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1.
Genet Med ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36112137

RESUMO

PURPOSE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles. METHODS: Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining. RESULTS: We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance. CONCLUSION: Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

2.
Appl Bionics Biomech ; 2022: 9708829, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35855840

RESUMO

Purpose: Abnormal methylation of Grainyhead-like 2 (GRHL2) is associated with a substantial role in the malignant phenotype of tumor patients. Our present research is aimed at studying the abnormal expression of GRHL2 and the association of methylation in patients with acute leukemia and its relationship with prognosis. Materials and Methods: We used quantitative real-time polymerase chain reaction (qRT-PCR) for detecting the aberrant expression level of GRHL2 in 60 patients with acute leukemia and 60 normal controls. We analyzed the significant correlation between the expression level of GRHL2 with clinicopathological features and patients' prognosis in acute leukemia using the corresponding statistical methods. Secondly, we employed qRT-PCR and Western blotting to detect the mRNA and protein levels of GRHL2 in leukemia cell lines. Next, we used methylation-specific polymerase chain reaction (MSP) technology for detecting the methylation of GRHL2 in clinical samples with acute leukemia and cell lines. Then we investigated the demethylating effect of arsenic trioxide and 5-azacitidine on the mRNA and protein expression levels of GRHL2 in cell lines of acute leukemia. Finally, we studied the effects of arsenide trioxide and 5-azacitidine on the proliferation of leukemia cells and the TGF-ß signaling pathway. Results: We found a lower level of GRHL2 expression not only in acute leukemia patients but also in cell lines when compared with normal controls. At the same time, the expression level of GRHL2 in patients with acute leukemia was significantly correlated with leukocyte count, platelet count, and cytogenetic risk grouping. In addition, the lower GRHL2 expression group showed a significantly lower overall survival rate in acute leukemia patients than that of patients with a higher GRHL2 expression group. Univariate and multivariate analyses revealed that the expression of GRHL2 is an independent risk factor in acute leukemia patients. The methylation level of the GRHL2 promoter region in acute leukemia patients and cell lines was significantly higher than the normal control group, and we found the elevated mRNA and protein levels of GRHL2 in acute leukemia cell lines after the use of the demethylation drug arsenic trioxide and 5-azacitidine. At the same time, arsenide trioxide and 5-azacitidine are associated with the inhibition of cellular proliferation of acute leukemia cells and also promote the elevated expression of TGF-ß signaling pathway-linked proteins, including TGF-ß, Smad2, Smad3, and Smad4. Conclusion: Increased expression and methylation level of GRHL2 are closely associated with the prognosis and malignant phenotype of acute leukemia patients and play an irreplaceable role in the occurrence and development of patients with acute leukemia.

3.
J Adv Res ; 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35618634

RESUMO

INTRODUCTION: Diminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function. OBJECTIVES: This study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD). METHODS: Eight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested. RESULTS: DHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aß burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein. CONCLUSION: DHA improves cognitive function by enhancing hippocampal insulin sensitivity.

4.
Brain Res ; 1788: 147937, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35568085

RESUMO

The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic microenvironment. All constituent cell types play indispensable roles in the BBB's integrity, and other structural BBB components, such as tight junction proteins, adherens junctions, and junctional proteins, can control the barrier permeability. Regarding the need to exchange nutrients and toxic materials, solute carriers, ATP-binding case families, and ion transporter, as well as transcytosis regulate the influx and efflux transport, while the difference in localisation and expression can contribute to functional differences in transport properties. Numerous chemical mediators and other factors such as non-physicochemical factors have been identified to alter BBB permeability by mediating the structural components and barrier function, because of the close relationship with inflammation. In this review, we highlight recently gained mechanistic insights into the maintenance and disruption of the BBB. A better understanding of the factors influencing BBB permeability could contribute to supporting promising potential therapeutic targets for protecting the BBB and the delivery of central nervous system drugs via BBB permeability interventions under pathological conditions.


Assuntos
Barreira Hematoencefálica , Encéfalo , Transporte Biológico/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Permeabilidade , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
5.
Phys Chem Chem Phys ; 24(16): 9384-9393, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35383793

RESUMO

The emerging semiconductor boron arsenide (BAs) with high thermal conductivity has attracted much attention recently, due to its promising application to overcome the bottleneck of high-density heat generated in power electronics and optoelectronic devices. In this work, based on first-principles calculations, we find that cubic BAs possesses high intrinsic electron/hole mobilities and the ionized impurity scattering plays a more important role in carrier scattering, compared with other scattering processes. The mobilities can be significantly enhanced by 14.9% and 76.2% for electrons and holes, respectively, by strain engineering. The investigation of the optoelectronic properties of indirect semiconductor cubic BAs by considering the many-body excitonic effects reveals that the contribution from finite-momentum excitons to optical properties is larger for photon energy ranging from 2.25 eV to 3.50 eV, compared with that from zero-momentum excitons. Finally, we observe that the phonon-electron couplings to total lattice thermal conductivities are non-trivial at low temperatures. These findings provide new insight into the transport and optoelectronic properties of cubic BAs, which are beneficial for the acceleration of the application of this revolutionary thermal management material.

6.
Fungal Genet Biol ; 160: 103674, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35227874

RESUMO

Candida albicans is a common conditional pathogenic fungus in the human body, and its infections have received widespread attention in recent years. Phosphatidylinositol and its derivatives have significant regulatory effects on many physiological processes, such as cell metabolism and growth. In this study, we identified and studied the function of the phosphatidylinositol synthase Pis1 in Candida albicans. The protein has a conserved CAPT motif and multiple transmembrane domains. GFP tagging revealed that Pis1 was located at the endoplasmic reticulum (ER). The PIS1 knockout mutant was constructed using an induction system regulated by the MET3 promoter. Growth assays showed that PIS1 is an essential gene for normal growth of Candida albicans. Overexpression of PIS1 led to high sensitivity to both ER stress and cell wall stress, and down-regulated expression of the genes involved in ER stress response and maintenance of cell wall integrity. Interestingly, PIS1 overexpression enhanced secretion of the extracellular hydrolases. Virulence assays further revealed that PIS1 overexpression increased the fungal virulence, leading to quicker death of the fungus-infected mice and more severe fungal burden in the mouse kidneys. In summary, Pis1 is involved in ER stress response, maintenance of cell wall integrity, and pathogenicity of Candida albicans.


Assuntos
CDP-Diacilglicerol-Inositol 3-Fosfatidiltransferase , Candida albicans , Proteínas Fúngicas , Animais , CDP-Diacilglicerol-Inositol 3-Fosfatidiltransferase/metabolismo , Candida albicans/metabolismo , Candida albicans/patogenicidade , Parede Celular/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas Fúngicas/metabolismo , Camundongos , Virulência
7.
Front Neurosci ; 16: 834683, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281512

RESUMO

Therapeutic treatment options for central nervous system (CNS) diseases are greatly limited by the blood-brain barrier (BBB). Electroacupuncture (EA) can be used to induce an increase in BBB permeability on rats, providing a potential approach for the delivery of drugs from the systemic circulation into the brain. However, there remains a large gap in our knowledge regarding the impact of EA on brain gene expression. This work is focused on investigating the transcriptional changes of rat cerebral cortex following EA and expression changes in genes and bioinformatic analysis was performed. We found that the potential mechanism of EA opening BBB involves receptor-mediated/carrier-mediated endocytosis (RMT/CMT), and related genes include solute carrier (SLC) transporter genes and ATP-binding cassette (ABC) transporter genes. The results also suggested that EA may affect the expression of tight junction (TJ) proteins in endothelial cells by affecting integrin binding, autophagy pathway and calcium signaling pathway, thus further affecting the permeability of blood-brain barrier. Our results provide a valuable resource that will guide mechanism research of EA opening BBB and other ways to mediate drug delivery into the brain.

8.
Procedia Comput Sci ; 200: 451-460, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35284026

RESUMO

The COVID-19 pandemic has forced a sudden change of traditional office works to smart working models, which however force many workers staying at home with a significant increase of sedentary lifestyle. Metabolic disorders, mental illnesses, and musculoskeletal injuries are also caused by the physical inactivity and chronic stress at work, threatening office workers' physical and physiological health. In the modern vision of smart workplaces, cyber-physical systems play a central role to augment objects, environments, and workers with integrated sensing, data processing, and communication capabilities. In this context, a work engagement system is proposed to monitor psycho-physical comfort and provide health suggestion to the office workers. Recognizing their activity, such as sitting postures and facial expressions, could help assessing the level of work engagement. In particular, head and body posture could reflects their state of engagement, boredom or neutral condition. In this paper we proposed a method to recognize such activities using an infrared sensor array by analyzing the sitting postures. The proposed approach can unobstructively sense their activities in a privacy-preserving way. To evaluate the performance of the system, a working scenario has been set up, and their activities were annotated by reviewing the video of the subjects. We carried out an experimental analysis and compared Decision Tree and k-NN classifiers, both of them showed high recognition rate for the eight postures. As to the work engagement assessment, we analyzed the sitting postures to give the users suggestions to take a break when the postures such as lean left/right with arm support, lean left/right without arm support happens very often.

9.
Molecules ; 27(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163951

RESUMO

Phosphorus in the form of phosphate (Pi) is an essential element for metabolic processes, including lipid metabolism. In yeast, the inositol polyphosphate kinase vip1 mediated synthesis of inositol heptakisphosphate (IP7) regulates the phosphate-responsive (PHO) signaling pathway, which plays an important role in response to Pi stress. The role of vip1 in Pi stress and lipid metabolism of Candida albicans has not yet been studied. We found that when vip1Δ/Δ was grown in glucose medium, if Pi was supplemented in the medium or mitochondrial Pi transporter was overexpressed in the strain, the lipid droplet (LD) content was reduced and membrane damage was alleviated. However, further studies showed that neither the addition of Pi nor the overexpression of the Pi transporter affected the energy balance of vip1Δ/Δ. In addition, the LD content of vip1Δ/Δ grown in Pi limitation medium PNMC was lower than that grown in SC, and the metabolic activity of vip1Δ/Δ grown in PNMC was also lower than that grown in SC medium. This suggests that the increase in Pi demand by a high energy metabolic rate is the cause of LD accumulation in vip1Δ/Δ. In addition, in the vip1Δ/Δ strains, the core transcription factor PHO4 in the PHO pathway was transported to the vacuole and degraded, which reduced the pathway activity. However, this does not mean that knocking out vip1 completely blocks the activation of the PHO pathway, because the LD content of vip1Δ/Δ grown in the medium with ß-glycerol phosphate as the Pi source was significantly reduced. In summary, the increased Pi demand and the decreased PHO pathway activity in vip1Δ/Δ ultimately lead to LD accumulation and cell membrane damage.


Assuntos
Metabolismo Energético/fisiologia , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Candida albicans/metabolismo , Membrana Celular/metabolismo , Expressão Gênica/genética , Regulação Fúngica da Expressão Gênica/genética , Fosfatos de Inositol , Gotículas Lipídicas/metabolismo , Fosfatos/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Fosfato)/fisiologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Vacúolos/metabolismo
10.
J Hum Genet ; 67(6): 347-352, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35022528

RESUMO

Müllerian anomaly (M.A.) is a group of congenital anatomic abnormalities caused by aberrations of the development process of the Müllerian duct. M.A. can either be isolated or be involved in Mendelian syndromes, such as Dandy-Walker syndrome, Holt-Oram syndrome and Bardet-Biedl syndrome, which are often associated with both uterus and kidney malformations. In this study, we applied a genotype-first approach to analyze the whole-exome sequencing data of 492 patients with M.A. Six potential pathogenic variants were found in five genes previously related to female urogenital deformities (PKD1, SON, SALL1, BMPR1B, ITGA8), which are partially overlapping with our patients' phenotypes. We further identified eight incidental findings in seven genes related to Mendelian syndromes without known association with reproductive anomalies (TEK, COL11A1, ANKRD11, LEMD3, DLG5, SPTB, BMP2), which represent potential phenotype expansions of these genes.


Assuntos
Anormalidades Múltiplas , Deformidades Congênitas das Extremidades Inferiores , Deformidades Congênitas das Extremidades Superiores , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Feminino , Genótipo , Humanos , Deformidades Congênitas das Extremidades Inferiores/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/patologia , Deformidades Congênitas das Extremidades Superiores/genética
11.
Biochem Biophys Res Commun ; 591: 88-94, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-34999259

RESUMO

Candida albicans is an important opportunistic fungus in the clinic. In recent years, with the widespread use of antibiotics, drug-resistant strains have been isolated in the clinic, so finding new drug targets has become an urgent problem to be solved. The vacuole and mitochondria patch (vCLAMP) and the ER-mitochondria encounter structure (ERMES) are new types of inner membrane junction systems in Saccharomyces cerevisiae. However, the functions in maintaining cell survival of the two structures have not yet been elucidated in C. albicans. In this study, VAM6 and MDM34 knockout mutants (vam6Δ/Δmet-MDM34) were constructed using an induction system regulated by the MET3 promoter. PI-positive assays showed that deletion of vCLAMP and ERMES led to abnormal growth of C. albicans. Furthermore, the vam6Δ/Δmet-MDM34 mutant exhibited obvious mitochondrial fragmentation, mtDNA damage, reduced ATP levels, and abnormal mitochondrial membrane potential, indicating its important role in maintaining the structures and functions of mitochondria. Moreover, deletion of vCLAMP and ERMES inhibited filamentous growth. Overall This study shows that vCLAMP and ERMES play important roles in maintaining the survival of C. albicans cells.


Assuntos
Candida albicans/citologia , Candida albicans/metabolismo , Retículo Endoplasmático/metabolismo , Membranas Intracelulares/metabolismo , Mitocôndrias/metabolismo , Vacúolos/metabolismo , Candida albicans/crescimento & desenvolvimento , Sobrevivência Celular , Proteínas Fúngicas/metabolismo , Hifas/crescimento & desenvolvimento
12.
Mater Horiz ; 8(4): 1253-1263, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34821918

RESUMO

The strategy of band convergence of multi-valley conduction bands or multi-peak valence bands has been widely used to search or improve thermoelectric materials. However, the phonon-assisted intervalley scatterings due to multiple band degeneracy are usually neglected in the thermoelectric community. In this work, we investigate the (thermo)electric properties of non-polar monolayer ß- and α-antimonene considering full mode- and momentum-resolved electron-phonon interactions. We also analyze thoroughly the selection rules on electron-phonon matrix-elements using group-theory arguments. Our calculations reveal strong intervalley scatterings between the nearly degenerate valley states in both ß- and α-antimonene, and the commonly-used deformation potential approximation neglecting the dominant intervalley scattering gives inaccurate estimations of the electron-phonon scattering and thermoelectric transport properties. By considering full electron-phonon interactions based on the rigid-band approximation, we find that, the maximum value of the thermoelectric figure of merits zT at room temperature reduces to 0.37 in ß-antimonene, by a factor of 5.7 compared to the value predicted based on the constant relaxation-time approximation method. Our work not only provides an accurate prediction of the thermoelectric performances of antimonenes, which reveals the key role of intervalley scatterings in determining the electronic part of zT, but also exhibits a computational framework for thermoelectric materials.

13.
J Acoust Soc Am ; 150(4): 2514, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34717451

RESUMO

A calculation method is proposed to investigate trapped modes in a rigid waveguide with rigid obstacles in the presence of non-potential steady mean flow in a two-dimensional coordinate system. This method facilitates the investigation of trapped modes in the presence of non-potential flow. A coupled calculation method that combines computational fluid dynamics and computational aeroacoustics is used. Galbrun's equation of aeroacoustics is used and discretized by the finite element method. The boundary condition corresponding to the unbounded domain is modeled by the perfectly matched layer technique. The proposed approach facilitates the investigation of the trapped modes generated by obstacles with different geometrical shapes. The effects of both the dimensions of different geometrical shapes (e.g., thin plate, rectangular, and elliptical) and the presence of the non-potential flow on the trapped modes are studied. It is observed that the non-potential flow alters the pressure distribution around the obstacle and the frequencies of the trapped modes. The results show good agreement with the literature. Also, experimental investigations are performed to validate the model.

14.
J Phys Chem A ; 125(28): 6096-6108, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34240862

RESUMO

Cytidine ribonucleosides were furnished at O5' with fixed-charge 6-trimethylammoniumhexan-1-aminecarbonyl tags and studied by UV-vis photodissociation action spectroscopy in the gas phase to probe isolated nucleobase chromophores in their neutral, protonated, and hydrogen-adduct radical forms. The action spectrum of the doubly charged cytidine conjugate showed bands at 310 and 270 nm that were assigned to the N3- and O2-protonated cytosine tautomers formed by electrospray, respectively. In contrast, cytidine conjugates coordinated to dibenzo-18-crown-6-ether (DBCE) in a noncovalent complex were found to strongly favor protonation at N3, forming a single-ion tautomer. This allowed us to form cytidine N3-H radicals by electron transfer dissociation of the complex and study their action spectra. Cytidine radicals showed only very weak absorption in the visible region of the spectrum for dipole-disallowed transitions to the low (A and B) excited states. The main bands were observed at 360, 300, and 250 nm that were assigned with the help of theoretical vibronic spectra obtained by time-dependent density functional theory calculations of multiple (>300) radical vibrational configurations. Collision-induced dissociations of cytidine radicals proceeded by major cleavage of the N1-C1' glycosidic bond leading to loss of cytosine and competitive loss of N3-hydrogen atom. These dissociations were characterized by calculations of transition-state structures and energies using combined Born-Oppenheimer molecular dynamics and DFT calculations. Overall, cytidine radicals were found to be kinetically and thermodynamically more stable than previously reported analogous adenosine and guanosine radicals.

15.
Biomaterials ; 275: 120863, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139509

RESUMO

Transvaginal meshes repair for treating pelvic organ prolapse (POP) was halted by the U. S. Food and Drug Administration (FDA) because they can lead to severe complications. Therefore, investigations of new therapeutic strategies are urgently needed. Cell-based regenerative therapy holds great promise for the repair and restoration of damaged tissue. Here, we generated a bioengineered graft by seeding human umbilical cord mesenchymal stem cells (HUMSCs) on bioscaffolds to reconstruct the damaged vagina. In the in vitro study, HUMSCs proliferated well and the density was appropriate after 5 days of culture. Besides, we demonstrated that the differentiation potential of HUMSCs was maintained with external growth factor stimulation. The complete transcriptomic profile of HUMSCs revealed that HUMSCs cultured on grafts produced significantly higher levels of proangiogenic cytokines than cells cultured in tissue culture plates (TCPs). Three months after implantation of the bioengineered grafts into ovariectomized (OVX) rhesus monkeys via sacrocolpopexy, extracellular matrix reorganization, large muscle bundle formation, angiogenesis and, mechanical properties of the vagina were enhanced. To our knowledge, this is the first demonstration of the utility of stem cell-based bioengineered grafts for repairing damaged vaginal tissue in rhesus monkeys. These results elucidate a new approach for vagina repair and provide new ideas for treating POP.


Assuntos
Células-Tronco Mesenquimais , Prolapso de Órgão Pélvico , Animais , Matriz Extracelular , Feminino , Macaca mulatta , Cordão Umbilical
16.
Mycopathologia ; 186(4): 477-486, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34057669

RESUMO

Vacuole and mitochondria patches (vCLAMPs) are involved in the stress resistance of yeast, but their exact role in autophagy remains so far unclear. This study, for the first time, investigated the role of the vCLAMP core protein Vam6 in autophagy of Candida albicans. The experiments demonstrated that the deletion of VAM6 led to a growth defect under nitrogen starvation. Also, western blotting revealed that the vam6Δ/Δ mutant attenuated degradation of Atg8 (an autophagy indicator), Lap41 (an indicator of the cytoplasm to vacuole targeting pathway), and Csp37 (a mitophagy indicator). Moreover, the activity of carboxypeptidase Y and the levels of the vacuolar phospholipase Atg15 were significantly decreased in the mutant, which confirmed the defect of autophagy caused by deletion of VAM6. Overall, these results revealed that Vam6 is essential in maintaining the autophagic process under nitrogen starvation, and this provided new insights into the correlation between vCLAMPs and autophagy.


Assuntos
Autofagia , Candida albicans , Mitocôndrias , Vacúolos , Candida albicans/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Vacúolos/metabolismo
17.
J Am Soc Mass Spectrom ; 32(3): 772-785, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33567214

RESUMO

We report the generation of gas-phase riboguanosine radicals that were tagged at ribose with a fixed-charge 6-(trimethylammonium)hexane-1-aminocarbonyl group. The radical generation relied on electron transfer from fluoranthene anion to noncovalent dibenzocrown-ether dication complexes which formed nucleoside cation radicals upon one-electron reduction and crown-ether ligand loss. The cation radicals were characterized by collision-induced dissociation (CID), photodissociation (UVPD), and UV-vis action spectroscopy. Identification of charge-tagged guanosine radicals was challenging because of spontaneous dissociations by loss of a hydrogen atom and guanine that occurred upon storing the ions in the ion trap without further excitation. The loss of H proceeded from an exchangeable position on N-7 in guanine that was established by deuterium labeling and was the lowest energy dissociation of the guanosine radicals according to transition-state energy calculations. Rate constant measurements revealed an inverse isotope effect on the loss of either hydrogen or deuterium with rate constants kH = 0.25-0.26 s-1 and kD = 0.39-0.54 s-1. We used time-dependent density functional theory calculations, including thermal vibronic effects, to predict the absorption spectra of several protomeric radical isomers. The calculated spectra of low-energy N-7-H guanine-radical tautomers closely matched the action spectra. Transition-state-theory calculations of the rate constants for the loss of H-7 and guanine agreed with the experimental rate constants for a narrow range of ion effective temperatures. Our calculations suggest that the observed inverse isotope effect does not arise from the isotope-dependent differences in the transition-state energies. Instead, it may be caused by the dynamics of post-transition-state complexes preceding the product separation.

18.
Eur J Obstet Gynecol Reprod Biol ; 259: 12-17, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33550106

RESUMO

OBJECTIVE: The aim was to evaluate the voiding function and voiding dysfunction 3 months after laparoscopic uterosacral ligament suspension (LUSLS). We identified risk factors for postoperative voiding dysfunction. STUDY DESIGN: This retrospective study included 57 women with apical prolapse who underwent LUSLS with stage II or greater apical prolapse and without advanced anterior vaginal prolapse (stage III or IV). Data were collected from electronic medical records. Voiding function was assessed by uroflowmetry, PVR examination, and self-report questionnaires (the Pelvic Floor Distress Inventory-20 and the Urinary Impact Questionnaire) at baseline and 3 months after surgery. Voiding dysfunction was defined as an average flow rate (Qave)<10 ml/s, a maximum flow rate (Qmax)<15 ml/s, or a postvoid residual volume (PVR)>50 ml. Statistical analyses were performed using paired-sample t tests, χ2 tests, and multivariate logistic regression. RESULTS: Thirty-five percent of women suffered from voiding dysfunction preoperatively. Uroflowmetry parameters and PVR, objective symptoms including voiding difficulties, incomplete empty, frequency and urinary incontinence didn't show significant improvement postoperatively (all p>0.05). Low Qave was identified as an independent risk factor of post voiding dysfunction (odds ratio, 0.558; 95 % CI, 0.324-0.963). CONCLUSIONS: Approximately one-third of women suffering from apical prolapse without advanced anterior vaginal wall had evidence of voiding dysfunction preoperatively. LUSLS has no obvious effect on uroflowmetry parameters and clinical symptoms.


Assuntos
Laparoscopia , Prolapso de Órgão Pélvico , Prolapso Uterino , Feminino , Humanos , Ligamentos/cirurgia , Prolapso de Órgão Pélvico/cirurgia , Estudos Retrospectivos , Prolapso Uterino/cirurgia
19.
Menopause ; 28(5): 538-545, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33625108

RESUMO

OBJECTIVE: To evaluate the 5-year pessary continuation rate and identify clinical risk factors associated with discontinuation in patients with symptomatic pelvic organ prolapse (POP). METHODS: In this prospective observational study, 312 women with symptomatic POP received pessary treatment between November 2013 and July 2015 in Peking Union Medical College Hospital, China, a tertiary referral center. Patients were initially fitted with a ring pessary with support. Those who failed were fitted with a Gellhorn pessary. A successful pessary fitting was defined as a patient who was fitted and continued to use the pessary 2 weeks later. Patients with successful pessary fitting were followed for 5 years. Data analysis was performed with t tests, nonparametric tests, chi-square tests, and logistic regression. RESULTS: In total, 265 patients (84.9%) had successful pessary fitting. After 5 years, 180 of 239 patients continued pessary use (75.3% continuation rate), with 26 lost to follow-up. The discontinuation rates decreased over time, from 8.7% at 1 year to 2.7% at 5 years. Total vaginal length < 7.5 cm (TVL, OR = 2.7, 95% CI 1.3-5.7, P = 0.007), improvement in Urinary Impact Questionnaire-7 scores < 50% at 3 months (OR = 2.1, 95% CI 1.1-4.2, P = 0.025), and incapability of self-care (OR = 2.6, 95% CI 1.3-5.1, P = 0.008) were potential discontinuation risk factors. CONCLUSION: Three-quarters of patients with symptomatic POP had successful pessary treatment at 5-year follow-up. TVL < 7.5 cm, poor urinary symptom relief at 3 months, and incapability of self-care were potential discontinuation risk factors.


Assuntos
Prolapso de Órgão Pélvico , Pessários , China , Feminino , Humanos , Prolapso de Órgão Pélvico/terapia , Estudos Prospectivos , Resultado do Tratamento , Vagina
20.
Antioxidants (Basel) ; 10(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478009

RESUMO

Candida albicans is one of the most common opportunistic fungal pathogens in human beings. When infecting host cells, C. albicans is often exposed to oxidative stress from the host immune defense system. Maintenance of mitochondrial and vacuolar functions is crucial for its resistance to oxidative stress. However, the role of vacuole and mitochondria patchs (vCLAMPs) in cellular oxidative stress resistance and in the maintenance of organelle functions remains to be elucidated. Herein, the function of the vCLAMP protein Vam6 in response to oxidative stress was explored. The results showed that the vam6∆/∆ mutant exhibited obvious mitochondrial swelling, mtDNA damage, reduced activity of antioxidant enzymes, and abnormal vacuolar morphology under H2O2 treatment, indicating its important role in maintaining the structures and functions of both mitochondria and vacuoles under oxidative stress. Further studies showed that deletion of VAM6 attenuated hyphal development under oxidative stress. Moreover, loss of Vam6 obviously affected host tissue invasion and virulence of C. albicans. Taken together, this paper reveals the critical role of vCLAMPs in response to oxidative stress in C. albicans.

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