Threonine Deficiency Increases Triglyceride Deposition in Primary Duck Hepatocytes by Reducing STAT3 Phosphorylation.

Liver lipid metabolism disruption significantly contributes to excessive fat buildup in waterfowl. Research suggests that the supplementation of Threonine (Thr) in the diet can improve liver lipid metabolism disorder, while Thr deficiency can lead to such metabolic disorders in the liver. The mechanisms through which Thr regulates lipid metabolism remain unclear. STAT3 (signal transducer and activator of transcription 3), a crucial transcription factor in the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway, participates in various biological processes, including lipid and energy metabolism. This research investigates the potential involvement of STAT3 in the increased lipid storage seen in primary duck hepatocytes as a result of a lack of Thr. Using small interfering RNA and Stattic, a specific STAT3 phosphorylation inhibitor, we explored the impact of STAT3 expression patterns on Thr-regulated lipid synthesis metabolism in hepatocytes. Through transcriptome sequencing, we uncovered pathways related to lipid synthesis and metabolism jointly regulated by Thr and STAT3. The results showed that Thr deficiency increases lipid deposition in primary duck hepatocytes (p < 0.01). The decrease in protein and phosphorylation levels of STAT3 directly caused this deposition (p < 0.01). Transcriptomic analysis revealed that Thr deficiency and STAT3 knockdown jointly altered the mRNA expression levels of pathways related to long-chain fatty acid synthesis and energy metabolism (p < 0.05). Thr deficiency, through mediating STAT3 inactivation, upregulated ELOVL7, PPARG, MMP1, MMP13, and TIMP4 mRNA levels, and downregulated PTGS2 mRNA levels (p < 0.01). In summary, these results suggest that Thr deficiency promotes lipid synthesis, reduces lipid breakdown, and leads to lipid metabolism disorders and triglyceride deposition by downregulating STAT3 activity in primary duck hepatocytes.

Transcriptome-Wide Analysis of Core Transcription Factors Associated with Defense Responses in Autotetraploid versus Diploid Rice under Saline Stress and Recovery.

Saline stress is a major abiotic stress that inhibits plant growth and yields worldwide. The plant transcription factor (TF) family plays an important role in converting abiotic stress signals into gene expression changes. In this study, a transcriptome-based comparative analysis was performed to investigate the global gene expression of all the TFs in diploid and autotetraploid rice during the early stage of NaCl stress and recovery period. The phenotypic data indicated that the tetraploid rice exhibited a superior salt-tolerant ability compared to the diploid rice. A total of 55 TF families were co-expressed in the tetraploid and diploid rice, and the cumulative number of TF-expressed genes was relatively higher in the diploid rice than in the tetraploid rice at all time points. Unlike the diploid rice, the overall gene expression levels of the tetraploid rice were comparable to the control during recovery. The number of differentially expressed TFs (DE-TFs) in the tetraploid rice decreased after recovery, whereas it increased to a large extent in the diploid rice. GO and KEGG pathway enrichment analysis of the DE-TFs discovered the early switching of the ABA-activated signaling pathway and specific circadian rhythm in the tetraploid rice. Combining the PPI network and heatmap analysis, some core DE-TFs were found that may have potential roles to play in tetraploid salt tolerance. This study will pave the way for elucidating the complex network regulatory mechanisms of salt tolerance in tetraploid rice.

Analysis of Selenium Levels in Osteosarcoma Patients and the Effects of Se-Methylselenocysteine on Osteosarcoma Cells In Vitro.

The form of selenium appears to be important for preventing cancer in humans. Here, we evaluated selenium levels in the serum and bone tissue samples from osteosarcoma patients using atomic absorption spectrometry. The in vitro effects of Se-methylselenocysteine (Se-MSC) on growth, cell cycle status, and apoptosis of osteosarcoma cells were assessed using the WST-1 assay, Hoechst 33342/propidium iodide staining, and flow cytometry, respectively. In osteosarcoma cases, the mean serum selenium levels in osteosarcoma tissue and normal bone were 0.08 mg/kg and 0.03 mg/kg, respectively (P < 0.05). Serum selenium levels in osteosarcoma and non-osteosarcoma cases were 0.09 mg/L and 0.08 mg/L, respectively (P > 0.05). Se-MSC-treated MG63 cells showed altered cellular morphology, decreased viability in a time- and dose-dependent manner, and an increase in the sub-G1 cell population. Se-MSC also downregulated Bcl-2 expression and upregulated Bax. Se-MSC inhibited the proliferation of the drug-resistant osteosarcoma cell line Saos-2/MTX300 and enhanced the inhibitory effect of pirarubicin on MG63 cells. Our data demonstrate that selenium levels are significantly higher in osteosarcoma tissue than normal bone tissue in osteosarcoma patients. The results also support the anticancer effects of Se-MSC in osteosarcoma. Further development of Se-MSC as an ancillary chemotherapy agent in osteosarcoma is warranted.

The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases.

Histone deacetylases 4 (HDAC4), -5, -7, and -9 form class IIa within the HDAC superfamily and regulate diverse physiological and pathological cellular programs. With conserved motifs for phosphorylation-dependent 14-3-3 binding, these deacetylases serve as novel signal transducers that are able to modulate histone acetylation and gene expression in response to extracellular cues. Here, we report that in a PKA-sensitive manner the tumor suppressor kinase LKB1 acts through salt-inducible kinase 2 (SIK2) and SIK3 to promote nucleocytoplasmic trafficking of class IIa HDACs. Both SIK2 and SIK3 phosphorylate the deacetylases at the conserved motifs and stimulate 14-3-3 binding. SIK2 activates MEF2-dependent transcription and relieves repression of myogenesis by the deacetylases. Distinct from SIK2, SIK3 induces nuclear export of the deacetylases independent of kinase activity and 14-3-3 binding. These findings highlight the difference among members of the SIK family and indicate that LKB1-dependent SIK activation constitutes an important signaling module upstream from class IIa deacetylases for regulating cellular programs controlled by MEF2 and other transcription factors.

Temporal Phenotyping for End-Stage Renal Disease Using Longitudinal Electronic Health Records.

End Stage Renal Disease (ESRD) is a highly heterogeneous disease with significant differences in prevalence, mortality, complications, and treatment modalities across age, sex, race, and ethnicity. An improved knowledge of disease characteristics results from the use of a data-driven phenotypic classification strategy to identify patients of different subtypes and expose the clinical traits of different subtypes. This study used topic models and process mining techniques to perform subtyping of ESRD patients on hemodialysis based on real-world longitudinal electronic health record data. The mined subtypes are interpretable and clinically significant, and they can reflect differences in the progression of the disease state and clinical outcomes.

Construction of direct Z-scheme Co9S8/CdS with tubular heterostructure through the simultaneous immobilization and in-situ reduction strategy for enhanced photocatalytic Cr(VI) reduction under visible light.

Tubular Co9S8/CdS heterostructures have been successfully synthesized by in-situ growing CdS onto Co9S8 nanotubes through a simultaneous immobilization and in-situ reduction strategy. It turned out that the so-obtained heterostructure with Co9S8/CdS molar ratio of 1/10 can display a broad light absorption edge and especially much enhanced capacity for photocatalytic reduction of Cr(VI) under visible light. The characterization analysis and experimental results suggested that an interfacial electrostatic field between Co9S8 and CdS elements in the heterostructure could be constructed due to their different Fermi levels, allowing for more quantities of highly reductive electrons to participate in the photocatalytic reaction. Therefore, the so-obtained Co9S8/CdS (1/10) heterostructures could achieve the photocatalytic reduction efficiency of 100% within 20 min, which was more than two and four times larger than that of pristine CdS and Co9S8, respectively. Moreover, the possible photocatalytic reaction mechanism for reducing Cr(VI) was investigated and found to follow the direct Z-scheme charge transfer pathway. This novel fabrication route for composite photocatalysts with tubular heterostructures could lead to the widespread implementations for the elimination of various harmful pollutants in the process of environmental governance.

The relationship between autoimmune disorders and intracranial aneurysms in East Asian and European populations: a bidirectional and multivariable two-sample Mendelian randomization study.

Background: It remains unclear about the pathogenesis of intracranial aneurysms (IAs) in the setting of autoimmune disorders (ADs). However, the underlying systemic inflammatory characteristics of ADs may affect IAs through shared inflammatory pathways. Therefore, this study was conducted to explore the relationship between ADs and IAs and assess causal effects. Methods: In this study, 6 common ADs were included to explore their causal relationship with IAs. Besides, a bidirectional two-sample univariable Mendelian randomization (UVMR) analysis was performed. In addition, the primary analysis was performed by the inverse variance weighted (IVW) and Bayesian weighted Mendelian randomization (BWMR) method, and a series of sensitivity analyses were performed to assess the robustness of the results. Further, the data related to ADs and IAs were collected from open genome-wide association study studies (GWASs) and the Cerebrovascular Disease Knowledge Portal (CDKP) (including 11,084 cases and 311,458 controls), respectively. These analyses were conducted based on both the East Asian and European populations. Moreover, 6 ADs were subject to grouping according to connective tissue disease, inflammatory bowel disease, and thyroid disease. On that basis, a multivariate MR (MVMR1) analysis was further performed to explore the independent causal relationship between each AD and IAs, and an MVMR 2 analysis was conducted to investigate such potential confounders as smoking, alcohol consumption, and systolic blood pressure. Finally, these results were verified based on the data from another GWAS of IAs. Results: The UVMR analysis results demonstrated that systemic lupus erythematosus (SLE) was associated with a high risk of IAs in the East Asian population (IVW OR, 1.06; 95%CI, 1.02-1.11; p = 0.0065, UVMR), which was supported by the results of BWMR (OR, 1.06; 95%CI, 1.02-1.11; p = 0.0067, BWMR), MVMR1 (OR, 1.06; 95%CI, 1.01-1.10; p = 0.015, MVMR1), MVMR2 (OR, 1.05; 95%CI, 1.00-1.11; p = 0.049, MVMR2), and sensitivity analyses. The results in the validation group also suggested a causal relationship between SLE and IAs (IVW OR, 1.04; 95% CI, 1.00-1.09; p = 0.046). The reverse MR analysis results did not reveal a causal relationship between IAs and ADs. Conclusion: In this MR study, SLE was validated to be a risk factor for IAs in the East Asian population. Therefore, the management of IAs in patients with SLE should be highlighted to avoid stroke events.

Risk factors for recurrent laryngeal nerve injury in microwave ablation of thyroid nodules: A multicenter study.

BACKGROUND AND PURPOSE: This study aimed to investigate the risk factors for recurrent laryngeal nerve (RLN) injury after microwave ablation (MWA) of thyroid nodules and to identify factors influencing the recovery time of post-procedure hoarseness. MATERIALS AND METHODS: We retrospectively analyzed data from patients who underwent MWA for thyroid nodules at five hospitals between November 2018 and July 2022. Patients were divided into malignant and benign nodule groups. Variables analyzed included nodule size and location, the shortest distance from nodules to the thyroid capsule and tracheoesophageal groove (TEG-D), and ablation parameters. Univariate and multivariate analyses were performed to identify risk factors. Kaplan-Meier and Cox analyses were used to evaluate the recovery time of hoarseness after MWA. RESULTS: The study included 1,216 patients (mean age 44 ± 12 [SD] years; 901 women) with 602 malignant nodules and 614 benign nodules. The posterior capsule distance (PCD) and TEG-D were identified as independent influencing factors for hoarseness in all patients (P = 0.014, OR = 0.068; P < 0.001, OR = 0.005; AUC = 0.869). TEG-D was a significant risk factor for hoarseness, with safe thresholds identified at 4.9 mm for malignant nodules and 2.2 mm for benign nodules. Among patients who developed hoarseness, those in the close-distance group (TEG-D≤2 mm) had a longer recovery time compared to the distant-distance group. TEG-D was an independent factor influencing recovery time (P = 0.008, HR = 11.204). CONCLUSION: Clinicians should consider several factors, particularly TEG-D and PCD, when assessing the risk of RLN injury before MWA. TEG-D was a vital independent factor influencing recovery time. SUMMARY: Clinicians should pay attention to several influencing factors for RLN injury before MWA and TEG-D was an independent influencing factor for recovery time of hoarseness after MWA.

Research Note: Transcriptome analysis reveals differentially expressed genes regulated muscle development in Pekin ducks during dietary threonine deficiency.

To investigate the underlying molecular mechanism of threonine (Thr) regulation on the development of breast muscle in Pekin ducks, 240 male Pekin ducks at 1 d of age were fed a Thr deficiency diet (Thr-D), Thr sufficiency diet (Thr-S), or Thr excess diet (Thr-E) for 21 d. The results showed that Thr-D reduced body weight (BW), average weight gain (ADG), and average feed intake (ADFI), and increased the feed/gain (F/G) in Pekin ducks (P < 0.05), and Thr-E did not affect BW, ADG, ADFI, or F/G (P > 0.05), compared with Thr-S. The diameter and cross-sectional area of the breast muscle fibers in the Thr-S group were larger than those in the Thr-D group (P < 0.05). RNA sequencing revealed 1,300 differential expressed genes (DEGs) between the Thr-D and Thr-S groups, of which 625 were upregulated and 675 were downregulated by Thr-D. KEGG analysis showed that the upregulated genes were enriched in mTOR, FoxO, Wnt, fat digestion and absorption, and other signaling pathways. The downregulated genes were enriched in the MAPK signaling, glycolysis/gluconeogenesis, adipocytokine signaling, and biosynthesis of unsaturated fatty acids signaling pathways. The genes of Wnt family member 3a (Wnt3a), myogenin, myozenin 2, and insulin like growth factor 2 mRNA binding protein were upregulated, and platelet derived growth factor subunit B, PDGF receptor beta and Wnt4 were downregulated by Thr deficiency, which involving in muscle development. Our findings indicated that Thr increased breast fiber size, perhaps because Thr affected the proliferation and differentiation of satellite cells in breast muscle of ducks after hatch. Our results provide novel insights into new understanding of the molecular mechanisms underlying breast muscle development in ducks subjected to dietary Thr.

Eye movements and ERP biomarkers for face processing problems in avoidant attachment-style individuals.

Background: Avoidant attachment poses a serious risk to intimate relationships and offspring. However, there are few studies on the face-processing characteristics and impairments of avoidant individuals based on basic emotion theory. Therefore, this study investigated the issues of emotional processing and deactivation strategies in individuals with avoidant attachment. Methods: Avoidant and secure individuals were recruited to participate in an eye-tracking experiment and a two-choice oddball task in which they had to distinguish facial expressions of basic emotions (sadness, anger, fear, disgust, and neutral). Eye fixation durations to various parts of the face, including the eyes, nose, and mouth, were measured, and three event-related potentials (ERP) components (P100, N170, and P300) were monitored. Results: Avoidant individuals could not process facial expressions as easily as secure individuals. Avoidant individuals focused less on the eyes of angry faces when compared to secure individuals. They also exhibited a more positive P100 component and a less negative N170 component when processing faces and a larger amplitude of the P300 component than secure individuals when processing emotional expressions. Conclusion: Avoidant individuals use deactivating strategies and exhibit specific characteristics at different stages, which are of great significance in social interaction.

Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase.

The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T(FH)) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T(FH) generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4(+) T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T(FH) cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T(FH) and suggest that CD28 and ICOS play differential roles during a multistep process of T(FH) differentiation.

Neurotransmitters and Electrophysiological Changes Might Work as Biomarkers for Diagnosing Affective Disorders.

Affective disorders are the leading causes of human disability worldwide; however, the diagnosis is still hard to define, because emotion is the least study subjects in psychology. Recent emotional studies suggest that human emotions are developed from basic emotions, which are evolved for fundamental human lives. Even though most psychologists agree upon the idea that there are some basic emotions, there is little agreement on how many emotions are basic, which emotions are basic, and why they are basic. In our previous papers, we suggested that there are three basic emotions: joy, fear, and disgust. These basic emotions depend on the peptides and monoamines: dopamine-joy (peptides-reward), norepinephrine-fear (anger), and serotonin-disgust (sadness). Further tests with event-related potentials (ERP) found that joy, fear, and disgust showed the fastest response compared with other emotions, suggesting that they are fast automatic responses, which confirmed that these three emotions are prototypical emotions. Other basic emotions, anger and sadness, are due to object induced behaviors instead of sensation of object, so they developed secondary to prototypical emotions. Thus, we concluded that only joy, fear, and disgust are prototypical emotions, which can mix into other emotions, like the primary colors. In all, the neural substrates for all emotions, including the affections, are possibly monoamine neuromodulators: joy-dopamine (peptides), fear (anger)-norepinephrine, and disgust-serotonin. We hope these basic emotional studies will offer some neural mechanisms for emotional processing and shed lights on the diagnosis of affective disorders.

Effects of Coronavirus-19 Induced Loneliness on Mental Health: Sleep Quality and Intolerance for Uncertainty as Mediators.

Objective: The aim of the study is to investigate effects of loneliness on individual's mental health and the mediating effects of intolerance of uncertainty and sleep quality in the post Coronavirus-19 period, especially for the young people. Methods: The questionnaires used in this study include UCLA loneliness scale (UCLA-3), the Pittsburgh Sleep Quality Index (PSQI), intolerance for uncertainty (IU) and the Chinese version of DASS-21. A total number of 289 subjects were recruited in the study, which includes 209 females (72.3%), 80 males (27.7%); and 212 students (73.4%), 77 working staffs (26.6%). Results: The results showed that: (1) people have high levels of loneliness, anxiety, depression and stress, and poor sleep quality; (2) the mediating effect of intolerance for uncertainty in the relationship of loneliness and mental health is significant (effect size = 0.178, 95% CI confidence interval: [0.115, 0.241]), and the mediating effects of sleep quality in the relationship between loneliness and mental health is significant (effect size = 0.127, 95% CI confidence interval: [0.017, 0.239]). Conclusion: Loneliness invokes a stronger self-concerned inadaptability to threat response and may lead to more mental diseases through more serious intolerance for uncertainty and insomnia.

Analog memristive synapse based on topotactic phase transition for high-performance neuromorphic computing and neural network pruning.

Inspired by the human brain, nonvolatile memories (NVMs)-based neuromorphic computing emerges as a promising paradigm to build power-efficient computing hardware for artificial intelligence. However, existing NVMs still suffer from physically imperfect device characteristics. In this work, a topotactic phase transition random-access memory (TPT-RAM) with a unique diffusive nonvolatile dual mode based on SrCoO x is demonstrated. The reversible phase transition of SrCoO x is well controlled by oxygen ion migrations along the highly ordered oxygen vacancy channels, enabling reproducible analog switching characteristics with reduced variability. Combining density functional theory and kinetic Monte Carlo simulations, the orientation-dependent switching mechanism of TPT-RAM is investigated synergistically. Furthermore, the dual-mode TPT-RAM is used to mimic the selective stabilization of developing synapses and implement neural network pruning, reducing ~84.2% of redundant synapses while improving the image classification accuracy to 99%. Our work points out a new direction to design bioplausible memristive synapses for neuromorphic computing.

Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.

The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. Lysine acetylation has been shown to modulate MEF2 function, but it is not so clear which deacetylase(s) is involved. We report here that treatment of HEK293 cells with trichostatin A or nicotinamide upregulated MEF2D acetylation, suggesting that different deacetylases catalyze the deacetylation. Related to the trichostatin A sensitivity, histone deacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little deacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated MEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize primarily the MEF2-specific domain, we found that HDAC3 interacts directly with the MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo.

Long-term defects of nasal epithelium barrier functions in patients with nasopharyngeal carcinoma post chemo-radiotherapy.

BACKGROUND AND PURPOSE: Chronic and recurrent upper respiratory tract infection and inflammation is common in patients with nasopharyngeal carcinoma (NPC) post chemo-radiotherapy (CRT). Whether it is due to intrinsic (e.g., host-defense mechanisms of the epithelium), epigenetic or extrinsic factors is not fully understood. MATERIALS AND METHODS: Tissue biopsies of the middle turbinate (MT) and inferior turbinate (IT) from NPC patients after CRT (mean of 3 years, n = 39) were compared with the IT biopsies from healthy subjects (n = 44). The epithelial ultrastructure was examined by transmission electron microscope (TEM). mRNA and protein expressions of epithelial stem/progenitor cells markers, as well markers of cell proliferation and differentiation markers was analyzed. RESULTS: Abnormal epithelial architecture was observed in all tissue samples of NPC patients. Significantly decreased expression levels of mRNA and protein levels for p63 (basal cells), Ki67 (cell proliferation), p63+/KRT5+ (epithelial stem/progenitor cells), MUC5AC and MUC5B (secretary proteins from goblet cells), alpha-tubulin, beta-tubulin and TAp73 (ciliated cells), DNAH5 and DNAI1 and RSPH4A (microtubule assemblies of motile cilia), FOXJ1 and CP110 (ciliogenesis-associated markers) were evident in MT and IT biopsies from NPC patients when compared to healthy controls. CONCLUSION: CRT causes long-term defects of epithelial barrier functions and increases the susceptibility of these patients to upper respiratory tract infection and inflammation.

p63+Krt5+ basal cells are increased in the squamous metaplastic epithelium of patients with radiation-induced chronic Rhinosinusitis.

BACKGROUND: Squamous metaplasia (SM) is an irreversible form of airway epithelial remodeling. Hyperproliferation of basal cells was observed in squamous metaplastic epithelium of chronically inflamed airway. However, the association of such aberrant proliferation of basal cells with SM in the nasal epithelium after radiation damage remains unclear. The aim of this study was to investigate SM and accompanying levels of p63+Krt5+ (basal cell markers) cells in the nasal epithelium of patients with radiation-induced chronic rhinosinusitis (CRSr) and patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared to healthy controls. METHODS: We assessed the prevalence of SM and the expression of p63+, Krt5+, p63+Krt5+, and Ki67+ cells through immunofluorescence(IF) staining of the inferior turbinate (IT) tissues from patients with CRSr (n = 36), CRSsNP (n = 33) and controls (n = 28). RESULTS: The prevalence of SM and the number of p63+Krt5+ cells were both significantly increased in patients with CRSr compared to patients with CRSsNP and controls. The number of Ki67+ cells were both significantly increased in patients with CRSr and CRSsNP compared to controls, but the ratio of Ki67+ cells to p63+Krt5+ cells was significantly lower in patients with CRSr compared to patients with CRSsNP. In patients with CRSr, an increased number of p63+Krt5+ basal cells was observed in SM epithelium compared to non-SM epithelium. CONCLUSION: SM is increased in the nasal epithelium of patients with CRSr, in which aberrant levels of p63+Krt5+ basal cells serves as an important pathologic feature in the squamous metaplastic epithelium.

YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease.

How extracellular cues are transduced to the nucleus is a fundamental issue in biology. The paralogous WW-domain proteins YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif; also known as WWTR1, for WW-domain containing transcription regulator 1) constitute a pair of transducers linking cytoplasmic signaling events to transcriptional regulation in the nucleus. A cascade composed of mammalian Ste20-like (MST) and large tumor suppressor (LATS) kinases directs multisite phosphorylation, promotes 14-3-3 binding, and hinders nuclear import of YAP and TAZ, thereby inhibiting their transcriptional coactivator and growth-promoting activities. A similar cascade regulates the trafficking and function of Yorkie, the fly orthologue of YAP. Mammalian YAP and TAZ are expressed in various tissues and serve as coregulators for transcriptional enhancer factors (TEFs; also referred to as TEADs, for TEA-domain proteins), runt-domain transcription factors (Runxs), peroxisome proliferator-activated receptor gamma (PPARgamma), T-box transcription factor 5 (Tbx5), and several others. YAP and TAZ play distinct roles during mouse development. Both, and their upstream regulators, are intimately linked to tumorigenesis and other pathogenic processes. Here, we review studies on this family of signal-responsive transcriptional coregulators and emphasize how relative sequence conservation predicates their function and regulation, to provide a conceptual framework for organizing available information and seeking new knowledge about these signal transducers.