Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model.

JOURNAL/nrgr/04.03/01300535-202503000-00030/figure1/v/2024-06-17T092413Z/r/image-tiff Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

Identification of stable reference genes for relative quantification of long RNA expression in urinary extracellular vesicles.

Urinary extracellular vesicles (uEVs) are rich in valuable biomolecule information which are increasingly recognized as potential biomarkers for various diseases. uEV long RNAs are among the critical cargos capable of providing unique transcriptome information of the source cells. However, consensus regarding ideal reference genes for relative long RNAs quantification in uEVs is not available as of date. Here we explored stable reference genes through profiling the long RNA expression by RNA-seq following unsupervised analysis and validation studies. Candidate reference genes were identified using four algorithms: NormFinder, GeNorm, BestKeeper and the Delta Ct method, followed by validation. RNA profile showed uEVs contained abundant long RNAs information and the core transcriptome was related to cellular structures, especially ribosome which functions mainly as translation, protein and RNA binding molecules. Analysis of RNA-seq data identified RPL18A, RPL11, RPL27, RACK1, RPSA, RPL41, H1-2, RPL4, GAPDH, RPS27A as candidate reference genes. RT-qPCR validation revealed that RPL41, RPSA and RPL18A were reliable reference genes for long RNA quantification in uEVs from patients with diabetes mellitus (DM), diabetic nephropathy (DN), IgA nephropathy (IgAN) and prostate cancer (PCA). Interestingly, RPL41 also outperformed traditional reference genes in renal tissues of DN and IgAN, as well as in plasma EVs of several types of cancers. The stable reference genes identified in this study may facilitate development of uEVs as novel biomarkers and increase the accuracy and comparability of biomarker studies.

Progress of Research into Preformed Particle Gels for Profile Control and Water Shutoff Techniques.

Gel treatment is an economical and efficient method of controlling excessive water production. The gelation of in situ gels is prone to being affected by the dilution of formation water, chromatographic during the transportation process, and thus controlling the gelation time and penetration depth is a challenging task. Therefore, a novel gel system termed preformed particle gels (PPGs) has been developed to overcome the drawbacks of in situ gels. PPGs are superabsorbent polymer gels which can swell but not dissolve in brines. Typically, PPGs are a granular gels formed based on the crosslinking of polyacrylamide, characterized by controllable particle size and strength. This work summarizes the application scenarios of PPGs and elucidates their plugging mechanisms. Additionally, several newly developed PPG systems such as high-temperature-resistant PPGs, re-crosslinkable PPGs, and delayed-swelling PPGs are also covered. This research indicates that PPGs can selectively block the formation of fractures or high-permeability channels. The performance of the novel modified PPGs was superior to in situ gels in harsh environments. Lastly, we outlined recommended improvements for the novel PPGs and suggested future research directions.

Unraveling the role of carboxylate groups and elastin particle size in medial calcification.

While it is known that calcium phosphate (CaP) minerals deposit in elastin-rich medial layers of arteries during medial calcification, their nucleation and growth sites are still debated. Neutral carbonyl groups and carboxylate groups are possible candidates. Also, while it is known that elastin degradation leads to calcification, it is unclear whether this is due to formation of new carboxylate groups or elastin fragmentation. In this work, we disentangle effects of carboxylate groups and particle size on elastin calcification; in doing so, we shed light on CaP mineralization sites on elastin. We find carboxylate groups accelerate calcification only in early stages; they mainly function as Ca2+ ion chelation sites but not calcification sites. Their presence promotes formation (likely on Ca2+ ions adsorbed on nearby carbonyl groups) of CaP minerals with high calcium-to-phosphate ratio as intermediate phases. Larger elastin particles calcify slower but reach similar amounts of CaP minerals in late stages; they promote direct formation of hydroxyapatite and CaP minerals with low calcium-to-phosphate ratio as intermediate phases. This work provides new perspectives on how carboxylate groups and elastin particle size influence calcification; these parameters can be tuned to study the mechanism of medial calcification and design drugs to inhibit the process.

Erratum: Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum.

[This corrects the article DOI: 10.7150/thno.54550.].

Total Syntheses and Antibacterial Studies of Natural Isoflavones: Scandenone, Osajin, and 6,8-Diprenylgenistein.

Isoflavones are a class of natural products that exhibit a wide range of interesting biological properties, including antioxidant, hepatoprotective, antimicrobial, and anti-inflammatory activities. Scandenone (1), osajin (2), and 6,8-diprenylgenistein (3) are natural prenylated isoflavones that share the same polyphenol framework. In this research, the key intermediate 15 was used for the synthesis of the natural isoflavones 1-3, establishing a stereoselective synthetic method for both linear and angular pyran isoflavones. The antibacterial activities of 1-3 were also evaluated, and all of them displayed good antibacterial activity against Gram-positive bacteria. Among them, 2 was the most potent one against MRSA, with a MIC value of 2 µg/mL, and the SEM assay indicated that the bacterial cell membranes of both MRSA and E. faecalis could be disrupted by 2. These findings suggest that this type of isoflavone could serve as a lead for the development of novel antibacterial agents for the treatment of Gram-positive bacterial infections.

Resilience of Canola to Plasmodiophora brassicae (Clubroot) Pathotype 3H under Different Resistance Genes and Initial Inoculum Levels.

In this study, we explored the resilience of a clubroot resistance (CR) stacking model against a field population of Plasmodiophora brassicae pathotype 3H. This contrasts with our earlier work, where stacking CRaM and Crr1rutb proved only moderately resistant to pathotype X. Canola varieties carrying Rcr1/Crr1rutb and Rcr1 + Crr1rutb were repeatedly exposed to 3H at low (1 × 104/g soil) and high (1 × 107/g soil) initial resting spore concentrations over five planting cycles under controlled environments to mimic intensive canola production. Initially, all resistant varieties showed strong resistance. However, there was a gradual decline in resistance over time for varieties carrying only a single CR gene, particularly with Crr1rutb alone and at the high inoculum level, where the disease severity index (DSI) increased from 9% to 39% over five planting cycles. This suggests the presence of virulent pathotypes at initially low levels in the 3H inoculum. In contrast, the variety with stacked CR genes remained resilient, with DSI staying below 3% throughout, even at the high inoculum level. Furthermore, the use of resistant varieties, carrying either a single or stacked CR genes, reduced the total resting spore numbers in soil over time, while the inoculum level either increased or remained high in soils where susceptible Westar was continuously grown. Our study demonstrates greater resistance resilience for stacking Rcr1 and Crr1rutb against the field population of 3H. Additionally, the results suggest that resistance may persist even longer in fields with lower levels of inoculum, highlighting the value of extended crop rotation (reducing inoculum) alongside strategic CR-gene deployment to maximize resistance resilience.

Dietary High Levels of Coconut Oil Replacing Fish Oil Did Not Affect Growth, but Promoted Liver Lipid Deposition of Orange-Spotted Groupers (Epinephelus coioides).

In this study, we conducted an 8-week feeding trial to investigate the effects of replacing fish oil (FO) with coconut oil (CO) on the growth performance, blood components, tissue fatty acid (FA) profile, and mRNA levels of genes related to lipid metabolism in the liver of the orange-spotted grouper (Epinephelus coioides). Five isolipidic and isoproteic diets were formulated through increasing the CO levels (0, 25%, 50%, 75%, and 100%, respectively). Triplicate groups of twenty-five fish (initial wet weight of about 22.4 g/fish) were fed one of the diets twice daily to apparent satiety. The 25% CO diet had the highest growth rate and feed utilization, and the 100% CO diet exhibited a comparable growth and feed utilization with that of the control diet, indicating a suitable FO substitute. Moreover, the hepatosomatic index, intraperitoneal fat rate, liver lipid content, as well as the serum HDL-C content and ALT activity had positive linear and/or quadratic responses, but the serum TC and LDL-C contents exhibited the opposite trend, with an increasing CO inclusion level. The FA profile in the liver and muscle generally mirrored the FA profile in the feed. Furthermore, the mRNA levels of the fas, acc, g6pd, srebp-1c, and δ6fad genes in the liver had positive linear and/or quadratic responses, but the mRNA levels of elovl 4 and elovl 5 had the opposite trend, with increasing dietary CO inclusion levels. When compared with the control diet, 25% and 50% CO diets up-regulated the mRNA levels of cpt 1, while the 75% and 100% CO diets down-regulated its mRNA levels. The hsl and atgl were down-regulated through the addition of dietary CO. The mRNA level of lpl was not affected by dietary treatments. Results showed that CO could completely replace FO without affecting growth performance, but high CO will lead to the significant liver lipid deposition and lower LC-PUFAs contents of fish flesh.

H-151 attenuates lipopolysaccharide-induced acute kidney injury by inhibiting the STING-TBK1 pathway.

Sepsis is a severe systemic infectious disease that often leads to multi-organ dysfunction. One of the common and serious complications of sepsis is renal injury. In this study, we aimed to investigate the potential mechanistic role of a novel compound called H-151 in septic kidney injury. We also examined its impact on renal function and mouse survival rates. Initially, we confirmed abnormal activation of the STING-TBK1 signaling pathway in the kidneys of septic mice. Subsequently, we treated the mice with H-151 and observed significant improvement in sepsis-induced renal dysfunction. This was evidenced by reductions in blood creatinine and urea nitrogen levels, as well as a marked decrease in inflammatory cytokine levels. Furthermore, H-151 substantially improved the seven-day survival rate of septic mice, indicating its therapeutic potential. Importantly, H-151 also exhibited an inhibitory effect on renal apoptosis levels, further highlighting its mechanism of protecting against septic kidney injury. These study findings not only offer new insights into the treatment of septic renal injury but also provide crucial clues for further investigations into the regulatory mechanisms of the STING-TBK1 signaling pathway and potential drug targets.

Comparative transcriptome analysis of canola carrying a single vs stacked resistance genes against clubroot.

Pyramiding resistance genes may expand the efficacy and scope of a canola variety against clubroot (Plasmodiophora brassicae), a serious threat to canola production in western Canada. However, the mechanism(s) of multigenic resistance, especially the potential interaction among clubroot resistance (CR) genes, are not well understood. In this study, transcriptome was compared over three canola (Brassica napus L.) inbred/hybrid lines carrying a single CR gene in chromosome A03 (CRaM, Line 16) or A08 (Crr1rutb, Line 20), and both genes (CRaM+Crr1rutb, Line 15) inoculated with a field population (L-G2) of P. brassicae pathotype X, a new variant found in western Canada recently. The line16 was susceptible, while lines 15 and 20 were partially resistant. Functional annotation identified differential expression of genes (DEGs) involved in biosynthetic processes responsive to stress and regulation of cellular process; The Venn diagram showed that the partially resistant lines 15 and 20 shared 1,896 differentially expressed genes relative to the susceptible line 16, and many of these DEGs are involved in defense responses, activation of innate immunity, hormone biosynthesis and programmed cell death. The transcription of genes involved in Pathogen-Associated Molecular Pattern (PAMP)-Triggered and Effector-Triggered Immunity (PTI and ETI) was particularly up-regulated, and the transcription level was higher in line 15 (CRaM + Crr1rutb) than in line 20 (Crr1rutb only) for most of the DEGs. These results indicated that the partial resistance to the pathotype X was likely conferred by the CR gene Crr1rutb for both lines 15 and 20 that functioned via the activation of both PTI and ETI signaling pathways. Additionally, these two CR genes might have synergistic effects against the pathotype X, based on the higher transcription levels of defense-related DEGs expressed by inoculated line 15, highlighting the benefit of gene stacking for improved canola resistance as opposed to a single CR gene alone.

Lysine-mediated surface modification of cellulose nanocrystal films for multi-channel anti-counterfeiting.

Utilizing advanced multiple channels for information encryption offers a powerful strategy to achieve high-capacity and highly secure data protection. Cellulose nanocrystals (CNCs) offer a sustainable resource for developing information protection materials. In this study, we present an approach that is easy to implement and adapt for the covalent attachment of various fluorescence molecules onto the surface of CNCs using the Mannich reaction in aqueous-based medium. Through the use of the Mannich reaction-based surface modification technique, we successfully achieved multi-color fluorescence in the resulting CNCs. The resulting CNC derivatives were thoroughly characterized by two dimensional heteronuclear single quantum coherence nuclear magnetic resonance (2D HSQC NMR) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and X-ray photoelectron (XPS) spectroscopy. Notably, the optical properties of CNCs were well maintained after modification, resulting in films exhibiting blue and red structural colors. This enables the engineering of highly programmable and securely encoded anti-counterfeit labels. Moreover, subsequent coating of the modified CNCs with MXene yielded a highly secure encrypted matrix, offering advanced security and encryption capabilities under ultraviolet, visible, and near-infrared wavelengths. This CNC surface-modification enables the development of multimodal security labels with potential applications across various practical scenarios.

Decoding the Qu-aroma of medium-temperature Daqu starter by volatilomics, aroma recombination, omission studies and sensory analysis.

Qu-aroma is of great significance for evaluation the quality of Daqu starter. This study aimed to decode the Qu-aroma of medium-temperature Daqu (MT-Daqu) via "top-down" and "bottom-up" approaches. Firstly, 52 aroma descriptors were defined to describe the MT-Daqu aroma by quantitative descriptive analysis. Secondly, 193 volatile organic compounds (VOCs) were identified from 42 MT-Daqu samples by HS-SPME-GC-MS, and 43 dominant VOCs were screened out by frequence of occurrence or abundance. By Thin Film (TF)-SPME-GC-O-MS, 27 odors and 90 VOCs were detected in MT-Daqu mixture, and 14 odor-active VOCs were screened out by odor intensity. Thirdly, a five-level MT-Daqu aroma wheel was constructed by matching 52 aroma descriptors and 37 aroma-active VOCs. Finally, Qu-aroma of MT-Daqu was reconstructed with 37 aroma-active VOCs and evaluated by omission experiments. Hereinto, 26 key aroma-active VOCs were determined by OAV value ≥1, including isovaleric acid, 1-hexanol, isovaleraldehyde, 2-octanone, trimethylpyrazine, γ-nonalactone, 4-vinylguaiacol, etc.

Myo-inositol rescued insulin resistance and dyslipidemia in db/db mice.

Myo-inositol (MI), present in a variety of foods, is essential in several important processes of cell physiology. In this study, we explored the protective effects of MI against hyperglycemia and dyslipidemia in db/db mice, a typical animal model of type 2 diabetes mellitus (T2DM). MI supplement effectively suppressed the high plasma glucose and insulin levels and markedly relieved the insulin resistance (IR) in the db/db mice, comparable to metformin's effects. In MIN6 pancreatic ß cells, MI also restrained the upsurge of insulin secretion stimulated by high-concentration glucose but had no impact on the promoted cell proliferation. Moreover, MI abated the enhanced plasma triglyceride and total cholesterol levels in the db/db mice. Notably, the lipid droplet formation of mesenchymal stem cells (MSCs) from db/db mice was significantly diminished after the treatment of MI, indicating that MI could effectively inhibit the differentiation of db/db mouse MSCs into adipocytes. However, MI regretfully failed to control obesity in db/db mice. This work proved that MI significantly helped db/db mice's metabolic disorders, indicating that MI has potential as an effective adjunctive treatment for hyperglycemia and dyslipidemia in T2DM patients.

20-Week intramuscular toxicity study of rotigotine behenate extended-release microspheres for injection via intramuscular injection in cynomolgus monkeys.

Continuous dopaminergic stimulation (CDS) has become an important strategy for the development of drugs to treat Parkinson's disease (PD). Rotigotine behenate extended-release microspheres (RBEM) for injection represents a new treatment regime for CDS and is being applied for clinical trial. Our study in cynomolgus monkeys was a 20-week repeat dose toxicity investigation with RBEM at dosages of 90, 180, 360, with a 12-week recovery period. The results observed some irritations in the application site and surrounding tissues in Placebo microspheres and each dose of RBEM, was accompanied with increased white blood count and fibrinogen. RBEM-treated monkeys were additionally noted with a pharmacological action-related decrease in prolactin. These findings showed certain reversibility after the 12-week recovery phase. No clear sex difference was noted in the plasma exposure to rotigotine. The exposure generally increased in a dose-proportional manner. In summary, major toxicological effects are associated with the dopamine agonist-related properties of rotigotine, and the removal of foreign bodies caused by p oly (lactide-co-glycolide) (PLGA)and sodium carboxymethyl cellulose (SCMC), and the no-observed-adverse-effect-level (NOAEL) was 360 mg/kg.

Preoperative and postoperative MRI-based models versus clinical staging systems for predicting early recurrence in hepatocellular carcinoma.

BACKGROUND: To predict the early recurrence of HCC patients who received radical resection using preoperative variables based on Gd-EOB-DTPA enhanced MRI, followed by the comparison with the postoperative model and clinical staging systems. METHODS: One hundred and twenty-nine HCC patients who received radical resection were categorized into the early recurrence group (n = 48) and the early recurrence-free group (n = 81). Through COX regression analysis, statistically significant variables of laboratory, pathologic, and Gd-EOB-DTPA enhanced MRI results were identified. The preoperative and postoperative models were established to predict early recurrence, and the prognostic performances and differences were compared between the two models and clinical staging systems. RESULTS: Six variables were incorporated into the preoperative model, including alpha-fetoprotein (AFP) level, aspartate aminotransferase/platelet ratio index (APRI), rim arterial phase hyperenhancement (rim APHE), peritumoral hypointensity on hepatobiliary phase (HBP), CERHBP (tumor-to-liver SI ratio on hepatobiliary phase imaging), and ADC value. Moreover, the postoperative model was developed by adding microvascular invasion (MVI) and histological grade. The C-index of the preoperative model and postoperative model were 0.889 and 0.901 (p = 0.211) respectively. Using receiver operating characteristic curve analysis (ROC) and decision curve analysis (DCA), it was determined that the innovative models we developed had superior predictive capabilities for early recurrence in comparison to current clinical staging systems. HCC patients who received radical resection were stratified into low-, medium-, and high-risk groups on the basis of the preoperative and postoperative models. CONCLUSION: The preoperative and postoperative MRI-based models built in this study were more competent compared with clinical staging systems to predict the early recurrence in hepatocellular carcinoma.

[2+1] Cycloadditions Modulate the Hydrophobicity of Ni-N4 Single-Atom Catalysts for Efficient CO2 Electroreduction.

Microenvironment regulation of M-N4 single-atom catalysts (SACs) is a promising way to tune their catalytic properties toward the electrochemical CO2 reduction reaction. However, strategies that can effectively introduce functional groups around the M-N4 sites through strong covalent bonding and under mild reaction conditions are highly desired. Taking the hydrophilic Ni-N4 SAC as a representative, we report herein a [2+1] cycloaddition reaction between Ni-N4 and in situ generated difluorocarbene (F2C:), and enable the surface fluorocarbonation of Ni-N4, resulting in the formation of a super-hydrophobic Ni-N4-CF2 catalyst. Meanwhile, the mild reaction conditions allow Ni-N4-CF2 to inherit both the electronic and structural configuration of the Ni-N4 sites from Ni-N4. Enhanced electrochemical CO2-to-CO Faradaic efficiency above 98 % is achieved in a wide operating potential window from -0.7 V to -1.3 V over Ni-N4-CF2. In situ spectroelectrochemical studies reveal that a highly hydrophobic microenvironment formed by the -CF2- group repels asymmetric H-bonded water at the electrified interface, inhibiting the hydrogen evolution reaction and promoting CO production. This work highlights the advantages of [2+1] cycloaddition reactions on the covalent modification of N-doped carbon-supported catalysts.

Microbiome in gynecologic malignancies: a bibliometric analysis from 2012 to 2022.

Microbiome and microbial dysbiosis have been proven to be involved in the carcinogenesis and treatment of gynecologic malignancies. However, there is a noticeable gap in the literature, as no comprehensive papers have covered general information, research status, and research frontiers in this field. This study addressed this gap by exploring the relationship between the gut and female reproductive tract (FRT) microbiome and gynecological cancers from a bibliometric perspective. Using VOSviewer 1.6.18, CiteSpace 6.1.R6, and HistCite Pro 2.1 software, we analyzed data retrieved from the Web of Science (WOS) Core Collection (WoSCC) database. Our dataset, consisting of 204 articles published from 2012 to 2022, revealed a consistent and upward publication trend. The United States and the United Kingdom were the primary driving forces, attributed to their prolificacy, high-quality output, and extensive cooperation. The University of Arizona Cancer Center, which is affiliated with the United States, ranked first among the top ten most prolific institutions. Frontiers in Cellular and Infection Microbiology emerged as the leading publisher. Herbst-Kralovetz MM led as the most productive author. Mitra A was the most influential author. Cervical cancer is notably associated with the microbiome, while endometrial and ovarian cancers are receiving increased attention in the last year. Intersections between the gut microbiome and estrogen are of growing importance. Current research focuses on identifying specific microbial species for etiological diagnosis, while frontiers mainly focus on the anticancer potential of microorganisms, such as regulating the effects of immune checkpoint inhibitors. In conclusion, this study sheds light on a novel and burgeoning direction of research, providing a one-stop overview of the microbiome in gynecologic malignancies. Its findings aim to help young researchers to identify research directions and future trends for ongoing investigations.

Basic and Informative Photographic Standards for Cleft Lip Patients.

BACKGROUND: Standardized and reliable medical photographs are crucial for preoperative and postoperative comparisons and academic communication in the medical field. There is limited research on photographic techniques in patients with cleft lip. Deformities of the lip and nose in patients with cleft lip are not only associated with morphological abnormalities but also with abnormalities of muscle function. METHODS: Considering the morphology and function of the lips and nose in cleft lip patients, the study captured the deformity of cleft lip patients in 6 positions: frontal view, 45 degrees left-right tilted side view, 90 degrees left-right tilted side view, and basal view, and in 5 facial expressions: tightly closed lips, slightly open mouth, smiling, teeth bared, and pout. RESULTS: In 6 different positions and 5 different expressions, we took pictures of lip and nasal deformities covering most of the common deformities in patients with cleft lip, such as white lip scarring, interruption of continuity of vermillion border, lip prolapse, asymmetric corners of the mouth, collapsed ala nasi, loss of the nasal base and deviated nasal septum. CONCLUSIONS: This paper suggests a set of effective, easy-to-follow, and precise photographic protocols to assist cleft lip surgeons in capturing suitable and informative, high-quality 2D digital photographs. LEVEL OF EVIDENCE: Level-V.

Identification of a Novel TP63 Variant in a Chinese Patient with Orofacial Clefts and Ectrodactyly: Case Report and Literature Review.

The TP63 gene is essential for epithelial proliferation, differentiation, and maintenance during embryogenesis. Despite considerable clinical variability, TP63-related symptoms are characterized by ectodermal dysplasia, distal limb malformations, and orofacial clefts. We identified a novel TP63 variant (c.619A > G, p.K207E) in a seven-month-old Chinese patient with orofacial clefts and ectrodactyly but no evident signs of ectodermal dysplasia. This phenotype was rarely reported before. We summarized the presence of the three main TP63-related manifestations in the literature and noted different distributions of CP- and CL/P-related variants regarding p63 structural domains.