Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification

INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. Highlights: We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease

Green criminology: shining a critical lens on environmental harm

Green criminology provides for inter-disciplinary and multi-disciplinary engagement with environmental crimes and wider environmental harms. Green criminology applies a broad ‘‘green’’ perspective to environmental harms, ecological justice, and the study of environmental laws and criminality, which includes crimes affecting the environment and non-human nature. Within the ecological justice and species justice perspectives of green criminology there is a contention that justice systems need to do more than just consider anthropocentric notions of criminal justice, they should also consider how justice systems can provide protection and redress for the environment and other species. Green criminological scholarship has, thus, paid direct attention to theoretical questions of whether and how justice systems deal with crimes against animals and the environment; it has begun to conceptualize policy perspectives that can provide contemporary ecological justice alongside mainstream criminal justice. Moving beyond mainstream criminology’s focus on individual offenders, green criminology also explores state failure in environmental protection and corporate offending and environmentally harmful business practices. A central discussion within green criminology is that of whether environmental harm rather than environmental crime should be its focus, and whether green ‘‘crimes’’ should be seen as the focus of mainstream criminal justice and dealt with by core criminal justice agencies such as the police, or whether they should be considered as being beyond the mainstream. This article provides an introductory overview that complements a multi- and inter-disciplinary article collection dedicated to green criminological thinking and research

A blood-based multi-pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups

INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed

Novel non-invasive algorithm to identify the origins of re-entry and ectopic foci in the atria from 64-lead ECGs: A computational study.

Atrial tachy-arrhytmias, such as atrial fibrillation (AF), are characterised by irregular electrical activity in the atria, generally associated with erratic excitation underlain by re-entrant scroll waves, fibrillatory conduction of multiple wavelets or rapid focal activity. Epidemiological studies have shown an increase in AF prevalence in the developed world associated with an ageing society, highlighting the need for effective treatment options. Catheter ablation therapy, commonly used in the treatment of AF, requires spatial information on atrial electrical excitation. The standard 12-lead electrocardiogram (ECG) provides a method for non-invasive identification of the presence of arrhythmia, due to irregularity in the ECG signal associated with atrial activation compared to sinus rhythm, but has limitations in providing specific spatial information. There is therefore a pressing need to develop novel methods to identify and locate the origin of arrhythmic excitation. Invasive methods provide direct information on atrial activity, but may induce clinical complications. Non-invasive methods avoid such complications, but their development presents a greater challenge due to the non-direct nature of monitoring. Algorithms based on the ECG signals in multiple leads (e.g. a 64-lead vest) may provide a viable approach. In this study, we used a biophysically detailed model of the human atria and torso to investigate the correlation between the morphology of the ECG signals from a 64-lead vest and the location of the origin of rapid atrial excitation arising from rapid focal activity and/or re-entrant scroll waves. A focus-location algorithm was then constructed from this correlation. The algorithm had success rates of 93% and 76% for correctly identifying the origin of focal and re-entrant excitation with a spatial resolution of 40 mm, respectively. The general approach allows its application to any multi-lead ECG system. This represents a significant extension to our previously developed algorithms to predict the AF origins in association with focal activities

Successful reduced-intensity SCT from unrelated cord blood in three patients with X-linked SCID

We describe three males with X-linked SCID (X-SCID) who were successfully treated by reduced-intensity SCT from unrelated cord blood (CB). Mean age at transplant was 5.7 months (range, 3–9 months). Pre-transplant conditioning for all patients consisted of fludarabine (FLU) (30 mg/m2 per day) from day −7 to day −2 (total dose 180 mg/m2) and BU 4 mg/kg per day from day −3 to day −2 (total dose 8 mg/kg). All CB units were serologically matched at HLA-A, B and DR loci. Although two patients had suffered from fungal or bacterial pneumonia before transplantation, there were no other infectious complications during transplantation. All patients engrafted and achieved 100% donor chimerism. We also confirmed full donor chimerism of both T and B cells. Only one patient developed acute GVHD grade III, which was resolved by increasing the dose of oral corticosteroid. None of the patients has developed chronic GVHD during follow up for 21–77 months. None of the patient received i.v. Ig replacement post transplant, or showed delay in psychomotor development. Reduced-intensity conditioning consisting of FLU and BU and transplantation from unrelated CB was an effective and safe treatment for these patients with X-SCID

Inhibition of ER stress-mediated apoptosis in macrophages by nuclear-cytoplasmic relocalization of eEF1A by the HIV-1 Nef protein

HIV-1 Nef protein has key roles at almost all stages of the viral life cycle. We assessed the role of the Nef/eEF1A (eukaryotic translation elongation factor 1-alpha) complex in nucleocytoplasmic shuttling in primary human macrophages. Nuclear retention experiments and inhibition of the exportin-t (Exp-t) pathway suggested that cytoplasmic relocalization of eEF1A, mediated by Exp-t, occurs in Nef-treated monocyte-derived macrophages (MDMs). We observed the presence of tRNA in the Nef/eEF1A complexes. Nucleocytoplasmic relocalization of the Nef/eEF1A complexes prevented stress-induced apoptosis of MDMs treated with brefeldin-A. Blockade of stress-induced apoptosis of MDMs treated with HIV-1 Nef resulted from enhanced nucleocytoplasmic transport of eEF1A with decreased release of mitochondrial cytochrome c, and from increased tRNA binding to cytochrome c, ultimately leading to an inhibition of caspase activation. Our results indicate that HIV-1 Nef, through the nucleocytoplasmic relocalization of eEF1A and tRNAs, enhances resistance to stress-induced apoptosis in primary human macrophages