Just when you thought it was safe to go into the membrane: the growing complexities of extra-nuclear progesterone signaling

The diversity of membrane-initiated progesterone actions has made characterization and establishment of its biological importance a complicated endeavor. A new study by Zuo and colleagues shows that progesterone via endogenous membrane progesterone receptor-α acts as a negative regulator of proliferation and epithelial to mesenchymal transition in a breast cancer cell line. These progesterone-mediated actions appear to be regulated through epidermal growth factor receptor and phosphatidylinositol 3-kinase signaling localized in caveolae. Moreover, the study shows expression of membrane progesterone receptor-α in benign and malignant breast cancer tissues. These data bring forth novel concepts with regard to progesterone actions in the breast; however, further work is warranted to fully characterize the physiologic actions of extra-nuclear progesterone signaling in the breast

The Golden Meteorite Fall: Fireball Trajectory, Orbit and Meteorite Characterization

The Golden (British Columbia, Canada) meteorite fall occurred on Oct 4, 2021 at 0534 UT with the first recovered fragment (1.3 kg) landing on an occupied bed. The meteorite is an unbrecciated, low-shock (S2) ordinary chondrite of intermediate composition, typed as an L/LL5. From noble gas measurements the cosmic ray exposure age is 25 Ma while gas retention ages are all >2 Ga. Short-lived radionuclides and noble gas measurements of the pre-atmospheric size overlap with estimates from infrasound and lightcurve modelling producing a preferred pre-atmospheric mass of 70-200 kg. The orbit of Golden has a high inclination (23.5 degs) and is consistent with delivery from the inner main belt. The highest probability (60%) of an origin is from the Hungaria group. We propose that Golden may originate among the background S-type asteroids found interspersed in the Hungaria region. The current collection of 18 L and LL chondrite orbits shows a strong preference for origins in the inner main belt, suggesting multiple parent bodies may be required to explain the diversity in CRE ages and shock states.Comment: 92 Pages, 20 Tables, 21 Figures, plus 3 appendices, accepted in Meteoritics and Planetary Science Oct 26 202

Expression and Membrane Topology of Anopheles gambiae Odorant Receptors in Lepidopteran Insect Cells

A lepidopteran insect cell-based expression system has been employed to express three Anopheles gambiae odorant receptors (ORs), OR1 and OR2, which respond to components of human sweat, and OR7, the ortholog of Drosophila's OR83b, the heteromerization partner of all functional ORs in that system. With the aid of epitope tagging and specific antibodies, efficient expression of all ORs was demonstrated and intrinsic properties of the proteins were revealed. Moreover, analysis of the orientation of OR1 and OR2 on the cellular plasma membrane through the use of a novel ‘topology screen’ assay and FACS analysis demonstrates that, as was recently reported for the ORs in Drosophila melanogaster, mosquito ORs also have a topology different than their mammalian counterparts with their N-terminal ends located in the cytoplasm and their C-terminal ends facing outside the cell. These results set the stage for the production of mosquito ORs in quantities that should permit their detailed biochemical and structural characterization and the exploration of their functional properties

Functional hemizygosity in the human genome: direct estimate from twelve erythrocyte enzyme loci

Cord blood samples from 2020 unrelated newborns were screened for levels of enzyme activity for twelve enzymes. The level of enzymatic activity for 100 determinations were consistent with the existence of an enzyme-deficiency allele. The frequency of deficiency alleles in the Black population (0.0071) was four times higher (after removal of the G6PD * A - variant) than in the Caucasian sample (0.0016). These frequencies are approximately double the frequency of rare electrophoretic mobility variants at similar loci in the same population. Given the number of functionally important loci in the human genome, these enzyme deficiency variants could constitute a significant health burden.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47620/1/439_2004_Article_BF00284477.pd

Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny.

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate