New designs based on S0 Lamb modes in AlN thin layer resonating structures coupled with the implementation of structural elements in SiO2, are theoretically analyzed by the Finite Element Method (FEM). This study compares the typical characteristics of different interdigital transducer (IDTs) configurations, involving either a continuous SiO2 cap layer, or structured SiO2 elements, showing their performance in the usual terms of electromechanical coupling coefficient (K2), phase velocity, and temperature coefficient of frequency (TCF), by varying structural parameters and boundary conditions. This paper shows how to reach temperature-compensated, high-performance resonator structures based on ribbon-structured SiO2 capping. The addition of a thin diamond layer can also improve the velocity and electromechanical coupling coefficient, while keeping zero TCF and increasing the solidity of the membranes. Beyond the increase in performance allowed by such resonator configurations, their inherent structure shows additional benefits in terms of passivation, which makes them particularly relevant for sensing applications in stern environments.

Diabetes, which is characterized by an increase in blood glucose concentration, is accompanied by low bone turnover, increased fracture risk, and the formation of embryonic skeletal malformations. Yet, there are few studies elucidating the underlying alterations in signaling pathways leading to these osteogenic defects. We hypothesized here that bone formation deficiencies in a high glucose environment result from altered activity of beta-catenin (CTNNB1), a key contributor to osteogenic differentiation, dysregulation of which has also been implicated in the development of diabetes.
To test this hypothesis, we used a previously established embryonic stem cell (ESC) model of differentiation that mimics the diabetic environment of the developing embryo. We differentiated murine ESCs within osteogenic-inducing media containing either high (diabetic) or low (physiological) levels of D-glucose and performed time course analyses to study the influence of high glucose on early and late bone cell differentiation.
Endpoint measures for osteogenic differentiation were reduced in a glucose-dependent manner and expression of precursor-specific markers altered at multiple time points. Furthermore, transcriptional activity of the lymphoid enhancer factor (LEF)/T cell factor (TCF) transcription factors during precursor formation stages was significantly elevated while levels of CTNNB1 complexed with Forkhead box O 3a (FOXO3a) declined. Modulation of AKT, a known upstream regulator of both LEF/TCF and FOXO3a, as well as CTNNB1 rescued some of the reductions in osteogenic output seen in the high glucose condition.
Within our in vitro model, we found a clear involvement of LEF/TCF and FOXO3a signaling pathways in the regulation of osteogenic differentiation, which may account for the skeletal deficiencies found in newborns of diabetic mothers.

WNT/β-catenin signaling controls gene expression across biological contexts from development and stem cell homeostasis to diseases including cancer. How β-catenin is recruited to distinct enhancers to activate context-specific transcription is unclear, given that most WNT/ß-catenin-responsive transcription is thought to be mediated by TCF/LEF transcription factors (TFs). With time-resolved multi-omic analyses, we show that SOX TFs can direct lineage-specific WNT-responsive transcription during the differentiation of human pluripotent stem cells (hPSCs) into definitive endoderm and neuromesodermal progenitors. We demonstrate that SOX17 and SOX2 are required to recruit β-catenin to lineage-specific WNT-responsive enhancers, many of which are not occupied by TCFs. At TCF-independent enhancers, SOX TFs establish a permissive chromatin landscape and recruit a WNT-enhanceosome complex to activate SOX/ß-catenin-dependent transcription. Given that SOX TFs and the WNT pathway are critical for specification of most cell types, these results have broad mechanistic implications for the specificity of WNT responses across developmental and disease contexts.

Hypochlorous acid/hypochlorite (HOCl/ClO-) plays important roles in killing bacterial and causing damage to living tissues, and its abnormal levels could lead to many diseases. Although great efforts have been devoted, fluorescent probes for HOCl/ClO- with near-infrared fluorescence, good selectivity/sensitivity, and low background are still important and urgent. In this work, a novel double-bond-linked TCF-aza-BODIPY-based near-infrared fluorescent probe (3) was rationally designed, successfully prepared, and applied for sensing HOCl/ClO- in both solutions and living RAW264.7 cells, showing good selectivity and fluorescence \"turn-on\" phenomenon at 670 nm with low background. The limit of detection towards ClO- was determined to be 0.36 μM through the linear fluorescence changes at 670 nm in a broad ClO--concentration range of 0-150 μM. Furthermore, the sensing mechanism was investigated by mass spectrometry and compared with 1, suggesting that the remarkable spectroscopic changes could be ascribed to the oxidization of the double bond to the aldehyde group, accompanied with the leaving of the TCF group. Confocal imaging experiments also confirmed the remarkable intracellular fluorescence enhancements through incubation of ClO- and phorbol ester 12-myristate 13-acetate (PMA) in RAW264.7 cells. Therefore, for the first time, we reported a near-infrared TCF-aza-BODIPY-based fluorescent probe for highly sensitive and fluorescence \"turn-on\" detection of both exogenous and endogenous HOCl in living RAW264.7 cells through the quick oxidation of a conjugated double bond.

The Dishevelled gene was first identified in Drosophila mutants with disoriented hair and bristle polarity and subsequent work has now demonstrated its importance in critical and diverse aspects of biology. Since those early discoveries, Dishevelled has been shown to coordinate a plethora of developmental and cellular processes that range from controlling cell polarity during gastrulation to partnering with chromatin modifying enzymes to regulate histone methylation at genomic loci. While the role of DVL in development is well-respected and the cytosolic function of DVL has been studied more extensively, its nuclear role continues to remain murky. In this review we highlight some of the seminal discoveries that have contributed to the field, but the primary focus is to discuss recent advances with respect to the nuclear role of Dishevelled. This nuclear function of Dishevelled is a dimension which is proving to be increasingly important yet remains enigmatic.

Serum response factor (SRF) is a representative transcription factor that plays crucial roles in various biological phenomena by regulating immediate early genes (IEGs) and genes related to cell morphology and motility, among others. Over the years, the signal transduction pathways activating SRF have been clarified and SRF-target genes have been identified. In this overview, we initially briefly summarize the basic biology of SRF and its cofactors, ternary complex factor (TCF) and megakaryoblastic leukemia (MKL)/myocardin-related transcription factor (MRTF). Progress in the generation of nervous system-specific knockout (KO) or genetically modified mice as well as genetic analyses over the last few decades has not only identified novel SRF-target genes but also highlighted the neurochemical importance of SRF and its cofactors. Therefore, here we next present the phenotypes of mice with nervous system-specific KO of SRF or its cofactors by depicting recent findings associated with brain development, plasticity, epilepsy, stress response, and drug addiction, all of which result from function or dysfunction of the SRF axis. Last, we develop a hypothesis regarding the possible involvement of SRF and its cofactors in human neurological disorders including neurodegenerative, psychiatric, and neurodevelopmental diseases. This overview should deepen our understanding, highlight promising future directions for developing novel therapeutic strategies, and lead to illumination of the mechanisms underlying higher brain functions based on neuronal structure and function.

T-cell-like factor (TCF)7l2, a key effector of canonical Wnt signaling, is highly expressed in bone but nothing is known about its role in regulating osteoblast function. To test this, we generated mice with conditional disruption of Tcf7l2 gene in osteoblast lineages using Tcf7l2 floxed and Col1α2-Cre mice. Skeletal parameters were evaluated using heterozygous conditional knockdown (HCKD) mice since homozygous conditional knockout died during pregnancy or immediately after birth. At 5 wk of age, trabecular bone mass of long bones was reduced by 35% as measured by microcomputed tomography (μCT). Histology data showed a 42% reduction in femur trabecular bone mass caused by reduced bone formation. Knockdown of Tcf7l2 expression in osteoblasts decreased proliferation and differentiation by 20%-40%. Expression levels of genes (Hif1α, Vegf, and β-catenin) targeted by TCF7L2 were decreased by 50% in Tcf7l2-deficient osteoblasts and bones of HCKD mice. We found that the Hif1α gene promoter contained multiple putative TCF7L2 motifs and stabilization of HIF1α protein levels rescued expression of TCF7L2 target genes and alkaline phosphatase (ALP) activity in Tcf7l2-deficient osteoblasts. Furthermore, Tcf7l2 overexpression increased proliferation in the presence of canonical Wnt3a that was not affected by β-catenin inhibitor providing evidence for a noncanonical signaling in mediating TCF7L2 effects. Tcf7l2 expression was increased in response to mechanical strain (MS) in vitro and in vivo, and disruption of Tcf7l2 expression in osteoblasts reduced MS-induced ALP activity by 35%. We conclude that Tcf7l2, a mechanoresponsive gene, is an important regulator of osteoblast function acting, in part, via hypoxia signaling.NEW & NOTEWORTHY TCF7L2 is expressed by bone but it was not known whether TCF7L2 expression influenced bone development. By using a mouse model with conditional disruption of Tcf7l2 in osteoblast lineage cells, we have demonstrated for the first time, that TCF7L2 plays an important role in regulating osteoblasts via a noncanonical pathway.

Serum response factor (SRF) is an essential transcription factor that influences many cellular processes including cell proliferation, migration, and differentiation. SRF directly regulates and is required for immediate early gene (IEG) and actin cytoskeleton-related gene expression. SRF coordinates these competing transcription programs through discrete sets of cofactors, the ternary complex factors (TCFs) and myocardin-related transcription factors (MRTFs). The relative contribution of these two programs to in vivo SRF activity and mutant phenotypes is not fully understood. To study how SRF utilizes its cofactors during development, we generated a knock-in SrfaI allele in mice harboring point mutations that disrupt SRF-MRTF-DNA complex formation but leave SRF-TCF activity unaffected. Homozygous SrfaI/aI mutants die at E10.5 with notable cardiovascular phenotypes, and neural crest conditional mutants succumb at birth to defects of the cardiac outflow tract but display none of the craniofacial phenotypes associated with complete loss of SRF in that lineage. Our studies further support an important role for MRTF mediating SRF function in cardiac neural crest and suggest new mechanisms by which SRF regulates transcription during development.

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The mechanisms of neural crest cell induction and specification are highly conserved among vertebrate model organisms, but how similar these mechanisms are in mammalian neural crest cell formation remains open to question. The zinc finger of the cerebellum 1 (ZIC1) transcription factor is considered a core component of the vertebrate gene regulatory network that specifies neural crest fate at the neural plate border. In mouse embryos, however, Zic1 mutation does not cause neural crest defects. Instead, we and others have shown that murine Zic2 and Zic5 mutate to give a neural crest phenotype. Here, we extend this knowledge by demonstrating that murine Zic3 is also required for, and co-operates with, Zic2 and Zic5 during mammalian neural crest specification. At the murine neural plate border (a region of high canonical WNT activity) ZIC2, ZIC3, and ZIC5 function as transcription factors to jointly activate the Foxd3 specifier gene. This function is promoted by SUMOylation of the ZIC proteins at a conserved lysine immediately N-terminal of the ZIC zinc finger domain. In contrast, in the lateral regions of the neurectoderm (a region of low canonical WNT activity) basal ZIC proteins act as co-repressors of WNT/TCF-mediated transcription. Our work provides a mechanism by which mammalian neural crest specification is restricted to the neural plate border. Furthermore, given that WNT signaling and SUMOylation are also features of non-mammalian neural crest specification, it suggests that mammalian neural crest induction shares broad conservation, but altered molecular detail, with chicken, zebrafish, and Xenopus neural crest induction.