Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. Several LSD1 inhibitors have advanced into clinical trials. Following our last annual ...review on LSD1 inhibitors in 2020 (Eur. J. Med. Chem. 2021, 214, 113254), in this review we aim to update LSD1 inhibitors including natural products, synthetic compounds and cyclic peptides reported during 2021. Design strategies, structure-activity relationships, binding model analysis and modes of action are highlighted. In particular, two FDA-approved antihypertensive drugs raloxifene and fenoldopam were repurposed as reversible LSD1 inhibitors. The clinical candidate TAK-418 for treating neurodevelopmental disorders and PET imaging agent 18F30 for LSD1 were identified. Moreover, dual inhibitors targeting both LSD1 and HDAC6 or tubulin displayed enhanced anti-cancer effects than single agents. These compounds further enrich the structural types of LSD1 inhibitors.
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•LSD1 is a promising epigenetic target for disease treatment.•Compounds with novel scaffolds enrich the structural diversity of LSD1 inhibitors.•Clinical candidate TAK-418 shows therapeutic potential for neurodevelopmental disorders.
The study of phosphorylase kinase (PhK)-regulated glycogen metabolism has contributed to the fundamental understanding of protein phosphorylation; however, the molecular mechanism of PhK remains ...poorly understood. Here we present the high-resolution cryo-electron microscopy structures of human muscle PhK. The 1.3-megadalton PhK α
β
γ
δ
hexadecamer consists of a tetramer of tetramer, wherein four αβγδ modules are connected by the central β
scaffold. The α- and β-subunits possess glucoamylase-like domains, but exhibit no detectable enzyme activities. The α-subunit serves as a bridge between the β-subunit and the γδ subcomplex, and facilitates the γ-subunit to adopt an autoinhibited state. Ca
-free calmodulin (δ-subunit) binds to the γ-subunit in a compact conformation. Upon binding of Ca
, a conformational change occurs, allowing for the de-inhibition of the γ-subunit through a spring-loaded mechanism. We also reveal an ADP-binding pocket in the β-subunit, which plays a role in allosterically enhancing PhK activity. These results provide molecular insights of this important kinase complex.
(1) Background: Labeling is one of the significant strategies to guide sustainable consumption behaviors. Nowadays, multi labels being displayed on the front-of-pack of food products is a common ...phenomenon. However, labels seldom operate solo, and competition or complement effects may be exerted on different labels. Therefore, the research objective is to explore the interaction effect when nutrition and low-carbon labels appear simultaneously; (2) Methods: Across four scenario-based experiments, including ice cream, yogurt, steak, and toast, this study manipulated the separate and joint occurrences of low-carbon and nutrition labels, the interaction effect of joint labels was tested, and the serial mediation model, which includes resource allocation and anticipated enjoyment of food consumption, was verified; (3) Results: Results show that people have a positive preference for the nutrition label and the carbon label, respectively, while these two labels working simultaneously attenuate the positive effect of the single label. When facing nutrition and carbon labels simultaneously, people would infer partial resources are allocated to healthy and environmental aspects so they have a lower anticipated enjoyment from food consumption. Thus, these two labels working simultaneously attenuate the positive effect of the single label, and consumers have a lower evaluation of food products. In addition, the joint backfire on the effect is only exerted on people with a higher level of zero-sum bias and only when joint labels have a high consistency of labels; (4) Conclusions: This study solved the contradictory problem of the joint effect of positive labels. The findings in this research contribute to promote sustainable food consumption. We suggest that similar labels should be avoided in the same front-of-pack of food, and manufacturers need to use ads to bring down consumers' zero-sum bias.
Prostate transmembrane androgen inducible protein 1 (PMEPA1) can promote or inhibit prostate cancer cell growth based on the cancer cell response to the androgen receptor (AR). Further, it can be ...upregulated by transforming growth factor (TGF), which downregulates transforming growth factor-β (TGF-β) signaling by interfering with R-Smad phosphorylation to facilitate TGF-β receptor degradation. Studies have indicated the increased expression of PMEPA1 in some solid tumors and its functioning as a regulator of multiple signaling pathways. This review highlights the multiple potential signaling pathways associated with PMEPA1 and the role of the
gene in regulating prognosis, including transcriptional regulation and epithelial mesenchymal transition (EMT). Moreover, the relevant implications in and outside tumors, for example, as a biomarker and its potential functions in lysosomes have also been discussed.
In the modern global economic environment, innovation has become a crucial driving force for enhancing the competitiveness of enterprises and ensuring their sustainable development. Therefore, in the ...context of contemporary economic realities where innovation has become a strategic component of firm success, and the influence of top management on the innovation process can have a significant impact, there is a particular relevance in studying the relationships between managerial authority and corporate innovation. This research aims to establish the relationship between top management authority and two types of innovation - exploitative and exploratory while exploring the moderating role of absorptive capacity and resources in this relationship. To conduct this research, a sample of 6,717 firm observations traded on the Shanghai and Shenzhen stock exchanges during the period from 2010 to 2020 was selected. Data on the financial status of companies, corporate governance, and characteristics of top executives were obtained from the CSMAR (China Stock Market and Accounting Research) database, while data on patents for measuring ambidextrous innovations were collected using a search engine and processed with Python software. The obtained results demonstrate that top management authority has a significant impact on both types of innovation. Furthermore, absorptive capacity and absorptive weakness effectively mitigate the negative relationship between managerial authority and exploitative innovations, whereas unabsorbed weakness amplifies the negative influence of managerial authority on exploitative innovations and the positive influence on exploratory innovations. The findings are valuable both in terms of enriching the academic understanding of the relationships between managerial authority and corporate innovation and in shaping prospective directions for future research. Moreover, this research may be pertinent to corporate governance practitioners seeking to enhance innovation effectiveness in the real economic sector. The contribution of this study lies in expanding knowledge regarding the influence of top management authority on innovation activity and the moderating role of factors in this process, which can be beneficial to company executives and researchers in the field of corporate governance.
Anterior colporrhaphy (AC) is a conventional surgical repair technique for cystocele but with high recurrence rate. We present a novel technique: Cable-suspended structure (CSS) by non-absorbable ...suture combined with "bridge" formation in surgical treatment of cystocele. This study aimed to evaluate and compare the long-term outcome of CSS technique for anterior vaginal wall repair with AC.
A retrospective review was performed on patients who underwent anterior vaginal wall repair between January 2012 and March 2017 at our center. All the patients were under a follow-up survey. The primary outcomes were objective cure (anterior prolapse POP-Q ≤ stage 1) and subjective cure (no symptoms of bulge or retreatment for prolapse). Secondary outcomes included quality of life (QOL) and patients' satisfaction, outcomes of site-specific POP-Q points Aa, Ba and C, as well as postoperative complications.
Of 91 included participants, 43 underwent AC and 48 underwent CSS. The proportion of sarcrospinous ligament fixation in the CSS group was higher than in the AC group (81.4% vs. 77.1%, P < 0.05). At a median follow-up of 69 months, the CSS group showed significantly higher objective cure rate compared with the AC group (72.9% vs. 51.2%, odds ratio 2.57, 95%CI 1.07-6.16). After adjusting for sarcrospinous ligament fixation, the CSS group still significantly showed higher objective cure rate (adjusted odds ratio 2.88, 95%CI 1.16-7.21). The proportion of the patients with POP-Q 0 stage in the CSS group was particularly higher than the AC group (25% vs. 7.0%, P = 0.025). There was no difference between the groups with respect to subjective cure, patients' satisfaction and postoperative complication.
The CSS technique showed better objective outcome than AC, however, subjective cure rate did not significantly differ between the two. Future prospective trial with large-scale should confirm the effectiveness and safety of CSS in sexually active women.
The current detection of fetal chromosomal abnormalities by non-invasive prenatal testing (NIPT) mainly relies on the cell free DNA(cfDNA) in the maternal blood. However, a gestational age of less ...than 12 weeks or a high maternal BMI affects cfDNA fetal fraction and further the detection by NIPT negatively. In this study, we aim to retrieve the trophoblast cells from the maternal cervix to develop a new sampling method for NIPT enabling an earlier use of NIPT.
We enrolled three patients who wanted to undergo induced abortion at Beijing Hospital between January 2022 and March 2022. Peripheral blood, cervix specimen, and the abortion tissue were collected and processed for each patient. Allele frequencies of the mutated gene loci of the maternal blood and the cervix sample were compared and the Sex Determining Region Y (SRY) gene was tested.
The allele frequencies of the mutated gene loci showed no significant difference between the maternal blood and the cervix sample. But we successfully detected signal of the SRY gene in the cervix sample of the only patient carrying a male fetus.
The detection of the SRY gene in a cervix sample indicated a successful retrieval of trophoblast cells from the cervix canal. Further study needs to be conducted to verify our finding before its application to the clinical settings.
To observe and evaluate the correlation between single-nucleotide polymorphisms (SNPs) and messenger RNA (mRNA) level related to tristetraprolin (TTP) in Chinese rheumatoid arthritis (RA). TapMan SNP ...was used for genotyping analysis in 580 RA patients and 554 healthy people. Association between
TTP
gene polymorphisms (rs251864 and rs3746083) and RA was obtained. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) technology was applied for the detection of TTP mRNA level in peripheral blood mononuclear cells (PBMCs) in 36 RA patients and 37 healthy people. We observed that the allele T of
TTP
rs3746083 increased RA susceptibility (
p
= 0.019). A significant difference was found under the dominant model of rs3746083 (
p
= 0.037). Further analysis showed the allele distribution of rs3746083 was nominally correlated with RF phenotype of RA patients (
p
= 0.045). Nevertheless, the association between
TTP
rs251864 and the incidence of RA was no statistically significant (
p
> 0.05). The TTP expression level in PBMCs of RA patients was significantly reduced (
p
< 0.001). In conclusion, the results of this experiment support that TTP may be involved in the pathogenesis of RA.
The percentages of low birth weight (LBW) increased from 7.7% in 2005 to 11.3% in 2011 and declined to 8.1% in 2017. For very low birth weight (VLBW) individuals, the proportion declined -1.0% ...annually, from 2.5% in 2005 to 1.4% in 2017. Among moderately low birth weight (MLBW) individuals, the proportion first increased 12.8% annually, from 5.0% in 2005 to 9.3% in 2011, and then declined -3.8% annually, from 9.4% in 2011 to 7.0% in 2017. The percentages of macrosomia monotone decreased from 4.0% in 2005 to 2.5% in 2017, an annual decline of -4.0%. Multiple regression analyses showed that boys, maternal age, hypertensive disorders complicating pregnancy (HDCP), and diabetes were significant risk factors for LBW. Boys, maternal age, gestational age, HDCP, diabetes, and maternal BMI were significant risk factors for macrosomia. Although the relevant figures declined slightly in our study, it is likely that LBW and macrosomia will remain a major public health issue over the next few years in China. More research aimed at control and prevention of these risk factors for LBW and macrosomia and their detrimental outcome in the mother and perinatal child should be performed in China.
This study aims to explore the application of agricultural information classification combined with the Internet of Things technology in agricultural production and economic management in the context ...of deep learning (DL). The agricultural information classification system is built based on DL. In terms of experimental methods, qualitative and quantitative methods are used to compare the extractive forward and the generative reverse generation algorithm in the abstract generation method. Typical extraction methods that directly extract important sentences are relatively ineffective. The model parameter tuning and training of generative (regenerating new sentences) are difficult, and the effect does not reach the level of agricultural scientific research. Qualitative and quantitative evaluation practice proves that the effect is better. In the data training effect of Rice Digest, after nine days of iterative training for about 1400 steps, the loss value is 1.33, which is equal to the standard data set. In the data training effect of Wheat Digest, after nine days of iterative training for about 1400 steps, the loss value is 1.496, which is equal to the standard data set. Later, the existing original model is adjusted to fit the model of the agricultural dataset scale. Among them, the minimum learning rate is reduced from 0.01 to 0.003 to expand the learning rate drop rate. In the visual training comparison, when training to about 1400 steps, the cross-entropy loss function values are about 1.43 and 1.29, respectively. The curve smoothing factor is set to 0.97 to observe the overall change in target loss value. The results show that when the parameter settings remain unchanged, the loss value of the model starts to increase linearly at about 1400 steps, and the effect reaches the expected value. This study improves the relevance, completeness, and accuracy of information acquisition in the field of agricultural science and technology information and improves the utilization of agricultural information.
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