DEPP Deficiency Contributes to Browning of White Adipose Tissue.

Decidual protein induced by progesterone (DEPP) was originally identified as a modulator in the process of decidualization in the endometrium. Here, we define that DEPP is involved in adipose tissue thermogenesis, which contributes to metabolic regulation. Knockdown of DEPP suppressed adipocyte differentiation and lipid accumulation in 3T3-L1 cells, induced expression of brown adipose tissue (BAT) markers in primary brown adipocyte and induced mouse embryonic fibroblasts (MEFs) differentiation to brown adipocytes. Moreover, DEPP deficiency in mice induced white adipocyte browning and enhanced BAT activity. Cold exposure stimulated more browning of white adipose tissue (WAT) and maintained higher body temperature in DEPP knockout mice compared to that in wild-type control mice. DEPP deficiency also protected mice against high-fat-diet-induced insulin resistance. Mechanistic studies demonstrated that DEPP competitively binds SIRT1, inhibiting the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) and Sirtuin 1 (SIRT1). Collectively, these findings suggest that DEPP plays a crucial role in orchestrating thermogenesis through regulating adipocyte programs and thus might be a potential target for the treatment of metabolic disorders.

Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex.

Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.

Ultracompliant Heterogeneous Copper-Tin Nanowire Arrays Making a Supersolder.

Due to the substantial increase in power density, thermal interface resistance that can constitute more than 50% of the total thermal resistance has generally become a bottleneck for thermal management in electronics. However, conventional thermal interface materials (TIMs) such as solder, epoxy, gel, and grease cannot fulfill the requirements of electronics for high-power and long-term operation. Here, we demonstrate a high-performance TIM consisting of a heterogeneous copper-tin nanowire array, which we term "supersolder" to emulate the role of conventional solders in bonding various surfaces. The supersolder is ultracompliant with a shear modulus 2-3 orders of magnitude lower than traditional solders and can reduce the thermal resistance by two times as compared with the state-of-the-art TIMs. This supersolder also exhibits excellent long-term reliability with >1200 thermal cycles over a wide temperature range. By resolving this critical thermal bottleneck, the supersolder enables electronic systems, ranging from microelectronics and portable electronics to massive data centers, to operate at lower temperatures with higher power density and reliability.

Visible-Light-Driven Photocatalytic Degradation of Organic Water Pollutants Promoted by Sulfite Addition.

Solar-driven heterogeneous photocatalysis has been widely studied as a promising technique for degradation of organic pollutants in wastewater. Herein, we have developed a sulfite-enhanced visible-light-driven photodegradation process using BiOBr/methyl orange (MO) as the model photocatalyst/pollutant system. We found that the degradation rate of MO was greatly enhanced by sulfite, and the enhancement increased with the concentration of sulfite. The degradation rate constant was improved by 29 times in the presence of 20 mM sulfite. Studies using hole scavengers suggest that sulfite radicals generated by the reactions of sulfite (sulfite anions or bisulfite anions) with holes or hydroxyl radicals are the active species for MO photodegradation using BiOBr under visible light. In addition to the BiOBr/MO system, the sulfite-assisted photocatalysis approach has been successfully demonstrated in BiOBr/rhodamine B (RhB), BiOBr/phenol, BiOI/MO, and Bi2O3/MO systems under visible light irradiation, as well as in TiO2/MO system under simulated sunlight irradiation. The developed method implies the potential of introducing external active species to improve photodegradation of organic pollutants and the beneficial use of air pollutants for the removal of water pollutants since sulfite is a waste from flue gas desulfurization process.

Kr/Xe Separation over a Chabazite Zeolite Membrane.

Herein we demonstrate that chabazite zeolite SAPO-34 membranes effectively separated Kr/Xe gas mixtures at industrially relevant compositions. Control over membrane thickness and average crystal size led to industrial range permeances and high separation selectivities. Specifically, SAPO-34 membranes can separate Kr/Xe mixtures with Kr permeances as high as 1.2 × 10 (-7) mol/m(2) s Pa and separation selectivities of 35 for molar compositions close to typical concentrations of these two gases in air. In addition, SAPO-34 membranes separated Kr/Xe mixtures with Kr permeances as high as 1.2 × 10 (-7) mol/m(2) s Pa and separation selectivities up to 45 for molar compositions as might be encountered in nuclear reprocessing technologies. Molecular sieving and differences in diffusivities were identified as the dominant separation mechanisms.

Egr1 protein acts downstream of estrogen-leukemia inhibitory factor (LIF)-STAT3 pathway and plays a role during implantation through targeting Wnt4.

Embryo implantation is a highly synchronized process between an activated blastocyst and a receptive uterus. Successful implantation relies on the dynamic interplay of estrogen and progesterone, but the key mediators underlying embryo implantation are not fully understood. Here we show that transcription factor early growth response 1 (Egr1) is regulated by estrogen as a downstream target through leukemia inhibitory factor (LIF) signal transducer and activator of transcription 3 (STAT3) pathway in mouse uterus. Egr1 is localized in the subluminal stromal cells surrounding the implanting embryo on day 5 of pregnancy. Estrogen rapidly, markedly, and transiently enhances Egr1 expression in uterine stromal cells, which fails in estrogen receptor α knock-out mouse uteri. STAT3 is phosphorylated by LIF and subsequently recruited on Egr1 promoter to induce its expression. Our results of Egr1 expression under induced decidualization in vivo and in vitro show that Egr1 is rapidly induced after deciduogenic stimulus. Egr1 knockdown can inhibit in vitro decidualization of cultured uterine stromal cells. Chromatin immunoprecipitation data show that Egr1 is recruited to the promoter of wingless-related murine mammary tumor virus integration site 4 (Wnt4). Collectively, our study presents for the first time that estrogen regulates Egr1 expression through LIF-STAT3 signaling pathway in mouse uterus, and Egr1 functions as a critical mediator of stromal cell decidualization by regulating Wnt4.

Transformer-CNN hybrid network for improving PET time of flight prediction.

Objective.In positron emission tomography (PET) reconstruction, the integration of time-of-flight (TOF) information, known as TOF-PET, has been a major research focus. Compared to traditional reconstruction methods, the introduction of TOF enhances the signal-to-noise ratio of images. Precision in TOF is measured by full width at half maximum (FWHM) and the offset from ground truth, referred to as coincidence time resolution (CTR) and bias.Approach.This study proposes a network combining transformer and convolutional neural network (CNN) to utilize TOF information from detector waveforms, using event waveform pairs as inputs. This approach integrates the global self-attention mechanism of Transformer, which focuses on temporal relationships, with the local receptive field of CNN. The combination of global and local information allows the network to assign greater weight to the rising edges of waveforms, thereby extracting valuable temporal information for precise TOF predictions. Experiments were conducted using lutetium yttrium oxyorthosilicate (LYSO) scintillators and silicon photomultiplier (SiPM) detectors. The network was trained and tested using the waveform datasets after cropping.Main results.Compared to the constant fraction discriminator (CFD), CNN, CNN with attention, long short-term memory (LSTM) and Transformer, our network achieved an average CTR of 189 ps, reducing it by 82 ps (more than 30%), 13 ps (6.4%), 12 ps (6.0%), 16 ps (7.8%) and 9 ps (4.6%), respectively. Additionally, a reduction of 10.3, 8.7, 6.7 and 4 ps in average bias was achieved compared to CNN, CNN with attention, LSTM and Transformer.Significance.This work demonstrates the potential of applying the Transformer for PET TOF estimation using real experimental data. Through the integration of both CNN and Transformer with local and global attention, it achieves optimal performance, thereby presenting a novel direction for future research in this field.

Combined analysis of microRNome and 3'-UTRome reveals a species-specific regulation of progesterone receptor expression in the endometrium of rhesus monkey.

The establishment of endometrial receptivity is a prerequisite for successful pregnancy, which is controlled by a complex mechanism. MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as important regulators of gene expression. However, the contribution of miRNAs in endometrial receptivity is still unknown. Here we used rhesus monkey as an animal model and compared the endometrial miRNA expression profiles during early-secretory (pre-receptive) phase and mid-secretory (receptive) phase by deep sequencing. A set of differentially expressed miRNAs were identified, 8 of which were selected and validated using quantitative RT-PCR. To facilitate the prediction of their target genes, the 3'-UTRome was also determined using tag sequencing of mRNA 3'-termini. Surprisingly, about 50% of the 10,677 genes expressed in the rhesus monkey endometrium exhibited alternative 3'-UTRs. Of special interest, the progesterone receptor (PGR) gene, which is necessary for endometrial receptivity, processes an ultra long 3'-UTR (~10 kb) along with a short variant (~2.5 kb). Evolutionary analysis showed that the 3'-UTR sequences of PGR are poorly conserved between primates and rodents, suggesting a species-biased miRNA binding pattern. We further demonstrated that PGR is a valid target of miR-96 in rhesus monkey and human but not in rodents, whereas the regulation of PGR by miR-375 is rhesus monkey-specific. Additionally, we found that miR-219-5p regulates PGR expression through a primate-specific long non-coding RNA immediately downstream of the PGR locus. Our study provides new insights into the molecular mechanisms underlying endometrial receptivity and presents intriguing species-specific regulatory roles of miRNAs.

Progesterone and DNA damage encourage uterine cell proliferation and decidualization through up-regulating ribonucleotide reductase 2 expression during early pregnancy in mice.

Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus.

Thermal conductivity and secondary porosity of single anatase TiO2 nanowire.

Single anatase TiO2 nanowire is synthesized using the electrospinning technique with the sol-gel method and is suspended over a pre-processed 100 µm-wide TEM grid for further characterization. The diameters of the nanowires fall in the range of 250-400 nm. The transient electrothermal (TET) method is adopted to acquire the voltage-time (U-t) profile of the Ir-coated nanowire under step Joule heating. The intrinsic thermal diffusivity of single anatase TiO2 nanowires varies from 1.3 to 4.6 × 10⁻6 m² s⁻¹, and the thermal conductivity changes distinctly from 1.3 to 5.6 W m⁻¹ K⁻¹, much lower than the value of the bulk counterpart: 8.5 W m⁻¹ K⁻¹. The density and thermal conductivity increase significantly with the diameter, largely because at larger diameters less secondary porosity is left by decomposition of organic composites and their escape from the wire during calcination. The density of TiO2 nanowires is found to be much lower than that of the bulk counterpart. This is supported by the SEM image of the secondary porous surface. High secondary porosity is observed for TiO2 nanowires, ranging from 18% to 63%. This very high secondary porosity confirms that the decomposition of PVP content may distort the fibrous matrix and leave vacancies. In addition, the transition from amorphous to anatase phase could also create a porous state due to crystal particle aggregation.

Characterization of the Tumor Microenvironment in Osteosarcoma Identifies Prognostic- and Immunotherapy-Relevant Gene Signatures.

The osteosarcoma (OS) microenvironment is composed of tumor cells, immune cells, and stromal tissue and is emerging as a pivotal player in OS development and progression. Thus, microenvironment-targeted strategies are urgently needed to improve OS treatment outcomes. Using principal component analysis (PCA), we systematically examined the tumor microenvironment (TME) and immune cell infiltration of 88 OS cases and constructed a TME scoring system based on the TMEscore high and TMEscore low phenotypes. Our analysis revealed that TMEscore high correlates with longer survival in OS patients, elevated immune cell infiltration, increased immune checkpoints, and increased sensitivity to chemotherapy. TMEscore low strongly correlated with immune exclusion. These observations were externally validated using a GEO dataset (GSE21257) from 53 OS patients. Our laboratory data also proved our findings. This finding enhances our understanding of the immunological landscape in OS and may uncover novel targeted therapeutic strategies.

A SOX17-PDGFB signaling axis regulates aortic root development.

Developmental etiologies causing complex congenital aortic root abnormalities are unknown. Here we show that deletion of Sox17 in aortic root endothelium in mice causes underdeveloped aortic root leading to a bicuspid aortic valve due to the absence of non-coronary leaflet and mispositioned left coronary ostium. The respective defects are associated with reduced proliferation of non-coronary leaflet mesenchyme and aortic root smooth muscle derived from the second heart field cardiomyocytes. Mechanistically, SOX17 occupies a Pdgfb transcriptional enhancer to promote its transcription and Sox17 deletion inhibits the endothelial Pdgfb transcription and PDGFB growth signaling to the non-coronary leaflet mesenchyme. Restoration of PDGFB in aortic root endothelium rescues the non-coronary leaflet and left coronary ostium defects in Sox17 nulls. These data support a SOX17-PDGFB axis underlying aortic root development that is critical for aortic valve and coronary ostium patterning, thereby informing a potential shared disease mechanism for concurrent anomalous aortic valve and coronary arteries.

Effects of Aging Process on the Damping Performance of ZK60 Magnesium Alloys Prepared by Large Strain Rolling.

In this study, the effects of an aging treatment (T5) and a solution + aging treatment (T6) on the microstructure and damping properties of a ZK60 magnesium alloy prepared by large strain rolling (LSR) were studied by an optical microscope (OM), scanning electron microscopy (SEM), X-ray diffraction (XRD), and dynamic thermomechanical analysis (DMA). The results showed that both the T5 and T6 processes had a great impact on the microstructure and damping properties of the ZK60 magnesium alloy. With the increase in aging time, the grain size was basically unchanged, and the amount of the second phase increased, resulting in a gradual decrease in the damping performance. However, compared with the damping performance of the un-aged ZK60 magnesium alloy, the damping performance of the 4 h-aged ZK60 magnesium alloy was enhanced. At the same aging time, the increase in the aging temperature promoted the precipitation of the second phase, thereby reducing the damping performance of the ZK60 magnesium alloy. It was found that the T6-treated ZK60 magnesium alloy had a larger grain size, which led to a better damping performance; in addition, the T6-treated ZK60 magnesium alloy exhibited a damping plateau, which was determined by the distribution and amount of the second phase.

An integrated electrocoagulation - Electrocatalysis water treatment process using stainless steel cathodes coated with ultrathin TiO2 nanofilms.

Anodic electrocoagulation processes can remove broad varieties of pollutants in industrial wastewater. However, some stubborn contaminants may still remain in effluents after the treatment and cause environmental issues. To further improve the efficiency of pollutant removal, we have coupled electrocatalysis with electrocoagulation and applied an atomic layer deposition (ALD) enabled TiO2 ultrathin overcoating at a nanometer scale on a stainless steel cathode. The electrocatalytic overcoating increased the elimination efficiency of organics and microorganisms, likely due to the electro-generation of adequate reactive oxygen species (ROS). The thickness of TiO2 nanofilm was controlled by the number of ALD cycles, and it was found that nanofilms processed with 50-100 cycles led to the maximum benefit of pollutant removal. By using the novel electrocoagulation-electrocatalysis cell to treat synthetic wastewater, a remarkable removal of 99.92% of E. Coli, 92.1% of suspended solids, 98.3% of heavy metal ions, and 88.8% of methylene blue was observed. This hybrid electrochemical treatment process may have the potential to treat wastewater at a larger scale.

Effect of the Strain Rate on the Damping and Mechanical Properties of a ZK60 Magnesium Alloy.

High strain rate rolling (HRSS) of a ZK60 magnesium alloy at 300 °C with a strain rate from 5 s-1 to 25 s-1 was used to research the effect of the rate on the mechanical properties and damping capacity of the ZK60 alloy. The results show that as the strain rate increases, the tensile strength decreases from 355 MPa at 25 s-1 to 310 MPa at 5 s-1. Two damping peaks (P1 and P2) are detected in the high strain rate rolled ZK60 alloys at different strain rates. The P1 peak appears at low temperatures and is caused by grain boundaries sliding. The P2 peak appears at high temperatures and is caused by recrystallization. As the strain rate increases from 5 to 20 s-1, the dynamic recrystallization (DRX) volume percent rises and the dislocation density decreases, both of which cause the P1 peak to become more and more obvious, and activation energy rises. At the same time, the dislocation density decreases and leads to a decrease in the storage energy, which reduces the recrystallization driving force and shifts the P2 peak to high temperatures. When the strain rate reaches 20 and 25 s-1, DRX occurs fully in the sheet, so the activation energy of the P1 peak and the temperature where the P2 peak appears are basically equal.

Photocatalytic degradation of phenol in water under simulated sunlight by an ultrathin MgO coated Ag/TiO2 nanocomposite.

Phenol is one of the most widespread, toxic and recalcitrant compounds in water sources. Due to its persistent nature, conventional wastewater treatment methods are not effective to remove or degrade phenol from water. In this work, novel photocatalysts were developed to effectively degrade phenol under simulated sunlight. The catalysts were composed of one-dimensional titanium dioxide (TiO2) nanorods decorated with silver (Ag) nanoparticles, coated by an ultrathin magnesium oxide (MgO) overlayer through atomic layer deposition (ALD). Material properties of prepared catalysts were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and UV-vis diffuse reflectance spectroscopy (UV-Vis DRS). The photocatalytic performance of phenol degradation under simulated sunlight was evaluated and correlated with the material properties. The Ag nanoparticles promoted light absorption and transfer of photo-induced electron-hole pairs from within TiO2 nanorods to the catalyst surface. The ultrathin MgO overlayer with a sub-nanometer thickness did not hinder charge transfer to the surface, but rather, it further increased the light absorption and inhibited surface charge recombination through a surface passivation effect, promoting phenol degradation. The photocatalytic reaction mechanism was investigated by examining hydroxyl and superoxide radical production in the photocatalytic system. The results from this work demonstrated a new strategy for fabricating efficient solar-driven photocatalysts for the degradation of persistent water contaminants.

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.

Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL.