Metastatic site influences driver gene function in pancreatic cancer.

Driver gene mutations can increase the metastatic potential of the primary tumor, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of - a transcriptional effector of TGFβ signaling - which is a hallmark of multiple gastrointestinal malignancies. inactivation mediates TGFβ's remarkable anti- to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis.

High-throughput evaluation of genetic variants with prime editing sensor libraries.

Tumor genomes often harbor a complex spectrum of single nucleotide alterations and chromosomal rearrangements that can perturb protein function. Prime editing has been applied to install and evaluate genetic variants, but previous approaches have been limited by the variable efficiency of prime editing guide RNAs. Here we present a high-throughput prime editing sensor strategy that couples prime editing guide RNAs with synthetic versions of their cognate target sites to quantitatively assess the functional impact of endogenous genetic variants.

Lake surface cooling drives littoral-pelagic exchange of dissolved gases.

The extent of littoral influence on lake gas dynamics remains debated in the aquatic science community due to the lack of direct quantification of lateral gas transport. The prevalent assumption of diffusive horizontal transport in gas budgets fails to explain anomalies observed in pelagic gas concentrations. Here, we demonstrate through high-frequency measurements in a eutrophic lake that daily convective horizontal circulation generates littoral-pelagic advective gas fluxes one order of magnitude larger than typical horizontal fluxes used in gas budgets.

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium.

Generation of precision preclinical cancer models using regulated in vivo base editing.

Although single-nucleotide variants (SNVs) make up the majority of cancer-associated genetic changes and have been comprehensively catalogued, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a mouse system for temporal and regulatable in vivo base editing. The inducible base editing (iBE) mouse carries a single expression-optimized cytosine base editor transgene under the control of a tetracycline response element and enables robust, doxycycline-dependent expression across a broad range of tissues in vivo.

Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.

The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci.

Pain Levels of Women Diagnosed with Endometriosis: Is There a Difference in Younger Women?

Study Objective: Early diagnosis and treatment of endometriosis affecting adolescent women are important in preventing chronic pain. Our aim was to analyze the clinical characteristics and severity of symptoms in adolescent patients with endometriosis compared with older patients.

Methods: This single-center retrospective cohort study in a tertiary referral hospital analyzed women whose first consultation at the certified endometriosis center of Bern University Hospital between January 2017 and December 2020 resulted in the clinical diagnosis of endometriosis.

Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity.

Unlabelled: Cellular senescence involves a stable cell-cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune-competent liver cancer model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels the cell-surface proteome to alter how tumor cells sense environmental factors, as exemplified by type II interferon (IFNγ). Compared with proliferating cells, senescent cells upregulate the IFNγ receptor, become hypersensitized to microenvironmental IFNγ, and more robustly induce the antigen-presenting machinery-effects also recapitulated in human tumor cells undergoing therapy-induced senescence.

Mycobacterium abscessus pathogenesis identified by phenogenomic analyses.

The medical and scientific response to emerging and established pathogens is often severely hampered by ignorance of the genetic determinants of virulence, drug resistance and clinical outcomes that could be used to identify therapeutic drug targets and forecast patient trajectories. Taking the newly emergent multidrug-resistant bacteria Mycobacterium abscessus as an example, we show that combining high-dimensional phenotyping with whole-genome sequencing in a phenogenomic analysis can rapidly reveal actionable systems-level insights into bacterial pathobiology. Through phenotyping of 331 clinical isolates, we discovered three distinct clusters of isolates, each with different virulence traits and associated with a different clinical outcome.

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants.

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems.

The Imprint of Primary Production on High-Frequency Profiles of Lake Optical Properties.

Water inherent optical properties (IOPs) contain integrative information on the optical constituents of surface waters. In lakes, IOP measurements have not been traditionally collected. This study describes how high-frequency IOP profiles can be used to document short-term physical and biogeochemical processes that ultimately influence the long-term trajectory of lake ecosystems.

The Red Harmful Plague in Times of Climate Change: Blooms of the Cyanobacterium Triggered by Stratification Dynamics and Irradiance.

is a harmful planktonic cyanobacterium, forming concentrated metalimnetic populations in deep oligo- and mesotrophic lakes, even after successful restoration. In Lake Zurich (Switzerland), emerged as a keystone species with annual mass developments since the 1970s. Its success was partly attributed to effects of lake warming, such as changes in thermal stratification and seasonal deep mixing.

Increasing Carbon-to-Phosphorus Ratio (C:P) from Seston as a Prime Indicator for the Initiation of Lake Reoligotrophication.

Decline in total phosphorus (TP) during lake reoligotrophication does not apparently immediately influence carbon assimilation or deep-water oxygen levels. Traditional monitoring and interpretation do not typically consider the amount of organic carbon exported from the productive zone into the hypolimnion as a measure of net ecosystem production. This research investigated the carbon-to-phosphorus ratios of suspended particles in the epilimnion, (C:P), as indicators of changing productivity.

Meteolakes: An operational online three-dimensional forecasting platform for lake hydrodynamics.

Environmental management depends on high-quality monitoring and its meaningful interpretation. The combination of local weather dynamics, regional anthropogenic stresses and global environmental changes make the evaluation of monitoring information in dynamic freshwater systems a challenging task. While the lake ecosystems gather many complex biogeochemical interactions, they remain constrained by the same physical environment of mixing and transport.

Oxygen consumption in seasonally stratified lakes decreases only below a marginal phosphorus threshold.

Areal oxygen (O) consumption in deeper layers of stratified lakes and reservoirs depends on the amount of settling organic matter. As phosphorus (P) limits primary production in most lakes, protective and remediation efforts often seek to reduce P input. However, lower P concentrations do not always lead to lower O consumption rates.

Enlarged posterior fossa on prenatal imaging: differential diagnosis, associated anomalies and postnatal outcome.

Introduction: The primary aim of this study was to ascertain the prevalence of the individual conditions and of associated anomalies in fetuses with the prenatal diagnosis of enlarged posterior fossa (PF) and to explore the diagnostic accuracy of ultrasound in these anomalies. The secondary aim was to evaluate the postnatal outcome of children affected by PF anomalies.

Material And Methods: All fetuses with enlarged PF detected by prenatal sonography at a referral center from 2001 to 2015 were analyzed retrospectively.

A conceptual framework for hydropeaking mitigation.

Hydropower plants are an important source of renewable energy. In the near future, high-head storage hydropower plants will gain further importance as a key element of large-scale electricity production systems. However, these power plants can cause hydropeaking which is characterized by intense unnatural discharge fluctuations in downstream river reaches.

Application of remote sensing for the optimization of in-situ sampling for monitoring of phytoplankton abundance in a large lake.

Directives and legislations worldwide aim at representatively and continuously monitoring the ecological status of surface waters. In many countries, chlorophyll-a concentrations (CHL) are used as an indicator of phytoplankton abundance and the trophic level of lakes or reservoirs. In-situ measurements of water quality parameters, however, are time-consuming, costly and of unknown but naturally limited spatial representativeness.

Characterisation of the subaquatic groundwater discharge that maintains the permanent stratification within Lake Kivu; East Africa.

Warm and cold subaquatic groundwater discharge into Lake Kivu forms the large-scale density gradients presently observed in the lake. This structure is pertinent to maintaining the stratification that locks the high volume of gases in the deepwater. Our research presents the first characterisation of these inflows.

Retrieval of vertical particle concentration profiles by optical remote sensing: a model study.

Water-leaving radiance is subject to depth variability of the water constituents. The optical penetration depth is strongly dependent on the wavelength λ, which allows to retrieve a non-uniform vertical profile of an optically-active constituent CTSM(z) from remote-sensing reflectance Rrs(λ,Cz). We define the apparent particle concentration CTSM,app(λ) of a vertically homogeneous water column whose Rrs(λ,Cconst) matches Rrs(λ,Cz).

Accelerated water quality improvement during oligotrophication in peri-alpine lakes.

Monitoring of four eutrophic Swiss lakes undergoing oligotrophication during more than 25 years (i.e., gradually decreasing nutrient loading, productivity, and associated symptoms of eutrophication) revealed that phosphorus (P) net sedimentation rates (the fraction of a lake's total P content that is buried within its sediments each year) and P export rates (the fraction of the lakes' total P content that is exported via the outlet each year) increased as the lakes' P contents decreased.