Enhanced polarization switching characteristics of HfO2 ultrathin films via acceptor-donor co-doping.

In the realm of ferroelectric memories, HfO2-based ferroelectrics stand out because of their exceptional CMOS compatibility and scalability. Nevertheless, their switchable polarization and switching speed are not on par with those of perovskite ferroelectrics. It is widely acknowledged that defects play a crucial role in stabilizing the metastable polar phase of HfO2. Simultaneously, defects also pin the domain walls and impede the switching process, ultimately rendering the sluggish switching of HfO2. Herein, we present an effective strategy involving acceptor-donor co-doping to effectively tackle this dilemma. Remarkably enhanced ferroelectricity and the fastest switching process ever reported among HfO2 polar devices are observed in La3+-Ta5+ co-doped HfO2 ultrathin films. Moreover, robust macro-electrical characteristics of co-doped films persist even at a thickness as low as 3 nm, expanding potential applications of HfO2 in ultrathin devices. Our systematic investigations further demonstrate that synergistic effects of uniform microstructure and smaller switching barrier introduced by co-doping ensure the enhanced ferroelectricity and shortened switching time. The co-doping strategy offers an effective avenue to control the defect state and improve the ferroelectric properties of HfO2 films.

The Effect of Process Parameters on the Temperature and Stress Fields in Directed Energy Deposition Inconel 690 Alloy.

Additive manufacturing (AM) technology has the advantages of designability, short process times, high flexibility, etc., making it especially suitable for manufacturing complex high-performance components for high-end industrial systems. However, the intensive temperature gradients caused by the rapid heating and cooling processes of AM can generate high levels of residual stresses, which directly affect the precision and serviceability of the components. Taking Inconel 690 alloy, which is widely used in nuclear power plants, as the research object, a thermo-coupled mechanical model of temperature field and residual stress field of directed energy deposition (DED) of Inconel 690 was established based on ABAQUS 2019 finite element software to study the influence of process parameters on the temperature history and the distribution of residual stresses in the DED process. The experimental results show that the peak temperature of each layer in the fabrication process increases with the increase in laser power and preheating temperature, and decreases with the increase in scanning speed and interlayer dwell time. Substrate preheating only has a large effect on the peak temperature of the first four layers. Residual stresses are mainly concentrated in the upper and middle parts, the bottom of the substrate, and the sides combined with the substrate, and the residual stresses increase with the increasing laser power and decrease with the increasing interlayer dwell time. Decreasing laser power, longer dwell time, higher preheating temperature, and appropriate scanning speed are beneficial for the reduction in residual stresses in Inconel 690 components. This research has important significance for the process design and residual stress modulation in the additive manufacturing of Inconel 690 alloy.

Inhibiting Glutaminase Exerts Opposite Effects on Ovariectomy-Induced and Age-Related Reductions in Murine Bone Mass.

Recent studies have provided links between glutamine metabolism and bone remodeling, but little is known about its role in primary osteoporosis progression. We aimed to determine the effects of inhibiting glutaminase (GLS) on two types of primary osteoporosis and elucidate the related metabolism. To address this issue, age-related and ovariectomy (OVX)-induced bone loss mouse models were used to study the in vivo effects of CB-839, a potent and selective GLS inhibitor, on bone mass and bone turnover. We also studied the metabolic profile changes related with aging and GLS inhibition in primary bone marrow stromal cells (BMSC) and that related with OVX and GLS inhibition in primary bone marrow-derived monocytes (BMM). Besides, we studied the possible metabolic processes mediating GLS blockade effects during aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation respectively via in vitro rescue experiments. We found that inhibiting GLS via CB-839 prevented OVX-induced bone loss while aggravated age-related bone loss. Further investigations showed that effects of CB-839 treatment on bone mass were associated with alterations of bone turnover. Moreover, CB-839 treatment altered metabolic profile in different orientations between BMSC of aged mice and BMM of ovariectomized mice. In addition, rescue experiments revealed that different metabolic processes mediated glutaminase blockade effects between aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation. Taken together, our data demonstrated the different outcomes caused by CB-839 treatment between two types of osteoporosis in mice, which were tightly connected to the suppressive effects on both aging-impaired osteoblastogenesis and OVX-enhanced osteoclastogenesis mediated by different metabolic processes downstream of glutaminolysis.

Inhibition of FAAH suppresses RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss partially through repressing the IL17 pathway.

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.

Brain extracellular matrix attenuates photodynamic cytotoxicity of glioma cells.

Glioma is the most common tumor in the central nervous system, which is often accompanied by poor prognosis. Brain extracellular matrix (ECM) plays an important role in regulating the growth and migration of glioma. Photodynamic therapy (PDT) has been an effective method for the treatment of solid tumors by oxidative modifications in recent years, and ECM may have an impact on the cytotoxicity of photodynamic therapy. In this work, we prepared decellularized brain ECM by chemical method to investigate the influence of the photodynamic effect of glioma C6 cells. Compared with decellularized liver ECM, brain ECM reduces PDT cytotoxicity. By observing the content of reactive oxygen species produced by near-infrared light active indocyanine green in cells, it was found that ECM did not affect the production of reactive oxygen species. Therefore, it is speculated that brain ECM may enhance the oxidative stress adaptability of glioma cells through potential signal regulation, or protect photodynamic targeting biomolecules (such as proteins and other cellular components) from oxidation in PDT mediated by indocyanine green and 808 nm laser in glioma cells.

Dynamic detection of HER2 of circulating tumor cells in patients with gastric carcinoma and its clinical application.

The aim of the present study was to construct and characterize human epidermal growth factor receptor 2 (HER2) lipid magnetic ball (H­LMB) for separating circulating tumor cells (CTCs) in patients with gastric carcinoma (GC) and to compare the result of separated CTC counts with that of next­generation sequencing (NGS) for single­gene analysis to verify the consistency for evaluating the association between the detection results and the progress of clinical treatment, so as to facilitate early diagnosis and dynamic monitoring of GC. A lipid magnetic ball (LMB), coated with Fe3O4 nanoparticles, was synthesized by microemulsion technique and an anti­HER2 antibody was conjugated to the surface of LMB to form H­LMB, followed by the characterization of the prepared H­LMB. The detection of capture efficiency of LMBs in GC cells was tested by MTT and expression of HER2 mRNA was determined by reverse transcription­quantitative PCR. The positive detection rate of HER2 was verified by HER2­fluorescence in situ hybridization (FISH) test on the separated CTCs from GC. Further verification was performed based on the consistency between the result of separated CTCs and that of single­gene NGS assay of HER2, associated with the determination of clinical consistency. The constructed H­LMB exhibited good stability and specificity. The mutation rate of HER2 by the FISH test was 14% in the blood samples of 50 patients with GC and was 14% by NGS assay. The mutation rate of HER2 was 12% in H­LMB and the positive detection rate was 85.7% compared with the results of the FISH test, indicating consistency with the clinical diagnosis and pathological examination results. In conclusion, the anti­HER2 antibody­modified LMB can separate CTCs with HER2 abnormal expression, which exhibits an application potential in GC diagnosis and treatment and is of great clinical significance for the diagnosis and evaluation of its therapeutic effect on GC.

Mitochondrial pyruvate carrier blockade results in decreased osteoclastogenesis and bone resorption via regulating mitochondrial energy production.

It's widely accepted that increasing mitochondrial respiration plays a pivotal role during osteoclastogenesis. Mitochondrial pyruvate carrier (MPC) is the key transporter that links glycolysis to mitochondrial respiration but little is known about its role during osteoclastogenesis. Our goal was to determine the effects of its blockade on osteoclastogenesis and bone resorption in vivo and in vitro. To address this issue, we performed gene knockdown or pharmacologically inhibited MPC in primary bone marrow-derived monocytes (BMMs) or in an ovariectomized mouse model. We also studied the metabolic changes in RANKL-induced differentiating BMMs with MPC blockade and performed rescue experiments. We found that MPC blockade resulted in decreased osteoclastogenesis both in vivo and in vitro and inhibiting MPC significantly alleviated ovariectomy-induced trabecular bone loss. Further investigations showed that MPC blockade significantly reversed the metabolic profile related to RANK activation, including decreased intermediates involved in citric acid cycle and glutamine metabolism. Moreover, metabolic flux analysis verified that MPC blockade decreased pyruvate flux into TCA cycle with no significant effect on glycolysis. Besides, MPC blockade resulted in suppressed mitochondrial biogenesis in addition to oxidative phosphorylation. Rescue experiments revealed that inhibiting pyruvate dehydrogenase kinase (PDK) via sodium dichloroacetate (DCA), but not targeting glutamine metabolism, could reverse the effects of MPC blockade on osteoclastogenesis. These implied that the effects of MPC blockade were mediated by reduced pyruvate fuel into citric acid cycle in multiple aspects. Taken together, our data demonstrated the inhibitory effects of MPC blockade on osteoclastogenesis, which was mediated by decreased mitochondrial energy production.

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.

Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine-triphosphate (ATP) to S-adenosylmethionine (SAM), a general methyl-group donor in vitro. MAT2A has been reported to participate in the NF-κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG-270 or genetic silencing by MAT2A-shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG-270 also prevented OVX-induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi-targeted metabolomics assay performed by LC-MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.

An Injectable Hydrogel Scaffold Loaded with Dual-Drug/Sustained-Release PLGA Microspheres for the Regulation of Macrophage Polarization in the Treatment of Intervertebral Disc Degeneration.

Due to the unique physical characteristics of intervertebral disc degeneration (IVDD) and the pathological microenvironment that it creates, including inflammation and oxidative stress, effective self-repair is impossible. During the process of intervertebral disc degeneration, there is an increase in the infiltration of M1 macrophages and the secretion of proinflammatory cytokines. Here, we designed a novel injectable composite hydrogel scaffold: an oligo [poly (ethylene glycol) fumarate]/sodium methacrylate (OPF/SMA) hydrogel scaffold loaded with dual-drug/sustained-release PLGA microspheres containing IL-4 (IL-4-PLGA) and kartogenin (KGN-PLGA). This scaffold exhibited good mechanical properties and low immunogenicity while also promoting the sustained release of drugs. By virtue of the PLGA microspheres loaded with IL-4 (IL-4-PLGA), the composite hydrogel scaffold induced macrophages to transition from the M1 phenotype into the M2 phenotype during the early induced phase and simultaneously exhibited a continuous anti-inflammatory effect through the PLGA microspheres loaded with kartogenin (KGN-PLGA). Furthermore, we investigated the mechanisms underlying the immunomodulatory and anti-inflammatory effects of the composite hydrogel scaffold. We found that the scaffold promoted cell proliferation and improved cell viability in vitro. While ensuring mechanical strength, this composite hydrogel scaffold regulated the local inflammatory microenvironment and continuously repaired tissue in the nucleus pulposus via the sequential release of drugs in vivo. When degenerative intervertebral discs in a rat model were injected with the scaffold, there was an increase in the proportion of M2 macrophages in the inflammatory environment and higher expression levels of type II collagen and aggrecan; this was accompanied by reduced levels of MMP13 expression, thus exhibiting long-term anti-inflammatory effects. Our research provides a new strategy for promoting intervertebral disc tissue regeneration and a range of other inflammatory diseases.

Global incidence, prevalence, and disability of vertebral fractures: a systematic analysis of the global burden of disease study 2019.

BACKGROUND CONTEXT: In the context of the population growing and aging worldwide, the epidemiology, and burden of vertebral fracture have not been comprehensively analyzed. PURPOSE: To delineate the global number and rate of incidence, prevalence and burden of vertebral fracture in 2019, and the temporal trends from 1990 to 2019 by location, age, sex, and the socio-demographic index (SDI). STUDY DESIGN/SETTING: A cross-sectional study using data from the Global Burden of Disease Study 2019 (GBD study 2019). PATIENT SAMPLE: Patients with vertebral fracture documented in medical records or registrations and included in the GBD study 2019 from different countries worldwide. OUTCOME MEASURES: Age standardized incidence rate (ASIR), age standardized prevalence rate (ASPR), and age standardized years lived with disability (YLDs). METHODS: The GBD study 2019 was used to obtain data for this analysis. The incidence, prevalence and disability were analyzed by location, year, sex, age, and SDI. DisMod-MR 2.1, a Bayesian meta-regression tool, was used to produce the estimates for each value after adjustment for age, sex, and other variables. Estimated annual percentage change (EAPC) was calculated to represent the temporal trends from 1990 to 2019. Spearman's rank order correlation was used to determine the correlation between SDI and the incidence and burden of vertebral fracture. This work was supported by the Key Research and Development Program of Hubei Province of China (No. 2020BCB049), and no conflicts of interest-associated biases existed in this study. RESULTS: Globally, there were 8.6 million (95% uncertainty interval [UI], 6,6-11,3 million) incident cases, 5.3 million (95% UI, 4.6-6.2 million) prevalent cases, and 0.55 million (95% UI, 0.37-0.77 million) YLDs of vertebral fracture. Compared with 1990, the number of incident cases and YLDs in 2019 increased by 38% (95% UI, 23%-48%) and 75% (95% UI, 65%-85%), respectively, while the ASIR (EAPC, -0.28; 95% CI, -0.41 to -0.14), ASPR (EAPC, -0.12; 95% CI, -0.22 to -0.02) and age standardized YLD rate (ASYR) (EAPC, -0.13; 95% CI, -0.23 to -0.04) decreased during this period. High ASIR, ASPR and ASYR were commonly seen in high-SDI countries, such as high-income North America, Australia, Central and Eastern Europe. In the country level, positive correlations were observed between SDI and ASIR (rho, 0.596; p<.001) and ASYR (rho, 0.413; p<.001). Males had higher ASIR and ASYR worldwide in each year from 1990 to 2019. However, the incidence, and YLD rates in females surpassed that in males after 65 years of age. Increasing trends were observed for both incidence and YLD rates with age. Falls were the leading cause for vertebral fracture across all ages. CONCLUSIONS: The past thirty years have seen increasing numbers but decreasing rates of global incidence, prevalence, and disability of vertebral fractures, resulting from the growing population worldwide. With population aging, efforts are still in urgent need to address vertebral fracture related health outcomes.

A Review of Research Progress in Selective Laser Melting (SLM).

SLM (Selective Laser Melting) is a unique additive manufacturing technology which plays an irreplaceable role in the modern industrial revolution. 3D printers can directly process metal powder quickly to obtain the necessary parts faster. Shortly, it will be possible to manufacture products at unparalleled speeds. Advanced manufacturing technology is used to produce durable and efficient parts with different metals that have good metal structure performance and excellent metal thermal performance, to lead the way for laser powder printing technology. Traditional creative ways are usually limited by time, and cannot respond to customers' needs fast enough; for some parts with high precision and complexity, conventional manufacturing methods are inadequate. Contrary to this, SLM technology offers some advantages, such as requiring no molds this decreases production time and helps to reduce costs. In addition, SLM technology has strong comprehensive functions, which can reduce assembly time and improve material utilization. Parts with complex structures, such as cavities and three-dimensional grids, can be made without restricting the shape of products. Products or parts can be printed quickly without the use of expensive production equipment. The product quality is better, and the mechanical load performance is comparable to traditional production technologies (such as forging). This paper introduces in detail the process parameters that affect SLM technology and how they affect SLM, commonly used metal materials and non-metallic materials, and summarizes the current research. Finally, the problems faced by SLM are prospected.

Tripartite Motif Protein 6 Promotes Colorectal Cancer Cell Migration and Metastasis via SOCS2-STAT3 Signaling.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with most mortalities being caused by metastases. However, the underlying molecular mechanism of CRC metastases remains largely unknown. Emerging evidence has shown the role of the tripartite motif family, especially tripartite motif protein 6 (TRIM6), in carcinogenesis. In this study, we used CRC cell lines with TRIM6 knockdown and overexpression to investigate the function of TRIM6 in CRC metastasis. We found that TRIM6 promotes CRC cell migration and invasion both in vitro and in vivo. TRIM6 knockdown slows down the migration and invasion processes, whereas TRIM6 overexpression accelerates CRC cell migration and invasion. TRIM6 is potentially the upstream regulatory factor for signal transducer and activator of transcription 3 (STAT3) via the suppressor of cytokine signaling 2 (SOCS2). A total of 70 samples from patients with CRC further confirmed that TRIM6 expression level is positively correlated with STAT3 phosphorylation and negatively correlated with SOCS2 expression. Therefore, TRIM6 could be a potential therapeutic target for CRC metastasis.

Inhibition of ACLY Leads to Suppression of Osteoclast Differentiation and Function Via Regulation of Histone Acetylation.

ATP-citrate lyase (ACLY), generating most of the nucleocytosolic acetyl coenzyme A (acetyl-CoA) for histone acetylation, links cell metabolism to epigenetic regulation. Recent investigations demonstrated that ACLY activated by metabolic reprogramming played an essential role in both M1 and M2 macrophage activation via histone acetylation. Previous studies also revealed that histone methylation and acetylation were critical for transcriptional regulation of osteoclast-specific genes. Considering that osteoclast differentiation also undergoes metabolic reprogramming and the activity of ACLY is always Akt-dependent, we inferred that receptor activator of NF-κB (RANK) activation might enhance the activity of ACLY through downstream pathways and ACLY might play a role in osteoclast formation. In the current study, we found that ACLY was gradually activated during RANK ligand (RANKL)-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs). Both ACLY knock-down and small molecular ACLY inhibitor BMS-303141 significantly decreased nucleocytosolic acetyl-CoA in BMMs and osteoclasts and suppressed osteoclast formation in vitro. BMS-303141 also suppressed osteoclast formation in vivo and prevents ovariectomy (OVX)-induced bone loss. Further investigations showed that RANKL triggered ACLY translocation into nucleus, consistent with increasing histone H3 acetylation, which was correlated to ACLY. The H3 lysine residues influenced by ACLY were in accordance with GCN5 targets. Using GCN5 knock-down and overexpression, we showed that ACLY and GCN5 functioned in the same pathway for histone H3 acetylation. Analysis of pathways downstream of RANK activation revealed that ACLY was Akt-dependent and predominately affected Akt pathway. With the help of RNA-sequencing, we discovered Rac1 as a downstream regulator of ACLY, which was involved in shACLY-mediated suppression of osteoclast differentiation, cytoskeleton organization, and signal transduction and was transcriptionally regulated by ACLY via histone H3 acetylation. To summarize, our results proved that inhibition of ATP-citrate lyase led to suppression of osteoclast differentiation and function via regulation of histone acetylation. Rac1 could be a downstream regulator of ACLY. © 2021 American Society for Bone and Mineral Research (ASBMR).

Identifying potential metabolic tissue biomarkers for papillary thyroid cancer in different iodine nutrient regions.

PURPOSE: To investigate the applicability of metabolomics to select thyroid cancer-associated biomarkers and discover the effects of iodine on metabolic changes in thyroid cancer. METHODS: In this study, a total of 33 papillary thyroid cancer (PTC) patients from areas with iodine excess and 32 PTC patients from areas with adequate iodine were recruited, and their cancerous tissue and paracancerous tissue were collected. These specimens were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/QTOF/MS) in conjunction with multivariate statistical analysis. RESULTS: Good separations were obtained for PTC tissue vs. paracancerous tissue, and 15 metabolites, including L-octanoylcarnitine, N-arachidonoylglycine, and others were found to be disturbed in PTC tissue. Moreover, the metabolic profile presented considerable separation between PTC tissue from different iodine areas, and 15 metabolomic biomarkers were found to be differentially expressed. Among them, 10 metabolites, including arachidonoylcarnitine and LysoPCs, were related to thyroid cancer and excess iodine. These biomarkers play a role in arachidonic acid metabolism pathways and others. In addition, biomarkers such as 3,5-tetradecadiencarnitine and oxidized glutathione were significantly correlated with thyroid function, and biomarkers such as L-octanoylcarnitine and arachidonic acid were significantly correlated with the clinical characteristics of PTC. CONCLUSIONS: Distinct differences in metabolic profiles were found to exist between PTCs from areas with different levels of iodine nutrition. The identified biomarkers have significant potential for diagnosing PTC and investigating its underlying mechanisms.

Intraviral interactome of Chikungunya virus reveals the homo-oligomerization and palmitoylation of structural protein TF.

Chikungunya virus (CHIKV) is a re-emerging mosquito-transmitted RNA virus causing joint and muscle pain. Although the protein-protein interactions (PPIs) between nonstructural proteins of CHIKV have been extensively established, the complete CHIKV intraviral interactome remains to be elucidated. In this study, we examined all possible CHIKV intraviral PPIs by immunoprecipitation and constructed the intraviral interactome of CHIKV. We reported 19 novel PPIs including the homo-oligomerization of TF. Disulfide bonds promoted the oligomerization of CHIKV TF protein. 2-BP, a palmitoylation inhibitor reduced the palmitoylation of TF and increased TF oligomerization. A quadruple mutant of Cys33, Cys35, Cys41, and Cys43 in TF blocked its palmitoylation and reduced oligomerization. Furthermore, we determined the association of TF with nsP1 and nsP3 in a palmitoylation-dependent manner. Construction of intraviral interactome of CHIKV provides the basis for further studying the function of CHIKV proteins.

STAT3 Phosphorylation Mediating DMSO's Function on Fetal Cardiomyocyte Proliferation with Developmental Changes.

Endogenous cardiac regeneration has been focused for decades as a potential therapy for heart diseases with cell loss, and dimethyl sulfoxide (DMSO) has been proposed as a treatment for many diseases. In this study, we aimed to investigate the function of DMSO on fetal cardiomyocyte proliferation. By tracing BrdU+/α actinin+ cells or Ki67+/α actinin+ cells with immunohistochemical staining, we found that DMSO remarkably promoted fetal cardiomyocytes proliferation, and at the late developmental stage (LDS), such effects were more efficient than that at early developmental stage (EDS). Western blot data revealed a significant increase in STAT3 phosphorylation under DMSO treatments at LDS, while not at EDS. Consistently, STAT3 phosphorylation blocker STA21 could greatly reverse DMSO's function at LDS whereas hardly at EDS. Moreover, hearts at the EDS had less total STAT3 protein, but relatively much higher level of phosphorylated STAT3. This suggests that DMSO promote fetal cardiomyocytes proliferation, and STAT3 phosphorylation play a pivotal role in DMSO's function. With maturation, DMSO exerted a better ability to favor cardiomyocyte proliferation depending on STAT3 phosphorylation. Therefore, DMSO could serve as an effective, economic, and safe therapy for heart diseases with cell loss.

Fatty Acid Synthase Promotes the Palmitoylation of Chikungunya Virus nsP1.

Chikungunya virus (CHIKV) is transmitted to people by mosquitoes, and CHIKV infection causes fever and joint pain. Fatty acid synthase (FASN) has been identified as a proviral factor for CHIKV. How FASN participates in CHIKV replication remains to be elucidated. In this study, we demonstrated that palmitic acid (PA) can restore the suppression of CHIKV replication by FASN inhibitors. The palmitoylation and plasma membrane localization of CHIKV nsP1 were reduced by FASN inhibitors. Triple mutation of Cys417, Cys418, and Cys419 in nsP1 blocked its palmitoylation and severely disrupted CHIKV replication. Furthermore, two zinc finger DHHC domain-containing palmitoyltransferases (ZDHHCs), ZDHHC2 and ZDHHC19, promoted nsP1 palmitoylation and CHIKV replication. Our results not only identified the key enzymes for the palmitoylation of nsP1 but also provided mechanistic insights into the roles of FASN in CHIKV replication.IMPORTANCE S-palmitoylation is an important form of lipid posttranslational modification, which affects the function of proteins by regulating their transport, stability, and localization. Previous studies have shown that FASN is critical for CHIKV replication; however, the mechanism for this function of FASN remains unknown. The key zinc finger DHHC domain-containing palmitoyltransferases involved in the palmitoylation of nsP1 are not clear. We demonstrated that FASN promoted CHIKV replication through nsP1 palmitoylation. ZDHHC2 and ZDHHC19 were identified as the major enzymes for nsP1 palmitoylation. Since nsP1 proteins are conserved in alphaviruses, our results highlight the mechanisms by which alphavirus nsP1 is palmitoylated.

Tuning the Weak Ferromagnetic States in Dysprosium Orthoferrite.

RFeO3 orthoferrites, where R is a rare-earth ion of the lanthanide series, are attracting attention mostly because of their promising fast spin dynamics. The magnetic properties of these materials seem to crucially depend on whether the magnetizations of the R and Fe ions' weak ferromagnetic (WFM) components are parallel or antiparallel to each other. Here, we report an extensive investigation of a high-quality DyFeO3 single crystal in which the induced Dy3+ magnetization (FDy) has a natural tendency to be antiparallel to Fe3+ sublattice magnetization (FFe) within a large temperature window. Moreover, we find that specific variations of temperature and applied magnetic fields allow us to make FDy parallel to FFe, or force a spin-flip transition in FFe, among other effects. We found three different magnetic states that respond to temperature and magnetic fields, i.e. linear versus constant or, alternatively, presenting either behavior depending on the history of the sample. An original magnetic field-versus-temperature phase diagram is constructed to indicate the region of stability of the different magnetic phases, and to reveal the precise conditions yielding sudden spin switching and reversals. Knowledge of such a phase diagram is of potential importance to applications in spintronics and magnetic devices.

Interplay of coupling between strain and rotation in ferroelectric SrZrO3/SrTiO3 superlattices.

The combination of oxygen octahedral rotation and epitaxial strain provides a unique opportunity to tune the ferroelectric properties of perovskite superlattices. Here, through first-principles calculations, we demonstrate that the oxygen octahedral rotation predominates the ground state and ferroelectric properties of SrZrO3/SrTiO3 superlattices. The predicted ground state combines the ferroelectric distortion and antiferrodistortive modes simultaneously. The structure-strain phase diagrams of the superlattices are calculated with and without octahedral rotations, which elucidate the interplay of coupling between epitaxial strain and octahedral rotation. It is found that the presence of octahedral rotation not only lowers the energy but also changes the sequence of phase transition from c-r-aa to c-r, in which the coupling of rotation and strain induces an out-of-plane polarization that transforms aa-phase into r-phase.