Fluorescence quenching of deprotonated phenylurea through twisting motion induced by an electron-donating substituent group.

The excited-state proton transfer (ESPT) reaction between anthracen-2-yl-3-phenylurea (PUA) derivatives and tetrabutylammonium acetate (TBAAc) in dimethyl sulfoxide (DMSO) solvent was theoretically investigated using time-dependent density functional theory. The electron-donating methoxy group (OMe) and electron-withdrawing trifluoromethyl group (CF3) were bonded to 2PUA to form OMe-2PUA and CF3-2PUA, respectively. Two hydrogen bonds formed in the 1 : 1 hydrogen-bonded complexes between the 2PUA derivative and acetate ion (AcO-), namely N1-H1⋯O1 and N2-H2⋯O2. Strong charge transfer (CT) due to the electron-donating OMe group led to H1 transfer in the S1 state for the OMe-2PUA:AcO- hydrogen-bonded complex. On the contrary, weak CT due to the electron-withdrawing CF3 group led to H2 transfer in the S1 state for CF3-2PUA. After the ESPT reaction, the binding energies of the hydrogen-bonded complexes strongly decreased in both cases, and this promoted the separation of contact-ion pairs (CIPs*) and formed different types of anionic species. CF3-2PUA- could keep its nearly planar structure in the S1 state and emit "abnormal" fluorescence. On the other hand, the anionic OMe-2PUA- underwent a twisting motion to form a twisted structure in the S1 state with very low energy, and this led to a rapid internal conversion (IC) to quench long-wave fluorescence in the emission spectra.

Golgi-resident TRIO regulates membrane trafficking during neurite outgrowth.

Neurite outgrowth requires coordinated cytoskeletal rearrangements in the growth cone and directional membrane delivery from the neuronal soma. As an essential Rho guanine nucleotide exchange factor (GEF), TRIO is necessary for cytoskeletal dynamics during neurite outgrowth, but its participation in the membrane delivery is unclear. Using co-localization studies, live-cell imaging, and fluorescence recovery after photobleaching analysis, along with neurite outgrowth assay and various biochemical approaches, we here report that in mouse cerebellar granule neurons, TRIO protein pools at the Golgi and regulates membrane trafficking by controlling the directional maintenance of both RAB8 (member RAS oncogene family 8)- and RAB10-positive membrane vesicles. We found that the spectrin repeats in Golgi-resident TRIO confer RAB8 and RAB10 activation by interacting with and activating the RAB GEF RABIN8. Constitutively active RAB8 or RAB10 could partially restore the neurite outgrowth of TRIO-deficient cerebellar granule neurons, suggesting that TRIO-regulated membrane trafficking has an important functional role in neurite outgrowth. Our results also suggest cross-talk between Rho GEF and Rab GEF in controlling both cytoskeletal dynamics and membrane trafficking during neuronal development. They further highlight how protein pools localized to specific organelles regulate crucial cellular activities and functions. In conclusion, our findings indicate that TRIO regulates membrane trafficking during neurite outgrowth in coordination with its GEF-dependent function in controlling cytoskeletal dynamics via Rho GTPases.

The absorption and fluorescence spectra of 4-(3-methoxybenzylidene)-2-methyl-oxazalone interpreted by Franck-Condon simulation in various pH solvent environments.

The absorption and fluorescence spectra of 4-(3-methoxybenzylidene)-2-methyl-oxazalone (m-MeOBDI) dissolved in neutral, acidic, and basic solvent environments have been investigated and assigned by using Franck-Condon (FC) simulations at the quantum TDDFT level. Four different structures of m-MeOBDI in the ground and excited states are optimized and are found to be responsible for the observed absorption and fluorescence spectra. The (absorption) fluorescence of m-MeOBDI in pure methanol and neutral/basic methanol/water (1/9 vol) mixed solvent is found to arise from the (ground neutral N-I) excited neutral N-I* and cationic C-III* species, respectively. In acidic solvent, the absorption is found to arise from ground acidic C-II species, and the excited divalent cation DC-IV* is found to be formed in its excited state due to the excess H+ in the solution, and then it emits ∼560 nm fluorescence. FC simulations have also been employed to confirm our assignments as well as interpret the vibronic band profiles. As expected, the simulated emission spectrum of the divalent cationic species is in good agreement with the experimental observation. Therefore, within the present FC simulation, the observed absorption and fluorescence spectra have been reasonably interpreted and novel fluorescence mechanisms of m-MeOBDI in various pH solvent environments have been proposed.

Mass Spectrometry Imaging of N-Glycans from Formalin-Fixed Paraffin-Embedded Tissue Sections Using a Novel Subatmospheric Pressure Ionization Source.

N-linked glycosylation, featuring various glycoforms, is one of the most common and complex protein post-translational modifications (PTMs) controlling protein structures and biological functions. It has been revealed that abnormal changes of protein N-glycosylation patterns are associated with many diseases. Hence, unraveling the disease-related alteration of glycosylation, especially the glycoforms, is crucial and beneficial to improving our understanding about the pathogenic mechanisms of various diseases. In past decades, given the capability of in situ mapping of biomolecules and their region-specific localizations, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been widely applied to the discovery of potential biomarkers for many diseases. In this study, we coupled a novel subatmospheric pressure (SubAP)/MALDI source with a Q Exactive HF hybrid quadrupole-orbitrap mass spectrometer for in situ imaging of N-linked glycans from formalin-fixed paraffin-embedded (FFPE) tissue sections. The utility of this new platform for N-glycan imaging analysis was demonstrated with a variety of FFPE tissue sections. A total of 55 N-glycans were successfully characterized and visualized from a FFPE mouse brain section. Furthermore, 29 N-glycans with different spatial distribution patterns could be identified from a FFPE mouse ovarian cancer tissue section. High-mannose N-glycans exhibited elevated expression levels in the tumor region, indicating the potential association of this type of N-glycans with tumor progression.

Predicting the Initial Thermal Decomposition Path of Nitrobenzene Caused by Mode Vibration at Moderate-Low Temperatures: Temperature-Dependent Anti-Stokes Raman Spectra Experiments and First-Principals Calculations.

The lack of understanding of the initial decomposition micromechanism of energetic materials subjected to external stimulation has hindered its safe storage, usage, and development. The initial thermal decomposition path of nitrobenzene triggered by molecular thermal motion is investigated using temperature-dependent anti-Stokes Raman spectra experiments and first-principles calculations to clarify the initial thermal decomposition micromechanism. The experiment shows that the symmetric nitro stretching, antisymmetric nitro stretching, and phenyl ring stretching vibration modes are active as increasing temperature below 500 K. The DFT method is used to examine the effects of the three mode vibrations on the initial decomposition of nitrobenzene by relaxed scan for each relevant change in bond lengths and bond angles to obtain the optimal reaction channel leading to initial thermal decomposition of nitrobenzene. The results demonstrate that the initial thermal decomposition is the isomerization of nitrobenzene to phenyl nitrite. The optimal reaction channel leading to the initial isomerization is the increase or decrease of angle O-N-C from the antisymmetric nitro stretching vibration, which causes the torsion of nitro group and the subsequent oxygen atom attacking carbon atom. The scanning energy barrier related to angle O-N-C is about 62.1 kcal/mol, which is very consistent with the calculated activation barrier of isomerization of nitrobenzene. This proves the reliability of our conclusions.

Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse.

The aberrant accumulation of toxic protein aggregates is a key feature of many neurodegenerative diseases, including Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease. As such, improving normal proteostatic mechanisms is an active target for biomedical research. Although they share common pathological features, protein aggregates form in different subcellular locations. Nε-lysine acetylation in the lumen of the endoplasmic reticulum has recently emerged as a new mechanism to regulate the induction of autophagy. The endoplasmic reticulum acetylation machinery includes AT-1/SLC33A1, a membrane transporter that translocates acetyl-CoA from the cytosol into the endoplasmic reticulum lumen, and ATase1 and ATase2, two acetyltransferases that acetylate endoplasmic reticulum cargo proteins. Here, we used a mutant form of α-synuclein to show that inhibition of the endoplasmic reticulum acetylation machinery specifically improves autophagy-mediated disposal of toxic protein aggregates that form within the secretory pathway, but not those that form in the cytosol. Consequently, haploinsufficiency of AT-1/SLC33A1 in the mouse rescued Alzheimer's disease, but not Huntington's disease or amyotrophic lateral sclerosis. In fact, intracellular toxic protein aggregates in Alzheimer's disease form within the secretory pathway while in Huntington's disease and amyotrophic lateral sclerosis they form in different cellular compartments. Furthermore, biochemical inhibition of ATase1 and ATase2 was also able to rescue the Alzheimer's disease phenotype in a mouse model of the disease. Specifically, we observed reduced levels of soluble amyloid-ß aggregates, reduced amyloid-ß pathology, reduced phosphorylation of tau, improved synaptic plasticity, and increased lifespan of the animals. In conclusion, our results indicate that Nε-lysine acetylation in the endoplasmic reticulum lumen regulates normal proteostasis of the secretory pathway; they also support therapies targeting endoplasmic reticulum acetyltransferases, ATase1 and ATase2, for a subset of chronic degenerative diseases.

Mechanism of Excited-State Intramolecular Proton Transfer for 1,2-Dihydroxyanthraquinone: Effect of Water on the ESIPT.

Mechanisms of excited-state intramolecular proton transfer (ESIPT) of 1,2-dihydroxyanthraquinone (ALR) in ethanol solvent and binary solvent of water and ethanol are investigated using the density functional theory and time-dependent density functional theory. The intramolecular hydrogen bond is found to be reinforced in the excited state based on the bond lengths, bond angles, and infrared vibrational spectra of relevant group. The reinforcement of intramolecular hydrogen bond is attributed to the charge transfer in the excited state, which leads the ESIPT to form a keto isomer. The absorption and fluorescence spectra of ALR in binary solvent with different water percentage are obtained and demonstrate the inhibition effect of water on the ESIPT process, which are consistent with the experimentally observation. Furthermore, more water molecules are considered near the carbonyl group and hydroxyl group related to the intramolecular proton transfer to form intermolecular hydrated hydrogen bond with ALR for clarifying the block mechanism of water on ESIPT. The potential energy curves, frontier molecular orbitals, and NBO analysis are calculated for the several complexes in the ground and excited states. The results show that the interrupt role of water on the ESIPT originated from the forming of hydrated hydrogen bond between the carbonyl oxygen atom and the water molecule, which weakens the intramolecular hydrogen bond associated with proton transfer, increases the energy barrier of ESIPT, and thus precludes the transition of ALR-E to ALR-K in the excited state. In addition, the weakening of intramolecular hydrogen bonds is increased as the water molecule number increases. So the inhibitory effect is enhanced by the water quantity, which reasonably explains the experimental attenuating of keto emission spectra as the water percentage in binary solvent increases.

Reaction Mechanism of 3,4-Dinitrofuroxan Formation from Glyoxime: Dehydrogenation and Cyclization of Oxime.

The reaction pathway of the formation of 3,4-dinitrofuroxan from glyoxime is theoretically investigated under experimental conditions with 25 % nitric acid and dinitrogentetroxide reagents to clarify the mechanism of formation of a furoxan ring by glyoxime. The geometric configurations of minima and transition-state species are optimized at the (U)B3LYP/6-311++G** level. The CCSD(T) and CASSCF(10e,8o)/CASSCF(9e,8o) single-point energy corrections at the same level are performed on top of the optimized geometries. A subsequent dynamic correlation by using NEVPT2/6-311++G**-level single-point energy calculations based on the CASSCF results is also performed to obtain accurate energy values. The formation reaction is analyzed from two processes: glyoxime nitration and 3,4-dinitroglyoxime (nitration product) oxidative cyclization. Calculation results indicate that the electrophilic substitution of nitronium ions from the protonated HNO3 and the abstraction of hydrogen ions by HNO3 molecules are requisites of glyoxime nitration. The formation of a furoxan ring from 3,4-dinitroglyoxime involves two possible mechanisms: 1) oxydehydrogenation by NO2 molecules and the subsequent torsion of NO radical groups to form a ring and 2) the alternation of dehydrogenation and cyclization. The intermediates and transition states in both routes exhibit monoradical and diradical characteristics. Singlet and triplet reactions are considered for the diradical species. Results show that the singlet reaction mechanism is more favorable for cyclization than the triplet reaction. The formation of a furoxan ring from oxime is in accordance with the stepwise intermolecular dehydrogenation and intramolecular torsion to the ring.

Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer.

The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.

Myosin light chain kinase (MLCK) regulates cell migration in a myosin regulatory light chain phosphorylation-independent mechanism.

Myosin light chain kinase (MLCK) has long been implicated in the myosin phosphorylation and force generation required for cell migration. Here, we surprisingly found that the deletion of MLCK resulted in fast cell migration, enhanced protrusion formation, and no alteration of myosin light chain phosphorylation. The mutant cells showed reduced membrane tether force and fewer membrane F-actin filaments. This phenotype was rescued by either kinase-dead MLCK or five-DFRXXL motif, a MLCK fragment with potent F-actin-binding activity. Pull-down and co-immunoprecipitation assays showed that the absence of MLCK led to attenuated formation of transmembrane complexes, including myosin II, integrins and fibronectin. We suggest that MLCK is not required for myosin phosphorylation in a migrating cell. A critical role of MLCK in cell migration involves regulating the cell membrane tension and protrusion necessary for migration, thereby stabilizing the membrane skeleton through F-actin-binding activity. This finding sheds light on a novel regulatory mechanism of protrusion during cell migration.

Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure.

Myosin light chain phosphatase with its regulatory subunit, myosin phosphatase target subunit 1 (MYPT1) modulates Ca(2+)-dependent phosphorylation of myosin light chain by myosin light chain kinase, which is essential for smooth muscle contraction. The role of MYPT1 in vascular smooth muscle was investigated in adult MYPT1 smooth muscle specific knock-out mice. MYPT1 deletion enhanced phosphorylation of myosin regulatory light chain and contractile force in isolated mesenteric arteries treated with KCl and various vascular agonists. The contractile responses of arteries from knock-out mice to norepinephrine were inhibited by Rho-associated kinase (ROCK) and protein kinase C inhibitors and were associated with inhibition of phosphorylation of the myosin light chain phosphatase inhibitor CPI-17. Additionally, stimulation of the NO/cGMP/protein kinase G (PKG) signaling pathway still resulted in relaxation of MYPT1-deficient mesenteric arteries, indicating phosphorylation of MYPT1 by PKG is not a major contributor to the relaxation response. Thus, MYPT1 enhances myosin light chain phosphatase activity sufficient for blood pressure maintenance. Rho-associated kinase phosphorylation of CPI-17 plays a significant role in enhancing vascular contractile responses, whereas phosphorylation of MYPT1 in the NO/cGMP/PKG signaling module is not necessary for relaxation.

Altered contractile phenotypes of intestinal smooth muscle in mice deficient in myosin phosphatase target subunit 1.

BACKGROUND & AIMS: The regulatory subunit of myosin light chain phosphatase, MYPT1, has been proposed to control smooth muscle contractility by regulating phosphorylation of the Ca(2+)-dependent myosin regulatory light chain. We generated mice with a smooth muscle-specific deletion of MYPT1 to investigate its physiologic role in intestinal smooth muscle contraction. METHODS: We used the Cre-loxP system to establish Mypt1-floxed mice, with the promoter region and exon 1 of Mypt1 flanked by 2 loxP sites. These mice were crossed with SMA-Cre transgenic mice to generate mice with smooth muscle-specific deletion of MYPT1 (Mypt1(SMKO) mice). The phenotype was assessed by histologic, biochemical, molecular, and physiologic analyses. RESULTS: Young adult Mypt1(SMKO) mice had normal intestinal motility in vivo, with no histologic abnormalities. On stimulation with KCl or acetylcholine, intestinal smooth muscles isolated from Mypt1(SMKO) mice produced robust and increased sustained force due to increased phosphorylation of the myosin regulatory light chain compared with muscle from control mice. Additional analyses of contractile properties showed reduced rates of force development and relaxation, and decreased shortening velocity, compared with muscle from control mice. Permeable smooth muscle fibers from Mypt1(SMKO) mice had increased sensitivity and contraction in response to Ca(2+). CONCLUSIONS: MYPT1 is not essential for smooth muscle function in mice but regulates the Ca(2+) sensitivity of force development and contributes to intestinal phasic contractile phenotype. Altered contractile responses in isolated tissues could be compensated by adaptive physiologic responses in vivo, where gut motility is affected by lower intensities of smooth muscle stimulation for myosin phosphorylation and force development.

Family Function and Problematic Social Media Use Among Adolescents in Vocational Schools: A Moderated Mediation Model.

With the outburst of social medias in current life, problematic use is prevalent in adolescents and has become a contemporary concern. Although family environment has been identified as a risk factor, little is known how family environment is associated with problematic social media use (PSMU). Drawing on Snyder's hope theory and Davis's cognitive-behavioral model, this study examines how family function is linked with PSMU via hope. The study also investigates the moderating effect of perceived social support (PSS) by analyzing how PSS, interacts with family function, affects hope and further influences PSMU. The moderated mediation analyses of data from 1373 adolescents from vocational schools (343 boys and 1030 girls, Mage = 15.56) reveal family function is negatively associated with adolescents' PSMU, and the association is partially mediated by hope. Furthermore, PSS buffers the negative relation between family function and hope.

Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease.

The endoplasmic reticulum acetylation machinery has emerged as a new branch of the larger endoplasmic reticulum quality control system. It regulates the selection of correctly folded polypeptides as well as reticulophagy-mediated removal of toxic protein aggregates with the former being a particularly important aspect of the proteostatic functions of endoplasmic reticulum acetylation. Essential to this function is the Nε-lysine acetyltransferase activity of acetyltransferase 1 and acetyltransferase 2, which regulates the induction of endoplasmic reticulum-specific autophagy through the acetylation of the autophagy-related protein 9A. Here, we used three mouse models of Charcot-Marie-Tooth disease, peripheral myelin protein 22/Tr-J, C3-peripheral myelin protein 22 and myelin protein zero/ttrr, to study spatial and translational selectivity of endoplasmic reticulum acetyltransferase inhibitors. The results show that inhibition of the endoplasmic reticulum acetyltransferases selectively targets misfolding/pro-aggregating events occurring in the lumen of the organelle. Therefore, they establish acetyltransferase 1 and acetyltransferase 2 as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the endoplasmic reticulum/secretory pathway.

CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.

Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.

MiR-23a inhibits myogenic differentiation through down regulation of fast myosin heavy chain isoforms.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that repress the expression of their target genes post-transcriptionally. MiRNAs participate in the regulation of a variety of biological processes, including development and diseases. However, the functional role and molecular mechanism by which miRNAs regulate skeletal muscle development and differentiation are not fully understood. In this report, we identified miR-23a as a key regulator of skeletal muscle differentiation. Using bioinformatics analyses, miR-23a is predicted to target multiple adult fast myosin heavy chain (Myh) genes, including Myh 1, 2 and 4. Luciferase reporter assays show that miR-23a directly targets the 3' untranslated regions (UTRs) of these mRNAs. Interestingly, the expression level of mature miR-23a is inversely correlated with myogenic progression in mouse skeletal muscle. Both gain- and loss-of-function studies using C2C12 myoblasts demonstrate that miR-23a inhibits myogenic differentiation. These findings therefore reveal a novel role of miR-23a in regulating myogenic differentiation via inhibiting the expression of fast myosin heavy chain isoforms.

Comprehension of the Synergistic Effect between m&t-BiVO4/TiO2-NTAs Nano-Heterostructures and Oxygen Vacancy for Elevated Charge Transfer and Enhanced Photoelectrochemical Performances.

Through the utilization of a facile procedure combined with anodization and hydrothermal synthesis, highly ordered alignment TiO2 nanotube arrays (TiO2-NTAs) were decorated with BiVO4 with distinctive crystallization phases of monoclinic scheelite (m-BiVO4) and tetragonal zircon (t-BiVO4), favorably constructing different molar ratios and concentrations of oxygen vacancies (Vo) for m&t-BiVO4/TiO2-NTAs heterostructured nanohybrids. Simultaneously, the m&t-BiVO4/TiO2-NTAs nanocomposites significantly promoted photoelectrochemical (PEC) activity, tested under UV-visible light irradiation, through photocurrent density testing and electrochemical impedance spectra, which were derived from the positive synergistic effect between nanohetero-interfaces and Vo defects induced energetic charge transfer (CT). In addition, a proposed self-consistent interfacial CT mechanism and a convincing quantitative dynamic process (i.e., rate constant of CT) for m&t-BiVO4/TiO2-NTAs nanoheterojunctions are supported by time-resolved photoluminescence and nanosecond time-resolved transient photoluminescence spectra, respectively. Based on the scheme, the m&t-BiVO4/TiO2-NTAs-10 nanohybrids exhibited a photodegradation rate of 97% toward degradation of methyl orange irradiated by UV-visible light, 1.14- and 1.04-fold that of m&t-BiVO4/TiO2-NTAs-5 and m&t-BiVO4/TiO2-NTAs-20, respectively. Furthermore, the m&t-BiVO4/TiO2-NTAs-10 nanohybrids showed excellent PEC biosensing performance with a detection limit of 2.6 µM and a sensitivity of 960 mA cm-2 M-1 for the detection of glutathione. Additionally, the gas-sensing performance of m&t-BiVO4/TiO2-NTAs-10 is distinctly superior to that of m&t-BiVO4/TiO2-NTAs-5 and m&t-BiVO4/TiO2-NTAs-20 in terms of sensitivity and response speed.

ATase inhibition rescues age-associated proteotoxicity of the secretory pathway.

Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer's disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.

Menopause-specific quality of life during ovarian aging among Chinese women: A prospective cohort study.

OBJECTIVE: To describe the menopause-specific quality of life of Chinese urban women at midlife. STUDY DESIGN: Prospective cohort study. MAIN OUTCOME MEASURES: This study included 920 natural menopausal midlife Chinese women who were followed up for 10 years. The Menopause-Specific Quality of Life (MENQOL) questionnaire, which has four domains (vasomotor, psychosocial, physical, and sexual functioning symptoms), and other measures of physical and behavioral factors, were administered. Generalized estimating equations were used to assess the associations. RESULTS: The mean MENQOL scores in the four domains were 1.75 ± 1.32, 2.13 ± 1.16, 2.33 ± 1.11, and 2.20 ± 1.83, respectively. The occurrence of vasomotor symptoms (VMS) persisted in >50% of women in the perimenopausal and early postmenopausal stages. However, the prevalence of moderate/severe bothersome VMS was relatively low. More than 75% of the women presented with mild physical or psychological symptoms, whereas less than 5% of them had moderate/severe symptoms. Sexual problems were highly frequent and bothersome, and their occurrence increased with advancing menopausal stage and age. The prevalence of bothersome sexual symptoms and moderate/severe sexual symptoms ranged from 31.89 and 1.58% in premenopausal women to 78.09 and 39.35% in late postmenopausal women, respectively. Menopausal status, depressive symptoms, and poor health status were significantly associated with the four menopausal domains. CONCLUSION: VMS are among the menopausal symptoms most frequently rated as severe. Sexual problems become more prevalent with advancing age. Clinicians should have a broad understanding of changes that occur during the transition to maximize women's health.

Myosin light chain kinase is necessary for tonic airway smooth muscle contraction.

Different interacting signaling modules involving Ca(2+)/calmodulin-dependent myosin light chain kinase, Ca(2+)-independent regulatory light chain phosphorylation, myosin phosphatase inhibition, and actin filament-based proteins are proposed as specific cellular mechanisms involved in the regulation of smooth muscle contraction. However, the relative importance of specific modules is not well defined. By using tamoxifen-activated and smooth muscle-specific knock-out of myosin light chain kinase in mice, we analyzed its role in tonic airway smooth muscle contraction. Knock-out of the kinase in both tracheal and bronchial smooth muscle significantly reduced contraction and myosin phosphorylation responses to K(+)-depolarization and acetylcholine. Kinase-deficient mice lacked bronchial constrictions in normal and asthmatic airways, whereas the asthmatic inflammation response was not affected. These results indicate that myosin light chain kinase acts as a central participant in the contractile signaling module of tonic smooth muscle. Importantly, contractile airway smooth muscles are necessary for physiological and asthmatic airway resistance.