Genomic imputation of ancient Asian populations contrasts local adaptation in pre- and post-agricultural Japan.

Early modern humans lived as hunter-gatherers for millennia before agriculture, yet the genetic adaptations of these populations remain a mystery. Here, we investigate selection in the ancient hunter-gatherer-fisher Jomon and contrast pre- and post-agricultural adaptation in the Japanese archipelago. Building on the successful validation of imputation with ancient Asian genomes, we identify selection signatures in the Jomon, particularly robust signals from KITLG variants, which may have influenced dark pigmentation evolution. The Jomon lacks well-known adaptive variants (EDAR, ADH1B, and ALDH2), marking their emergence after the advent of farming in the archipelago. Notably, the EDAR and ADH1B variants were prevalent in the archipelago 1,300 years ago, whereas the ALDH2 variant could have emerged later due to its absence in other ancient genomes. Overall, our study underpins local adaptation unique to the Jomon population, which in turn sheds light on post-farming selection that continues to shape contemporary Asian populations.

OVOL2 induces mesenchymal-to-epithelial transition in fibroblasts and enhances cell-state reprogramming towards epithelial lineages.

Mesenchymal-to-epithelial transition (MET) is an important step in cell reprogramming from fibroblasts (a cell type frequently used for this purpose) to various epithelial cell types. However, the mechanism underlying MET induction in fibroblasts remains to be understood. The present study aimed to identify the transcription factors (TFs) that efficiently induce MET in dermal fibroblasts. OVOL2 was identified as a potent inducer of key epithelial genes, and OVOL2 cooperatively enhanced MET induced by HNF1A, TP63, and KLF4, which are known reprogramming TFs to epithelial lineages. In TP63/KLF4-induced keratinocyte-like cell-state reprogramming, OVOL2 greatly facilitated the activation of epithelial and keratinocyte-specific genes. This was accompanied by enhanced changes in chromatin accessibility across the genome. Mechanistically, motif enrichment analysis revealed that the target loci of KLF4 and TP63 become accessible upon induction of TFs, whereas the OVOL2 target loci become inaccessible. This indicates that KLF4 and TP63 positively regulate keratinocyte-associated genes whereas OVOL2 suppresses fibroblast-associated genes. The exogenous expression of OVOL2 therefore disrupts fibroblast lineage identity and facilitates fibroblast cell reprogramming into epithelial lineages cooperatively with tissue-specific reprogramming factors. Identification of OVOL2 as an MET inducer and an epithelial reprogramming enhancer in fibroblasts provides new insights into cellular reprogramming improvement for future applications.

Antigen 85 variation across lineages of Mycobacterium tuberculosis-implications for vaccine and biomarker success.

Mycobacterium tuberculosis secretes several hundred proteins; many of which elicit immune responses. As a result, many of these proteins have been explored for their potential as diagnostic and vaccine candidates. Of these, the Antigen 85 complex proteins, represented by Antigen85 A, B, and C, are the most studied from the mycobacterial secretome. However, vaccine constructs exploiting Antigen 85 as the sole antigen repertoire have not experienced the pre-clinical and clinical trials success originally anticipated. Anecdotal and biochemical evidence suggests that differences in protein abundance may explain this phenomenon. Here, biochemical, molecular, and mass spectrometry approaches were used to quantify Antigen 85 among six M. tuberculosis strains from four phylogenetically distinct clades. Our data demonstrates that the greatest variation in Antigen 85 is ascribed to protein quantities, whereas few transcriptional differences were found. In addition, the ratio of Antigen 85 A, to B, to C is conserved within clades and phylogenetic neighbors. In contrast, no such relationship between individual protein quantities was observed, and in the case of Antigen85 B, this variation even extends within biological replicates of individual isolates. The relevance of Antigen 85 protein quantities and vaccine efficacy remains to be defined. BIOLOGICAL SIGNIFICANCE: Absolute quantitation via multiple reaction monitoring mass spectrometry was used to determine the exact molar concentrations of Antigen 85A, B, and C; three key immunodominant proteins present in M. tuberculosis. Further, the concentration of these three proteins was compared among various clades of M. tuberculosis, and demonstrated differences in abundance of two of the three proteins. These proteins have been identified as key antigens in multiple vaccine and diagnostic platforms, thus the potential relevance of their abundance in various M. tuberculosis clades to the successful outcome of these interventions is discussed. This article is part of a Special Issue entitled: Trends in Microbial Proteomics.

Trends in indirect dentistry: 6. Provisional restorations, more than just a temporary.

The provision of well-fitting, functional provisional restorations is important for a wide variety of reasons, including maintenance of the stability of inter- and intra-arch relationships and positional stability of prepared teeth, and the preservation of occlusal function of anterior provisional restorations by providing appropriate protrusive and lateral guidance. Provisional restorations should be of sufficient strength to resist the forces of occlusion and should be luted with a cement that will resist the forces of removal, yet allow easy removal at the fit appointment without leaving a residue on the prepared tooth. This paper describes the use of provisional restorations in indirect restorative dentistry and suggests some specific techniques for clinical use.