Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.

The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.

Silver(I)-Based Molecular Perovskite Energetic Compounds with Exceptional Thermal Stability and Energetic Performance.

In recent years, molecular perovskite energetic materials have attracted more attention because of their simple synthesis processes, high thermal stabilities, excellent performances, and great significance as a design platform for energetic materials. To explore the possibility of the application of molecular perovskite energetic materials in heat-resistant explosives, four silver(I)-based molecular perovskite energetic compounds, (H2A)[Ag(ClO4)3], where H2A = piperazine-1,4-diium (H2pz2+) for PAP-5, 1-methyl-piperazine-1,4-diium (H2mpz2+) for PAP-M5, homopiperazine-1,4-diium (H2hpz2+) for PAP-H5, and 1,4-diazabicyclo[2.2.2]octane-1,4-diium (H2dabco2+) for DAP-5, were synthesized by a one-pot self-assembly strategy and structurally characterized. The single-crystal structures indicated that PAP-5, PAP-M5, and DAP-5 possess cubic perovskite structures while PAP-H5 possesses a hexagonal perovskite structure. Differential thermal analyses showed that their onset decomposition temperatures are >308.3 °C. For PAP-5 and DAP-5, they have not only exceptional calculated detonation parameters (D values of 8.961 and 8.534 km s-1 and P values of 42.4 and 37.9 GPa, respectively) but also the proper mechanical sensitivity (impact sensitivities of ≤10 J for PAP-5 and 3 J for DAP-5 and friction sensitivities of ≤5N for both PAP-5 and DAP-5) and thus are of interest as potential heat-resistant primary explosive components.

Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2.

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.

The Assessment of Sleep Quality in Patients Following Valve Repair and Valve Replacement for Infective Endocarditis: A Retrospective Study at a Single Center.

BACKGROUND The aim of this study was to measure sleep quality among patients who underwent infective endocarditis (IE) surgery and identify the risk factors involved in sleep disorders. MATERIAL AND METHODS In this study, we used actigraphy, the Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleep Scale (ESS) to determine the clinical characteristics of sleep disorders in 116 patients with IE who were in rehabilitation after surgery. RESULTS Our results showed that 46 (39.7%) patients had sleep efficiency over 85%, while 70 (60.3%) patients had sleep efficiency below 85%. The correlation analysis showed that sleep efficiency was related to the duration of the disease, with a longer duration leading to lower sleep efficiency (P=0.031). The sleep efficiency of patients with IE following surgery was also affected by alcohol consumption; however, surprisingly, patients with "heavy" alcohol consumption had higher sleep efficiency (P=0.030). We found a significant correlation between sleep efficiency and postoperative interleukin-6 (IL) levels, C-reactive protein (CRP) levels, and preoperative erythrocyte sedimentation rate (P<0.05). No significant correlation was found between brain natriuretic peptide levels and sleep efficiency, PSQI score, or ESS score. Postoperative hemoglobin (Hb) level was associated with sleep efficiency (R=0.194, P=0.036), but there was no statistically significant correlation between the PSQI and ESS scores. Postoperative alanine transaminase (ALT) showed a significant negative correlation with sleep efficiency (R=-0.27, P=0.003). CONCLUSIONS We found a high prevalence of sleep disorders in patients with IE along with an increase in inflammatory factors, including postoperative IL-6, CRP, ALT, and Hb levels.

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases.

An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic intervention. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent to an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination of a number of regulatory mechanisms, including redox modulation, allosteric regulation, and protein oligomerization, that control PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.

A potent and selective inhibitor for the UBLCP1 proteasome phosphatase.

The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) has been implicated as a negative regulator of the proteasome, a key mediator in the ubiquitin-dependent protein degradation. Small molecule inhibitors that block UBLCP1 activity would be valuable as research tools and potential therapeutics for human diseases caused by the cellular accumulation of misfold/damaged proteins. We report a salicylic acid fragment-based library approach aimed at targeting both the phosphatase active site and its adjacent binding pocket for enhanced affinity and selectivity. Screening of the focused libraries led to the identification of the first potent and selective UBLCP1 inhibitor 13. Compound 13 exhibits an IC50 of 1.0µM for UBLCP1 and greater than 5-fold selectivity against a large panel of protein phosphatases from several distinct families. Importantly, the inhibitor possesses efficacious cellular activity and is capable of inhibiting UBLCP1 function in cells, which in turn up-regulates nuclear proteasome activity. These studies set the groundwork for further developing compound 13 into chemical probes or potential therapeutic agents targeting the UBLCP1 phosphatase.

Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations.

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme's catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation.

Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations.

SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan syndromes, two of several autosomal-dominant conditions characterized by gain-of-function mutations in the Ras pathway. Interestingly, Noonan syndrome SHP2 mutants are constitutively active, whereas LEOPARD syndrome SHP2 mutants exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD syndrome mutants engender gain-of-function phenotypes? Our study reveals that LEOPARD syndrome mutations weaken the intramolecular interaction between the N-SH2 and phosphatase domains, leading to a change in SHP2 molecular switching mechanism. Consequently, LEOPARD syndrome SHP2 mutants bind upstream activators preferentially and are hypersensitive to growth factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates for the reduced phosphatase activity. The study provides a solid framework for understanding how individual SHP2 mutations cause diseases.

Protein tyrosine phosphatases as potential therapeutic targets.

Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma: A case report.

BACKGROUND: Multiple primary carcinomas (MPCs) are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual. Synchronous MPCs are rarer than solitary cancers or metachronous MPCs. Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases. CASE SUMMARY: A 64-year-old patient presented with dysphagia, without obvious cause. A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results. After multi-disciplinary consultations, combination chemotherapy (a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14) and esophageal cancer radiotherapy were initiated. Based on the results of genetic testing, we switched to a regimen of leucovorin + fluorouracil + oxaliplatin and cetuximab regimen for 8 cycles. Subsequently, capecitabine and bevacizumab were administered until the most recent follow-up, at which the tumor remained stable. CONCLUSION: Successful cetuximab chemotherapy treatment provides a reference for the non-operative and homogeneous treatment of different pathological types of synchronous MCPs.

Postcoital administration of asoprisnil inhibited embryo implantation and disturbed ultrastructure of endometrium in implantation window in mice.

Asoprisnil, a member of the selective progesterone receptor modulators, exerts high progesterone receptor selectivity, endometrial targeted advantages and significant anti-implantation effect in rats. The purpose of this study was to confirm the anti-implantation effect of asoprisil, investigate the ultrastructural changes of the peri-implantation endometrium in mice and explore the effect of asoprisnil on endometrial receptivity and its targeted contraceptive proficiency. Post-coitus mice were administered with different dosages (0.2, 0.1, 0.05 mg·g(-1)·day(-1)) of asoprisnil from day 1 of pregnancy to day 3. Then 3 animals in each group were killed on day 5 of pregnancy, and uteri were collected to examine the ultrastructural changes of endometria under a transmission electron microscope (TEM). A total of 80 animals were sacrificed on day 8 of pregnancy, and the uterine horns were examined for the presence or absence of nidation sites and the number of implantation embryos. The results showed that the implantation rate and the average number of implantation embryos in asoprisnil groups were statistically significantly decreased as compared with the vehicle control group (P<0.05). The TEM results revealed that, in vehicle control group, the tight junction between the luminal epithelia cells was short and straight, the gap was wide; the luminal epithelia cells were covered with plenty of short, clavate and neatly arranged microvilli; the endometril stromal cells were large with plenty of cytoplasm, and showed significant decidual change; there was more than one nucleus in stromal cells, and the karyotheca was integrity. In low dosage and high dosage asoprisnil groups, the tight junction was longer and more curve than in the vehicle control group; microvilli were uneven and asymmetrically distributed in luminal epithelia; the stromal cells were small and the decidual change was not significant; there were karyopyknosis and karyolysis in stromal cells; there were abnormal thick-wall vessels in the endometrium. It was suggested that asoprisnil changed the ultrastructure of the endometrium in implantation window, disturbed the endometrial receptivity and finally resulted in embryo implantation failure.

Periodate-based molecular perovskites as promising energetic biocidal agents.

Epidemics caused by pathogens in recent years have created an urgent need for energetic biocidal agents with the capacity of detonation and releasing bactericides. Herein we present a new type of energetic biocidal agents based on a series of iodine-rich molecular perovskites, (H2dabco)M(IO4)3 (dabco = 1,4-diazabicyclo[2.2.2]octane, M = Na+/K+/Rb+/NH4 + for DAI-1/2/3/4) and (H2dabco)Na(H4IO6)3 (DAI-X1). These compounds possess a cubic perovskite structure, and notably have not only high iodine contents (49-54 wt%), but also high performance in detonation velocity (6.331-6.558 km s-1) and detonation pressure (30.69-30.88 GPa). In particular, DAI-4 has a very high iodine content of 54.0 wt% and simultaneously an exceptional detonation velocity up to 6.558 km s-1. As disclosed by laser scanning confocal microscopy observation and a standard micro-broth dilution method, the detonation products of DAI-4 exhibit a broad-spectrum bactericidal effect against bacteria (E. coli, S. aureus, and P. aeruginosa). The advantages of easy scale-up synthesis, low cost, high detonation performance, and high iodine contents enable these periodate-based molecular perovskites to be highly promising candidates for energetic biocidal agents. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s40843-022-2257-6.

Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and identification of Src kinase-associated protein of 55 kDa homolog (SKAP-HOM) as a Lyp substrate.

A missense single-nucleotide polymorphism in the gene encoding the lymphoid-specific tyrosine phosphatase (Lyp) has been identified as a causal factor in a wide spectrum of autoimmune diseases. Interestingly, the autoimmune-predisposing variant of Lyp appears to represent a gain-of-function mutation, implicating Lyp as an attractive target for the development of effective strategies for the treatment of many autoimmune disorders. Unfortunately, the precise biological functions of Lyp in signaling cascades and cellular physiology are poorly understood. Identification and characterization of Lyp substrates will help define the chain of molecular events coupling Lyp dysfunction to diseases. In the current study, we identified consensus sequence motifs for Lyp substrate recognition using an "inverse alanine scanning" combinatorial library approach. The intrinsic sequence specificity data led to the discovery and characterization of SKAP-HOM, a cytosolic adaptor protein required for proper activation of the immune system, as a bona fide Lyp substrate. To determine the molecular basis for Lyp substrate recognition, we solved crystal structures of Lyp in complex with the consensus peptide as well as the phosphopeptide derived from SKAP-HOM. Together with the biochemical data, the structures define the molecular determinants for Lyp substrate specificity and provide a solid foundation upon which novel therapeutics targeting Lyp can be developed for multiple autoimmune diseases.

A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes.

Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small-molecule agents. We present a stepwise focused library approach that transforms a weak and general non-hydrolyzable pTyr mimetic (F(2)Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F(2)Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F(2)Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.

Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors.

Protein tyrosine phosphatases (PTPs) constitute a large and structurally diverse family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. Malfunction of PTP activity has significant implications in many human diseases, and the PTP protein family provides an exciting array of validated diabetes/obesity (PTP1B), oncology (SHP2), autoimmunity (Lyp), and infectious disease (mPTPB) targets. However, despite the fact that PTPs have been garnering attention as novel therapeutic targets, they remain largely an untapped resource. The main challenges facing drug developers by the PTPs are inhibitor specificity and bioavailability. Work over the last ten years has demonstrated that it is feasible to develop potent and selective inhibitors for individual members of the PTP family by tethering together small ligands that can simultaneously occupy both the active site and unique nearby peripheral binding sites. Recent results with the bicyclic salicylic acid pharmacophores indicate that the new chemistry platform may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. Structural analysis of PTP-inhibitor complexes reveals molecular determinants important for the development of more potent and selective PTP inhibitors, thus offering hope in the medicinal chemistry of a largely unexploited protein class with a wealth of attractive drug targets.

Mutant soluble ectodomain of fibroblast growth factor receptor-2 IIIc attenuates bleomycin-induced pulmonary fibrosis in mice.

We have developed a strong inhibitor (S252W mutant soluble ectodomain of fibroblast growth factor recptor-2 IIIc, msFGFR2) that binds FGFs strongly and blocks the activation of FGFRs. In vitro, msFGFR2 could inhibit the promoting effect of transforming growth factor (TGF)-ß1 on the proliferation of primary lung fibroblasts. In vivo, msFGFR2 alleviated lung fibrosis through inhibiting the expression of α-smooth muscle actin (SMA) and collagen deposit. In Western blotting of the right lung tissues and immunohistochemical assay, we found the level of p-FGFRs, p-mitogen activated protein kinase (MAPK) and p-Smad3 in the mice of bleomycin (BLM) group treated with msFGFR2 was down dramatically compared with the mice of BLM group, which suggested the activations of FGF and TGF-ß signals were blocked meanwhile. In summary, msFGFR2 attenuated BLM-induced fibrosis and is an attractive therapeutic candidate for human pulmonary fibrosis.

[Outlier sample discriminating methods for building calibration model in melons quality detecting using NIR spectra].

Outlier samples strongly influence the precision of the calibration model in soluble solids content measurement of melons using NIR Spectra. According to the possible sources of outlier samples, three methods (predicted concentration residual test; Chauvenet test; leverage and studentized residual test) were used to discriminate these outliers respectively. Nine suspicious outliers were detected from calibration set which including 85 fruit samples. Considering the 9 suspicious outlier samples maybe contain some no-outlier samples, they were reclaimed to the model one by one to see whether they influence the model and prediction precision or not. In this way, 5 samples which were helpful to the model joined in calibration set again, and a new model was developed with the correlation coefficient (r) 0. 889 and root mean square errors for calibration (RMSEC) 0.6010 Brix. For 35 unknown samples, the root mean square errors prediction (RMSEP) was 0.854 degrees Brix. The performance of this model was more better than that developed with non outlier was eliminated from calibration set (r = 0.797, RMSEC= 0.849 degrees Brix, RMSEP = 1.19 degrees Brix), and more representative and stable with all 9 samples were eliminated from calibration set (r = 0.892, RMSEC = 0.605 degrees Brix, RMSEP = 0.862 degrees).

MicroRNA-181a-5p Promotes Osteosarcoma Progression via PTEN/AKT Pathway.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents with poor prognosis. MicroRNA-181a-5p (miR-181a-5p) is involved in the progression of various tumors; however, its role and underlying mechanism in osteosarcoma remains unclear. In this study, we found that miR-181a-5p was upregulated in human osteosarcoma cells and tissues. miR-181a-5p mimic significantly promoted, while miR-181a-5p inhibitor blocked the proliferation, colony formation, migration, invasion, and cell cycle progression of osteosarcoma cells. Mechanistically, miR-181a-5p bound to the 3'-untranslational region of phosphatase and tensin homolog (PTEN) and reduced its protein expression, thereby activating protein kinase B (PKB/AKT) pathway. Either PTEN overexpression or AKT inhibition notably blocked the tumor-promoting effects of miR-181a-5p. Moreover, we observed that miR-181a-5p mimic further inhibited growth of human osteosarcoma cells in the presence of adriamycin or cisplatin. Overall, miR-181a-5p promotes osteosarcoma progression via PTEN/AKT pathway and it is a promising therapeutic target to treat osteosarcoma.

Sleep patterns and potential risk factors for disturbed sleep quality in patients after surgery for infective endocarditis.

BACKGROUND: The current study aimed to investigate the sleep quality of patients after valve replacement surgery due to infective endocarditis and identify risk factors for disturbed sleep post hospitalisation. METHODS: Eighty patients were assessed postoperatively using subjective scale measures, the Pittsburgh sleep quality index (PSQI) and the Epworth sleepiness scale, and an objective measure, actigraphy. Scale measures were assessed approximately 2 weeks and 6 months after surgery. Actigraphy monitoring was performed for 2 consecutive weeks during hospitalisation. Logistic regression was used to identify risk factors for disturbed sleep. RESULTS: The study population (n = 80) had an average age of 42.8 ± 14.2 years, and 67.5% were male. The median sleep efficiency was 85.3% in week 1 and 86.8% in week 2. The frequency of awakenings was significantly higher in week 1 (20.0 times vs. 19.3 times, p = 0.017). The scale measures showed significant improvement in sleep by 6 months after surgery compared to that during hospitalisation. Multivariable logistic regression analysis suggested that the possible risk factors for disturbed sleep 6 months after surgery included age (OR = 1.479, 95%CI 1.140-1.920) and a few parameters of early postoperative disturbed sleep quality (PSQI: OR = 2.921, 95%CI 1.431-5.963; sleep efficiency: OR = 0.402, 95%CI 0.206-0.783; and average duration of awakenings: OR = 0.006, 95%CI 0.000-0.827). CONCLUSIONS: Disturbed sleep quality was witnessed in postoperative patients during hospitalisation and up to 6 months after surgery. Over time, the patients' sleep quality improved significantly. Age and a few early postoperative sleep quality variables were risk factors for disturbed sleep 6 months after surgery.

Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors.

Protein tyrosine phosphatases constitute an important class of drug targets whose potential has been limited by the paucity of drug-like small-molecule inhibitors. We recently described a class of active-site-directed, moderately selective, and potent inhibitors of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive structure-based design and optimization effort that afforded inhibitors with vastly improved potency and specificity. The leading compound inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit favorable drug-like properties, such as low molecular weight, weak cytochrome P450 inhibition, high metabolic stability, moderate to high cell permeability (Papp > 0.2 nm/s), and moderate to good oral bioavailability (% F from 23 to 50% in mice), and therefore can be used as in vivo chemical probes to further dissect the complex biological as well as pathophysiological roles of LMW-PTP and for the development of therapeutics targeting LMW-PTP.