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"Wolf, L"
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The clinical relevance of OSM in inflammatory diseases: a comprehensive review
Oncostatin M (OSM) is a pleiotropic cytokine involved in a variety of inflammatory responses such as wound healing, liver regeneration, and bone remodeling. As a member of the interleukin-6 (IL-6) family of cytokines, OSM binds the shared receptor gp130, recruits either OSMRβ or LIFRβ, and activates a variety of signaling pathways including the JAK/STAT, MAPK, JNK, and PI3K/AKT pathways. Since its discovery in 1986, OSM has been identified as a significant contributor to a multitude of inflammatory diseases, including arthritis, inflammatory bowel disease, lung and skin disease, cardiovascular disease, and most recently, COVID-19. Additionally, OSM has also been extensively studied in the context of several cancer types including breast, cervical, ovarian, testicular, colon and gastrointestinal, brain,lung, skin, as well as other cancers. While OSM has been recognized as a significant contributor for each of these diseases, and studies have shown OSM inhibition is effective at treating or reducing symptoms, very few therapeutics have succeeded into clinical trials, and none have yet been approved by the FDA for treatment. In this review, we outline the role OSM plays in a variety of inflammatory diseases, including cancer, and outline the previous and current strategies for developing an inhibitor for OSM signaling.
Journal Article
IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth
Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and an aberrant microbiota of the lung. Microbial colonization contributes to chronic neutrophilic inflammation in COPD. Nontypeable
Haemophilus influenzae
(NTHi) is frequently found in lungs of stable COPD patients and is the major pathogen triggering exacerbations. The epithelial cytokine interleukin-17C (IL-17C) promotes the recruitment of neutrophils into inflamed tissues. The purpose of this study was to investigate the function of IL-17C in the pulmonary tumor microenvironment. We subjected mice deficient for IL-17C (IL-17C
−/−
) and mice double deficient for Toll-like receptor 2 and 4 (TLR-2/4
−/−
) to a metastatic lung cancer model. Tumor proliferation and growth as well as the number of tumor-associated neutrophils was significantly decreased in IL-17C
−/−
and TLR-2/4
−/−
mice exposed to NTHi. The NTHi-induced pulmonary expression of IL-17C was dependent on TLR-2/4.
In vitro
, IL-17C increased the NTHi- and tumor necrosis factor-α-induced expression of the neutrophil chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 in lung cancer cells but did not affect proliferation. Human lung cancer samples stained positive for IL-17C, and in non-small cell lung cancer patients with lymph node metastasis, IL-17C was identified as a negative prognostic factor. Our data indicate that epithelial IL-17C promotes neutrophilic inflammation in the tumor microenvironment and suggest that IL-17C links a pathologic microbiota, as present in COPD patients, with enhanced tumor growth.
Journal Article
The Influence of Paleoclimate on Present-Day Patterns in Biodiversity and Ecosystems
Earth's climate has experienced strong changes on timescales ranging from decades to millions of years. As biodiversity has evolved under these circumstances, dependence on these climate dynamics is expected. In this review, we assess the current state of knowledge on paleoclimatic legacies in biodiversity and ecosystem patterns. Paleoclimate has had strong impacts on past biodiversity dynamics, driving range shifts and extinctions as well as diversification. We outline theory for how these dynamics may have left legacies in contemporary patterns and review the empirical evidence. We report ample evidence that Quaternary glacial-interglacial climate change affects current patterns of species distributions and diversity across a broad range of organisms and regions. We also report emerging evidence for paleoclimate effects on current patterns in phylogenetic and functional diversity and ecosystem functioning and for legacies of deeper-time paleoclimate conditions. Finally, we discuss implications for Anthropocene ecology and outline an agenda to improve our understanding of paleoclimate's role in shaping contemporary biodiversity and ecosystems.
Journal Article
Urban Trees and Human Health: A Scoping Review
The urban forest is a green infrastructure system that delivers multiple environmental, economic, social and health services, and functions in cities. Environmental benefits of urban trees are well understood, but no review to date has examined how urban trees affect human health. This review provides a comprehensive summary of existing literature on the health impacts of urban trees that can inform future research, policy, and nature-based public health interventions. A systematic search used keywords representing human health, environmental health, and urban forestry. Following screening and appraisal of several thousand articles, 201 studies were conceptually sorted into a three-part framework. Reducing Harm, representing 41% of studies, includes topics such as air pollution, ultraviolet radiation, heat exposure, and pollen. Restoring Capacities, at 31%, includes attention restoration, mental health, stress reduction, and clinical outcomes. Building Capacities, at 28%, includes topics such as birth outcomes, active living, and weight status. The studies that were reviewed show substantial heterogeneity in purpose and method yet indicate important health outcomes associated with people’s exposure to trees. This review will help inform future research and practice, and demonstrates why urban forest planning and management should strategically promote trees as a social determinant of public health.
Journal Article
A Universal Probe Set for Targeted Sequencing of 353 Nuclear Genes from Any Flowering Plant Designed Using k-Medoids Clustering
Sequencing of target-enriched libraries is an efficient and cost-effective method for obtaining DNA sequence data from hundreds of nuclear loci for phylogeny reconstruction. Much of the cost of developing targeted sequencing approaches is associated with the generation of preliminary data needed for the identification of orthologous loci for probe design. In plants, identifying orthologous loci has proven difficult due to a large number of whole-genome duplication events, especially in the angiosperms (flowering plants). We used multiple sequence alignments from over 600 angiosperms for 353 putatively single-copy protein-coding genes identified by the One Thousand Plant Transcriptomes Initiative to design a set of targeted sequencing probes for phylogenetic studies of any angiosperm group. To maximize the phylogenetic potential of the probes, while minimizing the cost of production, we introduce a k-medoids clustering approach to identify the minimum number of sequences necessary to represent each coding sequence in the final probe set. Using this method, 5–15 representative sequences were selected per orthologous locus, representing the sequence diversity of angiosperms more efficiently than if probes were designed using available sequenced genomes alone. To test our approximately 80,000 probes, we hybridized libraries from 42 species spanning all higher-order groups of angiosperms, with a focus on taxa not present in the sequence alignments used to design the probes. Out of a possible 353 coding sequences, we recovered an average of 283 per species and at least 100 in all species. Differences among taxa in sequence recovery could not be explained by relatedness to the representative taxa selected for probe design, suggesting that there is no phylogenetic bias in the probe set. Our probe set, which targeted 260 kbp of coding sequence, achieved a median recovery of 137 kbp per taxon in coding regions, a maximum recovery of 250 kbp, and an additional median of 212 kbp per taxon in flanking non-coding regions across all species. These results suggest that the Angiosperms353 probe set described here is effective for any group of flowering plants and would be useful for phylogenetic studies from the species level to higher-order groups, including the entire angiosperm clade itself.
Journal Article
Plant phylogeny as a window on the evolution of hyperdiversity in the tropical rainforest biome
Tropical rainforest (TRF) is the most species-rich terrestrial biome on Earth, harbouring just under half of the world’s plant species in c. 7% of the land surface. Phylogenetic trees provide important insights into mechanisms underpinning TRF hyperdiversity that are complementary to those obtained from the fossil record. Phylogenetic studies of TRF plant diversity have mainly focused on whether this biome is an evolutionary ‘cradle’ or ‘museum’, emphasizing speciation and extinction rates. However, other explanations, such as biome age, immigration and ecological limits, must also be considered. We present a conceptual framework for addressing the drivers of TRF diversity, and review plant studies that have tested them with phylogenetic data. Although surprisingly few in number, these studies point to old age of TRF, low extinction and high speciation rates as credible drivers of TRF hyperdiversity. There is less evidence for immigration and ecological limits, but these cannot be dismissed owing to the limited number of studies. Rapid methodological developments in DNA sequencing, macroevolutionary analysis and the integration of phylogenetics with other disciplines may improve our grasp of TRF hyperdiversity in the future. However, such advances are critically dependent on fundamental systematic research, yielding numerous, additional, well-sampled phylogenies of TRF lineages.
Journal Article
Nature Contact and Human Health: A Research Agenda
At a time of increasing disconnectedness from nature, scientific interest in the potential health benefits of nature contact has grown. Research in recent decades has yielded substantial evidence, but large gaps remain in our understanding.
We propose a research agenda on nature contact and health, identifying principal domains of research and key questions that, if answered, would provide the basis for evidence-based public health interventions.
We identify research questions in seven domains:
) mechanistic biomedical studies;
) exposure science;
) epidemiology of health benefits;
) diversity and equity considerations;
) technological nature;
) economic and policy studies; and
) implementation science.
Nature contact may offer a range of human health benefits. Although much evidence is already available, much remains unknown. A robust research effort, guided by a focus on key unanswered questions, has the potential to yield high-impact, consequential public health insights. https://doi.org/10.1289/EHP1663.
Journal Article
Acute Fatty Liver Disease of Pregnancy: Updates in Pathogenesis, Diagnosis, and Management
Acute fatty liver of pregnancy (AFLP) is an obstetric emergency characterized by maternal liver failure and may have complications for the mother and fetus, including death. This review examines recent literature on the epidemiology, pathogenesis, diagnosis, and treatment of acute fatty liver of pregnancy. Pathogenesis of this disease has been linked to defects in fatty acid metabolism during pregnancy, especially in the setting of fetal genetic defects in fatty acid oxidation. The value of screening all patients for these genetic defects remains to be determined. Distinguishing AFLP from other high-risk liver diseases of pregnancy that have overlap features, such as HELLP and preeclampsia, can be challenging. Although sensitive diagnostic tools such as the Swansea criteria have been developed, further work is needed to diagnose AFLP more quickly. Although survival rates have improved in the past 30 years, delay in diagnosis and treatment of AFLP has life-threatening consequences; an algorithmic approach to AFLP may be a valuable resource for clinicians. Future epidemiological and long-term studies will improve our prediction of women at risk for developing AFLP and determine the long-term consequences of this condition.
Journal Article
LEA29Y expression in transgenic neonatal porcine islet-like cluster promotes long-lasting xenograft survival in humanized mice without immunosuppressive therapy
Genetically engineered pigs are a promising source for islet cell transplantation in type 1 diabetes, but the strong human anti-pig immune response prevents its successful clinical application. Here we studied the efficacy of neonatal porcine islet-like cell clusters (NPICCs) overexpressing LEA29Y, a high-affinity variant of the T cell co-stimulation inhibitor CTLA-4Ig, to engraft and restore normoglycemia after transplantation into streptozotocin-diabetic NOD-SCID IL2rγ
−/−
(NSG) mice stably reconstituted with a human immune system. Transplantation of
INS
LEA29Y expressing NPICCs resulted in development of normal glucose tolerance (70.4%) and long-term maintenance of normoglycemia without administration of immunosuppressive drugs. All animals transplanted with wild-type NPICCs remained diabetic. Immunohistological examinations revealed a strong peri- and intragraft infiltration of wild-type NPICCs with human CD45
+
immune cells consisting of predominantly CD4
+
and CD8
+
lymphocytes and some CD68
+
macrophages and FoxP3
+
regulatory T cells. Significantly less infiltrating lymphocytes and only few macrophages were observed in animals transplanted with
INS
LEA29Y transgenic NPICCs. This is the first study providing evidence that beta cell-specific LEA29Y expression is effective for NPICC engraftment in the presence of a humanized immune system and it has a long-lasting protective effect on inhibition of human anti-pig xenoimmunity. Our findings may have important implications for the development of a low-toxic protocol for porcine islet transplantation in patients with type 1 diabetes.
Journal Article