317 research outputs found
A biophysical model of prokaryotic diversity in geothermal hot springs
Recent field investigations of photosynthetic bacteria living in geothermal
hot spring environments have revealed surprisingly complex ecosystems, with an
unexpected level of genetic diversity. One case of particular interest involves
the distribution along hot spring thermal gradients of genetically distinct
bacterial strains that differ in their preferred temperatures for reproduction
and photosynthesis. In such systems, a single variable, temperature, defines
the relevant environmental variation. In spite of this, each region along the
thermal gradient exhibits multiple strains of photosynthetic bacteria adapted
to several distinct thermal optima, rather than the expected single thermal
strain adapted to the local environmental temperature. Here we analyze
microbiology data from several ecological studies to show that the thermal
distribution field data exhibit several universal features independent of
location and specific bacterial strain. These include the distribution of
optimal temperatures of different thermal strains and the functional dependence
of the net population density on temperature. Further, we present a simple
population dynamics model of these systems that is highly constrained by
biophysical data and by physical features of the environment. This model can
explain in detail the observed diversity of different strains of the
photosynthetic bacteria. It also reproduces the observed thermal population
distributions, as well as certain features of population dynamics observed in
laboratory studies of the same organisms
Nitrate- and silicate-competition among antarctic phytoplankton
Natural phytoplankton from antarctic waters in the Drake Passage were used for competition experiments in semicontinuous cultures. The outcome of interspecific competition for silicate and nitrate was studied at a range of Si:N ratios (from 2.6:1 to 425:1) and at three different dilution rates. For five species Monod kinetics of silicate-and nitrate-limited growth has been established. Comparison between theoretical predictions derived from Monod kinetics and the outcome of competition experiments showed only minor deviations. Contrary to literature data, considerable depletion of nitrate was found in antarctic seawater. Both the concentrations of soluble silicate and of nitrate were too low to support maximum growth rates of some of the diatom species under investigation
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Hematopoietic stem cell gene therapy for brain metastases using myeloid cell-specific gene promoters
Background:
Brain metastases (BrM) develop in 20-40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain due to the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems.
Methods:
Green fluorescent protein (GFP)-transduced murine and non-transduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene expression analysis and subsequent validation of a series of promoter-GFP-reporter constructs in mice (n = 5). One of the promoters was used to deliver TNF-related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL versus control group).
Results:
HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (37.6% [SD = 7.2%] of all infiltrating cells for murine HSC progeny; 27.9% [SD = 4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3-53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (8.8%, SD = 7.8%). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (19.0 [SD = 3.4] versus 15.0 [SD = 2.0] days for TRAIL versus control group; two-sided p = 0.006), demonstrating therapeutic and translational potential of our approach.
Conclusions:
Our study establishes HSC gene therapy using a myeloid cell-specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions
Notch signalling is a potential resistance mechanism of progenitor cells within patient-derived prostate cultures following ROS-inducing treatments
Low Temperature Plasma (LTP) generates reactive oxygen and nitrogen species, causing cell death, similarly to radiation. Radiation resistance results in tumour recurrence, however mechanisms of LTP resistance are unknown. LTP was applied to patient-derived prostate epithelial cells and gene expression assessed. A typical global oxidative response (AP-1 and Nrf2 signalling) was induced, whereas Notch signalling was activated exclusively in progenitor cells. Notch inhibition induced expression of prostatic acid phosphatase (PAP), a marker of prostate epithelial cell differentiation, whilst reducing colony forming ability and preventing tumour formation. Therefore, if LTP is to be progressed as a novel treatment for prostate cancer, combination treatments should be considered in the context of cellular heterogeneity and existence of cell type-specific resistance mechanisms
Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma
The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with “low”, “intermediate”, and “high” immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-κB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-κB pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma.
Significance: These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival
Disturbance-diversity relationships in two lakes of similar nutrient chemistry but contrasting disturbance regimes
Phytoplankton diversity was studied in two North German lakes of comparable nutrient chemistry but different exposure to winds. In both lakes, phytoplankton was primarily N-limited but diatoms were Si-limited. PluĂźsee had a very constant mixing depth during summer, while week-to-week changes of several meters were quite common in the more exposed Behler See. In PluĂźsee, phytoplankton biomass during summer came closer to the carrying capacity as defined by the available total N. In PluĂźsee there was a marked decline of diversity during the summer maximum of biomass, while this decline was less pronounced in Behler See. It is concluded that disturbances which prevented phytoplankton from reaching the carrying capacity also maintained a high level of diversity. A negative response of diversity to undisturbed conditions became apparent, after phytoplankton biomass had exceeded about 5% of the carrying capacity
Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma
Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments
Plankton ecology: The past two decades of progress
This is a selected account of recent developments
in plankton ecology. The examples have been
chosen for their degree of innovation during the
past two decades and for their general ecological
importance. They range from plankton autecology
over interactions between populations to community
ecology. The autecology of plankton is
represented by the hydromechanics of plankton
(the problem of life in a viscous environment) and
by the nutritional ecology of phyto- and zooplankton.
Population level studies are represented
by competition, herbivory (grazing), and zooplankton
responses to predation. Community
ecology is represented by the debate about bottom-
up vs. top-down control of community organization,
by the PEG model of seasonal plankton
succession, and by the recent discovery of the microbial
food web
Human iPSC-derived RPE and retinal organoids reveal impaired alternative splicing of genes involved in pre-mRNA splicing in PRPF31 autosomal dominant retinitis pigmentosa
Aspirations and realities in a North-South partnership for health promotion: lessons from a program to promote safe male circumcision in Botswana
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