Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

Peer reviewe

Estimating Carbon Budgets for Ambitious Climate Targets

Carbon budgets, which define the total allowable CO2 emissions associated with a given global climate target, are a useful way of framing the climate mitigation challenge. In this paper, we review the geophysical basis for the idea of a carbon budget, showing how this concept emerges from a linear climate response to cumulative CO2 emissions. We then discuss the difference between a “CO2-only carbon budget” associated with a given level of CO2-induced warming and an “effective carbon budget” associated with a given level of warming caused by all human emissions. We present estimates for the CO2-only and effective carbon budgets for 1.5 and 2 °C, based on both model simulations and updated observational data. Finally, we discuss the key contributors to uncertainty in carbon budget estimates and suggest some implications of this uncertainty for decision-making. Based on the analysis presented here, we argue that while the CO2-only carbon budget is a robust upper bound on allowable emissions for a given climate target, the size of the effective carbon budget is dependent on the how quickly we are able to mitigate non-CO2 greenhouse gas and aerosol emissions. This suggests that climate mitigation efforts could benefit from being responsive to a changing effective carbon budget over time, as well as to potential new information that could narrow uncertainty associated with the climate response to CO2 emissions

Developmental Dental Aberrations After the Dioxin Accident in Seveso

Children’s developing teeth may be sensitive to environmental dioxins, and in animal studies developing teeth are one of the most sensitive targets of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Twenty-five years after the dioxin accident in Seveso, Italy, 48 subjects from the contaminated areas (zones A and B) and in patches lightly contaminated (zone R) were recruited for the examination of dental and oral aberrations. Subjects were randomly invited from those exposed in their childhood and for whom frozen serum samples were available. The subjects were frequency matched with 65 subjects from the surrounding non-ABR zone for age, sex, and education. Concentrations of TCDD in previously analyzed plasma samples (zone ABR subjects only) ranged from 23 to 26,000 ng/kg in serum lipid. Ninety-three percent (25 of 27) of the subjects who had developmental enamel defects had been < 5 years of age at the time of the accident. The prevalence of defects in this age group was 42% (15 of 36) in zone ABR subjects and 26% (10 of 39) in zone non-ABR subjects, correlating with serum TCDD levels (p = 0.016). Hypodontia was seen in 12.5% (6 of 48) and 4.6% (3 of 65) of the zone ABR and non-ABR subjects, respectively, also correlating with serum TCDD level (p = 0.05). In conclusion, developmental dental aberrations were associated with childhood exposure to TCDD. In contrast, dental caries and periodontal disease, both infectious in nature, and oral pigmentation and salivary flow rate were not related to the exposure. The results support our hypothesis that dioxins can interfere with human organogenesis

SALSA - a sectional aerosol module for large scale applications

"The sectional aerosol module SALSA is introduced. The model has been designed to be implemented in large scale climate models, which require both accuracy and computational efficiency. We have used multiple methods to reduce the computational burden of different aerosol processes to optimize the model performance without losing physical features relevant to problematics of climate importance. The optimizations include limiting the chemical compounds and physical processes available in different size sections of aerosol particles; division of the size distribution into size sections using size sections of variable width depending on the sensitivity of microphysical processing to the particles sizes; the total amount of size sections to describe the size distribution is kept to the minimum; furthermore, only the relevant microphysical processes affecting each size section are calculated. The ability of the module to describe different microphysical processes was evaluated against explicit microphysical models and several microphysical models used in air quality models. The results from the current module show good consistency when compared to more explicit models. Also, the module was used to simulate a new particle formation event typical in highly polluted conditions with comparable results to more explicit model setup.""The sectional aerosol module SALSA is introduced. The model has been designed to be implemented in large scale climate models, which require both accuracy and computational efficiency. We have used multiple methods to reduce the computational burden of different aerosol processes to optimize the model performance without losing physical features relevant to problematics of climate importance. The optimizations include limiting the chemical compounds and physical processes available in different size sections of aerosol particles; division of the size distribution into size sections using size sections of variable width depending on the sensitivity of microphysical processing to the particles sizes; the total amount of size sections to describe the size distribution is kept to the minimum; furthermore, only the relevant microphysical processes affecting each size section are calculated. The ability of the module to describe different microphysical processes was evaluated against explicit microphysical models and several microphysical models used in air quality models. The results from the current module show good consistency when compared to more explicit models. Also, the module was used to simulate a new particle formation event typical in highly polluted conditions with comparable results to more explicit model setup.""The sectional aerosol module SALSA is introduced. The model has been designed to be implemented in large scale climate models, which require both accuracy and computational efficiency. We have used multiple methods to reduce the computational burden of different aerosol processes to optimize the model performance without losing physical features relevant to problematics of climate importance. The optimizations include limiting the chemical compounds and physical processes available in different size sections of aerosol particles; division of the size distribution into size sections using size sections of variable width depending on the sensitivity of microphysical processing to the particles sizes; the total amount of size sections to describe the size distribution is kept to the minimum; furthermore, only the relevant microphysical processes affecting each size section are calculated. The ability of the module to describe different microphysical processes was evaluated against explicit microphysical models and several microphysical models used in air quality models. The results from the current module show good consistency when compared to more explicit models. Also, the module was used to simulate a new particle formation event typical in highly polluted conditions with comparable results to more explicit model setup."Peer reviewe

Neurological Features and Enzyme Therapy in Patients With Endocrine and Exocrine Pancreas Dysfunction Due to CEL Mutations

OBJECTIVE—To further define clinical features associated with the syndrome of diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase (CEL) gene and to assess the effects of pancreatic enzyme substitution therapy

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe