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Continental-scale drainage reorganization is generally understood to result from landform evolution forced by the coupling between tectonic activity and climate change, attracting worldwide attention. Planation surfaces and river terraces constitute the most direct geomorphological archives for integrating the history of river systems and for reconstructing processes of drainage reorganization based on provenance analysis of the fluvial sediments. The Middle Yellow River has incised into the Ordos Block, which was previously levelled by a planation surface, creating the Jinshaan Gorge and linking the Hetao Basin to the north and the Fenwei Basin to the south. Multiple lines of evidence, from terraces correlation, sedimentary characteristics, and fluvial provenance, suggest that the Middle Yellow River catchment was occupied by fluvio-lacustrine systems before drainage integration, accumulating a sedimentary sequence derived from surrounding Red Clay and bedrocks during the period between 8.3 and 3.7 Ma. The planation surface was uplifted subsequently, forcing reorganization of the fluvio-lacustrine systems. Their integration resulted in the formation of the Jinshaan Gorge prior to 1.2 Ma. Numerous terraces were created during incision by the Middle Yellow River from north to south along the gorge. Our data, obtained from zircon U Pb dating and lithological composition of fluvial gravels, further points to a remarkable discrepancy in provenance between the fluvio-lacustrine systems overlying the planation surface and the terraces sequence formed by the integrated Middle Yellow River, confirming the drainage reorganization process constrained by the geomorphic records. • Fluvio-lacustrine systems occupied the Middle Yellow River before integration. • Yellow River terraces are different from fluvio-lacustrine systems in provenance. • The Middle Yellow River has been excavated and integrated during Plio–Pleistocene. [ABSTRACT FROM AUTHOR]

Strategic studies of gravel deposits, in particular using heavy-mineral analyses, have thrown light on the important unresolved question as to the timing of the initiation of the Yellow River drainage through the Sanmen Gorge, which linked the headwaters of that system in the Fenwei Basin and further upstream with the North China Plain and the Pacific Ocean in the east. Survey of the Sanmen Gorge reach revealed previously unrecognized gravel levels: a higher fifth terrace (T5) and a gravel that formed on a high-level planation surface that is preserved on the flanks of the gorge, below the Xiaoshan upland. This high-level gravel differs markedly from the Yellow River terraces, with a lack of material from the upstream catchment, and would appear to represent a small fluvial catchment that developed in the area during the formation of the planation surface, before the Sanmen Gorge was excavated. Comparison was also made with basin-fill gravels from the endorheic fluvio-lacustrine system that existed immediately upstream of the gorge, and was captured by the Yellow River when the latter was cut, and with the modern bedload gravel of the Yellow River in this reach. The former contains significant quantities of unstable hornblende, which implies more local derivation for the endorheic system, whereas the modern bedload resembles the terrace gravels in showing compositional maturity and long-distance transport from upstream within the catchment. The work reinforces a minimum age of 1.2 Ma for the formation of the Sanmen Gorge. • The gravel layer accumulated on the planation surface along the eastern front of the Xiaoshan represents a local river. • The local river sediments are different from the typical Yellow River gravels and the upper Sanmen Formation. • The Sanmen paleolake within the Fenwei basin was finally disrupted by the westward capture of this local river. • The Sanmen Gorge was excavated by the local river through the Xiaoshan separating the Fenwei basin and North China Plain. • The Yellow River integration may be attributed to the remarkable climatic fluctuation starting in the Mid-Pleistocene. [ABSTRACT FROM AUTHOR]

The upper–middle Yellow River flows through the Fenwei graben, a structure resulting from extensional tectonism that was formed and repeatedly extended during the Cenozoic. The drainage system within this graben was formerly isolated from the lower reaches of the Yellow River system by the Xiaoshan mountains, an actively growing ∼ NW–SE trending range. The modern course of the Yellow River takes it through this range along the Sanmen gorge, the formation of which was of great significance in that it initiated through-going drainage between the upper–middle and lower reaches of the system. The timing of this event, which was clearly a critical point in the evolution of the Yellow River, can be established by dating the terraces in the gorge. Intermittent deepening of this gorge by the Yellow River from a high-level planation surface capping the mountain range has resulted in the formation of five terraces. Magnetostratigraphic records from aeolian deposits accumulated on these surfaces provide a geochronological sequence for this geomorphic archive, in which the ages of the planation surface and of terraces T5, T4, T3, T2, and T1 have been determined as ∼3.63 Ma, ∼1.24 Ma, ∼0.86 Ma, ∼0.62 Ma, ∼129 ka, and ∼12 ka, respectively. Under the constraint of this chronological framework, a model for landscape evolution is proposed here. Uplift of the inner Fenwei graben and of the surrounding mountain ranges led to dissection of the 3.63 Ma old planation surface in conjunction with the formation of the Sanmen gorge. Drainage of the lake previously occupying the basin would have promoted incision into the fluvio-lacustrine graben sediments; indeed, gorge formation through the Xiaoshan may have been initiated or intensified by lake overflow. The ages obtained for the planation surface and uppermost terrace suggest that the formation of the Sanmen gorge and the initiation of the through-going eastward drainage of the Yellow River occurred between 3.63 and 1.24 Ma. Before the start of gorge entrenchment, the products of erosion in the modern upper catchment of the Yellow River were unable to reach the sea. The dramatic increase in deposition rates in the Bohai Gulf (at the mouth of the modern Yellow River in the East China Sea), ∼1.0 Ma ago, thus resulted from the initiation of an integral (enlarged) Yellow River catchment drainage through the Sanmen gorge; it does not imply an increase in erosion rates at that time. [ABSTRACT FROM AUTHOR]

In North China, the Ordos block located northeast of the Tibetan Plateau is regarded as a stable craton surrounded by the Yinchuan graben to the west, the Hetao graben to the north, and the Fenwei graben to the southeast. The major tectonic structure around this block in the Cenozoic reflects intensive extension as a response to the eastward extrusion of the Tibetan Plateau. Intermittent downcutting by the Yellow River, starting from the planation surface level on the Ordos block and penetrating the bedrock, resulted in the formation of the Jinshaan gorge. A series of well-preserved fluvial terraces was identified along this gorge, providing new insight into the far-field effect of the eastward extrusion of the Tibetan Plateau. Magnetostratigraphic records from the planation surface and uppermost terrace suggest that this gorge has been entrenched over its total length in the period from 3.7 to 1.2 Ma. A preliminary explanation is proposed here for the morphological evolution of the Yellow River in the Jinshaan gorge. On the basis of terrace correlation between seventeen geomorphic sections, multiwave headward erosion initiated by the Yellow River along this gorge has been reconstructed. This process may be attributed to the lowering of the base level (the Fenwei graben). This graben has been formed during the Cenozoic as the Tibetan Plateau extruded eastwards resulting in accelerated ground subsidence. A combined approach of magnetostratigraphy, pedostratigraphy, and optically stimulated luminescence (OSL) was adopted to establish a new geochronology for terraces in the gorge at 1.2 Ma, 1.1 Ma, 787 ka, 412 ka, 245 ka, 128 ka, 29 ka, and 11 ka. These ages provide an excellent framework for calculating the extension within the Fenwei graben. The average incision rate appears to be enhanced significantly since 412 ka, indicating a rapid extension within the Fenwei graben during this time. [ABSTRACT FROM AUTHOR]

El Niño‐Southern Oscillation (ENSO) is the most dominant interannual signal of climate variability and profoundly affects river flooding globally, especially in East Asia. However, ENSO also has ∼2,000 and ∼1,000‐year cycles, but due to the lack of flood records with sufficient length, little is known about the ENSO's impact on floods at these millennial timescales. Here we test this in the middle‐lower Yangtze River by reconstructing the first Holocene flood record with optically stimulated luminescence and 14C ages of flood deposits. We find the periods with high flooding probability generally correspond with intervals of weakened solar activity. Importantly, the flood record displays 2,000 and 1,000‐year cycles similar to the ENSO record, and band‐pass filter results show the two records are synchronous at these bands. Our results reveal a persistent control of ENSO on millennial‐scale hydroclimatic variability in the Yangtze basin and likely other basins. Plain Language Summary: El Niño‐Southern Oscillation (ENSO) is the prominent pattern of interannual climate variability, profoundly affecting the river flow and flooding at the global scale. However, the ENSO's interannual cycle was strongly damped or even non‐existent in most of the Holocene, compared with a more robust millennial periodicity. It remains unclear whether a link exists between the flood and ENSO at millennial timescales due to the lack of sufficiently long flood series. Here we test this in the Yangtze River (YR) because ENSO has the most significant impact on this drainage area. We compiled the most detailed flood ages over the middle and lower YR to reconstruct the Holocene flood record. We found that the flood variations have prominent 2,000 and 1,000‐year cycles, and they exhibit in‐phase relationship with ENSO at these cycles, suggesting a persistent modulation of ENSO on the flooding at millennial timescales in the middle and lower Yangtze basin. This study contributes to a more comprehensive understanding of the driving forces of floods in the Yangtze catchment at millennial timescales, thereby aiding to accurately assess flood hazards and flooding prediction in hydroclimatic modeling for the densely populated Yangtze basin. Key Points: We reconstructed the Holocene flood record for the middle and lower Yangtze River by compiling optically stimulated luminescence and 14C ages of flood depositsThe flood record displays clear 2,000 and 1,000‐year cyclesThe flood record is synchronous with El Niño‐Southern Oscillation at 2,000 and 1,000‐year cycles [ABSTRACT FROM AUTHOR]

The eastern Altun Shan is a crucial part of the Altun orogenic belt within the Tibetan Plateau. Study of the uplift rate and the related features in this area provides important clues for understanding the uplift mechanism of the Tibetan Plateau as a whole. As an important geomorphic element in landscape development, the fluvial system can record the relationship between tectonic activity and climatic change. In recent years, studies of the Channel Steepness Index K sn , have been conducted by many researchers, using the geomorphological model of equilibrium channel longitudinal profiles, combining bedrock uplift and river incision and thus making it possible to extract rock uplift history from river profiles. This research show that regional rock uplift rate is a major factor in affecting the K sn index. Regional tectonic activity and intensity, therefore, can be evaluated from variation in the K sn index, which can provide a sensitive measure of uplift rate. In this paper, the Digital Elevation Map 'ASTER GDEM', with a spatial resolution of 30 m, was utilized as basic data, and combined with ArcGIS and MATLAB software to extract the K sn index from the equilibrium channel longitudinal profiles model. Meanwhile, we employed statistical methods to analyze the K sn index. Our results suggest that averaged K sn indices, obtained from the subrange A，B，C，D, and E of the eastern Altun Shan (from west to east), are 70.93, 139.03, 108.85, 134.44 and 165.39, respectively. Further analysis implies that the variation in this index can be correlated with the distribution pattern of uplift rates within different regions. Its value increases gradually from west to east, reflecting regional uplift rate. Along the western section of the eastern Altun Shan, the uplift rate is slower and characterized by strike-slip movements, while its eastern part has uplifted faster and is controlled by thrust fault systems. Moreover, in contrast with the southern Altun Shan, the uplift rate of the northern part is high. These variations in uplift rate seem to be linked with "the imbricated thrusting transformation-limited extrusion model" of the Tibetan Plateau. Our results can be correlated with previous work on the active characteristics along the eastern Altyn Tagh Fault (ATF). • Along the eastern Altun Shan, the obtained index K sn shows a rough tendency of increasing eastward. • The index K sn from the north front of the eastern Altun Shan is higher than that from the south flank. • This distribution pattern of the index K sn is translated into the different uplift along the eastern Altun Shan. • The difference in uplift rate can be evaluated well by the fluvial incision rate obtained by terrace archives. • The analysis of the index Ksn provides an excellent insight into the extrusion model of the Tibetan Plateau. [ABSTRACT FROM AUTHOR]

Fluvial response to allogenic and autogenic controls concerns the understanding of landform evolution related to the interaction between tectonic movements, climate, surface process and human activity. Paleo-channels, as part of geomorphic archives, have been widely employed to study this issue during recent decades. Previous work has however concentrated on the mechanisms driving river migration. A new approach, in which multiple elements are considered, is employed here in the examination of paleo-channel formation in the Jiudong Basin, located at the northeastern margin of the Tibetan Plateau and characterized by active tectonic deformation, a dry climate and ancient human activity. Based on geomorphic and sedimentary analysis, eight paleo-channels formed by the Taolai and Hongshuiba rivers (two tributaries of the Beida River catchment) have been identified. AMS14C dating of the overlying lacustrine sediments defined their respective abandonment at ca. 22.2, 20.9, 15.3, 18.8, 13.9, 11.9, 3.5 and 1.1 cal. Ka BP. The migration histories of the two rivers have been reconstructed, and then well correlated with reference to archives of tectonic, climatic and human influence. Our results suggest that these controlling factors seem to be coupled and have a competitive relationship in driving river migration. In the northeastern margin of the Tibetan Plateau, channel migration can therefore be regarded as a result of fluvial response to the interaction between rapid tectonic activity, climatic fluctuation and human influence. • 8 paleo-channels have been identified in the northeastern margin of the Tibetan Plateau. • These paleo-channels have been constrained by AMS14C dating in the last glacial period. • These paleo-channels are coupled record of climate, tectonics and human influence. [ABSTRACT FROM AUTHOR]

The histone demethylase JMJD1C is associated with human platelet counts. The JMJD1C knockout in zebrafish and mice leads to the ablation of megakaryocyte–erythroid lineage anemia. However, the specific expression, function, and mechanism of JMJD1C in megakaryopoiesis remain unknown. Here, we used cell line models, cord blood cells, and thrombocytopenia samples, to detect the JMJD1C expression. ShRNA of JMJD1C and a specific peptide agonist of JMJD1C, SAH-JZ3, were used to explore the JMJD1C function in the cell line models. The actin ratio in megakaryopoiesis for the JMJDC modulation was also measured. Mass spectrometry was used to identify the JMJD1C-interacting proteins. We first show the JMJD1C expression difference in the PMA-induced cell line models, the thrombopoietin (TPO)-induced megakaryocyte differentiation of the cord blood cells, and also the thrombocytopenia patients, compared to the normal controls. The ShRNA of JMJD1C and SAH-JZ3 showed different effects, which were consistent with the expression of JMJD1C in the cell line models. The effort to find the underlying mechanism of JMJD1C in megakaryopoiesis, led to the discovery that SAH-JZ3 decreases F-actin in K562 cells and increases F-actin in MEG-01 cells. We further performed mass spectrometry to identify the potential JMJD1C-interacting proteins and found that the important Ran GTPase interacts with JMJD1C. To sum up, JMJD1C probably regulates megakaryopoiesis by influencing the actin network. [ABSTRACT FROM AUTHOR]

Mixed Lineage Leukemia rearranged acute myeloid leukemia (MLLr AML) predicts a poor prognosis. Histone demethylase JMJD1C is a potential druggable target of MLLr AML. However, little is known about how JMJD1C contributes to MLLr AML. Here we found that JMJD1C regulates lipid synthesis-associated genes including FADS2, SCD in MLLr AML cells. Lipid synthesis-associated protein FABP5 was identified as a specific interacting protein of JMJD1C and binds to the jumonji domain of JMJD1C. FABP5 also regulates JMJD1C mRNA and protein expression. JDI-10, a small molecular inhibitor of JMJD1C identified by us, represses MLLr AML cells, induces apoptosis, and decreases JMJD1C-regulated lipid synthesis genes. Moreover, JDI-10 mediated suppression of MLLr AML cells can be rescued by palmitic acid, oleic acid, or recombinant FABP5. In summary, we identified that JMJD1C-regulated lipid synthesis contributes to the maintenance of MLLr AML. Lipid synthesis repression may represent a new direction for the treatment of MLLr AML. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the clonal expansion and differentiation arrest of leukemic cells in peripheral blood and bone marrow. Though the treatment using cytarabine-based protocol for AML patients with t (8; 21) translocation has improved the 5-year overall survival rate, drug resistance continues to be the principal limiting factor for the cure of the disease. In addition, very few AML patients with mixed lineage leukemia gene rearrangements (MLLr) have a desirable outcome. This study evaluated the cell differentiation effect of a potent HDAC (histone deacetylase) inhibitor, I3, and its possible mechanism on the AML cells with t (8; 21) translocation or MLLr and leukemic stem-like cells (Kasumi-1, KG-1, MOLM-13, and THP-1). I3 exhibited efficient anti-proliferative activity on these cells via promoting cell differentiation, accompanied by the cell cycle exit at G0/G1. Importantly, I3 showed the properties of HDAC inhibition, as assessed by the acetylation of histones H3 and H4, which resulted in blocking the activation of the VEGF (vascular endothelial growth factor)-MAPK (mitogen-activated protein kinase) signaling pathway in the Kasumi-1 cell line. These data demonstrate that I3 could be a potent chromatin-remodeling agent to surmount the differentiation block in AML patients, including those with t (8; 21) translocation or MLLr, and could be a potent and selective agent for AML treatment. [ABSTRACT FROM AUTHOR]

We report sedimentology, geochronology, and provenance data from a drill core near the Sanmen Gorge. The results indicate that typical river channel deposits, with detritus from the Ordos Block, started to accumulate in the Sanmen Gorge at ∼1.25 Ma, which is consistent with a shift in the regional depositional environment from a closed saline lake to a fluvial-dominated system. Integrating with river terrace evidence suggest that the birth of the modern Yellow River, characterized by the square-shaped bend around the Ordos Block and flowed through the Sanmen Gorge eastward to the sea, occurred around ∼1.25 Ma. [Display omitted] The incision of the Sanmen Gorge marks the birth of the modern Yellow River, but its timing varies from the late Miocene-early Pliocene to the late Pleistocene (∼0.15 Ma), and the suggested forcing mechanisms vary from the uplift of the Tibetan Plateau to global climate change. Here, we report sedimentologic, geochronologic, and provenance data from a drill core near the Sanmen Gorge, the last gorge along the main course of the Yellow River. Our results indicate that typical river channel deposits, with detritus from the Ordos Block in the upstream regions, started to accumulate in the Sanmen Gorge at ∼1.25 Ma. When integrated with river terrace evidence from the upstream and downstream regions, the results provide robust evidence that the final integration of the modern Yellow River occurred at ∼1.25 Ma, consistent with the beginning of the Mid-Pleistocene transition (MPT). We propose that the accelerated lowering of eustatic sea level during the MPT may play as important a role as tectonism in driving the birth and evolution of the modern Yellow River. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the anti-leukemic effects of dihydroartemisinin (DHA) on T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Jurkat and Molt-4, and the underlying mechanisms. Cell Counting Kit-8 was performed to measure cell viability. Cell apoptosis and cell cycle distribution were assessed by flow cytometry. The expression levels of ATF4 and CHOP mRNA were assessed by reverse transcription-quantitative PCR, while the protein abundance of SLC7A11, GPX4, ATF4 and CHOP was determined by western blotting. Moreover, malondialdehyde, glutathione (GSH) and reactive oxygen species (ROS) assays were used to detect the levels of ferroptosis. The results showed that DHA suppressed T-ALL cell viability in vitro, and induced cell cycle arrest at S or G2/M phase. DHA also induced ROS burst, activated endoplasmic reticulum (ER) stress, disrupted the system Xc−-GSH-GSH peroxidase 4 antioxidant system, and increased lipid peroxide accumulation, resulting in cell death. By contrast, the pharmacological inhibition of ferroptosis alleviated DHA-induced cell death, confirming that DHA induces T-ALL cell death via ferroptosis. Mechanistically, the effect of DHA on ferroptosis was partly mediated by downregulating SLC7A11 and upregulating the ATF4-CHOP signaling pathway, which is associated with ER stress. These results indicated that DHA may induce ferroptosis in T-ALL cell lines and could represent a promising therapeutic agent for treating T-ALL. [ABSTRACT FROM AUTHOR]

The occurrence of endorheic basins on the Tibetan Plateau, both in its Pleistocene history and (fewer in number) at the present day, has been attributed to the 'basin-and-range' character of the orogen; the understanding of their conversion to exorheic drainage is key to interpreting the evolution of the Yellow River and other river systems of the plateau. However, such basins also occur in areas of lower altitude and relief and can be observed to have been considerably more common in pre-Quaternary times. In many areas, for example the Mediterranean region, such basins, previously having accumulated stacked sedimentary sequences, typically 'inverted' in the late Pliocene or at around the Pliocene–Pleistocene transition, possibly as part of a response to the cooling of global climate and its effect on surface processes. Some basins have inverted later, at around the time of the Mid-Pleistocene Revolution, coinciding with the increased severity of climate resulting from the 100 ka Milankovich cycles that followed that change. The progressive incision into the fills of these inverted sedimentary basins has also been linked to this climatic influence, perhaps taking effect as a result of erosional isostatic uplift, which would have replaced the accumulation-induced subsidence (also isostatic) of the basins. NW Europe, including Britain, had sediment-accumulating basins in the Early Cenozoic; the timing of their inversion is poorly known as a result of the paucity of preserved evidence from the Late Cenozoic in such areas. Endorheic basins that survive at the present day are mainly in regions of relative aridity and are often controlled by active tectonic structures, such as the pull-apart basins of the Dead Sea Fault Zone and similar examples. This review discusses the evidence from different climatic regions, tectonic settings and areas of different crustal type, with a view to elucidating meaningful patterns that might throw light on this phenomenon. • Late Cenozoic sedimentary basins are compared with reference to type and evolution. • Patterns have been determined in relation to crustal type and climate. • Internally (endorheic) draining basins show a post-Neogene decline in number. • Change to external drainage may be linked to increased climatic severity. • Yellow River basins may be atypical because of association with India–Asia collision. [ABSTRACT FROM AUTHOR]

The Jinsha River has attracted considerable attention for nearly a century due to the morphology of its drainage basin. To explain the evolution of the Jinsha drainage basin, most researchers have considered that the present-day Jinsha (the upper reach of the Yangtze) was once a tributary of a single, southward-flowing river system called the Paleo-Red River, which drained into the South China Sea and was captured by the Upper Yangtze River, after which the flow direction changed to eastwards. The sudden disappearance, at 5.5 Ma, of the Red River submarine fan, which was fed primarily by the Paleo-Red River system, provides an important chronological constraint on the drainage reorganization and the capture event. However, until now, no geomorphic evidence has been presented to support this hypothesized age. Considering this problem, nine well-preserved terraces (T9 to T1) at Jinjiangjie in the Middle Jinsha River were evaluated in this study. To establish the chronological framework of these terraces, a combined dating approach was employed, incorporating electron spin resonance dating, cosmogenic nuclide (26Al/10Be) burial dating, and optically stimulated luminescence dating. We obtained a complete chronological sequence for terraces T9–T1, with ages of approximately 1.07 (T9), 0.70 (T8), 0.65 (T7), 0.51 (T6), 0.47(T5), 0.44(T4), 0.30 (T3), 0.18 (T2), and 0.047 (T1) Ma, respectively. Constrained by this framework, we calculated an average long-term fluvial incision rate of ~147 mm/ka. The reconstruction of the paleo-topography and paleo-drainage, based on digital elevation model data for the re-filling of the deeply incised river valley, indicates that the present drainage pattern in the Middle Jinsha system was established after the disruption of the paleo-landscape surface at an elevation of ~2000 m above sea level. The age of the present-day Middle Jinsha drainage was determined at approximately 5.5 Ma by extrapolating the average valley incision rate, suggesting that the present-day Jinsha was formed at about this time. Our results agree with the previously estimated timing of the disappearance of the Red River submarine fan. • A flight of 9 fluvial terraces dated using ESR, 26Al/10Be and OSL dating in Jinsha River (the upper reach of Yangtze) • About 147 mm/ka of average incision rate in Middle Jinsha River since early Pleistocene • First age of Jinsha River achieving its present-day drainage pattern extrapolated from the average valley incision rate [ABSTRACT FROM AUTHOR]

Introduction: Proapoptotic peptide, (KLAKLAK)2, exhibits strong anti-tumor effect with the help of cell-penetrating peptides such as Pep2, targeting TLR2 with high expression in acute myeloid leukemia (AML). However, the applications are limited due to the peptide's instability and high cost of synthesis. Recombinant PP7 bacteriophage-like particles (VLPs) can protect the peptides from degradation by proteases, based on their ability to display foreign peptides. Methods: Here, we evaluated the feasibility of PP7 VLPs carrying Pep2 and (KLAKLAK)2 (2PP7-Pep2-KLAK VLPs) expressed in E. coli. We further investigated the characteristics including size, toxicity, thermal stability, penetrating ability, anti-tumor activity, and potential anti-tumor mechanism of 2PP7-Pep2-KLAK VLPs. Results: 2PP7-Pep2-KLAK VLPs was expressed in E. coli BL21(DE3) successfully with high yield and thermal stability. They penetrated the AML cells THP-1 rapidly after 30 min of incubation. Moreover, 2PP7-Pep2-KLAK VLPs were non-replicative, non-infectious, and non-toxic against normal cells, but inhibited the proliferation of THP-1 cells by inducing cell apoptosis after 24 h of exposure. This effect extends through 120 h of exposure, indicating their anti-proliferation effect was superior to that of synthetic peptides. In addition to the mitochondrial apoptotic pathway, the anti-tumor activity of 2PP7-Pep2-KLAK VLPs was also correlated with down-regulation of expression of enhancer of zeste homolog 2 (EZH2) and trimethylation of histone H3K27. Conclusions: We identified the feasibility to prepare the stable, active Pep2-KLAK peptide by using PP7 bacteriophage as the vehicle. We revealed this peptide was an inhibitor of EZH2. 2PP7-Pep2-KLAK VLPs may have significant clinical implications in the treatment of MLL-AF9 AML as an epigenetic modulator. [ABSTRACT FROM AUTHOR]

Forkhead box K2 (FOXK2) is a transcription factor involved in regulating the pathophysiological processes in many types of cancers. Functioning as either an oncogene or tumor suppressor, FOXK2 is involved in cell proliferation, metastasis, DNA damage, metabolism, and autophagy. However, the functions of FOXK2 in multiple myeloma (MM) are still unexplored. Here we show that FOXK2 silencing by small interfering RNA (siRNA) prevented the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) via dephosphorylation of an AMP-activated protein kinase (AMPK). Consistently, suppression of FOXK2 inhibited glycolysis and cell proliferation in MM cells. Furthermore, the correlation between FOXK2 expression and disease progression in MM was evaluated using the TCGA (The Cancer Genome Atlas) database. Taken together, we identified a novel FOXK2-dependent signaling pathway involved in the regulation of PFKFB3 expression in response to glycolysis, which might serve as a potential therapeutic target in MM. • Transcription factor FOXK2 promotes glycolysis in multiple myeloma. • Suppression of FOXK2 inhibits MM cell proliferation. • siRNA knockdown of FOXK2 prevents the expression of PFKFB3 via dephosphorylation AMPK. • FOXK2 expression is correlated with MM disease progression. [ABSTRACT FROM AUTHOR]

Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules. [ABSTRACT FROM AUTHOR]

Glacial extent mapping and dating indicate that the local last glacial maximum (LLGM) of the northeastern Tibetan Plateau occurred during mid-Marine Isotope Stage (MIS) 3. This is asynchronous with the global last glacial maximum (LGM) that occurred during MIS 2. The causes underlying this asynchronicity are the subject of ongoing debate, and paleoclimatic reconstructions are a key to advancing understanding of the climatic influence on the spatial and temporal patterns of paleoglaciation. We used multiple methods to reconstruct the equilibrium-line altitude (ELA) of the Die Shan paleo-ice cap on the northeastern Tibetan Plateau, and to infer past temperature for ice maximum positions believed to be mid-MIS 3 in age, based on regional correlation. Geomorphic ELA reconstructions combined with an energy and mass balance model yield a paleo-ELA of 4117±31 m asl (786 m lower than present) with temperature depressions of 3.8 to ~4.6°C compared to the present. This is less than the LGM reconstruction of temperature depression inferred from other climatic proxy records on the Tibetan Plateau and suggests that the LLGM glacial advance was a product of lower temperatures and slightly reduced precipitation compared to present, whereas the LGM was a more restricted advance in which much colder conditions were combined with much lower precipitation. [ABSTRACT FROM PUBLISHER]

KDM3B reportedly shows both tumor-suppressive and tumor-promoting activities in leukemia. The function of KDM3B is likely cell-type dependent and its seeming functional discordance may reflect its phenotypic dependence on downstream targets. Here, we first showed the underexpression of KDM3B in acute myeloid leukemia (AML) patients and AML cell lines with MLL-AF6/9 or PML-RARA translocations. Overexpression of KDM3B repressed colony formation of AML cell line with5qdeletion. We then performed global microarray profiling to identify potential downstream targets of KDM3B, notablyHOXA1, which was verified by real time PCR and Western blotting. We further showed KDM3B binding at retinoic acid response elements (RARE) but not at the promoter region ofHOXA1gene. KDM3B knockdown resulted in increased mono-methylation but decreased di-methylation of H3K9 at RARE while eschewing the promoter region ofHOXA1. Collectively, we found that KDM3B exhibits potential tumor-suppressive activity and transcriptionally modulates HOXA1 expressionviaRARE in AML. [ABSTRACT FROM AUTHOR]

Forkhead box K2 (FOXK2) is a central transcriptional regulator of embryonic development and cell homeostasis. Since its discovery, evidence has shown that FOXK2 mediates a variety of biological processes involving in genomic stability, DNA repair, cancer stem cell maintenance, cell proliferation, apoptosis and cell metabolism. The inherent structural characteristics of FOXK2 enable it as a transcriptional factor (TF) to cooperate with other active molecules in cancer development. FOXK2 mediates several significant chromatin events that are necessary for some chromatin accessibility and protein-protein interaction. FOXK2 is involved in the pathogenesis of a number of types of cancer as an oncoprotein or tumor suppressor depending on its interactive partners. Therefore, the loss of FOXK2 and its functions directly or indirectly affect the fate of cells. FOXK2 expresses differentially in a number of types of cancer and is involved in a number of aspects of carcinogenesis. However, its roles in tumorigenesis remain largely unexplored. The present review focused on the latest findings and evidence on the broad roles and possible mediating mechanisms of FOXK2 in carcinogenesis. The recent findings about FOXK2 may shed light on the direction of future FOXK2 research in tumorigenesis. [ABSTRACT FROM AUTHOR]

Cervical cancer is one of the most common types of gynecological tumors. Lysophosphatidic acid (LPA), as a bioactive lipid medium, plays an important role in numerous physiological and pathophysiological processes, including the stimulation of cell migration and tumor cell invasion. LPA is increased in the plasma of patients with cervical cancer. Doxorubicin hydrochloride (DOX) is used as a first-line drug in the treatment of cervical cancer in clinics, however, the effect and molecular mechanism of LPA on DOX-induced apoptosis in cervical cancer cells remain unclear. Therefore, the present study aimed to explore the effect and underlying molecular mechanism of LPA on DOX-induced apoptosis in cervical cancer cells. HeLa cells were treated as a control group or with LPA (10 µmol/l), DOX (4 µmol/l) or LPA (10 µmol/l) + DOX (4 µmol/l) for 24 h. Using transmission electron microscopy the results demonstrated that LPA reduced cell death and the degree of chromatin aggregation in DOX-induced HeLa cells. Reverse transcription-quantitative PCR demonstrated that LPA significantly downregulated caspase-3 mRNA expression levels in DOX-induced HeLa cells. Moreover, western blotting demonstrated that LPA significantly reduced caspase-3 and cleaved caspase-3 protein expression levels in DOX-induced HeLa, C33A and SiHa cells. Furthermore, flow cytometry demonstrated that LPA may prevent apoptosis in DOX-induced HeLa cells (P<0.05). Using dichloro-dihydro-fluorescein diacetate assay, it was demonstrated that LPA significantly reduced the intracellular ROS levels induced by DOX. In summary, the present study indicated that LPA may protect HeLa cells from apoptosis induced by DOX. These findings have provided experimental evidence that LPA may be a potential therapeutic target for the treatment of cervical cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • The terrace sequences of Datong River were dated using multiple dating methods. • Tectonic-climate forcing triggered the formation of the Datong River before ∼1.1 Ma. • The Datong River has been more sensitive to climate changes than the Yellow River. The formation of river terraces has been related to climate changes and surface uplift in the mountain regions. Although the formation mechanism of river terraces in the northeastern Tibetan Plateau has been extensively studied, the difference between the large river (trunk stream of Yellow River) and small rivers (tributaries of Yellow River) responding to external forcing is still poorly understood. Here, we employ multiple dating methods to date the terrace sequence of the Datong River in the northeastern Tibetan Plateau and then further correlate it with tectonic activity and climate records. Our results show that the modern Datong River in the Babaochuan Basin formed between 1.5 Ma and 1.1 Ma in response to the coupled effects of Asian monsoon enhancement and intense regional uplift. To further evaluate the effect of tectonic–climatic forcing on rivers of different scales, detailed comparison of terrace formation was carried out between the Datong River and Yellow River in the Lanzhou Basin. The comparison results indicate that under the context of relatively slow surface uplift during 0.6–0.13 Ma, the Datong River created three terraces probably ascribed to the glacial–interglacial cycles with high-amplitude fluctuations, whereas no terraces formed along the Yellow River in the Lanzhou Basin during the same interval. We conclude that the Datong River, as a smaller river than the trunk Yellow River, is probably more sensitive to the climate change. [ABSTRACT FROM AUTHOR]

Little is known about the susceptibility to acute myeloid leukemia. We aim to search non-protein coding regions of key hematopoiesis transcription factors for genetic variations associated with acute myeloid leukemia susceptibility. We genotyped SNPs ofRUNX1P1 promoter, P2 promoter, +23 enhancer, intron 5.2 enhancer,PU.1promoter,CEBPApromoter, andCEBPEpromoter from acute myeloid leukemia patients and healthy controls. Rs2249650 and rs2268276 atRUNX1intron 5.2 enhancer were found to be associated with acute myeloid leukemia susceptibility. Artificial reporters containing different rs2249650 and rs2268276 alleles showed differential activities in the K562 cell line, a human immortalized myeloid leukemia line. Rs2249650 contributes to reporter activities more than rs2268276. Gel shift assay is consistent with the luciferase assay. Supershift assay indicated that one potential binding protein was PU.1. To sum up, rs2268276 and especially rs2249650 may be qualified as new acute myeloid leukemia susceptibility-associated SNPs. [ABSTRACT FROM AUTHOR]

Theophylline has been reported to have considerable pharmacological activity for asthma, which is partly mediated by the anti-inflammatory effects of theophylline. Nevertheless, the wide application of theophylline was hampered due to its rapid metabolization and the poor patient compliance. Microspheres can be applied as targeted and sustained drug-release carriers. The purposes of the present study were to optimize spray-drying conditions and summarize the anti-asthma pharmacodynamics of the theophylline/chitosan/β-cyclodextrin microspheres. The yield, encapsulation efficiency, drug load, and water content were evaluated using ultraviolet spectrophotometry. The morphology of microspheres was observed by scanning electron microscope. Histopathological assessment of microspheres in a murine model of asthma was measured by H&E staining and immunohistochemistry. Levels of IL-4 and TNF-α protein in bronchoalveolar lavage fluid were measured using enzyme-linked immunosorbent assays. The optimal spray-drying conditions (Tgi = 150°C,Wff = 8 mL/min,Waf = 400 m3/h, andMw = 13 × 105) were selected by orthogonal experiment. The yield, encapsulation efficiency, drug load, and water content of the microspheres were 39.3 ± 1.2%, 76.0 ± 0.8%, 19.5 ± 1.5%, and 10.3 ± 0.6%, respectively. A scanning electron micrograph showed that the microspheres were predominantly spherical with smooth surface or slightly wrinkled. Theophylline/chitosan/β-cyclodextrin microspheres markedly decreased the number of infiltrated inflammatory cells, the levels of IL-4, and TNF-α protein in animal models. Based on lung histopathological studies, inflammatory cells, goblet cells, and NF-κB positive cells were inhibited in the theophylline/chitosan/β-cyclodextrin microspheres group compared with those in the model group. These results indicate that optimized theophylline/chitosan/β-cyclodextrin microspheres may be useful as a novelty pulmonary drug-delivery system in therapy for the treatment of bronchial asthma. [ABSTRACT FROM AUTHOR]