Histone lysine-specific demethylase 1 (LSD1/KDM1A) has become an important and promising anticancer target since it was first identified in 2004 and specially demethylates lysine residues of histone ...H3K4me1/2 and H3K9me1/2. LSD1 is ubiquitously overexpressed in diverse cancers, and abrogation of LSD1 results in inhibition of proliferation, invasion, and migration in cancer cells. Over the past decade, a number of biologically active small-molecule LSD1 inhibitors have been developed. To date, six
-2-phenylcyclopropylamine (TCP)-based LSD1 inhibitors (including TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, and ORY-2001) that covalently bind to the flavin adenine dinucleotide (FAD) within the LSD1 catalytic cavity have already entered into clinical trials. Here, we provide an overview about the structures, activities, and structure-activity relationship (SAR) of TCP-based LSD1 inhibitors that mainly covers the literature from 2008 to date. The opportunities, challenges, and future research directions in this emerging and promising field are also discussed.
Heavy rainfall has long been recognized as a key factor in the triggering of landslides, as large amounts of precipitation generally have strong weakening effects on anti-sliding forces along slip ...surfaces. However, it remains to be understood why the catastrophic Xintan landslide in China was triggered by only moderate rainfall rather than the area's heaviest historical downpour. In this study, we demonstrate that a locked segment (a natural sustaining arch) at Jiangjiapo on the Xintan slope strongly restrained the movement of the sliding mass and was the key internal factor governing the slope stability. When such a locked segment is damaged enough to reach its volume-expansion point, slip displacement starts to accelerate. When its peak-stress point is attained, this displacement decelerates due to the homogenization effect of resistance. Once the homogenization process concludes, the displacement acceleration resumes, and slope instability occurs soon after reaching its residual-strength point. A post-factum analysis of the Xintan landslide indicated that the damage behavior of a locked segment from the volume-expansion point follows specific mechanical rules. The evolution of a locked-segment-dominated slope toward instability is caused by the progressive damage of the locked segment, which is promoted by various external factors including rainfall. Such factors can neither alter the inherent mechanical rules nor trigger a landslide before the locked segment fails. This mechanism explains the seemingly paradoxical relationship between precipitation and the occurrence of landslides, and these findings can greatly improve our understanding of landslide mechanisms.
•A sustaining arch at Jiangjiapo on the Xintan slope serves as a locked segment.•The locked segment is the key internal factor governing the slope stability.•External factors cannot trigger a landslide before a locked segment fails.•The evolution of a locked-segment-dominated slope toward instability follows specific rules.
We sought to explore the prevalence and immediate clinical implications of acute myocardial injury in a cohort of patients with COVID-19 in a region of China where medical resources are less stressed ...than in Wuhan (the epicentre of the pandemic).
We prospectively assessed the medical records, laboratory results, chest CT images and use of medication in a cohort of patients presenting to two designated covid-19 treatment centres in Sichuan, China. Outcomes of interest included death, admission to an intensive care unit (ICU), need for mechanical ventilation, treatment with vasoactive agents and classification of disease severity. Acute myocardial injury was defined by a value of high-sensitivity troponin T (hs-TnT) greater than the normal upper limit.
A total of 101 cases were enrolled from January to 10 March 2020 (average age 49 years, IQR 34-62 years). Acute myocardial injury was present in 15.8% of patients, nearly half of whom had a hs-TnT value fivefold greater than the normal upper limit. Patients with acute myocardial injury were older, with a higher prevalence of pre-existing cardiovascular disease and more likely to require ICU admission (62.5% vs 24.7%, p=0.003), mechanical ventilation (43.5% vs 4.7%, p<0.001) and treatment with vasoactive agents (31.2% vs 0%, p<0.001). Log hs-TnT was associated with disease severity (OR 6.63, 95% CI 2.24 to 19.65), and all of the three deaths occurred in patients with acute myocardial injury.
Acute myocardial injury is common in patients with COVID-19 and is associated with adverse prognosis.
Despite remarkable luminescent performance of 0D lead halide perovskites, achieving highly efficient blue light emission is extremely challenging and crucial for this domain. Considering the high ...toxicity of Pb2+ ion, it is significant to explore water‐stable lead‐free 0D halides as highly efficient and stable blue emitting materials. To address these issues, a family of 0D hybrid zinc halides of AZnBr4 (A = EP, BP, and TMPDA) based on discrete ZnBr42− tetrahedrons is herein reported as desirable blue light emitters. The wide band gaps enable these 0D halides to display highly efficient blue light emissions (452–485 nm) with highest photoluminescence quantum yield (PLQY) of 35.47%. More importantly, all these 0D halides present extraordinary chemical stabilities in humid air and water for one month, and are also capable of withstanding extreme pH conditions in the range of 0–14, likely the widest observed pH range for perovskites. Notably, the ultrahigh chemical stabilities of 0D zinc halides are nearly unmatchable among all known literature perovskite materials to the best of the authors’ knowledge. Combined superiorities of unusual blue light emission, promising PLQY, ultrahigh stability, and non‐toxicity highlight the potential optoelectronic applications in wide chemical environments for these 0D zinc halides.
Ultrastable blue emitting 0D zinc halides are a new family of 0D hybrid zinc halides displaying highly efficient blue light emissions with highest photoluminescence quantum yield of 35.47%. These 0D zinc halides exhibit extraordinary high chemical stabilities in water and extreme pH conditions (0–14), which are nearly unmatchable among all known literature perovskite materials to the best of the authors’ knowledge.
Research has conducted in-depth discussions on how firms strategically respond to institutional complexity. However, such research has yet to resolve the issue of how firms respond to the extreme ...institutional complexity, which is the extreme institutional conflict between a powerful stakeholder and another important stakeholder. In this situation, competing institutional demands within the organization could not bargain or simultaneously coexist, and the external public does not view the claims of another important stakeholder as legitimate. Accordingly, organizational response strategies in the existing literature cannot address the extreme institutional complexity. We propose that under extreme institutional complexity, the more salient the powerful stakeholder, the more inclined the firm to combat another important stakeholder. However, when the firm has established a connection with a powerful stakeholder, the firm will not incline to combat another important stakeholder. Our empirical results provide strong support for these arguments based on event system theory and using a natural experiment based on the responses of Chinese firms under an extreme institutional conflict. Thus, we contribute to the strategic responses of firms under institutional complexity and enrich the legitimacy theory.
When rock samples are loaded until macroscopic fractures develop, the failure process can be divided into several stages based on axial and lateral strain responses or the acoustic emission sequence ...during uniaxial compression tests. Several stress thresholds may be identified: the crack closure stress
σ
cc
, crack initiation stress
σ
ci
, crack damage stress
σ
cd
, and uniaxial compressive strength
σ
ucs
; these may be used as a warning indicator for rock rupture. We investigated the crack damage stress
σ
cd
, its threshold, and a possible relationship between
σ
cd
and the uniaxial compressive strength. The
σ
cd
of different rock types were compiled from previous studies based on uniaxial compression tests. The results showed that the overall averages and standard deviations of
σ
cd
/σ
ucs
for igneous, metamorphic, and sedimentary rocks were ~0.78 (±0.11), ~0.85 (±0.11), and ~0.73 (±0.18), respectively. There were no significant differences in
σ
cd
/σ
ucs
between the different rock types, except that the sedimentary rock had a slightly larger standard deviation attributed to the variation of porosity in the samples, while the metamorphic rock had higher average
σ
cd
/σ
ucs
resulting from the small statistical sample size. By excluding the higher-porosity (>10 %) rock samples, the averages and standard deviations of
σ
cd
/σ
ucs
for igneous, metamorphic, and sedimentary rocks were ~0.78 (±0.09), ~0.85 (±0.09), and ~0.78 (±0.11), respectively. The results imply that the rock origin process (i.e., igneous, metamorphic, and sedimentary) has a minimal effect on
σ
cd
/σ
ucs
. The ratio
σ
cd
/
σ
ucs
could be an essential intrinsic property for low-porosity rocks, which could be used in rock engineering for predicting the failure process.
Recent years have witnessed an increase in scholarly and practitioner interest in the effects of toxic forms of leadership and “win or die” organizational cultures in which employees seek to maintain ...their own status at all costs, yet there is little research examining the interaction of this type of leadership style and organizational culture. In this survey study of working adults, we demonstrate an association between perceptions of toxic leadership and “masculinity contest cultures” (Berdahl, Cooper, Glick, Livingston, & Williams, 2018).norms, rituals, and belief systems valorizing social dominance, work above other parts of life, physical strength, and the avoidance of weakness. Independently, masculinity contest cultures were associated with higher stress, work/life conflict, intention to job search, work engagement and job meaning, while toxic leadership was associated with lower work engagement and job meaning and higher intention to job search. However, results show a slight increase in work engagement and meaningfulness among men (but not women) who viewed their workplace as a masculinity contest and who reported having a toxic leader. These surprising results provide important insights into how toxic cultures retain employees despite their largely detrimental effects on job attitudes and well‐being.
Distributed Permutation Flowshop Scheduling Problem (DPFSP) has become a hot issue in recent years. However, DPFSP with uncertain processing times (DPFSP_UPT) has not been addressed so far although ...real manufacturing systems often encounter various uncertain factors which make processing times uncertain. In this paper, two local-search based metaheuristics, i.e., an Iterated Greedy algorithm (sIG) and an Iterated Local Search algorithm (sILS), are presented to solve the DPFSP_UPT with makespan criterion. A robust model of expect-risk rule is used to describe the DPFSP_UPT. A valid heuristic based on the well-known NEH heuristic is proposed to initialize sIG and sILS. An acceleration algorithm is adapted to save computational efforts. A destruction procedure with dynamic sizes is presented to enhance the exploration capability for sIG. A feature with the characteristic that small changes in the solution can preserve the properties of good solutions in the iterative process is applied by sILS. Both sIG and sILS use multiple local search methods to produce promising solutions by exploiting diverse search areas. Extensive experiments show that the proposed sIG and sILS perform significantly better than the five competing algorithms adapted in the literature, but there is no significant difference between sIG and sILS and each has its own advantages for different instances.
•First study of the robust distributed permutation flowshop scheduling.•A MILP model is built to formulate this new problem.•A novel Iterated Greedy and a novel Iterated Local Search are proposed.•Destruction with dynamic sizes is provided to yield more diverse search areas.•Extensive experiments show the effectiveness of the proposed algorithms.
Uplift of the Tibetan Plateau is ultimately driven by the Cenozoic collision between the Indian and Eurasian plates and their continued convergence. One approach for studying the Tibetan Plateau ...uplift is to verify the paleoelevation changes from collision to present day. This is important for understanding both the tectonics and the climatic effects. The new high resolution palynological record of the uppermost Oligocene to the lowest Miocene strata from the Lunpola Basin indicates that the vegetation types during the latest Oligocene–earliest Miocene were dominated by mixed coniferous–broadleaved forests being different from the modern steppe vegetation. By using the Coexistence Approach to the fossil pollen records, after calibration the effects of temperature difference and the lapse rate, a maximum paleoelevation of 3190±100m asl was estimated in the Lunpola Basin in the latest Oligocene–earliest Miocene, being 1500 to 2000m lower compared with the previous oxygen isotope paleoelevation in the same region.
Display omitted
•Paleoelevation estimation is important for studying Tibetan tectonics.•Providing new time scale for late Oligocene–Miocene strata in central Tibet•Pollen record reveals vegetation evolutions between 26 and 20Ma ago.•A maximum paleo-elevation of 3190m asl in central Tibet was estimated.
Colorectal cancer (CRC) has become a concern because of its high recurrence rate and metastasis rate, low early diagnosis rate and poor therapeutic effect. At present, various studies have shown that ...autophagy is closely connected with the occurrence and progression of CRC. Autophagy is a highly cytosolic catabolic process involved in lysosomes in biological evolution. Cells degrade proteins and damaged organelles by autophagy to achieve material circulation and maintain cell homeostasis. Moreover, microRNAs are key regulators of autophagy, and their mediated regulation of transcriptional and post‐transcriptional levels plays an important role in autophagy in CRC cells. This review focuses on the recent research advances of how autophagy and related microRNAs are involved in affecting occurrence and progression of CRC and provides a new perspective for the study of CRC treatment strategies.
Regulatory relationship between miRNAs and autophagy in CRC. Autophagy consists of a series of activities, such as phagophore formation, elongation, autophagosome and fusion with lysosome to form autolysosome. MiRNAs exert dual regulatory effects on autophagy pathways related to CRC through indirect or direct pathways. In the figure, the purple box represents autophagy‐related proteins, which indirectly regulate the autophagy process (eg, Bcl‐2, mTOR), the green box represents autophagy‐associated proteins, which are directly involved in the occurrence or formation of autophagy (eg, Beclin 1, LC3), and the yellow box represents the cellular process.
PDF
