RESUMEN
Starvation- or stress-induced phosphatidylinositol 3-phosphate (PtdIns3P/PI3P) production at the endoplasmic reticulum (ER) subdomains organizes phagophore assembly and autophagosome formation. Coat protein complex II (COPII) vesicles budding from ER exit site (ERES) also contribute to autophagosome formation. Whether any PtdIns3P phosphatase functions at ERES to inhibit macroautophagy/autophagy is unknown. Here we report Myotubularin 2 (MTM2) of Arabidopsis as a PtdIns3P phosphatase that localizes to ERES and negatively regulates autophagy. MTM2 binds PtdIns3P with its PH-GRAM domain in vitro and acts toward PtdIns3P in vivo. Transiently expressed MTM2 colocalizes with ATG14b, a subunit of the phosphatidylinositol 3-kinase (PtdIns3K) complex, and overexpression of MTM2 blocks autophagic flux and causes over-accumulation of ATG18a, ATG5, and ATG8a. The mtm2 mutant has higher levels of autophagy and is more tolerant to starvation, whereas MTM2 overexpression leads to reduced autophagy and sensitivity to starvation. The phenotypes of mtm2 are suppressed by ATG2 mutation, suggesting that MTM2 acts upstream of ATG2. Importantly, MTM2 does not affect the endosomal functions of PtdIns3P. Instead, MTM2 specifically colocalizes with COPII coat proteins and is cradled by the ERES-defining protein SEC16. MTM2 interacts with SEC23A with its phosphatase domain and inhibits COPII-mediated protein secretion. Finally, a role for MTM2 in salt stress response is uncovered. mtm2 resembles the halophyte Thellungiella salsuginea in its efficient vacuolar compartmentation of Na+, maintenance of chloroplast integrity, and timely regulation of autophagy-related genes. Our findings reveal a balance between PtdIns3P synthesis and turnover in autophagosome formation, and provide a new link between autophagy and COPII function.
RESUMEN
The proper distribution of lipids within organelle membranes requires rapid interorganelle lipid transport, much of which occurs at membrane contact sites and is mediated by lipid transfer proteins (LTPs). Our current understanding of LTP mechanism and function is based largely on structural studies and in vitro reconstitution. Existing cellular assays for LTP function use indirect readouts, and it remains an open question as to whether substrate specificity and transport kinetics established in vitro are similar in cellular settings. Here, we harness bioorthogonal chemistry to develop tools for direct visualization of interorganelle transport of phospholipids between the plasma membrane (PM) and the endoplasmic reticulum (ER). Unnatural fluorescent phospholipid analogs generated by the transphosphatidylation activity of phospholipase D (PLD) at the PM are rapidly transported to the ER dependent in part upon extended synaptotagmins (E-Syts), a family of LTPs at ER-PM contact sites. Ectopic expression of an artificial E-Syt-based tether at ER-mitochondria contact sites results in fluorescent phospholipid accumulation in mitochondria. Finally, in vitro reconstitution assays demonstrate that the fluorescent lipids are bona fide E-Syt substrates. Thus, fluorescent lipids generated in situ via PLD activity and bioorthogonal chemical tagging can enable direct visualization of the activity of LTPs that mediate bulk phospholipid transport at ER-PM contact sites.
Asunto(s)
Retículo Endoplásmico , Fosfolípidos , Fosfolípidos/metabolismo , Fosfolípidos/química , Retículo Endoplásmico/metabolismo , Humanos , Transporte Biológico , Membrana Celular/metabolismo , Colorantes Fluorescentes/química , Fosfolipasa D/metabolismo , Mitocondrias/metabolismo , AnimalesRESUMEN
OBJECTIVES: To depict the seasonality and age variations of community-acquired pneumonia (CAP) incidence in the context of the COVID-19 impact. DESIGN: Retrospective cohort study. PARTICIPANTS: The observational cohort study was conducted at Soochow University Affiliated Children's Hospital from January 2017 to June 2021 and involved 132 797 children born in 2017 or 2018. They were followed and identified CAP episodes by screening on the Health Information Systems of outpatients and inpatients in the same hospital. OUTCOME: The CAP episodes were defined when the diagnoses coded as J09-J18 or J20-J22. The incidence of CAP was estimated stratified by age, sex, birth year, health status group, season and month, and the rate ratio was calculated and adjusted by a quasi-Poisson regression model. Stratified analysis of incidence of CAP by birth month was conducted to understand the age and seasonal variation. RESULTS: The overall incidence of CAP among children aged ≤5 years was 130.08 per 1000 person years. Children aged ≤24 months have a higher CAP incidence than those aged >24 months (176.84 vs 72.04 per 1000 person years, p<0.001). The CAP incidence increased from October, peaked at December and January and the highest CAP incidence was observed in winter (206.7 per 1000 person years, 95% CI 204.12 to 209.28). A substantial decline of CAP incidence was observed during the COVID-19 lockdown from February to August 2020, and began to rise again when the communities reopened. CONCLUSIONS: The burden of CAP among children is considerable. The incidence of CAP among children ≤5 years varied by age and season and decreased during COVID-19 lockdown.
Asunto(s)
COVID-19 , Infecciones Comunitarias Adquiridas , Neumonía , Niño , Humanos , Preescolar , Hospitalización , Estudios de Cohortes , Estudios Retrospectivos , Incidencia , Neumonía/epidemiología , Neumonía/etiología , COVID-19/epidemiología , COVID-19/complicaciones , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/complicaciones , China/epidemiología , Hospitales PediátricosRESUMEN
Children with special health care needs (CSHCNs) are at an increased risk of vaccine-preventable infections (VPDs), but they also face the dilemma of vaccine hesitancy. We obtained information on pediatric visits from the Referral and Assessment Information System for Vaccination (RAISV) and information on vaccination from the Jiangsu Province Immunization Information System (JSIIS). We followed the occurrence of Adverse Events Following Immunization (AEFIs) and VPDs by actively calling and querying the China Information System for Disease Control and Prevention (CISDCP). The Poisson test was used to compare the incidence of AEFIs between groups. A total of 5,037 children who visited a vaccination assessment clinic were followed-up in this study. The majority were children with developmental anomalies (28.5%), certain conditions originating in the perinatal period (12.1%), and nervous system disorders (9.0%). Most CSHCNs (66.9%) were advised to have all vaccines according to routine practice, 29.0% were advised to have partial vaccination, and 4.1% were advised to delay all vaccines and wait for future assessment. A total of 201 (4.0%) CSHCNs were not vaccinated, although they were assessed to be eligible for vaccination. By querying the immunization planning module in CISDCP, we observed 55 AEFI cases, which amounted to an incidence rate of 1.2 per 1,000, and the occurrence of abnormal reactions was not significantly different compared with the general population. The vaccination program following the designed workflow for CSHCNs was safe and could be recommended in other areas.
Asunto(s)
Inmunización , Vacunación , Femenino , Embarazo , Humanos , Niño , Estudios Retrospectivos , Vacunación/efectos adversos , China/epidemiología , Instituciones de SaludRESUMEN
Persistent infection with high-risk human papillomavirus (HR-HPV) is a known pathogenic factor of cervical cancer. To develop scientific guidance for cervical cancer screening and HPV vaccination, we analyzed HPV genotypes in Suzhou City, China. This study utilized data from the cervical cancer screening project in Suzhou from 2016 to 2021. A total of 444,471 female residents who voluntarily underwent HPV testing were included in the study. The overall HR-HPV prevalence was 10.2%. The three most common HR-HPV genotypes were HPV52 (2.81%), HPV58 (1.64%), and HPV16 (1.46%). The rate of HPV infection increased with age. Having a junior school education or higher was a protective factor compared to having an education level below junior school. The overall HPV infection rate showed a downwards trend from 2016 to 2021. HPV16 exhibited the fastest annual decline rate, followed by HPV18. As the severity of cervical intraepithelial neoplasia increases, the detection rate of HPV infection significantly increased. In conclusion, in addition to cervical cancer screening, it is important to pay attention to health promotion and education for low-educated women aged 45-59. Considering the distribution of HPV genotypes, prioritizing the administration of high-valency HPV vaccines to local seventh-grade female students is recommended.
Asunto(s)
Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/patología , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Virus del Papiloma Humano , Prevalencia , Detección Precoz del Cáncer , Genotipo , Papillomaviridae/genética , China/epidemiología , Papillomavirus Humano 16/genéticaRESUMEN
Project-based learning (PBL) has been identified as an effective pedagogy for instructors to help students to learn interdisciplinary knowledge, problem-solving skills, modes of thinking, and collaborative practices through solving problems in a real-world context. However, previous studies reported that instructors from K-12 to tertiary learning environments found it challenging to implement such a pedagogy for various reasons. The emergence of PBL E-learning platforms in the recent decade has attracted increasing interest in adoption and seems to provide a solution to tackle the difficulties in PBL implementation. Yet little is known about designing these platforms and how they facilitate the PBL learning process and management. In the current study, we conducted a multiple case survey study on 16 PBL learning platforms in English and Chinese, collected data on their features and functions, categorized them according to their services provided, and analyzed how they tackle the implementation challenges. Additionally, we identified four trends in PBL development as pedagogy, the skills, and competence required for teachers and students to successfully carry out PBL via e-learning platforms and provide suggestions to improve and refine the platform design for educational technologists and related stakeholders. The limitations of this study and the future research direction are included.
RESUMEN
The study evaluates the outcomes of including varicella vaccines (VarV) in the local expanded programme on immunization (EPI) on the seropositivity rates and corresponding protective effects for children aged 3-6 years in Suzhou. The study is observational. Varicella prevalence in children was assessed based on data from the China Information System for Disease Control and Prevention (CISDCP) and the Jiangsu Province Vaccination Integrated Service Management Information System (JPVISMIS). Seropositivity was determined using the enzyme-linked immunosorbent assay (ELISA). A total of 2,873 children aged 3-6 years were enrolled in this study. The seropositivity rates were 95.31% and 86.89% for children with and without the strategy, respectively. The difference in seropositivity rate in children using the different strategies was statistically significant (Trend χ2 = 0.397, P = .255). It is therefore suggested that Suzhou had a high rate of occult infection before the inclusion of varicella vaccine in the EPI. The difference in seroprevalence rate between children with no history of varicella vaccination and those with a history of varicella vaccination was statistically different (χ2 = 51.362, P < .001). The positive rates of antibodies increased with increasing doses of vaccination (χ2 = 56.252, P < .001). For the protective effect of one-dose and two-dose, it was found that the protection rates of one-dose were 72.98% and 100.00%, respectively. The varicella vaccine is an effective method to prevent varicella disease, which can increase serum seroprevalence levels and block the transmission of varicella disease.
Asunto(s)
Varicela , Humanos , Niño , Estudios Seroepidemiológicos , Varicela/epidemiología , Varicela/prevención & control , Vacuna contra la Varicela , Herpesvirus Humano 3 , Vacunación , Vacunas Atenuadas , Anticuerpos AntiviralesRESUMEN
As the autophagosome forms, its membrane surface area expands rapidly, while its volume is kept low. Protein-mediated transfer of lipids from another organelle to the autophagosome likely drives this expansion, but as these lipids are only introduced into the cytoplasmic-facing leaflet of the organelle, full membrane growth also requires lipid scramblase activity. ATG9 harbors scramblase activity and is essential to autophagosome formation; however, whether ATG9 is integrated into mammalian autophagosomes remains unclear. Here we show that in the absence of lipid transport, ATG9 vesicles are already competent to collect proteins found on mature autophagosomes, including LC3-II. Further, we use styrene-maleic acid lipid particles to reveal the nanoscale organization of protein on LC3-II membranes; ATG9 and LC3-II are each fully integrated into expanding autophagosomes. The ratios of these two proteins at different stages of maturation demonstrate that ATG9 proteins are not continuously integrated, but rather are present on the seed vesicles only and become diluted in the expanding autophagosome membrane.
Asunto(s)
Autofagosomas , Proteínas de la Membrana , Animales , Autofagosomas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Autofagia , Transporte de Proteínas , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Lípidos , Mamíferos/metabolismoRESUMEN
Estrogens in personal care products are harmful to customers. Conventional methods such as HPLC and LC-MS require tedious sample pretreatment and long analytical time. Paper-spray ionization mass spectrometry (PSI-MS) is a powerful tool for the determination of compounds with little time and minimal pretreatment procedures. Since most estrogens show poor responses in PSI-MS, we developed a chemical derivatization and PSI-MS method to determinate three estrogens: estradiol, estriol and ethinyloestradiol with estradiol valerate as the internal standard (I.S.). After derivatization with 2-fluoro-1-methyl-pyridinium-p-toluene-sulfonate, the three estrogens could be quantified in seconds. This method showed good linearity in the range of 0.1~30 µg·mL-1, with R2 > 0.999. Their recovery results were all between 85%~115%. The limits of detection (LOD) were 0.04 µg·mL-1, 0.02 µg·mL-1 and 0.02 µg·mL-1 for estradiol, estriol and ethinyloestradiol respectively, which improved around 200, 2000, and 900 times compared to non-derivative PSI-MS. The method could quantitatively determine estrogens in cosmetics.
Asunto(s)
Cosméticos , Estrógenos , Estrógenos/química , Espectrometría de Masas en Tándem/métodos , Estradiol/análisis , Estriol , EtinilestradiolRESUMEN
Background: The varicella vaccine is excluded from the Chinese national immunisation programme but is included in the local expanded programme on immunisation (EPI) in the Suzhou Prefecture. This study investigated the epidemiological characteristics of the varicella cases during the implementation of different immunisation strategies in the Suzhou Prefecture, Jiangsu Province. Methods: In this study, we used descriptive statistics. Information on reported instances from 2012 to 2021 was first retrieved. Data on varicella cases were collected from the China Information System for Disease Control and Prevention (CISDCP). Similarly, information on vaccinated children was obtained from the Jiangsu Province Vaccination Integrated Service Management Information System (JPVISMIS). The census data in this study was procured from the Suzhou Bureau of Statistics. Results: From 2012 to 2021, a total of 118,031 cases of varicella were reported in Suzhou, and the average annual reported incidence was 91.35 per 100,000. The average yearly incidence after implementing the two-dose varicella vaccination decreased by 41.57% compared with the implementation of one dose. This study demonstrates two annual incidence peaks, a small peak between April and July and a prominent peak between October and January. It is also possible that this seasonal distribution is related to the geography of Suzhou. The average annual reported incidence between districts with a statistically significant difference (χ2 = 98.077, p < 0.05). The one-dose varicella vaccination coverage gradually increased from 55.34% in 2012 to 89.06% in 2021 and the two-dose varicella vaccination coverage gradually increased from 0.27% in 2012 to 82.17% in 2021. Conclusions: Administering the varicella vaccine in the local EPI has significantly decreased the incidence rate and the total number of cases. A two-dose vaccination schedule is still the best vaccination strategy for varicella vaccine effectiveness.
RESUMEN
TMEM106B, a type II lysosomal transmembrane protein, has recently been associated with brain aging, hypomyelinating leukodystrophy, frontotemporal lobar degeneration (FTLD) and several other brain disorders. TMEM106B is critical for proper lysosomal function and TMEM106B deficiency leads to myelination defects, FTLD related pathology, and motor coordination deficits in mice. However, the physiological and pathological functions of TMEM106B in the brain are still not well understood. In this study, we investigate the role of TMEM106B in the cerebellum, dysfunction of which has been associated with FTLD and other brain disorders. We found that TMEM106B is ubiquitously expressed in neurons in the cerebellum, with the highest levels in the Purkinje neurons. Aged TMEM106B-deficient mice show significant loss of Purkinje neurons specifically in the anterior lobe of the cerebellum. Increased microglia and astrocyte activation, as well as an accumulation of ubiquitinated proteins, p62 and TDP-43 were also detected in the cerebellum of aged TMEM106B deficient mice. In the young mice, myelination defects and a significant loss of synapses between Purkinje and deep cerebellar nuclei neurons were observed. Interestingly, TMEM106B deficiency causes distinct lysosomal phenotypes in different types of neurons and glia in the cerebellum and frontal cortex. In humans, TMEM106B rs1990622 risk allele (T/T) is associated with increased Purkinje neuron loss. Taken together, our studies support that TMEM106B regulates lysosomal function in a cell-type-specific manner and TMEM106B is critical for maintaining synaptic integrity and neural functions in the cerebellum.
Asunto(s)
Encefalopatías , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Animales , Encefalopatías/genética , Demencia Frontotemporal/genética , Degeneración Lobar Frontotemporal/patología , Proteínas de la Membrana/genética , Ratones , Proteínas del Tejido Nervioso/genética , Células de Purkinje/patologíaRESUMEN
BACKGROUND: In China, 13-valent pneumococcal conjugate vaccine (PCV13) has been available since 2017, but only via the private market with low uptake rate. We assessed the direct effectiveness of PCV13 against community acquired pneumonia (CAP) associated with PCV13 serotype carriage (VT-CAP). METHODS: We conducted an observational cohort study of children born during 12-Dec-2016 to 30-Nov-2018 identified in the Suzhou Centers for Disease Control vaccine registry database, and who had at least one inpatient or outpatient record at the Suzhou University Affiliated Children's hospital (SCH) health-information-system (HIS) database. The vaccine registry cohort was followed through the HIS database through 30-Jun-2019 to identify hospitalized VT-CAP. Pneumococci were isolated from deep upper respiratory aspirates and serotyped with Quellung reactions. RESULTS: We included 139,127 children of whom 9024 (6.5%) received 1â¯+â¯PCV13 doses (95.8% received 2â¯+â¯doses). Within the total cohort, we identified 548 children hospitalized at SCH for VT-CAP, of whom 10 had received 2â¯+â¯PCV13 doses. Adjusted for demographics, receipt of other childhood vaccines, and underlying medical conditions, the first visit vaccine effectiveness among children who had received 2â¯+â¯PCV13 doses was 60.9% (95% CI: 25.8% to 79.4%) for VT-CAP and 17.9% (95% CI: 5.5% to 28.6%) for clinical CAP. Incidence rate reductions per 100,000 child-years of observation for all visits were 208 (95% CI: 118 to 298) for VT-CAP and 720 (95% CI: 304 to 1135) for clinical CAP. CONCLUSIONS: PCV13 was protective against hospitalized VT-CAP and clinical CAP with large associated incidence rate reductions among children living in Suzhou, China.
Asunto(s)
Infecciones Comunitarias Adquiridas , Infecciones Neumocócicas , Neumonía Neumocócica , Niño , China/epidemiología , Estudios de Cohortes , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/prevención & control , Humanos , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas , Neumonía Neumocócica/epidemiología , Neumonía Neumocócica/prevención & control , Serogrupo , Vacunas ConjugadasRESUMEN
During autophagy, LC3 and GABARAP proteins become covalently attached to phosphatidylethanolamine on the growing autophagosome. This attachment is also reversible. Deconjugation (or delipidation) involves the proteolytic cleavage of an isopeptide bond between LC3 or GABARAP and the phosphatidylethanolamine headgroup. This cleavage is carried about by the ATG4 family of proteases (ATG4A, B, C, and D). Many studies have established that ATG4B is the most active of these proteases and is sufficient for autophagy progression in simple cells. Here we examined the second most active protease, ATG4A, to map out key regulatory motifs on the protein and to establish its activity in cells. We utilized fully in vitro reconstitution systems in which we controlled the attachment of LC3/GABARAP members and discovered a role for a C-terminal LC3-interacting region on ATG4A in regulating its access to LC3/GABARAP. We then used a gene-edited cell line in which all four ATG4 proteases have been knocked out to establish that ATG4A is insufficient to support autophagy and is unable to support GABARAP proteins removal from the membrane. As a result, GABARAP proteins accumulate on membranes other than mature autophagosomes. These results suggest that to support efficient production and consumption of autophagosomes, additional factors are essential including possibly ATG4B itself or one of its proteolytic products in the LC3 family.
Asunto(s)
Proteínas Relacionadas con la Autofagia/metabolismo , Cisteína Endopeptidasas/metabolismo , Macroautofagia , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Cisteína Endopeptidasas/genética , Células HEK293 , Humanos , Proteínas Asociadas a Microtúbulos/metabolismoRESUMEN
BACKGROUND: Varicella-zoster virus (VZV) infection in children is an important public health problem in China. We performed the current study to explore the seroprevalence of VZV infection in Chinese children in order to provide more information for improvement of varicella vaccination in China. METHODS: Three thousand fourteen children were recruited from Chinese kindergarten students aged from four to six years. Anti-VZV IgG and IgM were assayed using enzyme-linked immunosorbent assay. Both ORF22 and ORF62 of VZV were amplified, sequenced, and analyzed by nested PCR. RESULTS: Among 3014 children, 43.9% of boys and 46.3% of girls were vaccinated with varicella vaccine, respectively. The seroprevalence of anti-VZV IgG was 54.4% in the children with varicella vaccination, which was significantly higher than those in unvaccinated children (49.2%) (χ2 = 8.206, P = 0.004). Among of the vaccinated children, the detection rates of VZV IgG antibody increased with age, with 49.4, 50.9 and 58.9% in 4, 5 and 6-year groups, respectively (Trend χ2 = 17.202, P = 0.002). However, there was no difference in anti-VZV IgG detection rates among those unvaccinated children in different age groups (Trend χ2 = 8.681, P = 0.070). In addition, 13 boys and 13 girls were positive for anti-VZV IgM, respectively. Among of them, eight children (0.6%) have received varicella vaccination, which was similar to those in unvaccinated children (1.1%). However, only one ORF22 sequence was isolated from an unvaccinated 5-year boy. Compared to the reference VZV sequences, the nucleotide homology was estimated to be 99.7% with genotype J. CONCLUSIONS: Our study indicated that about half of Chinese children aged four to six years have a high risk of VZV infection. It should be helpful for the evaluation on the necessity of varicella immunization in China.
Asunto(s)
Vacuna contra la Varicela/uso terapéutico , Infección por el Virus de la Varicela-Zóster/epidemiología , Anticuerpos Antiidiotipos/inmunología , Niño , Preescolar , China/epidemiología , Femenino , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/patogenicidad , Humanos , Masculino , Filogenia , Estudios Seroepidemiológicos , Vacunación/estadística & datos numéricos , Infección por el Virus de la Varicela-Zóster/inmunologíaRESUMEN
Chinese white wax solid lipid nanoparticles (cwSLNs) were prepared by high shear homogenization and ultrasound methods. Using an optimized formula, spherical cwSLNs with an average particle size of 401.9 ± 21.3 nm were obtained. The cwSLNs showed high entrapment efficiency, approximately 84.6%, for loading curcumin. The curcumin loaded cwSLNs (Cur-cwSLNs) exhibited sustained drug release properties. Notably, Cur-cwSLNs had a higher drug release rate at pH 4.5 than at pH 7.4, which suggested their applicability in an acidic environment. Cur-cwSLNs were able to inhibit the growth of Staphylococcus aureus and were more effective at reducing the biofilms produced by this bacterium compared to free curcumin. This study confirmed that cwSLNs may be novel carriers for increasing the bioavailability of curcumin with the potential to inhibit the formation of S. aureus biofilms.
RESUMEN
Two new series of tricyclic heterocycles, namely 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 and the related neutral, free bases 13 were synthesized from 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 and nitriles 9 in the presence of aluminium chloride by the [3+ + 2]-cycloaddition reaction of the in situ generated azocarbenium intermediates 14 followed by a ring-expansion rearrangement. In the rearrangement reaction, the phenyl substituent in the initially formed spiro-triazolium adducts 16 underwent a [1,2]-migration from C(3) to the electron-deficient N(2). This led to the ring expansion from 6-membered piperidine to 7-membered diazepine furnishing the tricyclic 1,2,4-triazole-fused 1,4-benzodiazepines.
RESUMEN
The bicyclic 1-aza-2-azoniaallenium salt intermediates, generated from the azoester species upon treatment with a Lewis acid, have been demonstrated to participate in Huisgen-type cycloaddition with nitriles to result in the formation of fused 6,7,8,9-tetrahydro-5 H-[1,2,4]triazolo[1,5- d][1,4]diazepinium salts. This transformation is interpreted as a regular [3++2] cycloaddition between intermediates as the reactive 1,3-monopole reactants and nitriles as the nucleophilic reagents followed by spontaneous [1,2]-cationic rearrangement. The azoester precursors were easily accessible via oxidation of the corresponding hydrazones using hypervalent iodine oxidant PhI(OAc)2 under mild conditions. The [1,2,4]triazolodiazepine compounds represent a class of N-containing biologically important heterocycles with a new type of scaffold.
RESUMEN
The purpose of this study was to develop an oral nanocarrier as budesonide delivery system and to evaluate its therapeutic potential for inflammatory bowel disease (IBD). The nanoparticles (NPs) based on an amphiphilic inulin polymer with 4-aminothiophenol (ATP) grafted onto carboxymethyl inulin (CMI) were prepared. The particle sizes were about 210.18â¯nm and had the obvious pH/redox sensitive swelling transitions. The drug-release study of NPs <-- >in vitro showed a low release rate (about 45â¯wt%) in GSH-free media, whereas high release rate (about 80â¯wt%) in the media containing 20â¯mM GSH, exhibiting a redox-responsive property. Further in vivo experiments found the NPs tended to accumulate in inflamed sites, and exerted excellent therapeutic efficacy in comparison to drug suspension in colitis mice model. All the results demonstrated that the redox-sensitive NPs, based on amphiphilic inulin, may be used as colon-targeted drug delivery for the treatment of IBD.
Asunto(s)
Compuestos de Anilina/química , Budesonida/química , Budesonida/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Nanopartículas/química , Compuestos de Sulfhidrilo/química , Budesonida/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Enfermedades Inflamatorias del Intestino/metabolismo , Inulina/metabolismo , Oxidación-ReducciónRESUMEN
Molecular markers are efficient tools for breeding and genetic studies. However, despite their ecological and economic importance, their development and application have long been hampered. In this study, we identified 524,170 simple sequence repeat (SSR), 267,636 intron length polymorphism (ILP), and 11,872 potential intron polymorphism (PIP) markers from 16 tree species based on recently available genome sequences. Larger motifs, including hexamers and heptamers, accounted for most of the seven different types of SSR loci. Within these loci, A/T bases comprised a significantly larger proportion of sequence than G/C. SSR and ILP markers exhibited an alternative distribution pattern. Most SSRs were monomorphic markers, and the proportions of polymorphic markers were positively correlated with genome size. By verifying with all 16 tree species, 54 SSR, 418 ILP, and four PIP universal markers were obtained, and their efficiency was examined by PCR. A combination of five SSR and six ILP markers were used for the phylogenetic analysis of 30 willow samples, revealing a positive correlation between genetic diversity and geographic distance. We also found that SSRs can be used as tools for duplication analysis. Our findings provide important foundations for the development of breeding and genetic studies in tree species.
Asunto(s)
Marcadores Genéticos/genética , Genoma de Planta/genética , Repeticiones de Microsatélite/genética , Polimorfismo Genético/genética , Árboles/genética , Cruzamiento/métodos , Mapeo Cromosómico/métodos , Sitios Genéticos/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Intrones/genética , FilogeniaRESUMEN
BACKGROUND: Seasonal influenza infections among young children in China lead to substantial numbers of hospitalizations and financial burden. This study assessed the seasonal influenza vaccine effectiveness (VE) against laboratory confirmed medically attended influenza illness among children in Suzhou, China, from October 2011-September 2012. METHODS: We conducted a test-negative case-control study among children aged 6-59 months who sought care at Soochow University Affiliated Children's Hospital (SCH) from October 2011-September 2012. A case was defined as a child with influenza-like illness (ILI) or severe acute respiratory infection (SARI) with an influenza-positive nasopharyngeal swab by rRT-PCR. Controls were selected from children presenting with ILI or SARI without laboratory confirmed influenza. We conducted 1:1 matching by age and admission date. Vaccination status was verified from the citywide immunization system database. VE was calculated with conditional logistic regression: (1-OR)×100%. RESULT: During the study period, 2634 children aged 6-59 months presented to SCH with ILI (1975) or SARI (659) and were tested for influenza. The vaccination records were available for 69% (1829; ILI: 1354, SARI: 475). Among those, 23% (427) tested positive for influenza, and were included as cases. Among influenza positive cases, the vaccination rates were 3.2% for SARI and 4.5% for ILI. Among controls, the vaccination rates were 13% for SARI, and 11% for ILI. The overall VE against lab-confirmed medically attended influenza virus infection was 67% (95% CI: 41-82). The VE for SARI was 75% (95% CI: 11-93) and for ILI was 64% (95% CI: 31-82). CONCLUSIONS: The seasonal influenza vaccine was effective against medically attended lab-confirmed influenza infection in children aged 6-59 months in Suzhou, China in the 2011-12 influenza season. Increasing seasonal influenza vaccination among young children in Suzhou may decrease medically attended influenza-associated ILI and SARI cases in this population.