel sensors for linear collider applications

Abstract The performance requirements of vertex detectors for future linear collider experiments is very challenging, especially for the detector's innermost sensor layers. The DEPleted Field Effect Transistor (DEPFET), combining detector and amplifier operation, is capable to meet these requirements. A silicon technology is presented which allows production of large sensor arrays consisting of linear DEPFET detector structures. The envisaged pixel array offers low noise and low power operation. To ensure a high radiation length a thinning technology based on direct wafer bonding is proposed

Unsupervised protein embeddings outperform hand-crafted sequence and structure features at predicting molecular function

This work was supported by Keygene N.V., a crop innovation company in the Netherlands and by the Spanish MINECO/FEDER Project TEC201680141-P with the associated FPI grant BES-2017-079792.The authors thank Dr. Elvin Isufi and Chirag Raman for their valuable comments and feedback.Motivation: Protein function prediction is a difficult bioinformatics problem. Many recent methods use deep neural networks to learn complex sequence representations and predict function from these. Deep supervised models require a lot of labeled training data which are not available for this task. However, a very large amount of protein sequences without functional labels is available. Results: We applied an existing deep sequence model that had been pretrained in an unsupervised setting on the supervised task of protein molecular function prediction. We found that this complex feature representation is effective for this task, outperforming hand-crafted features such as one-hot encoding of amino acids, k-mer counts, secondary structure and backbone angles. Also, it partly negates the need for complex prediction models, as a two-layer perceptron was enough to achieve competitive performance in the third Critical Assessment of Functional Annotation benchmark. We also show that combining this sequence representation with protein 3D structure information does not lead to performance improvement, hinting that 3D structure is also potentially learned during the unsupervised pretraining.Keygene N.V., a crop innovation company in the NetherlandsSpanish MINECO/FEDER TEC201680141-PFPI grant BES-2017-07979

Exploring the ATN classification system using brain morphology

BackgroundThe NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort.MethodsWe used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-A beta 42/A beta 40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups.ResultsThe ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead.ConclusionUsing the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy

Exploring the ATN classification system using brain morphology

BackgroundThe NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort.MethodsWe used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-A beta 42/A beta 40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups.ResultsThe ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead.ConclusionUsing the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy

Differential Effects of Vpr on Single-cycle and Spreading HIV-1 Infections in CD4+ T-cells and Dendritic Cells

The Vpr protein of human immunodeficiency virus type 1 (HIV-1) contributes to viral replication in non-dividing cells, specifically those of the myeloid lineage. However, the effects of Vpr in enhancing HIV-1 infection in dendritic cells have not been extensively investigated. Here, we evaluated the role of Vpr during infection of highly permissive peripheral blood mononuclear cells (PBMCs) and CD4+ T-cells and compared it to that of monocyte-derived dendritic cells (MDDCs), which are less susceptible to HIV-1 infection. Infections of dividing PBMCs and non-dividing MDDCs were carried out with single-cycle and replication-competent HIV-1 encoding intact Vpr or Vpr-defective mutants. In contrast to previous findings, we observed that single-cycle HIV-1 infection of both PBMCs and MDDCs was significantly enhanced in the presence of Vpr when the viral stocks were carefully characterized and titrated. HIV-1 DNA quantification revealed that Vpr only enhanced the reverse transcription and nuclear import processes in single-cycle HIV-1 infected MDDCs, but not in CD4+ T-cells. However, a significant enhancement in HIV-1 gag mRNA expression was observed in both CD4+ T-cells and MDDCs in the presence of Vpr. Furthermore, Vpr complementation into HIV-1 virions did not affect single-cycle viral infection of MDDCs, suggesting that newly synthesized Vpr plays a significant role to facilitate single-cycle HIV-1 infection. Over the course of a spreading infection, Vpr significantly enhanced replication-competent HIV-1 infection in MDDCs, while it modestly promoted viral infection in activated PBMCs. Quantification of viral DNA in replication-competent HIV-1 infected PBMCs and MDDCs revealed similar levels of reverse transcription products, but increased nuclear import in the presence of Vpr independent of the cell types. Taken together, our results suggest that Vpr has differential effects on single-cycle and spreading HIV-1 infections, which are dependent on the permissiveness of the target cell

Macrophage signaling in HIV-1 infection

The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection