[Clinical effects of free perforator propeller myocutaneous flap from buttock in repairing complex wounds in the buttock with deep dead cavity].

Objective: To investigate the feasibility and clinical effects of using free perforator propeller myocutaneous flap from buttock in repairing complex wounds in the buttock with deep dead cavity. Methods: A retrospective observational study was conducted. From June 2020 to June 2022, 9 patients with complex wounds in the buttock with deep dead cavity who met the inclusion criteria were admitted to Lanzhou University Second Hospital, including 6 males and 3 females, aged 26 to 62 years, with original wound area ranging from 4.0 cm×3.0 cm to 8.0 cm×7.0 cm and dead cavity depth of 7 to 11 cm. All the wounds were repaired with free perforator propeller myocutaneous flap from buttock, with flap area of 6.0 cm×2.5 cm to 13.0 cm×7.0 cm and muscle flap length of 6 to 11 cm. All the wounds in the donor area were closed and sutured directly. Postoperative myocutaneous flap survival, complications, as well as donor and recipient wound healing were observed, and the shape of donor and recipient areas were followed up. Results: Congestion occurred under the myocutaneous flap of one patient due to poor drainage on post surgery day 2, which was healed after 15 days of drainage and dressing change. The myocutaneous flaps of other patients survived successfully after surgery. The wounds in the donor and recipient areas were all well healed. During the follow-up of 3 to 10 months, the donor and recipient areas were full in shape, with little difference from the healthy side, and were able to bear pressure. Conclusions: The free perforator propeller myocutaneous flap from buttock can repair the deep dead cavity and surface wounds at the same time. The use of this myocutaneous flap in repairing complex wounds in the buttock with deep dead cavity results in minimal damage to the donor area, allows pressure-bearing of the donor and recipient areas after surgery, and ensures a full buttock shape.

Sodium-rich manganese oxide porous microcubes with polypyrrole coating as a superior cathode for sodium ion full batteries.

Highly conductive cathode material with enhanced Na+ diffusion kinetics is of great importance in the exploration of sodium ion batteries. In this work, Na0.91MnO2 porous microcube which is coated with highly conductive polypyrrole (PPy) is obtained. The high Na content in the layered sodium manganate oxide brings about wider interlayer distance resulting in high capacity and electrochemical kinetics. The higher sodium content of Na0.91MO2 makes capacity increase up to 50 mAh g-1 compared with Na0.7MnO2.05. Furthermore, the well-designed combination between porous structure and conductive PPy coating exhibits fast ion/electron transfer inside the electrode and high cycling stability. The PPy coated Na0.91MnO2 delivers a high initial capacity of 208 mAh g-1, encouraging capacity retention and rate capability. Based on the porous Na0.91MnO2@PPy cathode, the sodium ion full cells with puffed millet porous carbon anode show remarkably stable cycling and high-rate performances.

Molybdenum-doped tin oxide nanoflake arrays anchored on carbon foam as flexible anodes for sodium-ion batteries.

Tin oxide (SnO2) has been widely used as an anode material for sodium-ion storage because of its high theoretical capacity. However, it suffers from large volume expansion and poor conductivity. To overcome these limitations, in this study, we have designed and prepared Mo-doped SnO2 nanoflake arrays anchored on carbon foam (Mo-SnO2@C-foam with 38.41 wt% SnO2 and 3.7 wt% Mo content) by a facile hydrothermal method. The carbon foam serves as a three-dimensional conductive network and a buffer skeleton, contributing to improved rate performance and cycling stability. In addition, Mo doping enhances the kinetics of sodium-ion transfer, and the interlaced SnO2 nanoflake arrays is beneficial to promote the conversion reactions during the charge/discharge process. The as-prepared composite with a unique structure demonstrate a high initial capacity of 1017.1 mAh g-1 at 0.1 A g-1, with a capacity retention over three times higher than that of the control sample (SnO2@C-foam) at 1 A g-1, indicating a remarkable rate performance.

Niobium doped tungsten oxide mesoporous film with enhanced electrochromic and electrochemical energy storage properties.

Exploring high performance cathode materials is of great means for the development of bi-functional electrochromic energy storage devices. Herein, Nb-doped WO3 mesoporous films as integrated high-quality cathode are successfully constructed via a facile sol-gel method. Chemical state and crystallinity of the WO3 based films are significantly influenced by doping concentration. Compared with the pure WO3, the optimal Nb-doped film shows improved optical-electrochemical properties with high specific capacity (74.4 mAh g-1 at 2 A g-1), excellent high-rate capability, large optical contrast (61.7% at 633 nm), and ultra-fast switching speed (3.6 s and 2.1 s for coloring and bleaching process, respectively). These positive features suggest the potential application of Nb-doped WO3 mesoporous cathode. Our research paves the way for the development of multifunctional photoelectrochemical energy devices.

Analysis of the Mitochondrial 4977 Bp Deletion in Patients with Hepatocellular Carcinoma.

Mutations in the mitochondrial (mt) genome that result in mt dysfunction, have long been proposed to play important roles in the pathogenesis of hepatocellular carcinoma (HCC). Among these, the common mtDNA 4977 bp deletion is one of the most frequent mutations observed in various cancers. To understand the relationship between the mtDNA 4977 bp deletion and HCC, we performed mutational screening for the presence of this deletion in 105 HCC patients and 69 unrelated healthy subjects. After nested-polymerase chain reaction (nested-PCR) amplification, we found that there were 10 patients carrying the mtDNA 4977 bp deletion, and this deletion was absent in control subjects. Moreover, HCC patients carrying this deletion showed a marked increase in reactive oxygen species (ROS) level and mtDNA copy number when compared with the healthy controls. Taken together, our data indicated that the mtDNA 4977 bp deletion may play important role in the carcinogenesis of HCC, possibly via the alternation of mtDNA copy number and oxidative stress.

Phenotypic and molecular characteristics of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus in slaughterhouse pig-related workers and control workers in Guangdong Province, China.

Pig farmers and veterinarians have high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) due to the occupational livestock exposure, while few reported this association on slaughterhouse workers. We conducted this cross-sectional study to explore the phenotypic and molecular characteristics of S. aureus and MRSA in slaughterhouse pig-related workers and control workers in Guangdong Province, China. Participants were interviewed and provided two nasal swabs. Swabs were tested for S. aureus, and isolates were further tested for antimicrobial susceptibility, virulence genes and multi-locus sequence typing. Compared with control workers, pig-related workers have significantly higher prevalence of MRSA carriage (adjusted odd ratio (aOR) 3·70, 95% CI 1·63-8·40). The proportions of MRSA resistant to clindamycin, erythromycin, tetracycline or chloromycetin were significantly higher in pig-related workers than in control workers. The predominant phenotypes of S. aureus were resistant to penicillin, clindamycin, erythromycin and tetracycline. Three MRSA CC9 isolates with livestock-associated characteristics (resistance to tetracycline and absence of immune evasion cluster (IEC) genes) were detected in pig-related workers but not in control workers. For human-associated CCs (CC7, CC59, CC6, and CC188), there was no significant difference in IEC profile or antimicrobial resistance between the groups. These findings reveal that there may be a potential risk for livestock-to-human transmission of LA-MRSA and human-to-human transmission of human-associated MRSA.

A molecular epidemiological study of methicillin-resistant Staphylococci environmental contamination in railway stations and coach stations in Guangzhou of China.

Methicillin-resistant Staphylococcus aureus (MRSA) has caused a series of public health problems since it was first found in 1961. However, there are few research studies on the MRSA environmental contamination in railway stations and coach stations. Therefore, the aim of this study was to determine MRSA environmental contamination in public transport stations. Between December 2013 and January 2014, 380 surface samples from three railway stations (180) and four coach stations (200) in Guangzhou were collected to isolate and determine the prevalence and characteristics of Staphylococci strains. 39·21% of all samples were Staphylococci isolates, 1·58% of Staphylococci isolates were MRSA isolates, and 6·05% were methicillin-susceptible S. aureus. The proportion of multidrug resistant among 149 Staphylococci isolates was 75·84%. None of MRSA isolates was identified with the Panton-Valentine Leukocidin (PVL) genes, and one of them was identified with the qac gene. Four MRSA isolates were Staphylococcal Cassette Chromosome mec IVa, and the other two were nontypeable. Staphylococcus aureus isolates were classified into several sequence types (STs), and STs showed possible cross-transmissions of isolates from various sources. Methicillin-resistant Staphylococci contamination prevalence was high, and the environment of stations may be the vectors transmitting the Staphylococci to passengers. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to comprehensively report the prevalence, antibiotic resistance, and molecular characteristics of contamination of Staphylococci isolates in railway stations and coach stations of China. It will have great public health implications on infection control in community settings because of the serious hazard of Staphylococci, especially methicillin-resistant Staphylococci. Our findings have provided evidence for relevant departments to reduce the contamination of Staphylococci in environment of public transport stations.

Molecular cloning and expression analysis of heat-shock protein 70 in orange-spotted grouper Epinephelus coioides following heat shock and Vibrio alginolyticus challenge.

In this study, the complementary (c)DNA encoding heat-shock protein 70 (Hsp70) of orange-spotted grouper Epinephelus coioides (OsgHsp70) was cloned. OsgHsp70 was 2206 bp and encoded 652 amino acids with predicted molecular mass of 70·89 kDa and theoretical isoelectric point of 5·48. Three Hsp70 family signatures, bipartite nuclear localization signal sequence (NLS) and cytoplasmic characteristic motif (EEVD) were observed in the OsgHsp70, which shared high similarity in amino-acid sequences with the Hsp70 gene of other vertebrates. The results indicated that the OsgHsp70 is a member of the heat-shock protein 70 family. The Hsp70 messenger (m)RNA expressions were quantified by real-time PCR following heat shock, bacterial infection and immunization with formalin-killed Vibrio alginolyticus, a kind of bacterial pathogen that causes septicaemia. Hsp70 mRNA expression in gill, kidney, spleen, thymus gland, muscle and total-blood samples increased at first and then decreased gradually following heat shock. A similar time-dependent pattern was observed following V. alginolyticus pathogen challenge, in which Hsp70 mRNA expression peaked at 24 h after live bacterial infection and 3 days after dead bacterial vaccination. The results indicated that the Hsp70 gene was inducible and involved in the fish immune response.

Investigation of the neural substrates of voice recognition in Chinese schizophrenic patients with auditory verbal hallucinations: an event-related functional MRI study.

OBJECTIVE: Auditory hallucinations (AVHs), like real auditory perceptions, are often perceived as familiar voices. Given that neural correlates of AVHs involve the auditory cortex, it is likely that those brain regions responsible for recognition of voice identity are invoked during AVHs. METHOD: Schizophrenic patients with (n = 13) and without (n = 13) auditory hallucinations, and 13 healthy subjects performed a voice recognition task during functional magnetic resonance imaging at 1.5 T. In the task using prerecorded vocal stimuli, they classified voice as familiar and unfamiliar. RESULTS: Under the familiar minus unfamiliar contrasts, cerebral activation pattern is different in the three groups and patients with auditory hallucinations showed less activation in the right temporal lobe than controls. CONCLUSION: Voice recognition was impaired in patients with AVHs. Our results support that auditory association cortices play a role in the perception of AVHs.

Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells.

Interleukin-10 (IL-10) is intensely studied, yet little is known about the mechanisms that control IL-10 expression. We identified striking similarities between IL-10 and interferon-gamma (IFN-gamma) regulation in mouse natural killer (NK) cells. Like IFN-gamma, IL-10 expression is induced by IL-2 and IL-12 and IL-2+IL-12 stimulation is synergistic. Unlike IFN-gamma, neither IL-18 nor Ly-49D cross-linking induced IL-10 expression however. Additionally, the IL-12 homologs IL-23 and IL-27 also do not regulate NK cell-specific IL-10. We determined that a small population of NK cells accounts for IL-10 production. The induction of IL-10 by IL-2+IL-12 treatment in NK cells appears to be biphasic, with an initial burst of expression which diminishes by 12 h but spikes again at 18 h. We determined that much like IFN-gamma, Stat4 is largely required for IL-12-induced IL-10. Conversely, we observed normal induction of IL-10 in T-bet-deficient NK cells. We identified a Stat4-binding element in the fourth intron of the Il10 gene, which is completely conserved between mouse and human. This intronic Stat4 motif is within a conserved noncoding sequence, which is also a target for cytokine-induced histone acetylation. These findings highlight tissue- and receptor-specific IL-10 regulatory mechanisms, which may be part of an early feedback loop.

Atemoyacin E, a bis-tetrahydrofuran annonaceous acetogenin from Annona atemoya seeds.

Atemoyacin E (I), a new adjacent bis-tetrahydrofuran annonaceous acetogenin was isolated and characterized from the seeds of Annona atemoya.

N-terminal carboxyl and tetrazole-containing amides as adjuvants to Grb2 SH2 domain ligand binding.

High affinity binding of peptides to Src homology 2 (SH2) domains, often requires the presence of phosphotyrosyl (pTyr) or pTyr-mimicking moieties in the N-terminal position of the binding ligand. Several reports have shown that N(alpha)-acylation of the critical pTyr residue can result in increased SH2 domain binding potency. For Grb2 SH2 domains which recognize pTyr-Xxx-Asn-NH(2) motifs, significant potency enhancement can be incurred by N(alpha)-(3-amino)Z derivatization of tripeptides such as pTyr-Ile-Asn-NH(2). Using ligands based on the high affinity pY-Ac(6)c-Asn-(naphthylpropylamide) motif, (where Ac(6)c=1-aminocyclohexanecarboxylic acid), additional reports have shown moderate potentiating effects of N(alpha)-oxalyl derivatization. The current study examined variations of the N(alpha)-oxalyl theme in the context of a Xxx-Ac(6)c-Asn-(naphthylpropylamide) platform, where Xxx=the hydrolytically stable pTyr mimetics phosphonomethyl phenylalanine (Pmp) or carboxymethyl phenylalanine (Cmf). The effects of N(alpha)-(3-amino)Z derivatization were also investigated for this platform, to ascertain whether the large binding enhancement reported for tripeptides such as pTyr-Ile-Asn-NH(2) could be observed. In ELISA-based extracellular Grb2 SH2 domain binding assays, it was found for the Pmp-based series, that extending the oxalyl carboxyl out by one methylene unit or replacing carboxyl functionality with a tetrazole isostere, resulted in binding potency greater than the parent N(alpha)-acetyl-containing compound, with enhancement approximating that observed for the N(alpha)-oxalyl derivative. When Cmf was used as the pTyr mimetic, only modest differences in IC(50) values were observed for the series. Examination of the N(alpha)-(3-amino)Z derivatized Pmp-Ac(6)c-Asn-(naphthylpropylamide), showed that binding affinity was reduced relative to the parent N(alpha)-acetyl analogue, in contrast to the reported significant enhancement of affinity observed with other peptide ligands. Treatment of MDA-453 tumor cells, which are mitogenically driven through erbB-2 tyrosine kinase-dependent pathways, with Pmp-containing inhibitors resulted in growth inhibition, with the N(alpha)-oxalyl and N(alpha)-malonyl-containing compounds exhibiting IC(50) values (4.3 and 4.6 microM, respectively) approximately five-fold lower than the parent N(alpha)-acetyl-containing compound. Tetrazole and N(alpha)-(3-amino)Z-containing inhibitors were from two- to four-fold less potent than these latter analogues in the growth inhibition assays.

Phospho-Azatyrosine, a less effective protein-tyrosine phosphatase substrate than phosphotyrosine.

Azatyrosine (AzaTyr, 4) is a natural product isolated from Streptomyces chibanesis, whose structure is characterized by a nitrogen atom in the aryl ring of a tyrosyl residue. This seemingly minor modification to the tyrosyl residue results in profound physiological effects, as AzaTyr has been shown to promote permanent reversion of ras-dependent transformed cells to the normal phenotype in culture and to inhibit chemical induction of carcinogenesis in transgenic mice bearing oncogenic human ras. The mechanisms underlying these effects are not known, however ras-pathways involve an intricate balance between both protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). The present study was undertaken to examine the general utility of AzaTyr as a structural motif for PTP inhibitor design by examining the phospho-azatyrosine (pAzaTyr)-containing peptide Ac-Asp-Ala-Asp-Glu-pAzaTyr-Leu-amide (8) in a PTP1 enzyme system. Kinetic analysis indicated that 8 binds with a Km value of 210 microM and a catalytic turnover rate, kcat of 52 s(-1). This represents a greater than 50-fold reduction in binding affinity relative to the parent phosphotyrosine-containing peptide, indicating that the aryl nitrogen adversely affects binding affinity. The much lower PTP affinity of the pAzaTyr-containing peptide reduces the potential utility of the AzaTyr pharmacophore for PTP inhibitor design. These results are discussed from the point of view that incorporation of AzaTyr residues into proteins could result in perturbation of protein-tyrosine phosphorylation,dephosphorylation cascades that control signal transduction processes, including ras-dependent pathways.

Phosphoryltyrosyl mimetics in the design of peptide-based signal transduction inhibitors.

The central roles played by protein-tyrosine kinase (PTK)-dependent signal transduction in normal cellular regulation and homeostasis have made inappropriate or aberrant functions of certain of these pathways contributing factors to a variety of diseases, including several cancers. For this reason, development of PTK signaling inhibitors has evolved into an important approach toward new therapeutics. Since in these pathways phosphotyrosyl (pTyr) residues provide unique and defining functions either by their creation under the catalysis of PTKs, their recognition and binding by protein modules such as SH2 and phosphotyrosyl binding (PTB) domains, or their destruction by protein-tyrosine phosphatases, pTyr mimetics provide useful general starting points for inhibitor design. Important considerations in the development of such pTyr mimetics include enzymatic stability (particularly toward PTPs), high affinity recognition by target pTyr binding proteins, and good cellular bioavailability. Although small molecule, nonpeptide inhibitors may be ultimate objectives of inhibitor development, peptides frequently serve as display platforms for pTyr mimetics, which afford useful and conceptually straightforward starting points in the development process. Reported herein is a limited overview of pTyr mimetic development as it relates to peptide-based agents. Of particular interest are recent findings that highlight potential limitations of peptides as display platforms for the identification of small molecule leads. One conclusion that results from this work is that while peptide-based approaches toward small molecule inhibitor design are often intellectually satisfying from a structure-based perspective, extrapolation of negative findings to small molecule, nonpeptide contexts should be undertaken with extreme caution.

Potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion and branching morphogenesis by antagonists of Grb2 Src homology 2 domain interactions.

Hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of cellular targets during development, homeostasis and tissue regeneration. Inappropriate HGF signaling occurs in several human cancers, and the ability of HGF to initiate a program of protease production, cell dissociation, and motility has been shown to promote cellular invasion and is strongly linked to tumor metastasis. Upon HGF binding, several tyrosines within the intracellular domain of its receptor, c-Met, become phosphorylated and mediate the binding of effector proteins, such as Grb2. Grb2 binding through its SH2 domain is thought to link c-Met with downstream mediators of cell proliferation, shape change, and motility. We analyzed the effects of Grb2 SH2 domain antagonists on HGF signaling and observed potent blockade of cell motility, matrix invasion, and branching morphogenesis, with ED(50) values of 30 nm or less, but only modest inhibition of mitogenesis. These compounds are 1000-10,000-fold more potent anti-motility agents than any previously characterized Grb2 SH2 domain antagonists. Our results suggest that SH2 domain-mediated c-Met-Grb2 interaction contributes primarily to the motogenic and morphogenic responses to HGF, and that these compounds may have therapeutic application as anti-metastatic agents for tumors where the HGF signaling pathway is active.

Peptide mimicking antigenic and immunogenic epitope of double-stranded DNA in systemic lupus erythematosus.

Autoantibodies to double-stranded (ds) DNA are an important diagnostic marker and pathogenic factor for systemic lupus erythematosus (SLE). Identifying dsDNA mimotopes is a way to discover diagnostic and therapeutic candidates for SLE. 'Mono-specific' SLE anti-dsDNA antibodies were obtained by affinity purification using dsDNA-coupled Sepharose column. Using the anti-dsDNA antibodies to screen a phage peptide library, we were able to identify a mimotope that has a motif peptide sequence of RLTSSLRYNP. This chemically synthesized peptide could be recognized by 88% (37 out of 42) of anti-dsDNA antibody-positive SLE sera with a cut-off point at mean + 3 SD of the negative control sera at OD(492). The reaction of the peptide with SLE sera in ELISA was highly correlated with that of dsDNA (r = 0.809, P < 0.0001). Of particular interest, not only dsDNA but also single-stranded (ss) DNA and native RNA could inhibit the binding of the peptide with SLE sera, suggesting that the mimotope is shared by ds and ssDNAs as well as native RNA, whereas denatured RNA was not observed to inhibit the binding. The peptide was also able to elicit an immune response in rabbits and the anti-peptide rabbit serum was observed to cross-react with the peptide, ss and dsDNAs, and ss and dsDNAs could inhibit the binding of the anti-peptide serum and the peptide. However, the inhibition was not obtained with RNA. Our findings demonstrate the potential of the peptide mimic in diagnostic tests of SLE, and in the investigation of anti-DNA antibody origin and of DNA-anti-DNA antibody interaction.

Evaluation of a recombinant Listeria monocytogenes expressing an HIV protein that protects mice against viral challenge.

Vaccine strategies that utilize cell mediated immunity to control infection will be a necessary component of human immunodeficiency virus (HIV) vaccines. In previous studies we have shown that a Listeria monocytogenes recombinant expressing HIV-Gag elicits strong CD8+ and CD4+ T cell responses against HIV Gag in addition to its own secreted proteins. Here, we show that Lm-Gag can protect mice against a viral challenge with a recombinant vaccinia virus expressing Gag, in an antigen specific manner, and that this protection is T cell mediated. These results further support the use of L. monocytogenes as a vaccine approach for HIV through the induction of T cell immunity.

[Capillary array electrophoresis and high-throughput DNA sequencing].

Depending on the outputs of 10,080 DNA sequencing samples from the human genome project, technical features of capillary array electrophoresis are discussed. The results show that 88% of the total readlength were higher than 50 kbp/run. It means that most of the readlength could reach 500 bp or more with reasonable quality. The results were much better than expected when the technology of capillary array appeared about one year ago. A key parameter affecting the quality of DNA sequencing is the purity of sequencing template. Therefore, a batch agarose slab electrophoresis was applied to check the purity before loading. Other conditions, such as concentration of template and loading amount, are discussed as well. Finally, comparisons based on the electrophoresis timing, the pre-treatment of samples, the loading procedures and the results analysis between capillary array electrophoresis and slab gel electrophoresis have been made. From the point of view of high-throughput DNA sequencing, especially in the field of genome research, the capillary array electrophoresis should be the better choice as a more efficient technical platform.

Thermodynamic study of ligand binding to protein-tyrosine phosphatase 1B and its substrate-trapping mutants.

The binding of several phosphonodifluoromethyl phenylalanine (F(2)Pmp)-containing peptides to protein-tyrosine phosphatase 1B (PTP1B) and its substrate-trapping mutants (C215S and D181A) has been studied using isothermal titration calorimetry. The binding of a high affinity ligand, Ac-Asp-Ala-Asp-Glu-F(2)Pmp-Leu-NH(2), to PTP1B (K(d) = 0.24 microm) is favored by both enthalpic and entropic contributions. Disruption of ionic interactions between the side chain of Arg-47 and the N-terminal acidic residues reduces the binding affinity primarily through the reduction of the TDeltaS term. The role of Arg-47 may be to maximize surface contact between PTP1B and the peptide, which contributes to high affinity binding. The active site Cys-215 --> Ser mutant PTP1B binds ligands with the same affinity as the wild-type enzyme. However, unlike wild-type PTP1B, peptide binding to C215S is predominantly driven by enthalpy change, which likely results from the elimination of the electrostatic repulsion between the thiolate anion and the phosphonate group. The increased enthalpic contribution is offset by reduction in the binding entropy, which may be the result of increased entropy of the unbound protein caused by this mutation. The general acid-deficient mutant D181A binds the peptide 5-fold tighter than the C215S mutant, consistent with the observation that the Asp to Ala mutant is a better "substrate-trapping" reagent than C215S. The increased binding affinity for D181A as compared with the wild-type PTP1B results primarily from an increase in the DeltaH of binding in the mutant, which may be related to decreased electrostatic repulsion between the phosphate moiety and PTP1B. These results have important implications for the design of high affinity PTP1B inhibitors.