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Alzheimer’s disease (AD) pathogenesis features progressive neurodegeneration, amyloid-β plaque formation and neurofibrillary tangles. Ample evidence has indicated the involvement of epigenetic pathways in AD pathogenesis. Here, we show that the expression of microRNA 650 (miR-650) is altered in brains from AD patients. Furthermore, we found that the processing of primary miR-650 to mature miR-650 is misregulated. Bioinformatic analysis predicted that miR-650 targets the expression of three AD-associated components: Apolipoprotein E (APOE), Presenilin 1 (PSEN1), and Cyclin-Dependent Kinase 5 (CDK5), and we have experimentally confirmed that miR-650 is able to significantly reduce the expression of APOE, PSEN1, and CDK5 in vitro. Importantly, the overexpression of miR-650 was further shown to significantly alter the CDK5 level and ameliorate AD pathologies in APP-PSEN1 transgenic mice. Overall, our results indicate that miR-650 influences AD pathogenesis through regulation of CDK5.

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.

Natural plant polysaccharide as immune modulator is considered an effective strategy for healthy aquaculture to reduce medicine treatment. Salvia miltiorrhiza polysaccharides (SMP) had applications to regulate immune activity and enhance antioxidant in vertebrates, but the potential function has been rarely reported in crustaceans. In this study, the immunological effects of SMP on hemocytes of Procambarus clarkii were analyzed. Results showed that total superoxide dismutase (T-SOD), phenoloxidase (PO) activity and respiratory burst were up-regulated after SMP treatment. After high-throughput sequencing, 2170 differentially expressed genes (DEGs) including 1294 up-regulated and 876 down-regulated genes were identified. KEGG function enrichment analysis indicated that DEGs are involved in crustaceans cellular immune-related signaling pathways, including lysosome, phagosome and endocytosis. Transcriptome mining and qRT-PCR showed that SMP up-regulated humoral immunity factors gene expression. Diets supplemented with 0.8% SMP significantly up-regulated the total number of hemocytes (THC), T-SOD and PO activity, improved the survival of crayfish after Citrobacter freundii infection. This study suggested that SMP could improve the cellular and humoral immunity of P. clarkii. Furthermore, this finding supplied a molecular foundation for further comprehending the immunopotentiator effects of plant polysaccharides in crustaceans.

Continuous glucose monitoring (CGM) has the potential to improve glucose control in the intensive care unit (ICU) setting. We sought to evaluate the accuracy of the intermittently scanned CGM (isCGM) system in critically ill patients.Adult patients were consecutively enrolled from three ICUs from August 2020 to January 2021. The performance of FreeStyle Libre Pro was evaluated against the venous blood glucose samples as a reference. Numerical accuracy was examined by the mean absolute relative difference (MARD), the Bland-Altman analysis, and the International Organization for Standardization criteria. Clinical accuracy was assessed by performing the Clarke and consensus error grid analysis.A total of 122 patients were included and 3416 matched glucose pairs were analyzed. The overall MARD was 18.0%, and the highest MARD (33.1%) was observed in the hypoglycemic range (lt;70 mg/dL). The Bland-Altman analysis revealed a mean bias of -11.7 mg/dL, with the 95% limits of agreement of -73.0 to 49.5 mg/dL. The percentages of isCGM glucose values within ±15%/15, ±20%/20, and ±30%/30 mg/dL were 49.8%, 64.7%, and 84.5%, respectively. The Clarke and consensus error grid analysis showed acceptable clinical accuracy with 98.5% and 98.8% of glucose values falling into zones A and B.Our study demonstrated suboptimal overall accuracy of isCGM for critically ill patients. Whether the adjunctive use of isCGM could improve glucose management and health outcomes in the critically ill needs further investigation.ChiCTR2100042036, Chinese Clinical Trial Registry.

Pareuchiloglanis macrotrema is a glyptosternoid fish belonging to the Siluriform family and is endemic to the Qinghai-Tibet Plateau tributaries. P. macrotrema is an ideal model for studying the adaptive evolution of fish at high altitudes. P. macrotrema has two attaching livers connected to the main liver, a common feature in most Sisoridae fishes but is a special phenomenon relative to other vertebrates. Using RNA-Seq, 42 differentially expressed genes were found between the main liver and attaching liver, of which 31 were upregulated and 11 were downregulated in the main liver. The major differentially expressed genes between the main liver and attaching liver of P. macrotrema are related to metabolism, immunity, and digestive processes. Meanwhile, a comparative transcriptome analysis was carried out on P. macrotrema fish and six non-plateau Siluriformes fishes. We found 268 positively selected genes in P. macrotrema that are related to energy metabolism, immunity, and hypoxic responses. The findings of this study highlight the gene expression differences between the main liver and attaching livers of Sisoridae fishes and provide greater insight into the evolution of Tibetan fishes.

Epitheliocystis is an emerging and global aquaculture disease caused by a diverse range of bacteria of the order Chlamydiales. Here we report a case of epitheliocystis caused by a novel Chlamydia bacterium, which resulted in 40% mortality in cultured cyprinids (Spinibarbus denticulatus). The affected fish exhibited lethargy, were observed swimming near the oxygen pump and subsequently died. Histopathology analysis revealed that lesions were concentrated mainly on the gills. The epithelial cells of the damaged gill lamellae showed hyperplasia, fusion and adhesion, and were characterized by inflammation and necrosis. Inclusion bodies were observed in some proliferating epithelial cells at the tips of the gill lamellae and were accompanied by different degrees of mucous cell proliferation. Transmission electron microscopy examination clearly showed the morphological characteristics of chlamydia-like bacteria in epithelial cells. In addition, 16S rRNA sequencing (752 bp) and molecular phylogenetic analyses revealed that epitheliocystis agents detected in S. denticulatus belonged to a novel family, Chlamydiaceae. This is the first report of epitheliocystis in cultured fish in China, and the findings in this study increase the range of hosts affected by epitheliocystis.

of supporting mucosal immune barrier integrity and prevention of some pathogenic infections in aquatic species, are key areas of active study, often focusing on feed additives. The objectives of this study were to explore the effects of feeding cMOS (concentrated mannan oligosaccharide) on the gill and skin mucosal barriers of goldfish (Carassius auratus Linnaeus) and evaluate health status during Ichthyophthirius multifiliis infection. After feeding the cMOS-containing diet for 60 days, Hematoxylin and eosin (HE) staining showed greater length of gill lamella and thicker dermal dense layer, while Alcian Blue and Periodic acid-Schiff (AB-PAS) staining showed higher numbers of mucin cells in cMOS fed fish. Chemical analysis showed that fish fed cMOS had greater enzyme activity of lysozyme (LZM) and alkaline phosphatase (AKP) in gill and skin tissues, while qRT-PCR revealed higher expression of Muc-2 and IL-1β, as well as lower expression of IL-10. After Ichthyophthirius multifiliis challenge, goldfish fed the cMOS diet had lower mortality and infection rates, as well as fewer visible white spots on the body surfaces. Histologically, the gill and skin of these fish presented less tissue damage and fewer parasites, and had a greater number of mucus cells. In addition, the expression of Muc-2 and IL-10 were notably higher while the expression of IL-1β was significantly lower in cMOS fed goldfish than control fed fish. In this study, cMOS fed goldfish had stronger immune barrier function of skin and gill mucous, and better survival following Ichthyophthirius multifiliis infection.

A novel electrochemiluminescence (ECL) biosensor for hyaluronidase (HAase) based on the adjustable electrostatic interaction between the surface-charge-controllable nanoparticles and negatively charged electrode has been devised. Hyaluronic acid (HA)-coated amino-modified ruthenium bipyridine-doped silica nanoparticles (Ru@SiO

Yinchenhao Decoction (YD), a Chinese herbal medicine, has been traditionally used for treatment of metabolic liver diseases. A 10-week feeding trail was carried out to examine the effects of YD supplementation in a high carbohydrate diet (HCD) on liver histopathology, immune response, disease resistance, and expression of genes associated with endoplasmic reticulum stress, autophagy, apoptosis, necroptosis and inflammation in juvenile largemouth. A diet containing 9% carbohydrate was used as a low carbohydrate diet (LCD), and a HCD was formulated to contain 18% carbohydrate and supplemented with 0, 0.5, 1, 2 or 4% YD (HCD, HCD+0.5YD, HCD+1YD, HCD+2YD and HCD+4YD). Triplicate groups of fish (5.6 ± 0.2 g) were feed the test diets to visual satiety for 10 weeks. The highest survival rate after Nocardia seriolae challenge was recorded for the HCD+4YD group. YD application led to reduced ACP, AKP, AST and ALT activities. HCD-induced cells swelling, ruptured cell membrane, migrated nuclei and increasing inflammatory cells in hepatocytes were mitigated by YD addition. Moreover, YD decreased the expressions of pro-inflammation genes (TNF-α, IL-1β, IL-8, hepcidin1, NF-κB, COX2, CD80 and CD83) and increased the mRNA levels of anti-inflammation genes (IL-10 and IKBα). The mode of liver cell death was preferably changed to programed apoptosis rather than uncontrolled necroptosis by application of YD in HCD. Furthermore, the expression of UPR genes (IRE1, Eif2α, ATF6, XBP1 and GRP78/Bip) and autophagy genes (LC3-2, BNIP3 and P62) was increased by YD supplementation. In summary, our results demonstrated that YD addition in HCD enhances UPR, autophagy and programed apoptosis maintaining the homeostasis, and decreases uncontrolled necroptosis and inflammation, ultimately leading to improved immune response in largemouth bass.

Compressed polyhydrides have been regarded as an important platform for exploring high-temperature superconductors. The disordered states with high entropy could possess better superconducting properties than conventional periodic structures. Here, we have discovered a new high entropy superconducting La–Ce polyhydride (initial ratio La: Ce = 2.5–3.5:1), which is stable under low pressures with the giant enhancement of superconducting properties compared with the binary La-H and Ce-H system. Its superconductivity at 176 K was strikingly preserved to about 100 GPa, and the extrapolated upper critical field Hc2(0) reached 235 T, both of which are the record values among the synthesized polyhydrides at 100 GPa. We also performed the contrast experiments on binary lanthanum hydride that show a much lower Tc (up to 100 K) at the same pressure range. The experimental results and theoretical calculation indicate the disordering state of the La-Ce-H system with high configurational entropy. The aroused configurational entropy shifts the La-Ce-H system towards a dirty limit that not only enhanced the stability but also improved the superconducting properties by softening the phonon frequency (ω), shorting the electron mean free path (ℓ), and increasing the electron-phonon coupling parameter (λe−p). These results show how better superconductors can be engineered in this new class of hydrides.

Safe, high-quality and economical electric energy transportation is the basic requirements of modern power system operation. Transformer, as one of the core equipment of power system and national grid system, has the characteristics of diverse types, variable models and wide deployment. It is the basic equipment for power system to realize voltage change and electric energy distribution. Because the power system transformer needs to operate with load for a long time, the probability of failure is usually higher than that of other power equipment in general. This paper starts from the transformer fault and fault diagnosis. Firstly, the transformer fault types, traditional transformer fault diagnosis techniques and the advantages of machine learning in transformer fault diagnosis are reviewed. Secondly, the application of information system theory and information entropy in transformer fault diagnosis is introduced. Then it introduces machine learning technology, feature selection and extraction technology in transformer fault diagnosis, and machine learning algorithms such as support vector machine and extreme learning machine for transformer fault diagnosis. Finally, the potential development trend of information system theory, information entropy and machine learning in transformer fault diagnosis is forecasted. The combination of transformer fault prediction and machine learning algorithm is helpful for power system maintenance personnel to accurately predict the running state of power equipment, and also provides a new method and technology for the safe and reliable operation and regular maintenance of power system.

As compressed hydrides constantly refresh the records of superconducting critical temperatures (Tc) in the vicinity of room temperature, this further reinforces the confidence to find more high-temperature superconducting hydrides. In this process, metastable phases of superhydrides offer enough possibilities to access superior superconducting properties. Here we report a metastable hexagonal lanthanum superhydride (P63/mmc-LaH10) stabilized at 146 GPa by introducing an appropriate proportion of Al, which exhibits high-temperature superconductivity with Tc ∼ 178 K, and this value is enhanced to a maximum Tc ∼ 223 K at 164 GPa. A huge upper critical magnetic field value Hc2(0) reaches 223 T at 146 GPa. The small volume expansion of P63/mmc-(La, Al) H10 compared with the binary LaH10 indicates the possible interstitial sites of Al atoms filling into the La-H lattice, instead of forming conventional ternary alloy-based superhydrides. This work provides a new strategy for metastable high-temperature superconductors through the multiple-element system.

Figure S1.ABBV-744 exhibits potent anti-proliferative activity against AML cells through cell cycle arrest and induction of apoptosis.

Figure S5.Antitumor activity of ABBV-744/venetoclax in AML xenograft model and AML primary samples

Primary patient sample information

Suppl. Figure 1. Caspase inhibitor prevents caspase 3/7 activity; Suppl. Figure 2. Levels of BIM, BAD, BAX and BAK silencing by siRNA; Suppl. Figure 3. mRNA and protein expression of BCL2 and BCLxl upon treatment with ABBV-075.

Supplementary figure and table legends

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Tumor growth inhibition in cell line-based xenograft models and supporting statistics.

Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).

Figure S3.Comparison of ABBV-744 and GSK046 BD2 selective compounds.

290 genes that were modulated by MS417 in both NCI-H1299 and MiaPaCa-2 cells.

Figure S6.Identification of biomarker of response to ABBV-744/venetoclax therapy.

Expression change of 25 potential BET inhibitor responsive genes in NCI-H1299, MiaPaCa-2, and MX-1 cells treated with DMSO or 0.5 μM MS417 for 6 hours.

Figure S4.ABBV-744 displaces BRD4 from regulatory regions of BCL2, BCL2L1 and RUNX1 in sensitive AML cells but not insensitive AML line.

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Figure S2. ABBV-744 retains strong transcription regulatory activities in AML cells and it did not alter the baseline expression of representative IFN-r or PMA responsive genes.

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Supplemental Figure 1. Chemical structure and biochemical potency of BET inhibitors used in this study. Supplemental Figure 2. Rapid reversal of PD marker responses upon BET inhibitor washout in OPM-2 cells. Supplemental Figure 3. In vivo antitumor efficacies of ABBV-075 in the OPM-2 model at the 0.25 mg/kg, qdx21 and 1 mg/kg, qdx21 dose levels. Supplemental Figure 4. Identification of potential PD markers in skin. Supplemental Table 2. Common pathways regulated by MS417 in NCI-H1299 and MiaPaCa-2 cells Supplemental Table 4.Correlation of EC50s of MS417 and ABBV-075 in regulating PD makers vs. their anti-proliferative EC50s in OPM-2 cells. Supplemental Table 5. Identification of potential PD markers in whole blood.

Supplemental figure legends

High level of concomitant Bim and Bcl-2 expression correlates with sensitivity to ABBV-075-induced apoptosis

Apoptosis induction by MS417 across cancer cell lines

Restoration of Myc expression under BET inhibitor treatment failed to rescue cells from apoptosis or cell cycle arrest

ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. Cancer Res; 77(11); 2976–89. ©2017 AACR.

ABBV-075 inhibits Bcl-XL transcription and displace BRD4 from Bcl-XL regulatory regions

Apoptosis induction by ABBV-075 across cancer cell lines

Induction of apoptosis across cancer cell lines and CD34 normal cells

Anti-proliferative activity of ABBV-075 across cancer cell lines

ABBV-075 inhibits hypoxia induced transcription of proangiogenesis factors

Tumor environmental factors such as hypoxia or the presence of prosurvival cytokine such as IL-6 does not significantly change cellular sensitivity to ABBV-075

ABBV-075 induces differentiation markers in HL-60 cells