Neural crest cells are embryonic progenitors that generate numerous cell types in vertebrates. With single-cell analysis, we show that mouse trunk neural crest cells become biased toward neuronal ...lineages when they delaminate from the neural tube, whereas cranial neural crest cells acquire ectomesenchyme potential dependent on activation of the transcription factor
The choices that neural crest cells make to become sensory, glial, autonomic, or mesenchymal cells can be formalized as a series of sequential binary decisions. Each branch of the decision tree involves initial coactivation of bipotential properties followed by gradual shifts toward commitment. Competing fate programs are coactivated before cells acquire fate-specific phenotypic traits. Determination of a specific fate is achieved by increased synchronization of relevant programs and concurrent repression of competing fate programs.
P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular ...details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function.
In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). ...We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.
Reef-building corals are endangered animals with a complex colonial organization. Physiological mechanisms connecting multiple polyps and integrating them into a coral colony are still enigmatic. ...Using live imaging, particle tracking, and mathematical modeling, we reveal how corals connect individual polyps and form integrated polyp groups via species-specific, complex, and stable networks of currents at their surface. These currents involve surface mucus of different concentrations, which regulate joint feeding of the colony. Inside the coral, within the gastrovascular system, we expose the complexity of bidirectional branching streams that connect individual polyps. This system of canals extends the surface area by 4-fold and might improve communication, nutrient supply, and symbiont transfer. Thus, individual polyps integrate via complex liquid dynamics on the surface and inside the colony.
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•Surface-associated currents connect individual polyps in a coral colony•Surface currents show species-specific topography, complexity, and speed variation•Mucus plays a role in surface currents to different extent depending on the species•Complex flow in the gastrovascular system further integrates individual polyps
Bouderlique et al. reveal a new way of integrating individual coral polyps via complex-surface-associated currents. These mucus-containing currents show species-specific patterns connecting individual polyps, removing debris to keep the surface clean and to help polyps to control individual feeding territories on the colony’s surface.
Although γδTCRs were discovered more than 30 yr ago, principles of antigen recognition by these receptors remain unclear and the nature of these antigens is largely elusive. Numerous studies reported ...that T cell hybridomas expressing several Vγ1‐containing TCRs, including the Vγ1Vδ6 TCR of γδNKT cells, spontaneously secrete cytokines. This property was interpreted as recognition of a self‐ligand expressed on the hybridoma cells themselves. Here, we revisited this finding using a recently developed reporter system and live single cell imaging. We confirmed strong spontaneous signaling by Vγ1Vδ6 and related TCRs, but not by TCRs from several other γδ or innate‐like αβ T cells, and demonstrated that both γ and δ chains contributed to this reactivity. Unexpectedly, live single cell imaging showed that activation of this signaling did not require any interaction between cells. Further investigation revealed that the signaling is instead activated by interaction with negatively charged surfaces abundantly present under regular cell culture conditions and was abrogated when noncharged cell culture vessels were used. This mode of TCR signaling activation was not restricted to the reporter cell lines, as interaction with negatively charged surfaces also triggered TCR signaling in ex vivo Vγ1 γδ T cells. Taken together, these results explain long‐standing observations on the spontaneous reactivity of Vγ1Vδ6 TCR and demonstrate an unexpected antigen presentation‐independent mode of TCR activation by a spectrum of chemically unrelated polyanionic ligands.
Synthetic polyanionic ligands, and not a self‐antigen, can cause reactivity of Vγ1 TCRs; offers an alternative explanation to long‐standing observations regarding the spontaneous reactivity of Vγ1 TCRs.
.
It is becoming increasingly clear that the communities of microorganisms that populate the surfaces exposed to the external environment, termed microbiota, are key players in the regulation of ...pathogen-host cross talk affecting the onset as well as the outcome of infectious diseases. We have performed a multicenter, prospective, observational study in which nasal and oropharyngeal swabs were collected for microbiota predicting the risk of invasive fungal infections (IFIs) in patients with hematological malignancies. Here, we demonstrate that the nasal and oropharyngeal microbiota are different, although similar characteristics differentiate high-risk from low-risk samples at both sites. Indeed, similar to previously published results on the oropharyngeal microbiota, high-risk samples in the nose were characterized by low diversity, a loss of beneficial bacteria, and an expansion of potentially pathogenic taxa, in the presence of reduced levels of tryptophan (Trp). At variance with oropharyngeal samples, however, low Trp levels were associated with defective host-derived kynurenine production, suggesting reduced tolerance mechanisms at the nasal mucosal surface. This was accompanied by reduced levels of the chemokine interleukin-8 (IL-8), likely associated with a reduced recruitment of neutrophils and impaired fungal clearance. Thus, the nasal and pharyngeal microbiomes of hematological patients provide complementary information that could improve predictive tools for the risk of IFI in hematological patients.
The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological ...patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as
and
, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.
Purpose
Several anatomic risk factors associated with patellofemoral disorders have been described. The purpose of this study was to analyze the relationship between bony parameters commonly used to ...analyze and define patellofemoral malalignment.
Methods
Patients with patellofemoral disorders presenting between 2016 and 2018 who underwent a standardized radiographic workup including conventional radiographs, weight bearing full-leg radiographs, magnetic resonance imaging (MRI) of the knee, and torsional analysis using hip–knee–ankle MRI were initially included. Patients with a history of lower extremity fracture and a history of surgical procedures affecting bony alignment or partial/total arthroplasty were subsequently excluded. Radiographs and MRI of all included patients were analyzed by four independent observers. Parameters of interest were: femoral torsion, tibial torsion, trochlear dysplasia, tibial tuberosity–trochlear groove (TT–TG) distance, and frontal mechanical axis. All parameters were compared between patients with low grade and high grade trochlear dysplasia as well as between female and male patients. Correlation of continuous variables was assessed with the Pearson correlation coefficient. A binary logistic regression model was used for the calculation of odds ratio between different parameters. Interclass correlation coefficients (ICC) were calculated to determine the interobserver reproducibility.
Results
A total of 151 patients could be included for detailed analysis. Group comparison revealed that patients with high grade trochlear dysplasia showed significantly higher values for femoral torsion (low grade: 9.8° ± 11.0°, high grade: 16.8° ± 11.5°;
p
< 0.001) and significantly higher values for TT–TG distance (low grade: 19.0 mm ± 5.0 mm, high grade: 21.9 mm ± 5.4 mm;
p
= 0.002). No significant difference was found for age, tibial torsion, and frontal mechanical axis. With regard to gender, female patients had higher values for femoral torsion (female: 15.6° ± 11.3°, male: 11.0° ± 12.7°;
p
= 0.044). The correlation analysis found significant correlation between femoral torsion and tibial torsion (
r
= 0.244,
p
= 0.003), femoral torsion and TT–TG distance (
r
= 0.328,
p
< 0.001), femoral torsion and frontal mechanical axis (
r
= 0.291,
p
< 0.001), and tibial torsion and TT–TG distance (
r
= 0.182,
p
= 0.026).
Conclusion
Bony malalignment in patients with patellofemoral disorder is a complex problem given the significant correlation between femoral and tibial torsion, trochlear dysplasia, TT–TG distance, and frontal mechanical axis. Advanced imaging to analyze rotational and frontal plane alignment is recommended in patients with trochlear dysplasia and/or increased TT–TG on standard radiographs and knee MRI. Understanding of the bony pathology in patellofemoral disorders is key to improve the therapeutic and surgical decision.
Level of evidence
III, retrospective cohort study.
Aim
Paleohydrological dynamics are well‐documented for European river systems, promoting shifting phases of isolation and connectivity of their aquatic fauna. These conditions coupled with high rates ...of hybridisation found in freshwater fishes may introduce considerable complexity and potential mito‐nuclear discordance of phylogenetic patterns. We evaluate this hypothesis using the first large‐scale analysis of nuclear SNPs in European species of grayling (Thymallus) compared to mtDNA data with the aim of reassessing the evolutionary history of this group of rheophilic fishes.
Location
Freshwater systems in Europe.
Methods
Based on mitochondrial (mitogenomes, control region) and nuclear (ddRADseq) data, we applied population‐genetic, phylogenetic, and biogeographic tools to evaluate lineage diversity in the context of paleohydrological alterations.
Results
The results corroborated previously recognised high levels of lineage diversity, but revealed several cases of mito‐nuclear discordance and signals of both historical (natural) and human‐mediated introgression among major inter‐ and intraspecific lineages of Thymallus in Europe. A time‐calibrated phylogeny and ancestral area estimation, based on nuclear SNP data, supported a late Pliocene diversification of the genus in Europe and suggested an early colonisation of the Black Sea basin with subsequent dispersal into Central and Western Europe.
Main Conclusions
The genetic structure of Thymallus in Europe recovered by nuclear SNPs contrasts considerably with that supported by mtDNA. Several instances of mito‐nuclear discordance underscore frequent contact of allopatric lineages in a dynamic paleohydrological landscape and reveal the weakness of basing both taxonomic and conservation decisions on inferences based on mtDNA alone. The Danube and Rhine drainages were inferred as important zones of contact between divergent phylogeographic lineages. Additionally, our data cast doubt on the genetic integrity of the endangered T. aeliani. Its divergence from T. thymallus, using nuclear SNPs, appears minimal as samples of T. aeliani group within Danubian lineages, despite carrying highly divergent reciprocally monophyletic mtDNA.
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