47 research outputs found
Transient Receptor Potential Vanilloid 6 (TRPV6) Proteins Control the Extracellular Matrix Structure of the Placental Labyrinth
Calcium-selective transient receptor potential Vanilloid 6 (TRPV6) channels are expressed in
fetal labyrinth trophoblasts as part of the fetoâmaternal barrier, necessary for sufficient calcium supply,
embryo growth, and bone development during pregnancy. Recently, we have shown a less- compact
labyrinth morphology of Trpv6-deficient placentae, and reduced Ca2+ uptake of primary trophoblasts
upon functional deletion of TRPV6. Trpv6-/-
trophoblasts show a distinct calcium-dependent phenotype.
Deep proteomic profiling of wt and Trpv6-/- primary trophoblasts using label-free quantitative mass
spectrometry leads to the identification of 2778 proteins. Among those, a group of proteases,
including high-temperature requirement A serine peptidase 1 (HTRA1) and different granzymes
are more abundantly expressed in Trpv6-/-
trophoblast lysates, whereas the extracellular matrix
protein fibronectin and the fibronectin-domain-containing protein 3A (FND3A) were markedly
reduced. Trpv6-/- placenta lysates contain a higher intrinsic proteolytic activity increasing fibronectin
degradation. Our results show that the extracellular matrix formation of the placental labyrinth
depends on TRPV6; its deletion in trophoblasts correlates with the increased expression of proteases
controlling the extracellular matrix in the labyrinth during pregnancy
Mutations that affect the surface expression of TRPV6 are associated with the upregulation of serine proteases in the placenta of an infant
Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R(510)stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G(660)R) that, surprisingly, does not affect the Ca(2+) permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G(660)R and R(510)stop mutants and combinations with wild type TRPV6. We show that both the G(660)R and R(510)stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases
Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal
dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in
an in frame stop codon (R510stop) that leads to a truncated, nonfunctional TRPV6 channel, and
the second in a point mutation (G660R) that, surprisingly, does not affect the Ca2+ permeability of
TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child
by coexpressing the TRPV6 G660R and R510stop mutants and combinations with wild type TRPV6.
We show that both the G660R and R510stop mutant subunits are expressed and result in decreased
calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within
the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the
diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our
results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the
placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain
the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an
increase in the expression of proteases
Isotopic evidence of high reliance on plant food among Later Stone Age hunter-gatherers at Taforalt, Morocco
The transition from hunting-gathering to agriculture stands as one of the most important dietary revolutions in human history. Yet, due to a scarcity of well-preserved human remains from Pleistocene sites, little is known about the dietary practices of pre-agricultural human groups. Here we present the isotopic evidence of pronounced plant reliance among Late Stone Age hunter-gatherers from North Africa (15,000â13,000 cal BP), predating the advent of agriculture by several millennia. Employing a comprehensive multi-isotopic approach, we conducted zinc (ÎŽ66Zn) and strontium (87Sr/86Sr) analysis on dental enamel, bulk carbon (ÎŽ13C) and nitrogen (ÎŽ15N) and sulfur (ÎŽ34S) isotope analysis on dentin and bone collagen, and single amino acid analysis on human and faunal remains from Taforalt (Morocco). Our results unequivocally demonstrate a substantial plant-based component in the diets of these hunter-gatherers. This distinct dietary pattern challenges the prevailing notion of high reliance on animal proteins among pre-agricultural human groups. It also raises intriguing questions surrounding the absence of agricultural development in North Africa during the early Holocene. This study underscores the importance of investigating dietary practices during the transition to agriculture and provides insights into the complexities of human subsistence strategies across different regions
Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications
BACKGROUND: The 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs). METHODS: As a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis. RESULTS: Our pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome. CONCLUSION: We show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications
Stable isotopes show Homo sapiens dispersed into cold steppes ~45,000 years ago at Ilsenhöhle in Ranis, Germany
The spread of Homo sapiens into new habitats across Eurasia ~45,000âyears ago and the concurrent disappearance of Neanderthals represents a critical evolutionary turnover in our species' history. 'Transitional' technocomplexes, such as the Lincombian-Ranisian-Jerzmanowician (LRJ), characterize the European record during this period but their makers and evolutionary significance have long remained unclear. New evidence from Ilsenhöhle in Ranis, Germany, now provides a secure connection of the LRJ to H. sapiens remains dated to ~45,000âyears ago, making it one of the earliest forays of our species to central Europe. Using many stable isotope records of climate produced from 16 serially sampled equid teeth spanning ~12,500âyears of LRJ and Upper Palaeolithic human occupation at Ranis, we review the ability of early humans to adapt to different climate and habitat conditions. Results show that cold climates prevailed across LRJ occupations, with a temperature decrease culminating in a pronounced cold excursion at ~45,000-43,000âcalâBP. Directly dated H. sapiens remains confirm that humans used the site even during this very cold phase. Together with recent evidence from the Initial Upper Palaeolithic, this demonstrates that humans operated in severe cold conditions during many distinct early dispersals into Europe and suggests pronounced adaptability. [Abstract copyright: © 2024. The Author(s).
Stepwise rotation of the Îł-subunit of EF<sub>o</sub>F<sub>1</sub>-ATP synthase during ATP synthesis:a single-molecule FRET approach
Triple sulfur-oxygen-strontium isotopes probabilistic geographic assignment of archaeological remains using a novel sulfur isoscape of western Europe
International audienceSulfur isotope composition of organic tissues is a commonly used tool for gathering information about provenance and diet in archaeology and paleoecology. However, the lack of maps predicting sulfur isotope variations on the landscape limits the possibility to use this isotopic system in quantitative geographic assignments. We compiled a database of 2,680 sulfur isotope analyses in the collagen of archaeological human and animal teeth from 221 individual locations across Western Europe. We used this isotopic compilation and remote sensing data to apply a multivariate machine-learning regression, and to predict sulfur isotope variations across Western Europe. The resulting model shows that sulfur isotope patterns are highly predictable, with 65% of sulfur isotope variations explained using only 4 variables representing marine sulfate deposition and local geological conditions. We used this novel sulfur isoscape and existing strontium and oxygen isoscapes of Western Europe to apply triple isotopes continuous-surface probabilistic geographic assignments to assess the origin of a series of teeth from local animals and humans from Brittany. We accurately and precisely constrained the origin of these individuals to limited regions of Brittany. This approach is broadly transferable to studies in archaeology and paleoecology as illustrated in a companion paper (Colleter et al. 2021)
Transitions alimentaires au NĂ©olithique et Ă l'Ăąge du Bronze : les analyses isotopiques
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