YAP phosphorylation within integrin adhesions: insights from a computational model.

Mechanical and biochemical cues intricately activate YAP, which is pivotal for the cellular responses to these stimuli. Recent findings reveal an unexplored role of YAP in influencing the apoptotic process. It has been shown that on soft matrices YAP is recruited to small adhesions, phosphorylated at Y357, and translocated into the nucleus triggering apoptosis. Interestingly, YAP Y357 phosphorylation is significantly reduced in larger mature focal adhesions on stiff matrices. Building upon these novel insights, we have developed a stochastic model to delve deeper into the complex dynamics of YAP phosphorylation within integrin adhesions. Our findings emphasize several key points: firstly, increasing the cytosolic diffusion rate of YAP correlates with higher levels of phosphorylated YAP (pYAP), secondly, increasing the number of binding sites and distributing them across the membrane surface, mimicking smaller adhesions, leads to higher pYAP levels, particularly at lower diffusion rates. Moreover, we show that the binding and release rate of YAP to adhesions as well as adhesion lifetimes significantly influence the size-effect of adhesion-induced YAP phosphorylation. The results highlight the complex and dynamic interplay between adhesion lifetime, the rate of pYAP unbinding from adhesions, and dephosphorylation rates, collectively shaping overall pYAP levels. In summary, our work advances the understanding of YAP mechanotransduction and opens avenues for experimental validation.

YAP mediates apoptosis through failed integrin adhesion reinforcement.

Extracellular matrix (ECM) rigidity is a major effector of cell fate decisions. Whereas cell proliferation on stiff matrices, wherein Yes-associated protein (YAP) plays a pivotal role, is well documented, activation of apoptosis in response to soft matrices is poorly understood. Here, we show that YAP drives the apoptotic decision as well. We find that in cells on soft matrices, YAP is recruited to small adhesions, phosphorylated at the Y357 residue, and translocated into the nucleus, ultimately leading to apoptosis. In contrast, Y357 phosphorylation levels are dramatically low in large adhesions on stiff matrices. Furthermore, mild attenuation of actomyosin contractility allows adhesion growth on soft matrices, leading to reduced Y357 phosphorylation levels and resulting in cell growth. These findings indicate that failed adhesion reinforcement drives rigidity-dependent apoptosis through YAP and that this decision is not determined solely by ECM rigidity but rather by the balance between cellular forces and ECM rigidity.

Advances in Research on Pig Salivary Analytes: A Window to Reveal Pig Health and Physiological Status.

Saliva is an important exocrine fluid that is easy to collect and is a complex mixture of proteins and other molecules from multiple sources from which considerable biological information can be mined. Pig saliva, as an easily available biological liquid rich in bioactive ingredients, is rich in nucleic acid analytes, such as eggs, enzymes, amino acids, sugars, etc. The expression levels of these components in different diseases have received extensive attention, and the analysis of specific proteins, metabolites, and biological compositions in pig saliva has become a new direction for disease diagnosis and treatment. The study of the changes in analytes in pig saliva can provide a new strategy for early diagnosis, prognosis assessment, and treatment of diseases. In this paper, the detection methods and research progress of porcine salivary analytes are reviewed, the application and research progress of porcine salivary analytes in diseases are discussed, and the future application prospect is presented.

The biophysical property of the limbal niche maintains stemness through YAP.

The cell fate decisions of stem cells (SCs) largely depend on signals from their microenvironment (niche). However, very little is known about how biochemical niche cues control cell behavior in vivo. To address this question, we focused on the corneal epithelial SC model in which the SC niche, known as the limbus, is spatially segregated from the differentiation compartment. We report that the unique biomechanical property of the limbus supports the nuclear localization and function of Yes-associated protein (YAP), a putative mediator of the mechanotransduction pathway. Perturbation of tissue stiffness or YAP activity affects SC function as well as tissue integrity under homeostasis and significantly inhibited the regeneration of the SC population following SC depletion. In vitro experiments revealed that substrates with the rigidity of the corneal differentiation compartment inhibit nuclear YAP localization and induce differentiation, a mechanism that is mediated by the TGFß-SMAD2/3 pathway. Taken together, these results indicate that SC sense biomechanical niche signals and that manipulation of mechano-sensory machinery or its downstream biochemical output may bear fruits in SC expansion for regenerative therapy.

Comprehensive analysis of mitogenome of native Henan pig breeds with 58 worldwide pig breeds.

Mitochondria follow non-Mendelian maternal inheritance, and thus can be used to compare genetic diversity and infer the expansion and migration between animal populations. Based on the mitochondrial DNA sequences of 58 pig breeds from Asia, Europe, Oceania, and America, we observed a distinct division of Eurasian pig species into two main Haplogroups (A and B), with the exception of the Berkshire and Yorkshire breeds. Oceanian pigs were much more similar to European and American pigs in Haplogroup A. Additionally, native Chinese pigs exhibited the most abundant genetic polymorphisms and occupied the centre of Haplogroup B. Miyazaki (Japan) and Siberia (Russia) are two distant and disconnected regions; however, most pigs from these regions were clustered into a subcluster, while native pigs from Korea clustered into a second subcluster. This study is the first to report that pigs from Thailand and Vietnam had haplotypes similar to those of Henan, where the earliest evidence of domestic pigs was found from the Yellow River Basin of North China. Local Henan pig breeds are related to many Asian breeds while still having their own mutation identity, such as g.314 delins T>AC/AT/C of the 12S rRNA gene in Yuxi. Some pigs from Palawan, Itbayat, and Batan Islands of the Philippines and Lanyu Island of China were distinct from other Asian pigs and clustered together into Haplogroup C. These findings show that the complexity of domestication of worldwide pig breeds and mitochondria could reflect genetic communication between pig breeds due to geographical proximity and human activities.

The 'Yin and Yang' of Cancer Cell Growth and Mechanosensing.

In cancer, two unique and seemingly contradictory behaviors are evident: on the one hand, tumors are typically stiffer than the tissues in which they grow, and this high stiffness promotes their malignant progression; on the other hand, cancer cells are anchorage-independent-namely, they can survive and grow in soft environments that do not support cell attachment. How can these two features be consolidated? Recent findings on the mechanisms by which cells test the mechanical properties of their environment provide insight into the role of aberrant mechanosensing in cancer progression. In this review article, we focus on the role of high stiffness on cancer progression, with particular emphasis on tumor growth; we discuss the mechanisms of mechanosensing and mechanotransduction, and their dysregulation in cancerous cells; and we propose that a 'yin and yang' type phenomenon exists in the mechanobiology of cancer, whereby a switch in the type of interaction with the extracellular matrix dictates the outcome of the cancer cells.

Effects of Litter Size and Parity on Farrowing Duration of Landrace × Yorkshire Sows.

Litter size has increased and farrowing duration has also prolonged in recent years. The aim of this study was to analyze the effect of litter size and parity on farrowing duration (FAR) to estimate the possibility of selecting a short farrowing duration. We recorded 32,200 parturitions of 8420 Landrace × Yorkshire sows, determined farrowing duration, litter size, parity, gestation length. Results showed that total number of born (TNB) and parity obeyed a cubic (p = 0.0004, p = 0.004) relationship while number born alive (NBA) and number born dead (NBD) obeyed a linear (p = 0.0239, p = 0.0035) relationship with FAR. Gestation length obeyed a linear (p = 0.02) relationship with FAR. FAR of sows with stillbirth was longer than that of sows without stillbirth. Stillbirth rate increased rapidly from about 2% to 4%, especially when FAR was over 240 min. FAR gradually prolonged with the parities. FAR of 7th parity sows was longer than that of 1st~6th parity sows (p < 0.05), but different parity sows had little difference in the same FAR interval except for gilts. Results indicated it was possible and necessary to consider FAR into pig breeding without worrying about decreasing of live litter size or negative effect of parity if FAR was shorter than 300 min.

Is ß-cell aging involved in the pathogenesis of diabetes?

BACKGROUND: ß-Cells at different stages have different functions and capacity for proliferation, regenerative and apoptosis. The aim of the present study was to investigate whether there are changes in ß-cell phonotype in the development of diabetes to identify potential ß-cell targets to prevent the progression of diabetes. METHODS: A cross-sectional study was performed on pancreatic tissues obtained from 80 patients classified into three groups: 25 with type 2 diabetes (T2D), 25 with impaired fasting glucose (IFG), and 30 non-diabetics (ND). The ratio of the insulin-positive area to pancreatic area was used as an indirect marker of ß-cell mass. Insulin-positive duct cells and scattered ß-cells were defined as newly generated ß-cells, whereas insulin/neurogenin 3 (Ngn3), insulin/v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA) and insulin/P16 double-positive cells were defined as immature, mature, and senescent ß-cells, respectively; Ki67 was used as a marker of cell proliferation, and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) was used as a marker of cell apoptosis. Data were analyzed using the Kruskal-Wallis test. RESULTS: There were no significant differences in ß-cell mass, the prevalence of insulin-positive duct cells, scattered ß-cells, or insulin/Ngn3, insulin/MafA, and Insulin/Ki67 double-positive cells among groups. The incidence of insulin/P16 double-positive cells was significantly higher in T2D than ND. ß-Cell apoptosis was significantly higher in T2D and IFG than ND. CONCLUSION: The senescence and apoptosis of ß-cells may be involved in the course of diabetes.

Is Normocalcemic Primary Hyperparathyroidism Harmful or Harmless?

CONTEXT: Primary hyperparathyroidism (PHPT) is reported to be associated with an increased frequency of hypertension, however, information in this regard is sparse in relation to normocalcemic primary hyperparathyroidism (NPHPT). OBJECTIVE: The aim of this study was to determine the association between NPHPT and blood pressure. DESIGN, SETTING, AND PATIENTS: We retrospectively enrolled 940 patients who visited the Fujian Provincial Hospital between September 2010 and December 2013 with a measured serum parathyroid hormone (PTH) and calcium level. Among them, 11 patients were diagnosed with NPHPT, while 296 cases with normal PTH and albumin-adjusted serum calcium. MAIN OUTCOMES MEASURES: Systolic blood pressure (SBP), diastolic blood pressure (DBP), intact serum PTH, and serum calcium were recorded. RESULTS: There were no significant differences between subjects identified with NPHPT and those with normal PTH in terms of age, sex, body mass index, serum calcium, 25-Hydroxyvitamin D, serum creatinine, fasting plasma glucose, triglycerides, total cholesterol, high density lipoprotein, and low density lipoprotein. The subjects with a diagnosis of NPHPT had higher levels of SBP (141.9 ± 20.2 vs 131.2 ± 16.5, P = .041) and DBP (85.2 ± 12.4 vs 76.8 ± 10.3, P = .026) than the subjects in the cohort with normal PTH. After adjustment for all potential confounders, risks (odds ratios and 95% confidence interval) of SBP and DBP in NPHPT patients were 1.035 (1.000, 1.071) and 1.063 (1.004, 1.125), respectively (P < .05). CONCLUSIONS: The NPHPT had higher risk of high blood pressure than subjects with normal PTH. It is worth considering the necessity of more aggressive therapeutic intervention aimed to normalize PTH even if patients with NPHPT continue to be normocalcemic.

Sal-like protein 2 upregulates p16 expression through a proximal promoter element.

Sal-like protein 2 (Sall2), a homeotic transcription factor, is a putative tumor suppressor. We have previously shown that Sall2 activates the transcription of tumor suppressor gene p21 and suppresses tumorigenesis through cell cycle inhibition and induction of apoptosis. To investigate additional Sall2-regulated downstream genes, we analyzed the differences in mRNA expression profiles with and without exogenously expressed Sall2. We identified 1616 Sall2-responsive genes through gene expression arrays. Promoter-reporter assays of p16(INK4A) and several other tumor-related genes indicated that the Sall2 regulation of these promoters was not significantly different between the two major forms of Sall2 with alternative exon 1 or exon 1A. Additional analysis showed that Sall2-induced p16 promoter activation was Sall2 dose-dependent. Deletion and site-directed mutagenesis of the p16 promoter identified a consensus Sall2 binding site (GGGTGGG) proximal to the p16 transcription start site and was critical for p16 promoter activation. Finally, to confirm the significance of Sall2-activated p16 expression in cell cycle regulation, we co-transfected the SKOV3 cells with a Sall2 expression construct and a p16 minigene and also co-transfected the ES-2 cells with a Sall2 expression construct and the siRNA against p16 for flow cytometry analysis. Our results showed that Sall2 enhanced the p16 minigene blocking of cell cycle progression and p16 knockdown with siRNA abolished most of the Sall2 inhibition of cell cycle progression. These findings indicate that Sall2 targets multiple cell cycle regulators, including p16, through their promoters, adding knowledge to the understanding of Sall2 and p16 gene regulation, and how Sall2 deregulation may promote cancer formation.