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Abstract During the maturation of hematopoietic stem/progenitor cells (HSPCs) to fully differentiated mature B lymphocytes, developing lymphocytes may undergo malignant transformation and produce B-cell lymphomas. Emerging evidence shows that through the endothelial-hematopoietic transition, specialized endothelial cells called the hemogenic endothelium can differentiate into HSPCs. However, the contribution of genetic defects in hemogenic endothelial cells to B-cell lymphomagenesis has not yet been investigated. Here, we report that mice with endothelial cell-specific deletion of Fbw7 spontaneously developed diffuse large B-cell lymphoma (DLBCL) following Bcl6 accumulation. Using lineage tracing, we showed that B-cell lymphomas in Fbw7 knockout mice were hemogenic endothelium-derived. Mechanistically, we found that FBW7 directly interacted with Bcl6 and promoted its proteasomal degradation. FBW7 expression levels are inversely correlated with BCL6 expression. Additionally, pharmacological disruption of Bcl6 abolished Fbw7 deletion-induced B-cell lymphomagenesis. We conclude that selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin positive endothelial cells instigates diffuse large B-cell lymphoma via upregulation of BCL6 stability. In addition, the mice with endothelial cell-specific deletion of Fbw7 provide a valuable preclinical platform for in vivo development and evaluation of novel therapeutic interventions for the treatment of DLBCL.

Abstract Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a crucial energy sensor that regulates lipid and glucose metabolism. However, whether AMPK regulates ketone metabolism in whole body is unclear even though AMPK regulates ketogenesis in liver. Prolonged resulted in a significant increase in blood and urine levels of ketone bodies in wild-type (WT) mice. Interestingly, fasting AMPKα2–/– and AMPKα1–/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. BHB tolerance assays revealed that both AMPKα2–/– and AMPKα1–/– mice exhibited slower ketone consumption compared to WT mice, as indicated by higher blood BHB or urine BHB levels in the AMPKα2–/– and AMPKα1–/– mice even after the peak. Interestingly, fasting AMPKα2–/– and AMPKα1–/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. . Specifically, AMPKα2ΔMusc mice showed approximately a twofold increase in blood BHB levels, and AMPKα2ΔMyo mice exhibited a 1.5-fold increase compared to their WT littermates after a 48-h fasting. However, blood BHB levels in AMPKα1ΔMusc and AMPKα1ΔMyo mice were as same as in WT mice. Notably, AMPKα2ΔMusc mice demonstrated a slower rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1ΔMusc mice did not show such an effect. Declining rates of body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis, decreased in skeletal muscle of AMPKα2–/– mice. Moreover, SCOT protein ubiquitination increased in C2C12 cells either transfected with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition. AMPKα2 physiologically binds and stabilizes SCOT, which is dependent on AMPKα2 activity.

Abstract MYB-related genes, a subclass of MYB transcription factor family, have been documented to play important roles in biological processes such as secondary metabolism and stress responses that affect plant growth and development. However, the regulatory roles of MYB-related genes in drought stress response remain unclear in maize. In this study, we discovered that a 1R-MYB gene, ZmRL6, encodes a 96-amino acid protein and is highly drought-inducible. We also found that it is conserved in both barley (Hordeum vulgare L.) and Aegilops tauschii. Furthermore, we observed that overexpression of ZmRL6 can enhance drought tolerance while knock-out of ZmRL6 by CRISPR-Cas9 results in drought hypersensitivity. DAP-seq analyses additionally revealed the ZmRL6 target genes mainly contain ACCGTT, TTACCAAAC and AGCCCGAG motifs in their promoters. By combining RNA-seq and DAP-seq results together, we subsequently identified eight novel target genes of ZmRL6 that are involved in maize's hormone signal transduction, sugar metabolism, lignin synthesis, and redox signaling/oxidative stress. Collectively, our data provided insights into the roles of ZmRL6 in maize’s drought response.

In the bone marrow, dendritic cell development is governed by supporting cells, such as endothelial cells. Here authors show that expression of serine/threonine kinase 11 in endothelial cells regulates differentiation of dendritic cell precursors via modulating secretion of stem cell factor.

The construction industry has fared poorly in the process of digital transformation, while the main challenge is the digitalization of construction projects. Changes in project management approaches are urgently required in construction organizations to better align digital technology and organizational conditions. However, little literature has explored the pivotal role of the project management approach from an organizational perspective. To fill this gap, this research investigates ways of using a project governance model for integration to promote the digitalization of construction projects through a case study. The three integration dimensions, namely stakeholder integration, lifecycle integration, and project management knowledge integration, are identified, and governance elements under each dimension are displayed—and further stratified—based on the three levels of the governance model, including institutional level, organizational level, and behavioral level. The logical relationship between elements and their roles in project digitization is finally summarized. The developed conceptual model will provide an approach for construction enterprises to promote project digitalization.

Abstract Macrocycle‐induced formation of pure organic supramolecular aggregates is a challenge that has attracted considerable attention from researchers in the fields of chemistry, biology, and materials science. In particular, aggregation induced by water‐soluble cyclodextrins and calixarenes, which are two classic of macrocycles with a hydrophobic cavity and a hydrophilic external surface, has attracted interest because these host molecules can form aggregates with guest molecules via various noncovalent interactions, including hydrophobic interactions, van der Waals forces, hydrogen bonds, and electrostatic interactions. In this review, we focus mainly on some impressive recent progress, both by our group and other groups, on the construction of cyclodextrin‐ and calixarene‐based organic supramolecular aggregates, control of their topological morphology, and their use for biological applications such as molecular recognition and bioimaging, photodynamic therapy, light‐harvesting energy transfer, and targeted drug delivery. We also discuss shortcomings of the current reported results and future prospects for the development of multifunctional organic supramolecular aggregates for use in various fields.

Summary: Overwhelming evidence indicates that infiltration of tumors by Treg cells with elevated levels of FOXP3 suppresses the host antitumor immune response. However, the molecular mechanisms that maintain high expression of FOXP3 in tumor-infiltrating Treg cells remain elusive. Here, we report that AMP-activated protein kinase alpha1 (AMPKα1) enables high FOXP3 expression in tumor-infiltrating Treg cells. Mice with Treg-specific AMPKα1 deletion showed delayed tumor progression and enhanced antitumor T cell immunity. Further experiments showed that AMPKα1 maintains the functional integrity of Treg cells and prevents interferon-γ production in tumor-infiltrating Treg cells. Mechanistically, AMPKα1 maintains the protein stability of FOXP3 in Treg cells by downregulating the expression of E3 ligase CHIP (STUB1). Our results suggest that AMPKα1 activation promotes tumor growth by maintaining FOXP3 stability in tumor-infiltrating Treg cells and that selective inhibition of AMPK in Treg cells might be an effective anti-tumor therapy.

Cu coatings were deposited on acrylonitrile-butadiene-styrene copolymer (ABS) substrates by DC magnetron sputtering with Cu target. Cr ions generated by arc evaporation were used to bombard the ABS substrates before the Cu coating process. The influences of the Cr ion bombardment on the surface topography and chemical bonds of the ABS substrates and the adhesion of the Cu coatings on the ABS substrate were studied using scanning electron microscopy, Fourier transform infrared spectroscopy, and micro-Scratch Tester as a function of bias voltage and treatment duration. The results show that the Cr ion bombardment causes Cr particles to embed in the surface. The Cr particles can interlock with the Cu coatings and ABS substrate and significantly improve the coating adhesion. In addition, the Cr particles can act as the nucleation sites of the Cu coatings and facilitate the growth of columnar crystals. Increasing the duration of Cr ion bombardment increases the number of Cr particles and, thus, enhances the adhesion. However, the continuous bombardment results in the degeneration of the ABS surface, causing the formation of the coarse columnar structure of the Cu coatings. Increasing the bias voltage can increase the energy of the Cr particles without causing degeneration of the ABS. The Cu coating deposited on the ABS substrate treated by Cr ion with high-bias voltage and short duration shows a dense and smooth growth structure. In contrast, the bombardment of the Cr ions carried out at high-bias voltage induces the formation of an interfacial layer (amorphous carbon-rich phase) in the ABS surface, which decreases the coating adhesion. It is believed that Cu coatings with strong adhesion and dense structures could be acquired on ABS substrates by optimizing the bias voltage and duration of the Cr ion bombardment pre-treatment.

In this contribution, we experimentally determined the metastable zone width (MSZW) of adipic acid (AA) in different polar solvents to reveal the nucleation behavior. We performed analyses for different cooling rates, saturation temperatures and polar solvents. The findings showed that the MSZW increased as the cooling rate increased, or saturation temperature or polarity decreased. Here, we suggest that the hydrogen bond donor capacity decreases as the polarity of the solvent decreases, which weakens the solute and solvent interaction and makes the desolvation process more difficult during nucleation. Furthermore, we found that the MSZW is mainly determined by the cooling rate, when the cooling rate is large enough. On account of the classical nucleation theory, it was found that the sizes of the critical nucleus and Gibbs nucleation energy do not increase monotonously with increasing driving force. Moreover, this study confirms that solid–liquid interface tension is associated with crystallization driving force.

The ULK complex plays a well-known role in initiating autophagy, to recycle cellular components in response to nutritional stress. Here, the authors demonstrate a late role for ULK in auotophagosome–lysosome fusion and provide a direct link between macroautophagy and chaperone mediated autophagy.

Background/Aims: It has been demonstrated that KRAS mutations represent about 90% of cancer-associated mutations, and that KRAS mutations play an essential role in neoplastic transformation. Cancer-associated RAS mutations occur frequently in acute myeloid leukemia (AML), suggesting a functional role for Ras in leukemogenesis. Methods: We successfully established a mouse model of human leukemia by transplanting bone marrow cells co-transfected with the K-ras (G12D) mutation and AML1/ETO fusion protein. Results: Mice transplanted with AML/ETO+KRAS co-transduced cells had the highest mortality rate than mice transplanted with AML/ETO- or KRAS-transduced cells (115d vs. 150d). Upon reaching a terminal disease stage, EGFP-positive cells dominated their spleen, lymph nodes, peripheral blood and central nervous system tissue. Immunophenotyping, cytologic analyses revealed that AML/ETO+KRAS leukemias predominantly contained immature myeloid precursors (EGFP+/c-Kit+/Mac-1-/Gr-1-). Histologic analyses revealed that massive leukemic infiltrations were closely packed in dense sheets that effaced the normal architecture of spleen and thymus in mice transplanted with AML1/ETO + KRAS co-transduced cells. K-ras mRNA and protein expression were upregulated in bone marrow cells of the K-ras group and AML1/ETO + Kras group. The phosphorylation of MEK/ERK was significantly enhanced in the AML1/ETO + Kras group. The similar results of the AML1/ETO + Nras group were consistent with those reported previously. Conclusion: Co-transduction of KrasG12D and AML1/ETO induces acute monoblastic leukemia. Since expression of mutant K-ras alone was insufficient to induce leukemia, this model may be useful for investigating the multi-step leukemogenesis model of human leukemia.

While biomass has been recognized as an important renewable energy source which has a range of positive impacts on the economy, environment, and society, the existence of feedstock seasonality and risk of service disruptions at collection facilities potentially compromises the efficiency and reliability of the energy supply system. In this paper, we consider reliable supply chain design for biomass collection against feedstock seasonality and time-varying disruption risks. We optimize facility location, inventory, biomass quantity, and shipment decisions in a multi-period planning horizon setting. A real-world case in Hubei, China is studied to offer managerial insights. Our computational results show that: (1) the disruption risk significantly affects both the optimal facility locations and the supply chain cost; (2) no matter how the failure probability changes, setting backup facilities can significantly decrease the total cost; and (3) the feedstock seasonality does not affect locations of the collection facilities, but it affects the allocations of collection facilities and brings higher inventory cost for the biomass supply chain.

Improved drought tolerance is always a highly desired trait for agricultural plants. Significantly increased drought tolerance in Arabidopsis thaliana (Columbia-0) has been achieved in our work through the suppression of ESKMO1 (ESK1) gene expression with small-interfering RNA (siRNA) and overexpression of CBF genes with constitutive gene expression. ESK1 has been identified as a gene linked to normal development of the plant vascular system, which is assumed directly related to plant drought response. By using siRNA that specifically targets ESK1, the gene expression has been reduced and drought tolerance of the plant has been enhanced dramatically in the work. However, the plant response to external abscisic acid application has not been changed. ICE1, CBF1, and CBF3 are genes involved in a well-characterized plant stress response pathway, overexpression of them in the plant has demonstrated capable to increase drought tolerance. By overexpression of these genes combining together with suppression of ESK1 gene, the significant increase of plant drought tolerance has been achieved in comparison to single gene manipulation, although the effect is not in an additive way. Accompanying the increase of drought tolerance via suppression of ESK1 gene expression, the negative effect has been observed in seeds yield of transgenic plants in normal watering conditions comparing with wide type plant.

Pogostemon cablin possesses two morphologically and ontogenetically different types of glandular trichomes, one type of bristle hair on the surfaces of leaves and stems and one type of internal gland inside the leaves and stems. The internal gland originates from elementary meristem and is associated with the biosynthesis of oils present inside the leaves and stems. However, there is little information on mechanism for the oil biosynthesis and secretion inside the leaves and stems. In this study, we identified three kinds of glandular trichome types and two kinds of internal gland in the Pogostemon cablin. The oil secretions from internal glands of stems and leaves contained lipids, flavones and terpenes. Our results indicated that endoplasmic reticulum and plastids and vacuoles are likely involved in the biosynthesis of oils in the internal glands and the synthesized oils are transported from endoplasmic reticulum to the cell wall via connecting endoplasmic reticulum membranes to the plasma membrane. And the comparative analysis of the development, distribution, histochemistry and ultrastructures of the internal and external glands in Pogostemon cablin leads us to propose that the internal gland may be a novel secretory structure which is different from external glands.

Let us consider f as being an entire solution of the differential-difference equation G(z, f) + h(z)f m(z) = 0, (m ∈ ℕ), where h(z) is a transcendental entire function and G(z,f) is a differential-difference polynomial in f with entire coefficients. By considering the order and deficiency of h(z) and such coefficients, we mainly study the radial distribution of f, and establish a lower bound of measure for the set of common limiting directions of the Julia sets of derivatives and primitives of its shifts. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether MDV deregulation causes mitochondrial dysfunction in PH is unknown. The aim of this study was to determine MDV regulation in ECs and to elucidate how MDV deregulation in ECs leads to PH. MDV formation and mitochondrial morphology/dynamics were examined in ECs of EC-specific liver kinase B1 (LKB1) knockout mice (LKB1ec2/2), in monocrotalineinduced PH rats, and in lungs of patients with PH. Pulmonary ECs of patients with PH and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of the cristae network, together with defective MDV shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec2/2 mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDV shedding, and disequilibrium of the mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intratracheal delivery of adeno-associated virus LKB1 reversed PH, together with improved MDV shedding and mitochondrial function in rats in vivo. We conclude that LKB1 regulates MDV shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defects of LKB1-mediated MDV shedding from parental mitochondria instigate EC dysfunction and PH. [ABSTRACT FROM AUTHOR]