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Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.

Previous studies have suggested that parents may support the development of theory of mind (ToM) in their child by talking about mental states (mental state talk; MST). However, MST has not been sufficiently explored in deaf children with cochlear implants (CIs). This study investigated ToM and availability of parental MST in deaf children with CIs (n = 39, M[subscript age] = 62.92, SD = 15.23) in comparison with their peers with typical hearing (TH; n = 52, M[subscript age] = 52.48, SD = 1.07). MST was measured during shared storybook reading. Parents' narratives were coded for cognitive, emotional, literal, and non-mental references. ToM was measured with a parental questionnaire. Children with CIs had lower ToM scores than their peers with TH, and their parents used more literal references during shared storybook reading. There were no significant differences in the frequencies of cognitive and emotional references between groups. Parental emotional references contributed positively to children's ToM scores when controlling for the child's age and receptive grammar only in the CI group. These results indicated some distinctive features in parents of deaf children with CIs' MST and highlighted the role of MST in the development of ToM abilities in this group.

Gene regulatory divergence is thought to play a central role in determining human-specific traits. However, our ability to link divergent regulation to divergent phenotypes is limited. Here, we utilized human-chimpanzee hybrid induced pluripotent stem cells to study gene expression separating these species. The tetraploid hybrid cells allowed us to separate cis- from trans-regulatory effects, and to control for nongenetic confounding factors. We differentiated these cells into cranial neural crest cells, the primary cell type giving rise to the face. We discovered evidence of lineage-specific selection on the hedgehog signaling pathway, including a human-specific sixfold down-regulation of EVC2 (LIMBIN), a key hedgehog gene. Inducing a similar down-regulation of EVC2 substantially reduced hedgehog signaling output. Mice and humans lacking functional EVC2 show striking phenotypic parallels to human-chimpanzee craniofacial differences, suggesting that the regulatory divergence of hedgehog signaling may have contributed to the unique craniofacial morphology of humans.

Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a 'big data' resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

Theory of mind (ToM) is crucial for social interactions. Previous research has indicated that deaf and hard-of-hearing children born into hearing families (DoH) are at risk of delayed ToM development. However, it is unclear whether this is the case for DoH children who receive cochlear implants (CIs) before and around the second year of life. The present study aimed to investigate false belief understanding (FBU) in DoH children with CIs. The relationships between false belief task (FBT) performance, sentence comprehension, age at implantation, duration of CI use, and Speech Recognition Threshold were explored. A total of 94 children with typical levels of hearing (TH) and 45 DoH children (age range: 3-8), who received their first CI between 6 and 27 months of age, were tested on the FBT and a sentence comprehension test. Results showed that 4- and 5-year-old children with CIs performed significantly worse than their peers with TH on the FBT; 6- to 8-year-old children with CIs performed similarly to age-matched children with TH. Age at implantation and duration of CI use were correlated with sentence comprehension but not with the FBT. The results indicated that FBU was delayed until the age of 6 years in most of children with CIs.

The Site of National Remembrance in Łambinowice, Poland is a complex of former prisoner of war (PoW) and resettlement camps that operated near the village from the time of the Prussian-French War (1870–1871) through the First and Second World Wars, including the interwar period, until the liquidation of the labor camp established by the Polish communist authorities in 1945–1946. Since June 2022, The Central Museum of Prisoners of War has been carrying out a project, a key part of which is the integration of various archaeological research methods for mapping the material remains of the camps that have been preserved until the present day in the local, mostly forested, landscape. Among the most important research problems was the issue of unknown and unmarked PoW burial sites and mass graves. The applied research methodology allowed, among other things, the locating of 60 structures, which can currently be interpreted as the quarters of Italian PoWs interned in Stalag VIII B (344) Lamsdorf at the end of the Second World War. The excavations ended with the identification by name of the first two Italian soldiers. [ABSTRACT FROM AUTHOR]

The FaceBase Consortium, funded by the National Institute of Dental and Craniofacial Research, National Institutes of Health, is designed to accelerate understanding of craniofacial developmental biology by generating comprehensive data resources to empower the research community, exploring high-throughput technology, fostering new scientific collaborations among researchers and human/computer interactions, facilitating hypothesis-driven research and translating science into improved health care to benefit patients. The resources generated by the FaceBase projects include a number of dynamic imaging modalities, genome-wide association studies, software tools for analyzing human facial abnormalities, detailed phenotyping, anatomical and molecular atlases, global and specific gene expression patterns, and transcriptional profiling over the course of embryonic and postnatal development in animal models and humans. The integrated data visualization tools, faceted search infrastructure, and curation provided by the FaceBase Hub offer flexible and intuitive ways to interact with these multidisciplinary data. In parallel, the datasets also offer unique opportunities for new collaborations and training for researchers coming into the field of craniofacial studies. Here, we highlight the focus of each spoke project and the integration of datasets contributed by the spokes to facilitate craniofacial research.

DEAD-box RNA helicases are vital for the regulation of various aspects of the RNA life cycle, but the molecular underpinnings of their involvement, particularly in mammalian cells, remain poorly understood. Here we show that the DEAD-box RNA helicase DDX21 can sense the transcriptional status of both RNA polymerase (Pol) I and II to control multiple steps of ribosome biogenesis in human cells. We demonstrate that DDX21 widely associates with Pol I- and Pol II-transcribed genes and with diverse species of RNA, most prominently with non-coding RNAs involved in the formation of ribonucleoprotein complexes, including ribosomal RNA, small nucleolar RNAs (snoRNAs) and 7SK RNA. Although broad, these molecular interactions, both at the chromatin and RNA level, exhibit remarkable specificity for the regulation of ribosomal genes. In the nucleolus, DDX21 occupies the transcribed rDNA locus, directly contacts both rRNA and snoRNAs, and promotes rRNA transcription, processing and modification. In the nucleoplasm, DDX21 binds 7SK RNA and, as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, is recruited to the promoters of Pol II-transcribed genes encoding ribosomal proteins and snoRNAs. Promoter-bound DDX21 facilitates the release of the positive transcription elongation factor b (P-TEFb) from the 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes. Our results uncover the multifaceted role of DDX21 in multiple steps of ribosome biogenesis, and provide evidence implicating a mammalian RNA helicase in RNA modification and Pol II elongation control.

The paper presents recommendations concerning the surveillance of patients after the treatment of squamous-cell carcinoma (SCC), basal-cell carcinoma (BCC) and Merkel-cell carcinoma (MCC) based on the current European and American recommendations. This overview discusses the methodology and detailed recommendations concerning the post-treatment surveillance, with special attention to the clinical examination, dermatoscopy, imaging diagnostics and patient education. The recommendations emphasise the significance of early monitoring for recurrences, and early detection of new skin cancers, adapted to individual risk factors in a patient and the characteristics of primary cancer. Also the significance of patient education, with regards to the protection against sun radiation and the role of skin self-examination are stressed. [ABSTRACT FROM AUTHOR]