Emerging 2D Ferroelectric Devices for In-Sensor and In-Memory Computing.

The quantity of sensor nodes within current computing systems is rapidly increasing in tandem with the sensing data. The presence of a bottleneck in data transmission between the sensors, computing, and memory units obstructs the system's efficiency and speed. To minimize the latency of data transmission between units, novel in-memory and in-sensor computing architectures are proposed as alternatives to the conventional von Neumann architecture, aiming for data-intensive sensing and computing applications. The integration of 2D materials and 2D ferroelectric materials has been expected to build these novel sensing and computing architectures due to the dangling-bond-free surface, ultra-fast polarization flipping, and ultra-low power consumption of the 2D ferroelectrics. Here, the recent progress of 2D ferroelectric devices for in-sensing and in-memory neuromorphic computing is reviewed. Experimental and theoretical progresses on 2D ferroelectric devices, including passive ferroelectrics-integrated 2D devices and active ferroelectrics-integrated 2D devices, are reviewed followed by the integration of perception, memory, and computing application. Notably, 2D ferroelectric devices have been used to simulate synaptic weights, neuronal model functions, and neural networks for image processing. As an emerging device configuration, 2D ferroelectric devices have the potential to expand into the sensor-memory and computing integration application field, leading to new possibilities for modern electronics.

Multi-scenario investment forecast of new energy projects based on multiple linear regression and comprehensive evaluation model of differentiated project priorities.

As China's resource shortage and environmental pollution intensify, the demand for new energy and electric energy substitution is becoming higher and higher. Accurately predicting the investment scale of China's new energy projects is of great practical significance for improving the efficiency of resource allocation and economically meeting energy demand. This paper builds a scientific and precise investment model for new energy projects from both macro and micro perspectives. First, from a macro perspective, considering macro indicators such as the external environment and internal economy, an annual total investment forecast model based on multiple linear regression is constructed, in order to predict the annual total investment scale of new energy investment entities and achieve preliminary accurate investment; second, designed the evaluation index system of different project priorities from three perspectives of external environment, internal development of enterprises and social development, and constructed the comprehensive weight design method based on AN-EWM and the comprehensive evaluation method of TOPSIS, in order to realize the priority of differentiated projects. Sorting; finally, a new energy project located in a city in northern China is selected as the research subject, and a multi-scenario example analysis is carried out. The results show that the new energy project investment scale index system constructed in this paper can effectively evaluate the investment capacity of the main body of the new energy project, and can better predict the total investment of the new energy investment project, so that the deviation rate can be controlled within 5 %, and the priority evaluation model constructed in this paper can provide a complete calculation method and a reference method for the judgement of the investment priority, which can promote accurate investment.

Cold exposure induces vaso-occlusion and pain in sickle mice that depend on complement activation.

Vaso-occlusive pain episodes (VOE) cause severe pain in patients with sickle cell disease (SCD). Vaso-occlusive events promote ischemia/reperfusion pathobiology that activates complement. We hypothesized that complement activation is linked to VOE. We used cold to induce VOE in the Townes sickle homozygous for hemoglobin S (HbSS) mouse model and complement inhibitors to determine whether anaphylatoxin C5a mediates VOE. We used a dorsal skinfold chamber to measure microvascular stasis (vaso-occlusion) and von Frey filaments applied to the plantar surface of the hind paw to assess mechanical hyperalgesia in HbSS and control Townes mice homozygous for hemoglobin A (HbAA) mice after cold exposure at 10°C/50°F for 1 hour. Cold exposure induced more vaso-occlusion in nonhyperalgesic HbSS mice (33%) than in HbAA mice (11%) or HbSS mice left at room temperature (1%). Cold exposure also produced mechanical hyperalgesia as measured by paw withdrawal threshold in HbSS mice compared with that in HbAA mice or HbSS mice left at room temperature. Vaso-occlusion and hyperalgesia were associated with an increase in complement activation fragments Bb and C5a in plasma of HbSS mice after cold exposure. This was accompanied by an increase in proinflammatory NF-κB activation and VCAM-1 and ICAM-1 expression in the liver. Pretreatment of nonhyperalgesic HbSS mice before cold exposure with anti-C5 or anti-C5aR monoclonal antibodies (mAbs) decreased vaso-occlusion, mechanical hyperalgesia, complement activation, and liver inflammatory markers compared with pretreatment with control mAb. Anti-C5 or -C5aR mAb infusion also abrogated mechanical hyperalgesia in HbSS mice with ongoing hyperalgesia at baseline. These findings suggest that C5a promotes vaso-occlusion, pain, and inflammation during VOE and may play a role in chronic pain.

Vertically integrated spiking cone photoreceptor arrays for color perception.

The cone photoreceptors in our eyes selectively transduce the natural light into spiking representations, which endows the brain with high energy-efficiency color vision. However, the cone-like device with color-selectivity and spike-encoding capability remains challenging. Here, we propose a metal oxide-based vertically integrated spiking cone photoreceptor array, which can directly transduce persistent lights into spike trains at a certain rate according to the input wavelengths. Such spiking cone photoreceptors have an ultralow power consumption of less than 400 picowatts per spike in visible light, which is very close to biological cones. In this work, lights with three wavelengths were exploited as pseudo-three-primary colors to form 'colorful' images for recognition tasks, and the device with the ability to discriminate mixed colors shows better accuracy. Our results would enable hardware spiking neural networks with biologically plausible visual perception and provide great potential for the development of dynamic vision sensors.

The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease.

In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.

Definition and grading of anastomotic stricture/stenosis following low anastomosis after total mesorectal excision: A single-center study.

BACKGROUND: Anastomotic stricture/stenosis (AS) is an alarming complication after colorectal surgery, and there is still no recognized definition for AS. This study aimed to determine the status and change of AS after rectal surgery using a special AS definition and grading system, discuss various risk factors for AS. METHODS: This study included patients with rectal cancer who underwent total mesorectal excision between May 2014 and May 2021. A five-degree special AS definition and grading system was used to determine AS status, and clinical outcomes and risk factors for AS were investigated. RESULTS: A total of 473 patients were enrolled in this study. Univariate and multivariate analyses of patient-related and technical risk factors for AS were performed 3 months postoperatively. For univariate analysis, female sex was a lower risk factor for AS. Defunctioning stoma, neoadjuvant chemoradiotherapy, chemotherapy, and anastomotic leakage were higher risk factors for AS (all p < 0.05). For multivariate analysis, only neoadjuvant chemoradiotherapy, chemotherapy, and anastomotic leakage were still higher risk factors for AS (all p < 0.05). CONCLUSIONS: Through a special AS definition and grading system's evaluation, we noted that neoadjuvant chemoradiotherapy, chemotherapy, and anastomotic leakage were the higher risk factors for AS.

Sickle red blood cell-derived extracellular vesicles activate endothelial cells and enhance sickle red cell adhesion mediated by von Willebrand factor.

Endothelial activation and sickle red blood cell (RBC) adhesion are central to the pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV-mediated short-term non-transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2 h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin- or SS REV-induced microvascular stasis in SS mice with implanted dorsal skin-fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target.

Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease.

A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMß2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.

MASP-2 and MASP-3 inhibitors block complement activation, inflammation, and microvascular stasis in a murine model of vaso-occlusion in sickle cell disease.

Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothelial injury, complement activation, inflammation, vaso-occlusion, ischemia-reperfusion pathophysiology, and pain. Complement activation markers are increased in SCD in steady-state and further increased during vaso-occlusive crisis (VOC). However, the mechanisms driving complement activation in SCD have not been completely elucidated. Ischemia-reperfusion and heme released from hemoglobin during hemolysis, events that characterize SCD pathophysiology, can activate the lectin pathway (LP) and alternative pathway (AP), respectively. Here we evaluated the role of LP and AP in Townes sickle (SS) mice using inhibitory monoclonal antibodies (mAb) to mannose binding lectin (MBL)-associated serine protease (MASP)-2 or MASP-3, respectively. Townes SS mice were pretreated with MASP-2 mAb, MASP-3 mAb, isotype control mAb, or PBS before they were challenged with hypoxia-reoxygenation or hemoglobin. Pretreatment of SS mice with MASP-2 or MASP-3 mAb, markedly reduced Bb fragments, C4d and C5a in plasma and complement deposition in the liver, kidneys, and lungs collected 4 hours after challenge compared to control mAb-treated mice. Consistent with complement inhibition, hepatic inflammation markers NF-ĸB phospho-p65, VCAM-1, ICAM-1, and E-selectin were significantly reduced in SS mice pretreated with MASP-2 or MASP-3 mAb. Importantly, MASP-2 or MASP-3 mAb pretreatment significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation or hemoglobin. These studies suggest that the LP and the AP are both playing a role in promoting inflammation and vaso-occlusion in SCD. Inhibiting complement activation via the LP or the AP might inhibit inflammation and prevent VOC in SCD patients.

Degradation characteristics of biodegradable film and its effects on soil nutrients in tillage layer, growth and development of taro and yield formation.

This study investigated the degradation characteristics of different biodegradable film and its effects on soil nutrients in tillage layer, growth and development of taro and yield formation. Field experiment with biodegradable films, including poly-(butylene adipate-co-butylene terephthalate) PBAT, (poly-carbon dioxide) PCO2, (poly propylene carbonate) PPC, as well as common mulch film (CK1) and uncovered mulch film (CK2) were conducted on Longxiang taro in 2020 and 2021 respectively. The degradation rate of the three biodegradable films was PBAT > PPC > PCO2. Compared with CK1, the alkali-hydrolyzed N of PBAT at the growth stage and fruiting stage significantly increased in 2020 and 2021, respectively (both, P < 0.05). The average content of available P of PPC at seedling stage was higher than that in PCO2, and CK1 was significantly decreased compared with that in CK2 (all, P < 0.05). The content of soil available K and organic matter in different growth stages of taro in all film mulching treatments were decreased in comparison to CK2. Moreover, compared with CK2, PCO2 biodegradable film significantly increased plant height at seedling and growth stage, stem diameter at growth stage, and leaf area index at fruiting stage (all, P < 0.05). Similarly, the yield of mother and filial bulbs of PPC, PCO2 and PBAT were significantly higher than those of CK2 in 2020 and 2021, respectively (all, P < 0.05). However, no significant differences were found in starch, polysaccharide and protein contents among different treatments. The three biodegradable films, especially PCO2, can significantly affect soil nutrient content, promote plant growth and improve taro yield.

A Photoelectric Spiking Neuron for Visual Depth Perception.

The biological visual system encodes optical information into spikes and processes them by the neural network, which enables the perception with high throughput of visual processing with ultralow energy budget. This has inspired a wide spectrum of devices to imitate such neural process, while precise mimicking such procedure is still highly required. Here, a highly bio-realistic photoelectric spiking neuron for visual depth perception is presented. The firing spikes generated by the TaOX memristive spiking encoders have a biologically similar frequency range of 1-200 Hz and sub-micro watts power. Such spiking encoder is integrated with a photodetector and a network of neuromorphic transistors, for information collection and recognition tasks, respectively. The distance-dependent response and eye fatigue of biological visual systems have been mimicked based on such photoelectric spiking neuron. The simulated depth perception shows a recognition improvement by adapting to sights at different distances. The results can advance the technologies in bioinspired or robotic systems that may be endowed with depth perception and power efficiency at the same time.

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence.

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80-102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.

miR-140-3p inhibits colorectal cancer progression and its liver metastasis by targeting BCL9 and BCL2.

Recent studies have identified microRNAs (miRNAs) as a compelling novel class of biomarker in colorectal cancer (CRC) development and metastasis. Here, we demonstrated that the level of plasma exosomal miR-140-3p in CRC patients was lower than that in healthy controls. The decreased miR-140-3p level was also observed in CRC patients with liver metastasis. The expression of miR-140-3p in CRC tissues were significantly lower than that in matched normal tissues. Functionally, miR-140-3p overexpression suppressed proliferation, migration, invasion, and ß-catenin nuclear translocation, as well as promoted apoptosis in LoVo cells, while inhibition of miR-140-3p reversed these cellular processes in HCT 116 cells. Notably, BCL9 and BCL2 were recognized as direct targets of miR-140-3p. BCL9 knockdown abrogated miR-140-3p inhibitor-induced effects on HCT 116 cells with decreased proliferation, migration, and invasion. BCL2 knockdown increased apoptosis of miR-140-3p inhibitor-transfected HCT 116 cells. In vivo experiments revealed that miR-140-3p overexpression inhibited tumor growth in LoVo xenograft model and diminished metastatic nodules in nude mice liver. Taken together, this work supports that miR-140-3p exerts as a tumor suppressor in CRC progression via targeting BCL9 and BCL2, and suggests miR-140-3p-BCL9/BCL2 axis may be applied in miRNA-based therapy and prognostication of CRC.

Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated ß-catenin pathway and EMT in colorectal cancer.

Colorectal cancer (CRC) is a common malignancy with high mortality. However, the roles of miR-425-5p and its underlying mechanism in CRC remain unknown. Here, RT-qPCR confirmed that miR-425-5p expression was increased by miR-425-5p mimic in SW480 cells and decreased by miR-425-5p inhibitor in LOVO cells. CCK-8, flow cytometry, wound healing and transwell assays revealed that the increased miR-425-5p promoted cell viability, cell cycle entry, migration and invasion in CRC. Besides, miR-425-5p overexpression induced epithelial-mesenchymal transition (EMT) with upregulation of Fibronectin, N-cadherin, Vimentin, and downregulation of E-cadherin. Moreover, miR-425-5p overexpression induced c-myc, Cyclin D1 and MMP7 levels, and promoted ß-catenin translocation to the nucleus. Knockdown of miR-425-5p exerted opposite effects. Luciferase reporter assay indicated that miR-425-5p directly targeted CTNND1. Overexpression of miR-425-5p repressed CTNND1 expression at mRNA and protein levels. Silencing of CTNND1 had the inhibitory effect of miR-425-5p inhibitor on cell proliferation, migration, invasion, EMT, and the activation of ß-catenin signaling pathway. Furthermore, miR-425-5p promoted tumor growth and metastasis in vivo. In conclusion, miR-425-5p may promote tumorigenesis and metastasis through activating CTNND1-mediated ß-catenin pathway, which may provide therapeutic targets for human CRC.

Thrombin activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease.

Vaso-occlusive crisis (VOC) is the primary cause of morbidity and hospitalization in sickle cell disease (SCD); however, only 4 therapies (hydroxyurea, l-glutamine, crizanlizumab, and voxeletor) are currently approved in SCD. These agents limit the duration, severity, and frequency of crises. Activation of coagulation is a hallmark of SCD. Studies in animal models of SCD have shown that coagulation contributes to the chronic inflammation and end-organ damage associated with the disease; however, it is unknown whether coagulation directly contributes to the microvascular stasis that causes VOC. Herein, we demonstrate that inhibition of tissue factor (TF) and the downstream coagulation proteases factor Xa and thrombin significantly attenuates heme-induced microvascular stasis in mouse models of VOC. Pharmacologic inhibition of the principal thrombin receptor, protease activated receptor-1 (PAR-1), as well as deficiency of PAR-1 in all nonhematopoietic cells, also reduces stasis in sickle mice. PAR-1 deficiency was associated with reduced endothelial von Willebrand factor expression, which has been shown to mediate microvascular stasis. In addition, TF inhibition reduces lung vaso-occlusion in sickle mice mediated by arteriolar neutrophil-platelet microemboli. In sum, these results suggest that prophylactic anticoagulation might attenuate the incidence of VOC.

Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease.

Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-Tlr4-/- had similar complete blood counts and serum chemistries as SS-Tlr4+/+ mice. However, SS-Tlr4-/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-Tlr4+/+ mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia/reoxygenation (H/R). To define a potential mechanism for decreased microvascular stasis in SS-Tlr4-/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-Tlr4+/+ livers, SS-Tlr4-/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-Tlr4-/- or SS-Tlr4+/+ bone marrow into AA-Tlr4-/- or AA-Tlr4+/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-Tlr4-/- . These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.

A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease.

The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.

H3K27 acetylation-induced lncRNA EIF3J-AS1 improved proliferation and impeded apoptosis of colorectal cancer through miR-3163/YAP1 axis.

Long noncoding RNAs (lncRNAs) are found to be aberrantly expressed and pose significant impacts in colorectal cancer (CRC), the most prevalent type malignancy in the gastrointestinal tract. This study aimed to find out the regulation of lncRNA EIF3J antisense RNA 1 (EIF3J-AS1) on CRC progression. Expressions of EIF3J-AS1, microRNA-3163 (miR-3163), and Yes-associated protein 1 (YAP1) in tissues and cells were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Association of EIF3J-AS1 with CRC prognosis was analyzed through the online bioinformatics tool GEPIA. The biological function of EIF3J-AS1 in CRC was investigated by Cell Counting Kit-8, colony formation, caspase-3 activity, and TUNEL staining. Competitive endogenous RNA (ceRNA) network of EIF3J-AS1/miR-3163/YAP1 was determined by luciferase reporter and RNA immunoprecipitation assays. Results showed that EIF3J-AS1 was upregulated in CRC tissues and cell lines, indicating poor prognosis of CRC patients. The silence of EIF3J-AS1 led to reduced proliferation and facilitated apoptosis of CRC cells. Mechanistcally, EIF3J-AS1 was upregulated by cAMP-response element-binding protein-binding protein-mediated histone H3 on lysine 27 acetylation (H3K27ac) at the promoter region, and EIF3J-AS1 upregulated YAP1 expression through sponging miR-3163 in CRC cells. In conclusion, we first found that H3K27 acetylation-induced lncRNA EIF3J-AS1 improved proliferation and impeded apoptosis of colorectal cancer through the miR-3163/YAP1 axis, which might potentially provide a novel molecular-targeted strategy for CRC treatment.

Morphine promotes neovascularizing retinopathy in sickle transgeneic mice.

Neovascularizing retinopathy is a significant complication of sickle cell disease (SCD), occurring more frequently in HbSC than HbSS disease. This risk difference is concordant with a divergence of angiogenesis risk, as identified by levels of pro- vs anti-angiogenic factors in the sickle patient's blood. Because our prior studies documented that morphine promotes angiogenesis in both malignancy and wound healing, we tested whether chronic opioid treatment would promote retinopathy in NY1DD sickle transgenic mice. After 10 to 15 months of treatment, sickle mice treated with morphine developed neovascularizing retinopathy to a far greater extent than either of the controls (sickle mice treated with saline and wild-type mice treated identically with morphine). Our dissection of the mechanistic linkage between morphine and retinopathy revealed a complex interplay among morphine engagement with its µ opioid receptor (MOR) on retinal endothelial cells (RECs); morphine-induced production of tumor necrosis factor α and interleukin-6 (IL-6), causing increased expression of both MOR and vascular endothelial growth factor receptor 2 (VEGFR2) on RECs; morphine/MOR engagement transactivating VEGFR2; and convergence of MOR, VEGFR2, and IL-6 activation on JAK/STAT3-dependent REC proliferation and angiogenesis. In the NY1DD mice, the result was increased angiogenesis, seen as neovascularizing retinopathy, similar to the retinal pathology occurring in humans with SCD. Therefore, we conclude that chronic opioid exposure, superimposed on the already angiogenic sickle milieu, might enhance risk for retinopathy. These results provide an additional reason for development and application of opioid alternatives for pain control in SCD.

LncRNA FENDRR promotes high-glucose-induced proliferation and angiogenesis of human retinal endothelial cells.

The study aimed to investigate the role of lncRNA FENDRR in proliferation and angiogenesis of human retinal endothelial cells (HRECs). HRECs were cultured in high-glucose medium to mimic diabetic retinopathy (DR) model. We overexpressed or knocked down FENDRR in HRECs to evaluate the effect of FENDRR expression on cell proliferation, migration, and capillary morphogenesis of HRECs under either normal glucose or high glucose condition. Results showed that VEGF and FENDRR expression were increased in blood from DR patients compared with the control subjects. Furthermore, high glucose treatment upregulated expression of VEGF and FENDRR secreted from HRECs, in a dose- and time-dependent manner. Importantly, FENDRR overexpression significantly promoted the high-glucose-induced proliferation, migration, capillary morphogenesis, and VEGF expression in HRECs. In contrast, FENDRR knockdown exerted the opposite effects. In conclusion, lncRNA FENDRR promotes the high-glucose-induced proliferation and angiogenesis of HRECs and may serve as a potential target for anti-angiogenic therapy for DR.