Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators.

The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC50=67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects.

The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and cardiovascular disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure-activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors.

Paclitaxel Aggravating Radiation-Induced Pulmonary Fibrosis Is Associated with the Down-Regulation of the Negative Regulatory Function of Spry2.

Paclitaxel (PTX) is capable of aggravating radiation-induced pulmonary fibrosis (RIPF), but the mechanism is unknown. Spry2 is a negative regulator of receptor tyrosine kinase-related Ras/Raf/extracellular signal regulated kinase (ERK) pathway. This experiment was aimed at exploring whether the aggravation of RIPF by PTX is related to Spry2. The RIPF model was established with C57BL/6 mice by thoracic irradiation, and PTX was administered concurrently. Western blot was used to detect the expression level of ERK signaling molecules and the distribution of Spry2 in the plasma membrane/cytoplasm. Co-immunoprecipitation (co-IP) and immunofluorescence were used to observe the colocalization of Spry2 with the plasma membrane and tubulin. The results showed that PTX-concurrent radiotherapy could aggravate fibrotic lesions in RIPF, downregulate the content of membrane Spry2, and upregulate the levels of p-c-Raf and p-ERK in lung tissue. It was found that knockdown of Spry2 in fibroblast abolished the upregulation of p-c-Raf and p-ERK by PTX. Both co-IP results and immunofluorescence staining showed that PTX increased the binding of Spry2 to tubulin, and microtubule depolymerizing agents could abolish PTX's inhibition of Spry2 membrane distribution and inhibit PTX's upregulation of Raf/ERK signaling. Both nintedanib and ERK inhibitor were effective in relieving PTX-exacerbated RIPF. Taken together, the mechanism of PTX's aggravating RIPF was related to its ability to enhance Spry2's binding to tubulin, thus attenuating Spry2's negative regulation on Raf/ERK pathway. SIGNIFICANCE STATEMENT: This study revealed that paclitaxel (PTX) concurrent radiation therapy exacerbates radiation-induced pulmonary fibrosis during the treatment of thoracic tumors, which is associated with PTX restraining Spry2 and upregulating the Raf/extracellular signal regulated kinase signaling pathway, and provided drug targets for mitigating this complication.

Immunity-and-matrix-regulatory cells enhance cartilage regeneration for meniscus injuries: a phase I dose-escalation trial.

Immunity-and-matrix-regulatory cells (IMRCs) derived from human embryonic stem cells have unique abilities in modulating immunity and regulating the extracellular matrix, which could be mass-produced with stable biological properties. Despite resemblance to mesenchymal stem cells (MSCs) in terms of self-renew and tri-lineage differentiation, the ability of IMRCs to repair the meniscus and the underlying mechanism remains undetermined. Here, we showed that IMRCs demonstrated stronger immunomodulatory and pro-regenerative potential than umbilical cord MSCs when stimulated by synovial fluid from patients with meniscus injury. Following injection into the knees of rabbits with meniscal injury, IMRCs enhanced endogenous fibrocartilage regeneration. In the dose-escalating phase I clinical trial (NCT03839238) with eighteen patients recruited, we found that intra-articular IMRCs injection in patients was safe over 12 months post-grafting. Furthermore, the effective results of magnetic resonance imaging (MRI) of meniscus repair and knee functional scores suggested that 5 × 107 cells are optimal for meniscus injury treatment. In summary, we present the first report of a phase I clinical trial using IMRCs to treat meniscus injury. Our results demonstrated that intra-articular injection of IMRCs is a safe and effective therapy by providing a permissive niche for cartilage regeneration.

A bulk form Cu-based ferromagnetic semiconductor (La,Ba)(Cu,Mn)SO with the Curie temperature up to 170 K.

We report the ferromagnetism in a new bulk form Cu-based magnetic semiconductor (La,Ba)(Cu,Mn)SO, which is iso-structural to the prototypical iron-based 1111-type superconductor LaFeAsO. Starting from the parent compound LaCuSO, carriers are introduced via the substitutions of La for Ba while spins are introduced via the substitutions of Cu for Mn. Spins are mediated by carriers, which develops into the long range ferromagnetic ordering. The maximum Curie temperature [Formula: see text] reaches up to [Formula: see text] 170 K with the doping levels of 10% Ba and 5% Mn. By comparing to the (La,Sr)(Cu,Mn)SO where Sr and Mn are co-doped into LaCuSO, we demonstrate that negative chemical pressure would suppress the ferromagnetic ordering.

A feasibility study of applying two-dimensional photogrammetry for screening and monitoring of patients with adolescent idiopathic scoliosis in clinical practice.

Standing posteroanterior radiographs have been the golden standard to quantify the severity of scoliosis deformity. However, it exposes ionizing radiation to scoliosis patients, and cannot be used for routine screening and monitoring. This study aimed to develop a protocol of measuring postural indexes by using the noninvasive and radiation-free two-dimensional (2D) photogrammetry method and identify its clinical value in scoliosis screening and monitoring. The five postural indexes were measured from the posterior view of 110 participants. One-way ANOVA with post hoc Tukey HSD/Games-Howell analysis was used to compare the differences between the participants in the scoliosis group and the non-scoliosis group. Pearson coefficients of correlation were analyzed to identify the relationships between Cobb angles and each of the five quantitative postural indexes. Based on 2D photogrammetry, the postural indexes of C7 deviation (p = 0.02), shoulder alignment (p < 0.001), scapula alignment (p < 0.001), waist angle discrepancy (p < 0.001), and PSIS alignment (p < 0.001) could significantly differentiate scoliosis and non-scoliosis patients during screening. The waist angle discrepancy (r = 0.4, p = 0.01; r = 0.8, p = 0.03; r = 0.7, p = 0.01) and shoulder alignment (r = 0.6, p = 0.03) had moderate to strong positive correlations with the Cobb angles, which supported their clinical values in monitoring scoliotic curvature changes of adolescent idiopathic scoliosis (AIS) patients.

Efficacy and safety of ultra-short wave diathermy on COVID-19 pneumonia: a pioneering study.

Background: The ultra-short wave diathermy (USWD) is widely used to ameliorate inflammation of bacterial pneumonia, however, for COVID-19 pneumonia, USWD still needs to be verified. This study aimed to investigate the efficacy and safety of USWD in COVID-19 pneumonia patients. Methods: This was a single-center, evaluator-blinded, randomized controlled trial. Moderate and severe COVID-19 patients were recruited between 18 February and 20 April 2020. Participants were randomly allocated to receive USWD + standard medical treatment (USWD group) or standard medical treatment alone (control group). The negative conversion rate of SARS-CoV-2 and Systemic Inflammatory Response Scale (SIRS) on days 7, 14, 21, and 28 were assessed as primary outcomes. Secondary outcomes included time to clinical recovery, the 7-point ordinal scale, and adverse events. Results: Fifty patients were randomized (USWD, 25; control, 25), which included 22 males (44.0%) and 28 females (56.0%) with a mean (SD) age of 53 ± 10.69. The rates of SARS-CoV-2 negative conversion on day 7 (p = 0.066), day 14 (p = 0.239), day 21 (p = 0.269), and day 28 (p = 0.490) were insignificant. However, systemic inflammation by SIRS was ameliorated with significance on day 7 (p = 0.030), day 14 (p = 0.002), day 21 (p = 0.003), and day 28 (p = 0.011). Time to clinical recovery (USWD 36.84 ± 9.93 vs. control 43.56 ± 12.15, p = 0.037) was significantly shortened with a between-group difference of 6.72 ± 3.14 days. 7-point ordinal scale on days 21 and 28 showed significance (p = 0.002, 0.003), whereas the difference on days 7 and 14 was insignificant (p = 0.524, 0.108). In addition, artificial intelligence-assisted CT analysis showed a greater decrease in the infection volume in the USWD group, without significant between-group differences. No treatment-associated adverse events or worsening of pulmonary fibrosis were observed in either group. Conclusion: Among patients with moderate and severe COVID-19 pneumonia, USWD added to standard medical treatment could ameliorate systemic inflammation and shorten the duration of hospitalization without causing any adverse effects.Clinical Trial Registration: chictr.org.cn, identifier ChiCTR2000029972.

Case report: A case of incontinentia pigmenti.

Incontinentia pigmenti (IP) is a rare neuroectodermal dysplasia caused by mutations in the IKBKG gene. We present a case of a 4-month-old female infant with erythematous vesicular skin lesions on the trunk and extremities. Histopathologic examination of the blisters revealed an eosinophilic infiltrate. Further investigation revealed that her mother had three unexplained miscarriages and two normal uncomplicated pregnancies, resulting in the birth of two male infants. We performed a comprehensive genetic evaluation to rule out the interference of pseudogene IKBKGP, and the infant was finally diagnosed with IP. During the subsequent 2-year follow-up, we observed a significant improvement in her dermatologic symptoms, with no evidence of recurrence, and there were no other associated symptoms in the hair, nails, oral mucosa, eyes, or central nervous system.

Albumin nanostructure assisted ABZ anti-parasite immune therapy for T. spiralis muscle infection.

Currently, the treatment of Trichinella spiralis (T. spiralis) intracellular infection by oral administration of albendazole (ABZ) is hampered by its poor aqueous solubility and rapid metabolism. Herein, the nanoparticles with BSA and ABZ (ABZ-BSA Nps) were constructed by a desolvation technique in the study. The anti-parasite activity and pharmacokinetics of ABZ-BSA Nps were evaluated for T. spiralis muscle larvae during the encysted phase. The immune-responsive cytokines of ABZ-BSA Nps were quantitatively analyzed. The results showed that ABZ-BSA Nps could eliminate the muscle larvae by triggering the unbalance of Th1/Th2 immune-response in the infection mice. For ABZ-BSA Nps treatment group, the plasma concentration of ABZSO (ABZ active metabolite) was higher than ABZ and the muscle larvae were reduced by 70.2 %. In conclusion, the study had constructed a successful prospective protein nanoparticle delivery ABZ and evidenced the ABZ could be used for intracellular parasite therapy by triggering the anti-parasite immunity of hosts.

Design, synthesis and biological evaluation of KRASG12C-PROTACs.

Several small-molecule covalent inhibitors of KRASG12C have made breakthrough progress in the treatment of KRAS mutant cancer. However, the clinical application of KRASG12C small-molecule inhibitors may be limited by adaptive resistance. Emerging PROTAC strategy can achieve complementary advantages with small molecule inhibitors and improve anti-tumor efficacy. Based on AMG-510, a series of novel KRASG12C-PROTACs were designed and synthesized. The protein degradation assay showed that PROTACs I-1, II-1, III-2 and IV-1 had binding and degradation ability to KRASG12C. III-2 and IV-1 showed potent inhibitory effect on downstream p-ERK and were more potent than AMG-510. Mechanistic studies demonstrated that PROTACs exerted degradation effects through the ubiquitin-proteasome pathway. Using cell lines sensitive to KRASG12C, anti-proliferative activities of compounds were assessed. PROTACs tested showed overall anti-proliferative activities. Besides,the structure-activity relationships (SARs) of KRASG12C-PROTACs were summarized. These results supported the use of the PROTAC strategy to degrade oncogene KRASG12C and provided clues for structural optimization of KRASG12C-PROTACs.

The Application of Public Art Design Based on Digital Technology in Urban Landscape Environmental Monitoring.

Public art (PA) is a powerful tool for enhancing the environment in public spaces since it not only relieves the oppression caused by urban architecture but also enhances and beautifies urban public spaces. As DT (digital technology) develops so quickly nowadays, it offers PA significant technological assistance to achieve new functions, and changes in modern people's aesthetic preferences and psychological makeup also present new demands for PA. This essay explores the use of PA design in the creation of urban landscapes from the viewpoint of DT. In order to do this, this paper suggests a method for measuring the environmental impact of urban landscapes that combines landscape measurement and semantic assessment. Full-connection algorithm and greedy algorithm are introduced to identify urban functional types with high-dimensional characteristics for the boundary tree classification model of high-dimensional feature classification. The findings indicate that the public service area's producer and user accuracy are, respectively, 0.8783 and 0.7833. It offers a fresh concept for the identification of urban functional zones while solving the issues of low identification efficiency and poor accuracy.

Drastic improvement of Curie temperature by chemical pressure in N-type diluted magnetic semiconductor Ba(Zn,Co)[Formula: see text]As[Formula: see text].

We report the effect of chemical pressure on the ferromagnetic ordering of the recently reported n-type diluted magnetic semiconductor Ba(Zn[Formula: see text]Co[Formula: see text])[Formula: see text]As[Formula: see text] which has a maximum [Formula: see text] [Formula: see text] 45 K. Doping Sb into As-site and Sr into Ba-site induces negative and positive chemical pressure, respectively. While conserving the tetragonal crystal structure and n-type carriers, the unit cell volume shrink by [Formula: see text] 0.3[Formula: see text] with 15[Formula: see text] Sr doping, but drastically increase the ferromagnetic transition temperature by 18[Formula: see text] to 53 K. Our experiment unequivocally demonstrate that the parameters of Zn(Co)As[Formula: see text] tetrahedra play a vital role in the formation of ferromagnetic ordering in the Ba(Zn,Co)[Formula: see text]As[Formula: see text] DMS.

High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer's disease.

Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer's disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [1H-MRS]) with clinical outcomes after treatment. Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS with CT (i.e., real group) and (2) sham rTMS with CT (i.e., sham group). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then to stimulate the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment at baseline (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). The ratios of N-acetylaspartate/creatine (NAA/Cr), myoinositol/creatine (mI/Cr), and choline/creatine (Cho/Cr) in the stimulated cortex were measured using 1H-MRS at T0 and T1. Twenty-eight patients were treated with rTMS-CT for 4 weeks. Two patients in the sham group withdrew after being treated several times. Compared with the sham group, the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2. In the real group, compared with the sham group, the NAA/Cr ratio in the left DLPFC was significantly elevated (p = 0.045); however, in the left LTL, it only showed a tendency toward increase (p = 0.162). The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer's Disease Assessment Scale (ADAS-cog). This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD. The left DLPFC is a better candidate area than the left LTL.

A fatal diarrhoea outbreak in farm-raised Deinagkistrodon acutus in China is newly linked to potentially zoonotic Aeromonas hydrophila.

Deinagkistrodon acutus is a venomous pit viper commonly used in traditional Chinese medicine; farming these snakes has become a major industry. In 2017, an outbreak of fatal diarrhoea among farm-raised D. acutus in Hunan Province caused the deaths of 5,600 snakes within 3 weeks. We isolated a brand-new sequence type of Aeromonas hydrophila (ST516) from lesions and confirmed that this bacterium was the causal agent of the outbreak. Snakes infected with the bacterium in the laboratory showed similar clinical symptoms to those of snakes in the original outbreak. We also tested bacterial virulence in Kunming mice to examine the likelihood of zoonosis. Isolates were pathogenic to mice, causing diarrhoea within 4 hr post-challenge, which indicates that the bacterium can potentially infect mammals. Environmental analysis showed that polluted spring water likely caused the diarrhoea in snakes. This study is the first to report on a large-scale outbreak of fatal diarrhoea in farm-raised snakes, originating in a pathogen that can infect mammals. These results should raise awareness regarding potential anthropozoonosis among poikilotherms, mammals, and humans; appropriate prevention or control methods should be developed.