PTPσ inhibitors promote hematopoietic stem cell regeneration.

Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration

Inhibition of Protein Tyrosine Phosphatase-Sigma Promotes Hematopoietic Stem Cell Regeneration

Receptor tyrosine kinases, such as c-Kit, Flt-3, and Tie 2, regulate hematopoietic stem cell (HSC) proliferation, differentiation, and maintenance. Substantially less is known regarding the function of protein tyrosine phosphatases (PTPs) in regulating HSC fate. We recently discovered that receptor type protein tyrosine phosphatase-sigma (PTPσ) is highly expressed by murine and human HSCs. PTPσ was originally discovered in adult neurons and has shown to regulate neural regeneration. In the hematopoietic system, constitutive deletion of PTPσ in mouse bone marrow (BM) cells significantly increased HSC repopulating capacity compared to the wildtype. Furthermore, negative selection of human cord blood (CB) HSCs for PTPσ surface expression conferred more than 10-fold increase in human CB hematopoietic engraftment through 20 weeks in transplanted NSG mice. Additionally, PTPσ-deficient mice displayed significantly augmented recovery of BM colony forming cells at day +10 following 600 cGy total body irradiation. Based on these observations, we hypothesized that PTPσ may function as a negative regulator of HSC self-renewal and regeneration. Here we describe novel small molecule inhibitors of PTPσ that promote hematopoietic stem cell (HSC) regeneration in vivo. Systemic administration of DJ001, a PTPσ inhibitor, or its analog to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, following chemotherapy, DJ001 administration accelerates hematologic recovery in mice. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration

Refracture after plate removal of midshaft clavicle fractures after bone union—incidence, risk factors, management and outcomes

Abstract Introduction There is a great debate on the routine use of open reduction and internal fixation (ORIF) for midshaft clavicle fractures, and one concern is the adverse events after ORIF, such as implant removal after bone union. In this retrospective study, we assessed the incidence, risk factors, management and outcomes of refracture after plate removal of midshaft clavicle fractures after bone union. Materials and methods Three hundred fifty-two patients diagnosed with acute midshaft clavicle fractures who had complete medical records from primary fractures to refracture were recruited. Details of imaging materials and clinical characteristics were carefully reviewed and analysed. Results The incidence rate of refracture was 6.5% (23/352), and the average interval from implant removal to refracture was 25.6 days. Multivariate analysis showed that the risk factors were Robinson type-2B2 and fair/poor reduction. Females were 2.4 times more likely to have refracture, although it was not significant in multivariate analysis (p = 0.134). Postmenopausal females with a short interval (≤ 12 months) from primary surgery to implant removal had a significant risk for refracture. Tobacco use and alcohol use during bone healing were potential risk factors for male patients, although they were not significant in multivariate analysis. Ten patients received reoperation with or without bone graft, and they had a higher rate of bone union than 13 patients who refused reoperation. Conclusion The incidence of refracture following implant removal after bone union is underestimated, and severe comminute fractures and unsatisfactory reduction during primary surgery are risk factors. Implant removal for postmenopausal female patients is not recommended due to a high rate of refracture

Elemental Geochemical Characterization of Sedimentary Conditions and Organic Matter Enrichment for Lower Cambrian Shale Formations in Northern Guizhou, South China

The black shale deposited in the Niutitang Formation and its adjacent strata is considered to be a favorable source rock in northern Guizhou of south China and has become a target horizon for shale gas exploration in recent years. Based on SQ-1 and CY-1 core samples, the organic matter properties and geochemical elements were obtained through experimental analysis. Provenance, paleoredox, paleoclimate, paleoproductivity and deposition conditions were analyzed, and the sedimentary effects on organic matter enrichment were discussed. The results show that total organic carbon (TOC) is between 0.22–10.10 wt.% in SQ-1, with an average of 2.60 wt.%, and TOC is between 0.23–7.7 wt.% in CY-1, with an average of 1.45 wt.%. The geochemical data of the samples indicate that the black shale of the Niutitang Formation and adjacent strata are deposited in the tectonic background of the passive continental margin. The provenance shows moderate weathering, with hot and humid paleoenvironmental characteristics and fast deposition rate. Using multiple ancient redox indicators, it is concluded that the formation has undergone changes in the oxidizing environment and anaerobic environment during deposition. According to the (La/Yb)N value (the average value of SQ-1 is 1.23 and the average value of CY-1 is 1.26), it shows a faster deposition rate of the two wells and shortens the residence time of organic matter in the microbial degradation zone. The Babio indicates that the bottom has a high paleoproductivity when deposited. Considering the influencing factors, the paleoproductivity mainly controls the organic matter enrichment, followed by ancient redox conditions and the deposition rate. The research results provide a reference for deepening sedimentary understanding and shale gas exploration in the study area

Study on the Dynamic Response Characteristics and p–y Curve of Straight and Inclined Pile Groups in Saturated Sands

This paper is based on a shaking table test of 2 × 2 straight pile groups and 2 × 2 inclined pile groups in non-liquefied sand and saturated sand with different thicknesses. Under the sine wave with a certain peak acceleration and frequency, the lateral dynamic response characteristics, the distribution law of the maximum bending moment envelope diagram, and the p–y curve of the straight and inclined pile groups are studied. The results show that the bending moment of the straight pile group is 3~4 times that of the inclined pile group at the bottom section of the pile in the 300 mm saturated sand. When the thickness of the saturated sand increases to 380 mm, the maximum bending moment of the straight pile group is 6~7 times that of the inclined pile group at the bottom section of the pile. Through the comparison of indicators, it shows that the inclined pile group can have better bending resistance when subjected to the same lateral dynamic load

Study on the Dynamic Response Characteristics and p–y Curve of Straight and Inclined Pile Groups in Saturated Sands

This paper is based on a shaking table test of 2 × 2 straight pile groups and 2 × 2 inclined pile groups in non-liquefied sand and saturated sand with different thicknesses. Under the sine wave with a certain peak acceleration and frequency, the lateral dynamic response characteristics, the distribution law of the maximum bending moment envelope diagram, and the p–y curve of the straight and inclined pile groups are studied. The results show that the bending moment of the straight pile group is 3~4 times that of the inclined pile group at the bottom section of the pile in the 300 mm saturated sand. When the thickness of the saturated sand increases to 380 mm, the maximum bending moment of the straight pile group is 6~7 times that of the inclined pile group at the bottom section of the pile. Through the comparison of indicators, it shows that the inclined pile group can have better bending resistance when subjected to the same lateral dynamic load

Key district heating technologies for building energy flexibility: A review

In the background of the continued integration of renewable energy sources (RES) and the increasing flexibility on the demand side, the diversity and complexity of new technologies for heating present increased challenges for design and operation of district heating systems (DHS). This work first reviews the progress of the new generation of DHS, followed by providing an overview of investigations on building energy flexibility in the field of heating, with a focus on the characterization and quantification of energy flexibility, the realization of thermal flexibility, and the use of building thermal mass in demand side management (DSM). Different technologies were categorized and summarized according to the composition of the new generation of DHS. Control strategies such as model predictive control were also examined. In particular, the concept of building thermal battery is used to analyze buildings or prosumers thermal energy flexibility. Finally, new elements of DHS development and potential challenges were discussed

Self-Microemulsifying Drug Delivery System of Phillygenin: Formulation Development, Characterization and Pharmacokinetic Evaluation

Phillygenin, as an active ingredient of Forsythia suspensa, possesses a wide range of biological and pharmacological activity. However, its development and application are restricted due to its poor bioavailability and low solubility. Our work aimed to develop a self-microemulsifying drug delivery system to improve the oral bioavailability of phillygenin. The composition of the self-microemulsifying drug delivery system was preliminary screened by the pseudo-ternary phase diagram. Subsequently, the central composite design method was employed to optimize the prescription of the self-microemulsifying drug delivery system loaded with phillygenin. The prepared self-microemulsifying drug delivery system of phillygenin was characterized in terms of morphology, droplet size distribution, polydispersity index and stability. Then, the in vitro dissolution and the oral bioavailability were analyzed. The optimized self-microemulsifying drug delivery system of phillygenin consisted of 27.8% Labrafil M1944CS, 33.6% Cremophor EL, 38.6% polyethylene glycol 400 (PEG-400) and 10.2 mg/g phillygenin loading. The prepared self-microemulsifying drug delivery system of phillygenin exhibited spherical and uniform droplets with small size (40.11 ± 0.74 nm) and satisfactory stability. The in vitro dissolution experiment indicated that the cumulative dissolution rate of the self-microemulsifying drug delivery system of phillygenin was significantly better than that of free phillygenin. Furthermore, after oral administration in rats, the bioavailability of phillygenin was significantly enhanced by the self-microemulsifying drug delivery system. The relative bioavailability of the self-microemulsifying drug delivery system of phillygenin was 588.7% compared to the phillygenin suspension. These findings suggest that the self-microemulsifying drug delivery system of phillygenin can be a promising oral drug delivery system to improve the absorption of phillygenin

Polymersomes via Self-Assembly of Amphiphilic β‑Cyclodextrin-Centered Triarm Star Polymers for Enhanced Oral Bioavailability of Water-Soluble Chemotherapeutics

To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX·HCl), a widely used chemotherapeutic. We therefore developed a novel DOX·HCl-loaded polymersome (Ps-DOX·HCl) self-assembled by amphiphilic β-cyclodextrin-centered triarm star polymer (mPEG^2k-PLA^3k)₃-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX·HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX·HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX·HCl compared with free DOX·HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX·HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG^2k-PLA^3k)₃-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability