Latest Publications
Johannes Boltze publications
Mononuclear cell therapy of neonatal hypoxic-ischemic encephalopathy in preclinical versus clinical studies: a systematic analysis of therapeutic efficacy and study design
Scrutton A. M., Ollis F., Boltze J
Hypoxic-ischemic encephalopathy (HIE) is a devastating condition affecting around 8.5 in 1000 newborns globally. Therapeutic hypothermia (TH) can reduce mortality and, to a limited extent, disability after HIE. Nevertheless, there is a need for new and effective treatment strategies. Here, we conducted a systematic review and meta-analysis. and analyzed overall MNC efficacy in preclinical trials, the methodological quality of preclinical trials, and relevant design features in preclinical versus clinical trials. Based on the analyzed data, it is unlikely that therapeutic effect size is massively overestimated in preclinical studies. It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE. Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.
Neuroprotection. December 2023
MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease
Abdul Naeem, Ravi Prakash, Neha Kumari, Mohsin Ali Khan, Abdul Quaiyoom Khan, Shahab Uddin, Sandeep Verma, Avril AB Robertson, Johannes Boltze, Syed Shadab Raza
In this study, we investigated the potential therapeutic effects of MCC950 on NLRP3-mediated inflammasome-driven inflammation and autophagy in Alzheimer's disease (AD). . MCC950 effectively suppressed STZ-induced cognitive impairment and anxiety by inhibiting NLRP3-dependent neuroinflammation. Moreover, our findings indicate that MCC950 exerts neuroprotective effects by attenuating autophagy in neuronal cells. The inhibiting effects of MCC950 on inflammasome activation and autophagy were reproduced in vitro, provding further mechansistic insights into MCC950 therapeutic action. Our findings suggest that MCC950 impedes the progression of AD and may also improve cognitive function through the mitigation of autophagy and NLRP3 inflammasome.
Long noncoding RNA-mediated epigenetic regulation of auxin-related genes controls shade avoidance syndrome in Arabidopsis
María Florencia Mammarella, Leandro Lucero, Nosheen Hussain, Aitor Muñoz-Lopez, Ying Huang, Lucia Ferrero, Guadalupe L Fernandez-Milmanda, Pablo Manavella, Moussa Benhamed, Martin Crespi, Carlos L Ballare, Jose Gutierrez-Marcos, Pilar Cubas, Federico Ariel
The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA–DNA hybrids (R-loops) and modulating local three-dimensional chromatin conformation. Here, we show that APOLO regulates shade avoidance syndrome by dynamically modulating expression of key factors. We show that direct application of APOLO RNA to leaves results in a rapid increase in auxin signaling that is associated with changes in the plant response to far-red light. Collectively, our data support the view that lncRNAs coordinate shade avoidance syndrome in A. thaliana, and reveal their potential as exogenous bioactive molecules. Deploying exogenous RNAs that modulate plant–environment interactions may therefore become a new tool for sustainable agriculture.
SKN-1/NRF2 up-regulation by vitamin A is conserved from nematodes to mammals and is critical for lifespan extension in Caenorhabditis elegan
Chaweewan Sirakawin, Dongfa Lin, Ziyue Zhou, Xiaoxin Wang, Rhianne Kelleher, Shangyuan Huang, Weimiao Long, Andre Pires-da Silva, Yu Liu, Jingjing Wang, Ilya A. Vinnikov
Vitamin A (VA) is a micronutrient essential for the physiology of many organisms, but its role in longevity and age-related diseases remains unclear. In this work, we used Caenorhabditis elegans to study the impact of various bioactive compounds on lifespan. We demonstrate that VA extends lifespan and reduces lipofuscin and fat accumulation while increasing resistance to heat and oxidative stress. This resistance can be attributed to high levels of detoxifying enzymes called glutathione S-transferases, induced by the transcription factor skinhead-1 (SKN-1). Notably, VA upregulated the transcript levels of skn-1 or its mammalian ortholog NRF2 in both C. elegans, human cells, and liver tissues of mice. Moreover, the loss-of-function genetic models demonstrated a critical involvement of the SKN-1 pathway in longevity extension by VA. Our study thus provides novel insights into the molecular mechanism of anti-aging and anti-oxidative effects of VA, suggesting that this micronutrient could be used for the prevention and/or treatment of age-related disorders.
The Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes
Kaisa Thorell, Zilia Y Muñoz-Ramírez, Difei Wang, Santiago Sandoval-Motta, Rajiv Boscolo Agostini, Silvia Ghirotto, Roberto C Torres; HpGP Research Network (inc. Xavier Didelot); Daniel Falush, M Constanza Camargo, Charles S Rabkin
Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics.
James Nokes publications
Genetic and potential antigenic evolution of influenza A(H1N1)pdm09 viruses circulating in Kenya during 2009-2018 influenza seasons
D. Collins Owuor, Zaydah R. de Laurent, Bryan O. Nyawanda, Gideon O. Emukule, Rebecca Kondor, John R. Barnes, D. James Nokes, Charles N. Agoti and Sandra S. Chaves
Influenza viruses undergo rapid evolutionary changes, which requires continuous surveillance to monitor for genetic and potential antigenic changes in circulating viruses that can guide control and prevention decision making. We sequenced and phylogenetically analyzed A(H1N1)pdm09 virus genome sequences obtained from specimens collected from hospitalized patients of all ages with or without pneumonia between 2009 and 2018 from seven sentinel surveillance sites across Kenya. We compared these sequences with recommended vaccine strains during the study period to infer genetic and potential antigenic changes in circulating viruses and associations of clinical outcome. Our study highlights the necessity of timely genomic surveillance to monitor the evolutionary changes of influenza viruses. Routine influenza surveillance with broad geographic representation and whole genome sequencing capacity to inform on prioritization of antigenic analysis and the severity of circulating strains are critical to improved selection of influenza strains for inclusion in vaccines.
Scientific Reports. December 2023
Changes in the global hospitalisation burden or respiratory syncytial virus in young children during the COVID-19 pandemic: a systematic analysis
Bingbing Cong et al inc. D J Nokes.
We aimed to assess the hospitalisation burden of respiratory syncytial virus (RSV)-associated acute lower respiratory infection (ALRI) in children younger than 5 years during the pandemic period and the possible changes in RSV epidemiology from a global perspective. Our finding suggest that the hospitalisation burden of RSV-associated ALRI in children younger than 5 years was significantly reduced during the first year of the COVID-19 pandemic. The rebound in hospitalisation rates to pre-pandemic rates observed in the high-income region but not in the middle-income region by March, 2022, suggests a persistent negative impact of the pandemic on health-care systems and health-care access in the middle-income region. RSV surveillance needs to be established (or re-established) to monitor changes in RSV epidemiology, particularly in low-income and lower-middle-income countries.
Incidence of Human and Free-Ranging Wild Rodent Infections
Orin Courtenay, José F Marinho-Júnior, Maria Edileuza F Brito, Juliana FCLS Monteiro, Jeffrey J Shaw, Sinval P. Brandão-Filho
Human and wild rodent infection rates with Leishmania (Viannia) braziliensis are needed to differentiate transmission pathways in anthropogenically altered habitats. In this study, human participants in northeast Brazil were tested by the leishmanin skin test (LST) and inspected for lesions/scars characteristic of American clinical leishmaniasis (ACL). Molecular (PCR/qPCR) test records of free-ranging rodents were available from a concurrent capture–mark–recapture study. Force of Infection (λ) and recovery (ρ) rates were estimated from cross-sectional and longitudinal datasets. The results show human exposure to L. (V.) braziliensis continues to be high despite the substantial drop in reported ACL cases in recent years. Spill-over transmission risk to humans from rodents in peridomestic habitats is likely supported by a rodent infection/transmission corridor linking houses, plantations, and the Atlantic Forest.