Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

Insights into the function of the chloroplastic ribosome-associated GTPase high frequency of lysogenization X in Arabidopsis thaliana.

Ribosome-associated GTPases are conserved enzymes that participate in ribosome biogenesis and ribosome function. In bacteria, recent studies have identified HflX as a ribosome-associated GTPase that is involved in both ribosome biogenesis and recycling under stress conditions. Plants possess a chloroplastic HflX homolog, but its function remains unknown. Here, we characterized the role of HflX in the plant Arabidopsis thaliana. Our findings show that HflX does not affect normal plant growth, nor does it play an essential role in acclimation to several different stresses, including heat, manganese, cold, and salt stress under the conditions tested. However, we found that HflX is required for plant resistance to chloroplast translational stress mediated by the antibiotic lincomycin. Our results suggest that HflX is a chloroplast ribosome-associated protein that may play a role in the surveillance of translation. These findings provide new insight into the function of HflX as a ribosome-associated GTPase in plants and highlight the importance of investigating conserved proteins in different organisms to gain a comprehensive understanding of their biological roles.

Optimization of China's freight transportation structure based on adaptive genetic algorithm under the background of carbon peak.

Transportation is the key carbon emission source after energy supply and industrial production. Under the vision of carbon peak and carbon neutralization, the pressure of reducing carbon emissions in transportation will be greater in the future. This paper constructs a model that takes transportation carbon emission as the main target and freight transportation utility value as the auxiliary target. The constructed model satisfies the constraints of freight turnover in the whole society, freight economic and social benefits, and the ecological constraints of the freight system. With MATLAB, the freight turnover of roadways, railways, and waterways (excluding ocean transportation) in 2030 is solved by using the adaptive genetic algorithm. The results indicate that (I) compared with the current freight structure of China, the roadway freight sharing rate in 2030 will decrease by 8.07%, and the railway freight sharing rate and the waterway freight sharing rate (excluding ocean transportation) will increase by 0.93% and 7.13%, respectively. (II) After optimization, the energy consumption and carbon emission are reduced by 42,471,500 tons (10.3%) and 91,379,400 tons (10.2%) of standard coal, respectively. (III) The adaptive genetic algorithm outperforms the traditional genetic algorithm in terms of convergence speed and accuracy. (IV) As the weight coefficient of carbon emission increases, the utility value of freight transportation consistently decreases, and the sensitivity increases. Meanwhile, as the carbon emission weight coefficient increases, carbon emission keeps decreasing, and the sensitivity decreases.

HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models.

Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009's further clinical development for treating NHLs.

1 × 5 broadband photonic crystal power splitter designed by the Powell algorithm.

We propose a novel, to the best of our knowledge, 1×5 broadband power splitter based on the photonic crystal. The Powell algorithm is used to reverse-design the proposed broadband power splitter. The results show that the transmittance of each output port of the broadband photonic crystal power splitter can be adjusted by changing the radii and offsets of the dielectric rods at the junction area of each waveguide. According to the target splitting ratio, the reverse design of the structural parameters using the Powell algorithm significantly improves the optimization efficiency and splitting performance of the broadband power splitter. The designed power splitters have a wide working bandwidth of 1525-1565 nm, a flexible and designable power splitting ratio, excellent splitting performance, and a compact size, which have great application prospects in all-optical communication networks, high-density photon integration, and other fields.

Glutathione S-transferase genetic polymorphisms and fluoride-induced reproductive toxicity in men with idiopathic infertility.

Male infertility caused by idiopathic oligoasthenospermia (OAT) is known as idiopathic male infertility. Glutathione S-transferase (GST) and fluoride may play important roles in idiopathic male infertility, but their effects are still unknown. Our study examined the relationship between GST polymorphisms and fluoride-induced toxicity in idiopathic male infertility and determined the underlying mechanism. Sperm, blood, and urine samples were collected from 560 males. Fluoride levels were measured by a highly selective electrode method, and GST genotypes were identified using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Semen parameters, DNA fragmentation index (DFI), mitochondrial membrane potential (MMP), and oxidative stress (OS) biomarkers were statistically assessed at the P < 0.05 level. Compared with healthy fertile group, semen parameters, fluoride levels, OS biomarkers, sex hormone levels, and MMP and DFI levels were lower in the idiopathic male infertility group. For glutathione S-transferase M1 (GSTM1[-]) and glutathione S-transferase T1 (GSTT1[-]) or glutathione S-transferase P1 (GSTP1) mutant genotypes, levels of semen fluoride, OS, MMP, and DFI were considerably higher, and the mean levels of sperm parameters and testosterone were statistically significant in GSTM1(+), GSTT1(+), and GSTP1 wild-type genotypes. Both semen and blood fluoride levels were associated with oxidative stress in idiopathic male infertility patients. Elevated fluoride in semen with the genotypes listed above was linked to reproductive quality in idiopathic male infertility patients. In conclusion, GST polymorphisms and fluorine may have an indicative relationship between reproductive quality and sex hormone levels, and OS participates in the development of idiopathic male infertility.

Glutathione S-transferase genetic polymorphisms and fluoride-induced reproductive toxicity in men with idiopathic infertility / 亚洲男科学杂志(英文版)

Male infertility caused by idiopathic oligoasthenospermia (OAT) is known as idiopathic male infertility. Glutathione S-transferase (GST) and fluoride may play important roles in idiopathic male infertility, but their effects are still unknown. Our study examined the relationship between GST polymorphisms and fluoride-induced toxicity in idiopathic male infertility and determined the underlying mechanism. Sperm, blood, and urine samples were collected from 560 males. Fluoride levels were measured by a highly selective electrode method, and GST genotypes were identified using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Semen parameters, DNA fragmentation index (DFI), mitochondrial membrane potential (MMP), and oxidative stress (OS) biomarkers were statistically assessed at the P < 0.05 level. Compared with healthy fertile group, semen parameters, fluoride levels, OS biomarkers, sex hormone levels, and MMP and DFI levels were lower in the idiopathic male infertility group. For glutathione S-transferase M1 (GSTM1[-]) and glutathione S-transferase T1 (GSTT1[-]) or glutathione S-transferase P1 (GSTP1) mutant genotypes, levels of semen fluoride, OS, MMP, and DFI were considerably higher, and the mean levels of sperm parameters and testosterone were statistically significant in GSTM1(+), GSTT1(+), and GSTP1 wild-type genotypes. Both semen and blood fluoride levels were associated with oxidative stress in idiopathic male infertility patients. Elevated fluoride in semen with the genotypes listed above was linked to reproductive quality in idiopathic male infertility patients. In conclusion, GST polymorphisms and fluorine may have an indicative relationship between reproductive quality and sex hormone levels, and OS participates in the development of idiopathic male infertility.

The rapid appearance of homostyly in a cultivated distylous population of Primula forbesii.

Evolutionary breakdown from rigorous outbreeding to self-fertilization frequently occurs in angiosperms. Since the pollinators are not necessary, self-compatible populations often reduce investment in floral display characteristics and pollination reward. Primula forbesii is a biennial herb with distribution restricted to southwest China; it was initially a self-incompatible distylous species, but after 20 years of artificial domestication, homostyly appeared. This change in style provides an ideal material to explore the time required for plant mating systems to adapt to new environmental changes and test whether flower attraction has reduced following transitions to selfing. We did a survey in wild populations of P. forbesii where its seeds were originally collected 20 years ago and recorded the floral morph frequencies and morphologies. The floral morphologies, self-incompatibility, floral scent, and pollinator visitation between distyly and homostyly were compared in greenhouse. Floral morph frequencies of wild populations did not change, while the cultivated population was inclined to L-morph and produced homostyly. Evidence from stigma papillae and pollen size supports the hypothesis that the homostyly possibly originated from mutations of large effect genes in distylous linkage region. Transitions to self-compatible homostyly are accompanied by smaller corolla size, lower amounts of terpenoids, especially linalool and higher amounts of fatty acid derivatives. The main pollinators in the greenhouse were short-tongued Apis cerana. However, homostyly had reduced visiting frequency. The mating system of P. forbesii changed rapidly in just about 20 years of domestication, and our findings confirm the hypothesis that the transition to selfing is accompanied by decreased flower attraction.

Elevated red cell distribution width predicts residual dizziness in patients with benign paroxysmal positional vertigo.

Objective: The present study aimed to determine whether residual dizziness (RD) after successful repositioning treatment in benign paroxysmal positional vertigo (BPPV) patients could be predicted by red blood cell distribution width (RDW). Materials and methods: In this study, a total of 303 BBPV patients hospitalized at the neurology department were investigated. The enrolled patients were divided into two groups after successful repositioning treatment: non-RD group included patients who were completely cured, and RD group included patients with RD. We collected data on all subjects, including general information, blood routine examination, blood biochemical examination, and magnetic resonance imaging tests. Results: The mean RDW values of patients in the RD group were significantly higher than that in the non-RD group (13.63 ± 1.8 vs. 12.5 ± 0.8; p < 0.001). In subsequent multivariate analysis, elevated RDW levels were a statistically significant risk factor associated with the occurrence of RD [odds ratio = 2.62, 95% confidence interval (CI) 1.88-3.64, p < 0.001]. The area under the ROC curve was 0.723 in terms of its predictive ability to distinguish patients with RD. A cut-off point of 12.95% of RDW predicted RD with a sensitivity of 75.6% and a specificity of 69.5%. Moreover, the AUC for the ability of the RDW to predict recurrence were 0.692 (95% CI = 0.561-0.831; p < 0.014). Conclusions: Elevated RDW level was related to increased risk of RD among BPPV patients, requiring further efforts to clarify the actual underlying pathophysiology.

Red cell distribution width: a novel predictive biomarker for stroke risk after transient ischaemic attack.

OBJECTIVE: Predicting the prognosis of transient ischaemic attack (TIA) is difficult for many frontline clinicians. The purpose of this study was to determine whether subsequent stroke in TIA patients can be predicted via red blood cell distribution width (RDW). MATERIAL AND METHODS: A total of 360 consecutive patients with new-onset TIA in our stroke centre, were enrolled over the period studied. The patients were divided into three groups: 103 TIA patients, 206 ischaemic stroke (IS) patients and 51 patients with haemorrhagic stroke (HS) within 7 days after TIA. Complete blood count, biochemical parameters and brain imaging were performed on all patients. RESULTS: The mean RDW values of patients with IS and HS after TIA were significantly higher than patients with TIA (13.35 ± 1.59 vs 12.84 ± 1.19, 13.32 ± 1.08 vs 12.84 ± 1.19, respectively, all p ≤ .001). In a multivariate model, RDW was independently associated with stroke after TIA (IS: odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.46-3.35, p = .002; HS: OR = 1.511, 95% CI = 1.101-2.074, p = .011). Compared to ABCD2 scores, the diagnostic power of RDW in the differentiation of patients with IS after TIA was better (area under curve (AUC): 0.731 vs 0.613, p = .015). When an RDW cut-off value of 13.95% was accepted for differentiating patients with IS from TIA, the sensitivity and specificity were 73.7% and 74.3%, respectively. However, the AUC for the ability of the RDW to predict HS was 0.653 (95% CI = 0.589-0.716; p < .001). CONCLUSIONS: The early determination of RDW is a promising, rapid, easy and inexpensive biomarker to predict the subsequent stroke in TIA patients, especially for IS. KEY MESSAGESThe most important result of our study is to show that (1) the higher RDW, the earlier the stroke onset and (2) RDW ≥13.95% has a 2.52-fold risk of ischaemic stroke in TIA patients, and RDW ≥12.85% has a 1.51-fold risk of haemorrhagic stroke.As an economic and accessible hematological marker, baseline RDW may serve as a useful biomarker for risk stratification in TIA patients.

Metabolic enzyme gene polymorphisms predict the effects of antioxidant treatment on idiopathic male infertility.

To explore the relationship between genetic polymorphisms of metabolic enzymes such as CYP1A1, CYP2D6, GSTM1, GSTT1, and GSTP1 and idiopathic male infertility. By observing the efficacy of antioxidants in the treatment of idiopathic male infertility, the effect of metabolic enzyme gene polymorphisms on antioxidant therapy in patients with idiopathic male infertility was prospectively studied. This case-control study included 310 men with idiopathic infertility and 170 healthy controls. The cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) genotypes in peripheral blood samples were analyzed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). The idiopathic male infertility group was treated with vitamin C, vitamin E, and coenzyme Q10 for 3 months and followed up for 6 months. GSTM1(-), GSTT1(-), and GSTM1/T1(-/-) in the idiopathic male infertility groups were more common than those in the control group. The sperm concentration, motility, viability, mitochondrial membrane potential (MMP), and seminal plasma total antioxidant capacity (T-AOC) level in patients with GSTM1(-), GSTT1(-), and GSTM1/T1(-/-) were lower than those in wild-type carriers, and the sperm DNA fragmentation index (DFI), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and malondialdehyde (MDA) and nitric oxide (NO) levels were higher. Therefore, oxidative damage may play an important role in the occurrence and development of idiopathic male infertility, but antioxidant therapy is not effective in male infertility patients with GSTM1 and GSTT1 gene deletions.

Low Antioxidant Status of Serum Uric Acid, Bilirubin, Albumin, and Creatinine in Patients With Benign Paroxysmal Positional Vertigo.

Objective: To investigate the roles of serum uric acid (UA), bilirubin (BIL), albumin (ALB), and creatinine (CRE) as major intravascular antioxidants, in benign paroxysmal positional vertigo (BPPV). Methods: The serum levels of UA, BIL, ALB, and CRE were retrospectively analyzed in 70 patients with new-onset idiopathic BPPV and 140 age- and sex-matched healthy controls (HCs). Results: Serum UA, BIL, ALB, and CRE levels were significantly lower in the BPPV group than the HC group. Furthermore, serum levels of BIL and ALB were significantly lower in the BPPV group when compared by sex. Multiple stepwise logistic regression revealed that a reduction in serum ALB was independently related to BPPV (odds ratio = 0.688; 95% confidence interval = 0.607- 0.780). Receiver operating characteristic analyses revealed a cut-off value of 45.15 g/L for ALB with a sensitivity of 74.29% (62.97- 83.07%) and specificity of 73.57% (65.71- 80.18%). Conclusions: Serum levels of UA, BIL, ALB, and CRE were lower in BPPV patients, indicating a lower antioxidant status. Furthermore, a reduction in serum ALB was independently associated with BPPV. These results provide insights into the possible roles of oxidative stress in the pathogenesis of BPPV.

Treatment of Retroperitoneal Cavernous Lymphangioma: A Case Report.

A 32-year-old man who complained of recurrent nauseat and vomiting was admitted to our hospital. The contrast-enhanced computed tomography revealed a cystic mass located behind the duodenum which was suggestive of lymphangioma. Laparoscopic resection of the retroperitoneal mass was successfully performed. The postoperatively pathological examination confirmed the diagnosis of cavernous lymphangioma. Ultrasound and enhanced CT can be used for making a preoperative diagnosis. Once symptoms of the disease develop, complete surgical resection should be performed.

The general odorant receptor GmolOR9 from Grapholita molesta (Lepidoptera: Tortricidae) is mainly tuned to eight host-plant volatiles.

Grapholita molesta is one of the most destructive fruit pests distributed worldwide. Odorant receptors (ORs) located on the dendritic membrane of chemosensory neurons are deemed to be key molecules for sensing exogenous chemical signals. In this study, GmolOR9, a general OR from G. molesta, was functionally characterized. Quantitative real-time polymerase chain reaction revealed that GmolOR9 was more highly expressed in adults than in other stages, including eggs, larvae, and pupae. GmolOR9 expression was highly significantly more in the antennae of females than in those of males, and the highest level occurred in the antennae of 3-day-old female adults. GmolOR9 was broadly tuned to eight of 47 odorant components tested, including (Z)-3-hexenyl acetate, butyl propionate, ethyl hexanoate, ethyl heptanoate, 1-hexanol, (Z)-3-hexenol, 2-ethyl-1-hexanol, and linalool, by in vitro heterologous expression. Furthermore, electroantennogram responses indicated that the effects of dsOR9-injected females to (Z)-3-hexenyl acetate dramatically decreased. These results suggested that GmolOR9 might be involved in detecting host-plant volatiles. Moreover, (Z)-3-hexenyl acetate might serve as a potential attractant for the biological control of G. molesta.

Treatment of Retroperitoneal Cavernous Lymphangioma: A Case Report / 中国医学科学杂志(英文版)

A 32-year-old man who complained of recurrent nauseat and vomiting was admitted to our hospital. The contrast-enhanced computed tomography revealed a cystic mass located behind the duodenum which was suggestive of lymphangioma. Laparoscopic resection of the retroperitoneal mass was successfully performed. The postoperatively pathological examination confirmed the diagnosis of cavernous lymphangioma. Ultrasound and enhanced CT can be used for making a preoperative diagnosis. Once symptoms of the disease develop, complete surgical resection should be performed.

Guanosine tetraphosphate modulates salicylic acid signalling and the resistance of Arabidopsis thaliana to Turnip mosaic virus.

Chloroplasts can act as key players in the perception and acclimatization of plants to incoming environmental signals. A growing body of evidence indicates that chloroplasts play a critical role in plant immunity. Chloroplast function can be regulated by the nucleotides guanosine tetraphosphate and pentaphosphate [(p)ppGpp]. In plants, (p)ppGpp levels increase in response to abiotic stress and to plant hormones which are involved in abiotic and biotic stress signalling. In this study, we analysed the transcriptome of Arabidopsis plants that over-accumulate (p)ppGpp, and unexpectedly found a decrease in the levels of a broad range of transcripts for plant defence and immunity. To determine whether (p)ppGpp is involved in the modulation of plant immunity, we analysed the susceptibility of plants with different levels of (p)ppGpp to Turnip mosaic virus (TuMV) carrying a green fluorescent protein (GFP) reporter. We found that (p)ppGpp accumulation was associated with increased susceptibility to TuMV and reduced levels of the defence hormone salicylic acid (SA). In contrast, plants with lower (p)ppGpp levels showed reduced susceptibility to TuMV, and this was associated with the precocious up-regulation of defence-related genes and increased SA content. We have therefore demonstrated a new link between (p)ppGpp metabolism and plant immunity in Arabidopsis.

An Ancient Bacterial Signaling Pathway Regulates Chloroplast Function to Influence Growth and Development in Arabidopsis.

The chloroplast originated from the endosymbiosis of an ancient photosynthetic bacterium by a eukaryotic cell. Remarkably, the chloroplast has retained elements of a bacterial stress response pathway that is mediated by the signaling nucleotides guanosine penta- and tetraphosphate (ppGpp). However, an understanding of the mechanism and outcomes of ppGpp signaling in the photosynthetic eukaryotes has remained elusive. Using the model plant Arabidopsis thaliana, we show that ppGpp is a potent regulator of chloroplast gene expression in vivo that directly reduces the quantity of chloroplast transcripts and chloroplast-encoded proteins. We then go on to demonstrate that the antagonistic functions of different plant RelA SpoT homologs together modulate ppGpp levels to regulate chloroplast function and show that they are required for optimal plant growth, chloroplast volume, and chloroplast breakdown during dark-induced and developmental senescence. Therefore, our results show that ppGpp signaling is not only linked to stress responses in plants but is also an important mediator of cooperation between the chloroplast and the nucleocytoplasmic compartment during plant growth and development.

Sinomenine sensitizes multidrug-resistant colon cancer cells (Caco-2) to doxorubicin by downregulation of MDR-1 expression.

Chemoresistance in multidrug-resistant (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major obstacle to successful chemotherapy for colorectal cancer. Previous studies have indicated that sinomenine can enhance the absorption of various P-gp substrates. In the present study, we investigated the effect of sinomenine on the chemoresistance in colon cancer cells and explored the underlying mechanism. We developed multidrug-resistant Caco-2 (MDR-Caco-2) cells by exposure of Caco-2 cells to increasing concentrations of doxorubicin. We identified overexpression of COX-2 and MDR-1 genes as well as activation of the NF-κB signal pathway in MDR-Caco-2 cells. Importantly, we found that sinomenine enhances the sensitivity of MDR-Caco-2 cells towards doxorubicin by downregulating MDR-1 and COX-2 expression through inhibition of the NF-κB signaling pathway. These findings provide a new potential strategy for the reversal of P-gp-mediated anticancer drug resistance.