
January WeinerBerlin Institute of Health · CUBI (Core Unit Bioinformatics)
January Weiner
Ph.D.
About
150
Publications
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Introduction
I work as a computational biologist / statistician. See also http://logfc.wordpress.com.
Additional affiliations
September 1998 - April 2003
June 2009 - present
January 2005 - December 2008
Publications
Publications (150)
Streptococcus pneumoniae ( S.p. ) is the most common causative agent of community-acquired pneumonia worldwide. A key pathogenic mechanism that exacerbates severity of disease is the disruption of the alveolar-capillary barrier. However, the specific virulence mechanisms responsible for this in the human lung are not yet fully understood.
In this s...
Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein–protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor in...
Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-r...
Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited in...
Background
Despite currently available state-of-the art therapies, a substantial proportion of patients with inflammatory cardiomyopathy progresses to advanced heart failure. There is an urgent need for novel therapies to improve outcomes. We hypothesized that elevated cyto-kine levels in inflammatory cardiomyopathy may lead to cardiac injury and t...
Background&aims:
Long term improvement of body weight and metabolism is highly requested in obesity. The specific impact of weight loss associated temporary negative energy balance or modified body composition on metabolism and weight regain is unclear.
Methods:
We randomly assigned 80 post-menopausal women (BMI 33.9 (32.2-36.8)kg/m2) to an inte...
Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two lon...
Scientists employing omics in life science studies face challenges such as the modeling of multiassay studies, recording of all relevant parameters, and managing many samples with their metadata. They must manage many large files that are the results of the assays or subsequent computation. Users with diverse backgrounds, ranging from computational...
Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection...
A common application of differential expression analysis is finding genes that are differentially expressed upon treatment in only one out of several groups of samples. One of the approaches is to test for significant difference in expression between treatment and control separately in the two groups, and then select genes that show statistical sig...
The development of atopic dermatitis (AD) in infancy, and subsequent allergic rhinitis, food allergies, and asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, yet the course of disease indicates the contribution of inter-epithelial crosstalk, through to the onset of inflammation in the skin and progression to...
Background
Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as po...
Group-aggregated responses to tuberculosis (TB) have been well characterized on a molecular level. However, human beings differ and individual responses to infection vary. We have combined a novel approach to individual gene set analysis (GSA) with the clustering of transcriptomic profiles of TB patients from seven datasets in order to identify ind...
Rationale:
Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T-cells recognising peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection.
Objectives:
To investigate the kinetics, phenotypes and function of influenz...
Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycan...
Background
The World Health Organization recommends standardised treatment durations for patients with tuberculosis. We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-tuberculosis.
Methods
Adult patients with pulmonary tubercul...
Systems vaccinology has been applied to detect signatures of human vaccine induced immunity but its ability, together with high definition in vivo clinical imaging is not established to predict vaccine reactogenicity. Within two European Commission funded high impact programs, BIOVACSAFE and ADITEC, we applied high resolution positron emission tomo...
Background
Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing demand to identify predictors of severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors. We...
Vaccination in pregnancy is an effective tool to protect both the mother and infant; vaccines against influenza, pertussis and tetanus are currently recommended. A number of vaccines with a specific indication for use in pregnancy are in development, with the specific aim of providing passive humoral immunity to the newborn child against pathogens...
Emerging multidrug-resistant tuberculosis is a major global health challenge. The World Health Organization currently recommends treatment durations of 9–18 months or more for patients with multidrug-resistant tuberculosis. We identified and validated a host-RNA signature to serve as a biomarker for individualized therapy durations for patients wit...
Background
People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of dia...
Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tu...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Background: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1, control the th...
Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alterations in the metabolic milieu could influence the outcome of...
Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-se...
Spying on bacterial signals
Many bacteria produce small molecules for monitoring population density and thus regulating their collective behavior, a process termed quorum sensing. Pathogens like Pseudomonas aeruginosa , which complicates cystic fibrosis disease, produce different quorum-sensing ligands at different stages of infection. Moura-Alves...
Background:
Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. This study aimed to identify correlates of protection against early Mtb infection.
Methods:
Two groups of Mtb-exposed contacts of TB patients were recruited and classified according to their Mtb infection status using Tuberculin skin test (TST; co...
As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocy...
Motivation:
Analysis of gene set enrichment is an essential part of functional omics studies. Here, we complement the established evaluation metrics of gene set enrichment algorithms with a novel approach to assess the practical reproducibility of scientific results obtained from gene set enrichment tests when applied to related data from differen...
Systems vaccinology approaches have been used to successfully define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate/surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, and three agonis...
Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate. Increased lactate turnover is shared by malignant and immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis -infected animals present elevated levels of Ldha and lactate. Such alteration in metabolic milieu could influence the outcome of interactions betwe...
There remains a pressing need for biomarkers that can predict who will progress to active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (MTB) bacterium. By analyzing cohorts of household contacts of TB index cases (HHCs) and a stringent non-human primate (NHP) challenge model, we evaluated whether integration of blood transcription...
There remains a pressing need for biomarkers that can predict who will progress to active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (MTB) bacterium. By analyzing cohorts of household contacts of TB index cases (HHCs) and a stringent non-human primate (NHP) challenge model, we evaluated whether integration of blood transcription...
Background: Despite recent advances in diagnosis and treatment, tuberculosis (TB) remains a major infectious disease killer in resource-poor settings. Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. By characterising natural protective immunity to Mtb infection we aimed to identify correlates of protection to...
New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control of the ongoing TB pandemic. In a prospective multisite study across Subsaharan Africa, we analyzed metabolic profiles in serum and plasma from HIV-negative, TB-exposed individuals who either progressed to TB 3–24 months post-exposure (progressors) or r...
As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocy...
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently ident...
Recent technological advances have provided deeper insights into the role of small molecules in biological processes. Metabolic profiling has thus entered the arena of -omics studies and rapidly proven its value both as stand-alone and as complement to other more advanced approaches, notably transcriptomics. Here we describe the potential of metabo...
Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of...
Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of...
Rationale:
Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.
Objectives:
We investigated biosignatures with predictive ability for incident tuberculosis.
Methods:
In a case-control study nes...
Mycobacterium tuberculosis (Mtb) primarily resides in the lung but can also persist in extrapulmonary sites. Macrophages are considered the prime cellular habitat in all tissues. Here we demonstrate that Mtb resides inside adipocytes of fat tissue where it expresses stress-related genes. Moreover, perigonadal fat of Mtb-infected mice disseminated t...
Mtb resides in perigonadal and subcutaneous fat post aerosol-infection of mice and in spleen and lung of donor mice and in spleen, lung and perigonadal fat of control mice in fat transfer experiments.
(A) log10 Mtb CFUs in in spleen, lung and AD and SVF fractions of perigonadal fat at different time points after aerosol infection. Data representati...
Numbers of CD4+, CD8+, CD8+ CD44+ TB10.4+ (Mtb-specific) populations in SVF of perigonadal fat and lung post aerosol-infection with Mtb.
Numbers of CD4+, CD8+ and CD8+ CD44+ TB10.4+ (Mtb-specific) populations in SVF of perigonadal fat (upper panel) and lung (lower panel) at day 14 and post infection. Data are representative of two independent exper...
Numbers of CD4+, CD8+, and NK IFN-γ or IL-4-producing cells in lung at day 14 post aerosol-infection with Mtb.
Numbers of CD4+, CD8+ and NK IFN-γ or IL-4-producing cells at day 14 post infection. Data are representative of two independent experiments (means); *p<0.05 (Student´s t-test).
(TIF)
Mtb infection does not alter adipocyte size in perigonadal fat.
(A) Adipocyte size at day 28 post aerosol-infection. (B) Free fatty acids in sera at day 14 and 28 post infection. Data representative of two independent experiments. Abbreviations: FFA, free fatty acids.
(TIF)
Effector CD8+ T cells are present in perigonadal fat post aerosol- infection.
Numbers of CD4+ CD44– CD69+ and CD8+ CD44– CD69+ cells in SVF of perigonadal fat (upper panel) or lung (lower panel) at day 28 post infection. Data are representative of two independent experiments (means); *p<0.05, and ****p<0.0001 (Student´s t-test). Abbreviations: SVF,...
Differential gene expression in perigonadal fat and lung post aerosol- infection with Mtb.
(A-B) Expression of Cd8a, Cd3d, Cd4, Ifng, Il4, Ccl5, Ccr7, Cxcl9, Cxcr3 (left panel) and Tbx21, Rorc and Gata3 (right panel) in perigonadal fat and lung, as measured with quantitative PCR at: (A) day 14 or (B) day 56 post infection. Data are representative o...
Numbers of CD4+, CD8+, and NK IFN-γ or IL-4-producing cells in SVF of perigonadal fat at day 14 post aerosol-infection with Mtb.
Numbers of CD4+, CD8+ and NK IFN-γ or IL-4-producing cells at day 14 post infection. Data are representative of two independent experiments (means). Abbreviations: SVF, stromal vascular fraction.
(TIF)
CD8+ CD44– CD103+ T cells are present in perigonadal fat post aerosol- infection.
Numbers of CD4+ CD44– CD103+ and CD8+ CD44– CD103+ cells in SVF of perigonadal fat (upper panel) or lung (lower panel) at day 28 post infection. Data are representative of two independent experiments (means); *p<0.05, and ****p<0.0001 (Student´s t-test). Abbreviations...
Numbers of CD4+, CD8+, and NK IFN-γ or IL-4-producing cells in lung at day 28 post aerosol-infection with Mtb.
Numbers of CD4+, CD8+ and NK IFN-γ or IL-4-producing cells in lung at day 28 post infection. Data are representative of two independent experiments (means); *p<0.05, ***p<0.001 and ****p<0.0001 (Student´s t-test).
(TIF)
Mtb infection modulates gene expression of Mtb-specific CD8+ T cells and NK cells in perigonadal fat.
(A) Heat maps of gene expression of CD4+, CD8+, Mtb-specific CD8+ T cells (CD8+ CD44+ TB10.4+) and NK cells sorted from perigonadal fat (right panel) or lung (left panel) at day 28 post infection. Colour corresponds to ΔCt values. Mtb infection mod...
Immunity in infection, inflammation and malignancy differs markedly in man and mouse. Still, we learn about human immunity in large extent from experimental mouse models. We propose a novel data integration approach which identifies concordant and discordant gene expression patterns of the immune responses in heterologous data sets. We have conduct...
Introduction: The most recent estimates on tuberculosis (TB) morbidity and mortality reveal that the global disease burden is even higher than previously assumed. Better drugs, diagnostics and vaccines are major requirements to control the ongoing TB pandemic. The high complexity of the infectious process and the underlying pathology, however, chal...
Background
There exist many methods for describing the complex relation between changes of gene expression in molecular pathways or gene ontologies under different experimental conditions. Among them, Gene Set Enrichment Analysis seems to be one of the most commonly used (over 10,000 citations). An important parameter, which could affect the final...
Tuberculosis (TB) remains the deadliest infectious disease. The widely used BCG vaccine offers only limited protection against TB. New vaccine candidates for TB include subunit vaccines, inactivated whole cell vaccines as well as live mycobacterial vaccines. In this review, we summarize current developments for TB vaccines.
High throughput techniques strive to guide new biomarkers helpful for tuberculosis (TB) diagnosis, treatment and prevention, but their analysis and interpretation pose considerable challenges. In this review, we report on recent developments in high throughput detection of host biomarkers in TB.
[This corrects the article DOI: 10.1371/journal.pone.0163662.].