Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice.

Characterizing atom clouds using a charge-coupled device for atom-interferometry-based G measurements.

Precise information of positions and sizes of atom clouds is required for atom-interferometry-based G measurements. In this work, characterizing atom clouds using a charge-coupled device (CCD) is presented. The parameters of atom clouds are extracted from fluorescence images captured by the CCD. For characterization, in-situ calibration of the magnification of the imaging system is implemented using the free-fall distance of atom clouds as the dimension reference. Moreover, influence of the probe beam on measuring the positions of atom clouds is investigated, and a differential measurement by reversing the direction of the probe beam is proposed to suppress the influence. Finally, precision at sub-mm level for characterizing atom clouds is achieved.

Omipalisib Inhibits Esophageal Squamous Cell Carcinoma Growth Through Inactivation of Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) and ERK Signaling.

BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a life-threatening digestive tract malignancy with no known curative treatment. This study aimed to investigate the antineoplastic effects of omipalisib and its underlying molecular mechanisms in ESCC using a high throughput screen. MATERIAL AND METHODS MTT assay and clone formation were used to determine cell viability and proliferation. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. Global gene expression and mRNA expression levels were determined by RNA sequencing and real-time PCR, respectively. Protein expression was evaluated in the 4 ESCC cell lines by Western blot analysis. Finally, a xenograft nude mouse model was used to evaluate the effect of omipalisib on tumor growth in vivo. RESULTS In the pilot screening of a 1404-compound library, we demonstrated that omipalisib markedly inhibited cell proliferation in a panel of ESCC cell lines. Mechanistically, omipalisib induced G0/G1 cell cycle arrest and apoptosis. RNA-seq, KEGG, and GSEA analyses revealed that the PI3K/AKT/mTOR pathway is the prominent target of omipalisib in ESCC cells. Treatment with omipalisib decreased expression of p-AKT, p-4EBP1, p-p70S6K, p-S6, and p-ERK, therefore disrupting the activation of PI3K/AKT/mTOR and ERK signaling. In the nude mouse xenograft model, omipalisib significantly suppressed the tumor growth in ESCC tumor-bearing mice without obvious adverse effects. CONCLUSIONS Omipalisib inhibited the proliferation and growth of ESCC by disrupting PI3K/AKT/mTOR and ERK signaling. The present study supports the rationale for using omipalisib as a therapeutic approach in ESCC patients. Further clinical studies are needed.

Test of the Universality of Free Fall with Atoms in Different Spin Orientations.

We report a test of the universality of free fall by comparing the gravity acceleration of the ^{87}Rb atoms in m_{F}=+1 versus those in m_{F}=-1, of which the corresponding spin orientations are opposite. A Mach-Zehnder-type atom interferometer is exploited to alternately measure the free fall acceleration of the atoms in these two magnetic sublevels, and the resultant Eötvös ratio is η_{S}=(0.2±1.2)×10^{-7}. This also gives an upper limit of 5.4×10^{-6} m^{-2} for a possible gradient field of the spacetime torsion. The interferometer using atoms in m_{F}=±1 is highly sensitive to the magnetic field inhomogeneity. A double differential measurement method is developed to alleviate the inhomogeneity influence, of which the effectiveness is validated by a magnetic field modulating experiment.

Turn-on fluorescence and unprecedented encapsulation of large aromatic molecules within a manganese(II)-triazole metal-organic confined space.

For the purpose of investigating the coordination behavior of sterically congested alkenes and exploring the possibility of cofacial complexation in the polycyclic aromatic system for the formation of extended polymeric networks, a new tetradentate ligand, 1,1,2,2-tetrakis[4-(1H-1,2,4-triazol-1-yl)phenyl]ethylene (TTPE), has been designed and synthesized. By using TTPE as a building block with regard to the self-assembly with MnCl2 ⋅4 H2 O, a novel two-dimensional coordination framework {[Mn(TTPE)Cl2 ]⋅4 CHCl3 }n (1) can be isolated. Anion-exchange and organic-group-functionalized aromatic guest TTPE-loaded host-guest complex experimental results indicate that coordinated Cl(-) anions in the 2D framework of 1 can be completely replaced with dissociative ClO4 (-) groups in an irreversible single-crystal-to-single-crystal transformation fashion, as evidenced by the anion-exchange products of {[Mn(TTPE)(H2 O)2 ](ClO4 )2 ⋅0.5 TTPE⋅5.25 H2 O}n (2). Interestingly, TTPE, acting as an organic template, was encapsulated in the confined space of the 2D grid of 2. To the best of our knowledge, such large organic molecules encapsulated in the reactive organic-group-functionalized aromatic-guest-loaded host-guest complex are unprecedented up to now. Luminescence measurements illustrate that 1 and 2 represent novel examples of sensing materials based on triazole derivatives. Further, 2 has been demonstrated by tuning the fluorescence response of porous metal-organic frameworks as a function of adsorbed small analytes.

Anion-exchange and anthracene-encapsulation within copper(II) and manganese(II)-triazole metal-organic confined space in a single crystal-to-single crystal transformation fashion.

A new multidentate ligand 1-(9-(1H-1,2,4-triazol-1-yl)anthracen-10-yl)-1H-1,2,4-triazole (tatrz) was designed and synthesized. Using tatrz as a building block, three novel coordination frameworks, namely, {[Cu(tatrz)2(NO3)2]·(CH3OH)·4H2O}n (1), {[Cu(tatrz)2(H2O)2](BF4)2}n (2), and [Mn(tatrz)2(SCN)2(CH3OH)]·2H2O (3) can be isolated. Anion-exchange experiment indicates that NO3(-) anions in the two-dimensional (2D) copper framework of 1 can be completely exchanged by ClO4(-) in an irreversible single crystal-to-single crystal (SC-SC) transformation fashion, as evidenced by the anion-exchange products of {[Cu(tatrz)2(H2O)2](ClO4)2·4CH3OH} (1a). Further, if 1a was employed as a precursor in N,N-dimethylformamide (DMF), an isomorphic solvate of {[Cu(tatrz)2(DMF)2](ClO4)2·2H2O}n (1b) can be generated during the reversible dynamic transformation process. When 1 was immersed in CH3OH, a distinct 2D layer {[Cu(tatrz)2(NO3)2]·4.4CH3OH·0.6H2O}n (1c) was isolated. Interestingly, the solvent-exchange conversion is also invertible between 1 and 1c, which exhibits spongelike dynamic behavior with retention of crystalline integrity. If the 2-fold interpenetrating three-dimensional (3D) framework 2 is selected, it can be transformed into another 2-fold interpenetrating 3D framework {[Cu(tatrz)2(H2O)2](ClO4)2·5.56H2O}n (2a) in a reversible SC-SC transformation fashion. However, when the light yellow crystals of mononuclear complex 3 were exposed to trichloromethane containing aromatic organic anthracene (atan), through our careful observation, the crystals of 3 were dissolved and reassembled into dark brown crystals of 2D crystalline coordination framework {[Mn(tatrz)2(SCN)2]·(atan)}n (3a). X-ray diffraction revealed that in 3a, atan acting as an organic template was encapsulated in the confined space of the 2D grid. Luminescent measurements illustrate that 3a is the first report of multidimensional polymers based on triazole derivatives as luminescent probes of Mg(2+).

Statin-Associated Liver Dysfunction and Muscle Injury: epidemiology, Mechanisms, and Management Strategies.

Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.

ABHD7-mediated depalmitoylation of lamin A promotes myoblast differentiation.

LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/ß hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.

Early transcriptomic adaptation to Na2CO3 stress altered the expression of a quarter of the total genes in the maize genome and exhibited shared and distinctive profiles with NaCl and high pH stresses.

Sodium carbonate (Na2CO3) presents a huge challenge to plants by the combined damaging effects of Na⁺, high pH, and CO3²â». Little is known about the cellular responses to Na2CO3 stress. In this study, the transcriptome of maize (Zea mays L. cv. B73) roots exposed to Na2CO3 stress for 5 h was compared with those of NaCl and NaOH stresses. The expression of 8,319 genes, representing over a quarter of the total number of genes in the maize genome, was altered by Na2CO3 stress, and the downregulated genes (5,232) outnumbered the upregulated genes (3,087). The effects of Na2CO3 differed from those of NaCl and NaOH, primarily by downregulating different categories of genes. Pathways commonly altered by Na2CO3, NaCl, and NaOH were enriched in phenylpropanoid biosynthesis, oxidation of unsaturated fatty acids, ATP-binding cassette (ABC) transporters, as well as the metabolism of secondary metabolites. Genes for brassinosteroid biosynthesis were specifically upregulated by Na2CO3, while genes involved in ascorbate and aldarate metabolism, protein processing in the endoplasmic reticulum and by N-glycosylation, fatty acid biosynthesis, and the circadian rhythm were downregulated. This work provides the first holistic picture of early transcriptomic adaptation to Na2CO3 stress, and highlights potential molecular pathways that could be manipulated to improve tolerance in maize.

Escitalopram-induced sinus bradycardia in coronary heart disease combined with depression: a case report and review of literature.

For patients with cardiovascular disease, using the antidepressant escitalopram may lead to unexpected adverse events. Here, a rare repeated sinus bradycardia event due to escitalopram is first reported. In an 82-year-old female patient with cardiac dysfunction using digoxin, tachycardia (average heart rate of 93 beats/min) was demonstrated by electrocardiogram (ECG). She began to take escitalopram and lorazepam due to depression, but sinus bradycardia (93.7% heart rate was <60 beats/min) and sinus arrest were first detected after 3 months. Its proportion decreased to 0.1% after discontinuation of digoxin and escitalopram for 1 day, and the rhythm returned to normal 2 weeks later. After 2 months, escitalopram was prescribed again in combination with quetiapine; then, 17.1% heart rate was <60 beats/min. After escitalopram and quetiapine withdrawal, the ECG showed the heart rhythm had normalized again. No other drug changes were made during these periods. Escitalopram was deemed to be a highly possible cause of sinus bradycardia according to its Naranjo's Algorithm score. Furthermore, literature on escitalopram-mediated cardiovascular adverse events was reviewed and analyzed. Empirically, escitalopram should be discontinued immediately if iatrogenic causes cannot be ruled out. Furthermore, ECG monitoring in escitalopram-related cardiovascular adverse events is highlighted, especially in patients receiving certain drug classes simultaneously (i.e., sinoatrial node inhibitors, antipsychotics).

Influence of magnetic field on the seismometer in vibration correction for atom gravimeters.

Vibration correction provides a simple and flexible method of suppressing ambient vibration noise in transportable atom gravimeters. However, in the seismometers used for vibration correction, a spurious output may be induced by the magnetic field of the magnetic-optical trap, introducing errors to the gravity measurements. This paper evaluates the influence of the magnetic field on the seismometer and the corresponding errors in the gravity measurements. It is found that an error level of order 10 µGal may be present if the seismometer is not configured carefully. The dependence of the influence on the orientation of the seismometer and the lasting time of the magnetic field are investigated. The effective suppression of the influence by shielding the seismometer is also demonstrated. Our results focus attention on the possible errors related to seismometers in high-precision gravity measurements by using atom gravimeters.

[Abundance Change of Antibiotic Resistance Genes During PDWW Recycling and Correlations with Environmental Factors].

Research on the distribution of antibiotic resistance genes (ARGs) in urban sewage treatment systems is extensive, but there is still insufficient research on their abundance in industrial wastewater recycling systems. In this study, a printing and dyeing wastewater (PDWW) recycling system was constructed, and 16S rDNA and high-throughput sequencing technology was used to analyze the microbial communities and ARG abundance during the treatment process. A total of 52 ARGs in nine categories were detected, of which the relative abundance of ß-lactam resistance genes was the highest. During the treatment cycle, the concentration of aromatic pollutants increased with an increase in the number of cycles, while the abundance of ß-lactam resistance genes increased first, decreased, and then increased (reaching 61.85% on the 100th day). At the same time, the abundance of Firmicutes, Actinobacteria, and Cyanobacteria related ARGs decreased significantly (by 84.66%, 64.38%, and 85.15%, respectively). More than 21 kinds of ARGs were significantly affected by the enrichment by the aromatic pollutants. Among them, 6 kinds of ARGs were significantly positively correlated with changes in the concentrations of the aromatic pollutants (P<0.01), while 6 were significantly negatively correlate (P<0.01). These results show that the abundance of ARGs was affected by the microbial communities and the aromatic pollutants, which increased at first, decreased, and then increased during the PPDW recycling process. This study reveals the effects of the enrichment of aromatic contaminants and changes in microbial communities on ARGs during PPDW recycling, and provides theoretical guidance for the recycling of PDWW to reduce environmental pollution associated with ARGs.

A dual-magneto-optical-trap atom gravity gradiometer for determining the Newtonian gravitational constant.

As part of a program to determine the gravitational constant G using multiple independent methods in the same laboratory, an atom gravity gradiometer is being developed. The gradiometer is designed with two magneto-optical traps to ensure both the fast simultaneous launch of two atomic clouds and an optimized configuration of source masses. Here, the design of the G measurement by atom interferometry is detailed, and the experimental setup of the atom gravity gradiometer is reported. A preliminary sensitivity of 3 × 10-9 g/Hz to differential gravity acceleration is obtained, which corresponds to 99 E/Hz (1 E = 10-9 s-2) for the gradiometer with a baseline of 0.3 m. This provides access to measuring G at the level of less than 200 parts per million in the first experimental stage.

Measuring the effective height for atom gravimeters by applying a frequency jump to Raman lasers.

As the existence of the gravity gradient, the output of gravimeters is actually the gravitational acceleration at the reference instrumental height. Precise knowledge of the reference height is indispensable in the utilization of gravity measurements, especially for absolute gravimeters. Here, we present an interferometric method to measure the distance between the atomic cloud and a reflecting mirror directly, which consequently determines the reference height of our atom gravimeter. This interferometric method is based on a frequency jump of Raman lasers applied at the π pulse of the atom interferometer, which induces an additional phase shift proportional to the interested distance. An uncertainty of 2 mm is achieved here for the distance measurement, and the effect of the gravity gradient on absolute gravity measurements can thus be constrained within 1 µGal. This work provides a concrete-object-based measurement of the reference height for atom gravimeters.