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1.
Sci Rep ; 13(1): 21833, 2023 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-38071256

RESUMEN

The purpose of this theoretical study is to explore the behavior of an electrically conducting micropolar fluid when subjected to a uniform magnetic field along the vertical axis between two stretching disks as the structure of the problem changes. In this context, structural changes refer to alterations in the distance between the two discs or the stretching rate of the two discs. The governing equations of this problem are a set of nonlinear coupled partial differential equations, which are transformed into a nonlinear coupled ordinary differential equation set by a similarity transformation. The transformation results in four dimensionless quantities and their derivatives that appear in the equations. Nine dimensionless parameters are derived via similarity variables, including stretching Reynolds number, magnetic parameter, radiation parameter, Prandtl number, Eckert number, Schmidt number, and three micropolar parameters. Previous similarity solutions focused on analyzing the effect of changes in each parameter on the four dimensionless quantities. However, this type of analysis is mainly mathematical and does not provide practical results. This study's primary novelty is to redefine the magnetic parameter, Eckert number, stretching Reynolds number, and two micropolar parameters to analyze physical parameters that depend on the stretching rate of the two discs or the distance between them. The semi-analytical hybrid analytical and numerical method (HAN-method) is used to solve the equations. The results demonstrate that structural changes affect all five quantities of radial velocity, axial velocity, microrotation, temperature, and concentration. The study's most significant finding is that an increase in the stretching rate of the two disks causes a sharp increase in temperature and Nusselt number. Conversely, increasing the distance between the two disks causes a sharp decrease in micro-rotation and wall couple stress. They were compared to a previous study in a specific case to validate the results' accuracy.

3.
JBRA Assist Reprod ; 2023 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-37768820

RESUMEN

OBJECTIVE: Ovarian cryopreservation is one of the effective methods to preserve fertility for cancer patients. Still, this approach has some problems, namely ROS, resulting in adverse effects on oocytes and ovarian follicles. Kisspeptin as an antioxidant to control ovarian function, directly or indirectly. In this study, the effect of kisspeptin on follicle maturation was evaluated in culture following ovarian cryopreservation. METHODS: Ovarian tissue samples of women between 20 and 35 years old (n=12) were laparoscopically collected. The samples were randomly divided into four groups: 1) control, 2) vitrification, 3) vitrified+1µM kisspeptin, and 4) vitrified+10µM kisspeptin. After vitrification and thawing processes, the tissues were cultured in DMEM medium for 7 days. H&E staining for histological evaluation, Real-Time PCR for GDF9 and BMP15 gene expression, and immunohistochemical staining for GDF9 and BMP15 protein expression were performed. RESULTS: In the vitrification group, ovarian tissue morphology was incoherent, and more primordial follicles than other follicle types were found. The expression of GDF9 and BMP15 genes and proteins were significantly decreased in this group compared with other groups (p<0.05). In the vitrification groups with kisspeptin (1 and 10 µM), the number of primary and secondary follicles was more than in the vitrification group. Besides, the expression of these genes and proteins was dramatically elevated in the vitrification groups with kisspeptin compared to the vitrification group alone (p<0.05). CONCLUSIONS: It seems that kisspeptin is an effective substance to improve the quality of the human ovarian cryopreservation medium by improving follicle maturation.

5.
Sci Rep ; 13(1): 13241, 2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37582817

RESUMEN

The motion of the fluid due to the swirling of a disk/sheet has many applications in engineering and industry. Investigating these types of problems is very difficult due to the non-linearity of the governing equations, especially when the governing equations are to be solved analytically. Time is also considered a challenge in problems, and times dependent problems are rare. This study aims to investigate the problem related to a transient rotating angled plate through two analytical techniques for the three-dimensional thin film nanomaterials flow. The geometry of research is a swirling sheet with a three-dimensional unsteady nanomaterial thin-film moment. The problem's governing equations of the conservation of mass, momentum, energy, and concentration are partial differential equations (PDEs). Solving PDEs, especially their analytical solution, is considered a serious challenge, but by using similar variables, they can be converted into ordinary differential equations (ODEs). The derived ODEs are still nonlinear, but it is possible to approximate them analytically with semi-analytical methods. This study transformed the governing PDEs into a set of nonlinear ODEs using appropriate similarity variables. The dimensionless parameters such as Prandtl number, Schmidt number, Brownian motion parameter, thermophoretic parameter, Nusselt, and Sherwood numbers are presented in ODEs, and the impact of these dimensionless parameters was considered in four cases. Every case that is considered in this problem was demonstrated with graphs. This study used modified AGM (Akbari-Ganji Method) and HAN (Hybrid analytical and numerical) methods to solve the ODEs, which are the novelty of the current study. The modified AGM is novel and has made the former AGM more complete. The second semi-analytical technique is the HAN method, and because it has been solved numerically in previous articles, this method has also been used. The new results were obtained using the modified AGM and HAN solutions. The validity of these two analytical solutions was proved when compared with the Runge-Kutta fourth-order (RK4) numerical solutions.

6.
Heliyon ; 9(6): e17535, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37408890

RESUMEN

In this article, the semi-analytical technique of the Hybrid Analytical and Numerical Method (the HAN Method) is used to study the non-transient forced non-Newtonian MHD Reiner-Rivlin viscoelastic fluid motion that is constrained between two plates. The magnetic field is also present in this model. The governing equations are in the PDE form and by using the Von Kármán similarity variables, they transformed into a set of ODEs. The HAN-method is applied to solve the ODEs and their associated boundary conditions, analytically. In addition, for the validation, the HAN solution results were compared with the HPM and numerical technique of Runge-Kutta results. And finally, new results were extracted from the HAN solutions in a quantitative form.

7.
Educ Inf Technol (Dordr) ; : 1-22, 2023 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-37361839

RESUMEN

In overcoming the obstacles of online learning with the current Covid-19 pandemic crisis, synchronous and asynchronous learning has been a significant part of teaching strategies applied by educators to construct a collaborative online environment with Malaysian university students. Synchronous learning has always been the most effective strategy for social learning, while asynchronous learning allows students to learn on their own schedule. Moreover, despite having many educational platforms created for higher educational settings, the practicality of selection between two teaching-learning approaches of text-presentation and video is still a debate among teachers/ lecturers with students' learning styles. Therefore, this paper explored Malaysian university students' preferences between synchronous and asynchronous learning modes with text-presentation or video. Qualitative and quantitative data from 178 participants from both public and private universities were collected via open and close-ended questions in the designed questionnaire. The findings indicated that 68% of the students preferred synchronous learning mode compared to asynchronous. Meanwhile, 39% of the students favoured both text-presentation and video learning tools to be implemented in synchronous and asynchronous approaches as it provided them better opportunities to grasp the learning content better. Thus, it can be concluded that the synchronous learning mode is preferred if only one method is provided as the students highly value the teacher's presence for ease of communication, but students prefer a range of delivery methods. Moreover, the students also displayed a strong preference for applying both text-presentation and video to achieve their learning outcomes. Thus, it is suggested that the university lecturers need to explore and apply interactive pedagogical methods in online teaching-learning process, while contributing to the development of motivation, participation, and engagement among the university students in acquiring their subjects. As such, the findings of this study have informed the pedagogical implications, and further studies are mandatory.

9.
Front Genet ; 13: 985214, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36246635

RESUMEN

Chronic otitis media, inflammation of the middle ear, is a sequel to acute otitis media in ∼8% of children. Chronic otitis media with effusion is the most common cause of childhood deafness and is characterised by effusion of white blood cells into the auditory bulla cavity. Skull flat bones have trans-cortical vessels which are responsible for the majority of blood flow in and out of the bone. In experimental models of stroke and aseptic meningitis there is preferential recruitment of myeloid cells (neutrophils and monocytes) from the marrow in skull flat bones. We report trans-cortical vessels in the mouse temporal bone connect to the bulla mucosal vasculature and potentially represent a means to recruit myeloid cells directly into the inflamed bulla. The mutant mouse strains Junbo (Mecom Jbo/+ ) and Jeff (Fbxo11 Jf/+ ) develop chronic otitis spontaneously; Mecom Jbo/+ mice have highly cellular neutrophil (90%) rich bulla exudates whereas Fbxo11 Jf/+ mice have low cellularity serous effusions (5% neutrophils) indicating differing demand for neutrophil recruitment. However we found peripheral leukograms of Mecom Jbo/+ and Fbxo11 Jf/+ mice are similar to their respective wild-type littermate controls with healthy bullae and infer preferential mobilization of myeloid cells from temporal bulla bone marrow may mitigate the need for a systemic inflammatory reaction. The cytokines, chemokines and haematopoietic factors found in the inflamed bulla represent candidate signalling molecules for myeloid cell mobilization from temporal bone marrow. The density of white blood cells in the bulla cavity is positively correlated with extent of mucosal thickening in Mecom Jbo/+ , Fbxo11 Jf/+ , and Eda Ta mice and is accompanied by changes in epithelial populations and bone remodelling. In Mecom Jbo/+ mice there was a positive correlation between bulla cavity WBC numbers and total bacterial load. The degree of inflammation varies between contralateral bullae and between mutant mice of different ages suggesting inflammation may wax and wane and may be re-initiated by a new wave of bacterial infection. Clearance of white blood cells and inflammatory stimuli from the bulla cavity is impaired and this may create a pro-inflammatory feedback loop which further exacerbates otitis media and delays its resolution.

10.
Dis Model Mech ; 15(3)2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35107126

RESUMEN

In mice, rats, dogs and humans, the growth and function of sebaceous glands and eyelid Meibomian glands depend on the ectodysplasin signalling pathway. Mutation of genes encoding the ligand EDA, its transmembrane receptor EDAR and the intracellular signal transducer EDARADD leads to hypohidrotic ectodermal dysplasia, characterised by impaired development of teeth and hair, as well as cutaneous glands. The rodent ear canal has a large auditory sebaceous gland, the Zymbal's gland, the function of which in the health of the ear canal has not been determined. We report that EDA-deficient mice, EDAR-deficient mice and EDARADD-deficient rats have Zymbal's gland hypoplasia. EdaTa mice have 25% prevalence of otitis externa at postnatal day 21 and treatment with agonist anti-EDAR antibodies rescues Zymbal's glands. The aetiopathogenesis of otitis externa involves infection with Gram-positive cocci, and dosing pregnant and lactating EdaTa females and pups with enrofloxacin reduces the prevalence of otitis externa. We infer that the deficit of sebum is the principal factor in predisposition to bacterial infection, and the EdaTa mouse is a potentially useful microbial challenge model for human acute otitis externa.


Asunto(s)
Conducto Auditivo Externo , Displasia Ectodermal Anhidrótica Tipo 1 , Otitis Externa , Animales , Ectodisplasinas , Femenino , Lactancia , Ratones
11.
Sci Rep ; 10(1): 13156, 2020 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-32753714

RESUMEN

Protein kinase Cß (PKCß) expressed in mammalian cells as two splice variants, PKCßI and PKCßII, functions in the B cell receptor (BCR) signaling pathway and contributes to B cell development. We investigated the relative role of PKCßII in B cells by generating transgenic mice where expression of the transgene is directed to these cells using the Eµ promoter (Eµ-PKCßIItg). Our findings demonstrate that homozygous Eµ-PKCßIItg mice displayed a shift from IgD+IgMdim toward IgDdimIgM+ B cell populations in spleen, peritoneum and peripheral blood. Closer examination of these tissues revealed respective expansion of marginal zone (MZ)-like B cells (IgD+IgM+CD43negCD21+CD24+), increased populations of B-1 cells (B220+IgDdimIgM+CD43+CD24+CD5+), and higher numbers of immature B cells (IgDdimIgMdimCD21neg) at the expense of mature B cells (IgD+IgM+CD21+). Therefore, the overexpression of PKCßII, which is a phenotypic feature of chronic lymphocytic leukaemia cells, can skew B cell development in mice, most likely as a result of a regulatory influence on BCR signaling.


Asunto(s)
Linfocitos B/enzimología , Regulación Enzimológica de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/enzimología , Proteínas de Neoplasias/biosíntesis , Proteína Quinasa C beta/biosíntesis , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Linfocitos B/patología , Inmunoglobulina D/genética , Inmunoglobulina D/metabolismo , Inmunoglobulina M/genética , Inmunoglobulina M/metabolismo , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Proteína Quinasa C beta/genética , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal
12.
J Lasers Med Sci ; 11(3): 305-309, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32802292

RESUMEN

Introduction: Urinary stone disease is the third most common affliction of the urinary tract that has been associated with an increasing incidence. Over decades, great advances have been made in the minimally invasive treatment of urinary stones. Recently, transurethral lithotripsy (TUL) by holmium laser was introduced as a possible therapeutic option. This study evaluated the effect of propofol on the success rate of TUL by holmium laser. Methods: A double-blind randomized controlled trial was conducted on 180 patients to investigate the effect of propofol on the success and complication rate of TUL by holmium laser. The enrolled patients were divided into two groups: the first group received sodium thiopental (n=89) while the second group received propofol (n=91). The two groups were compared in terms of the fluctuations of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), operation time, future stone-free rate (SFR), stone migration, post-operative fever, and ureteral complications such as perforation and mucosal damage. Other developed complications were also recorded. After data gathering, statistical analysis was performed with SPSS version 21. Results: the patients' data such as age, sex, stone diameter, stone laterality, duration of stone impaction, primary SBP, DBP and HR were not significantly different between the two groups (P>0.05). TUL and anesthesia duration, first-minute and fifth-minute SBP and DBP, and also changes of HR were significantly lower in the propofol group compared with the sodium thiopental group (P <0.001). Moreover, SFR of TUL was more evident in the propofol group. Ureteral mucosal damage was significantly less in the propofol group. Conclusion: Propofol was associated with a higher reduction in SBP and DBP, decreased duration of TUL, fewer fluctuations in HR, and an increased success rate of stone removal by TUL with holmium laser.

13.
Urol J ; 17(6): 626-630, 2020 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-32654111

RESUMEN

PURPOSE: Prevention and treatment of urethroplastic postoperative pain is a major challenge in post-surgery care. gabapentin can treat postoperative pain by preventing excessive sensitivity to the central nervous system. we have tried to compare the effect of gabapentin with the placebo on reducing the pain associated with posterior urethroplasty in patients. MATERIAL AND METHOD: This prospective, randomized, double-blind study was scheduled in Shohad e Tajrish hospital where a single dose of Gabapentin was compared with placebo given to patients preoperatively. In this study,100 patients with posterior urethral stricture were included for surgery with 50 patients in each arms .All patients underwent posterior urethroplasty. After surgery, the pain level is assessed and evaluated by the visual analog scale in two hours,four hours, six hours,eight hours, twelve hours, and 24 hours after the operation. RESULT: In this study, there was a significant difference in the pain level that was evaluated by the visual analog scale in two hours, four hours, six hours, eight hours, twelve hours, and 24 hours after the surgery (p.value <0.001). We also found a significant decrease in morphine consumption in the gabapentin group vs the placebo group. (p.value <0.001) The post-surgery assessments showed significant lower adverse effects such as vomiting, nausea, drowsiness, and pruritus in the gabapentin group vs. placebo group. CONCLUSION: The consequences of this study revealed that gabapentin effective in controlling posterior urethroplasty postoperative pain, consumption of opioid, nausea, vomiting, drowsiness, and pruritus compared with the placebo group.


Asunto(s)
Analgésicos/uso terapéutico , Gabapentina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Cuidados Preoperatorios , Uretra/cirugía , Estrechez Uretral/cirugía , Adulto , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Estudios Prospectivos , Procedimientos Quirúrgicos Urológicos
14.
J Vet Intern Med ; 34(4): 1454-1463, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32407559

RESUMEN

BACKGROUND: Middle ear effusion is common in brachycephalic dogs with similarities to otitis media with effusion in children. Association with the cranial and eustachian tube morphology and bacterial infection is suspected in both species. HYPOTHESIS/OBJECTIVES: To determine cytological and bacteriological features of middle ear effusions in dogs, provide information on histological features, and further assess the dog as a model of the human disease. ANIMALS: Sixteen live dogs, 3 postmortem cases of middle ear effusion, and 2 postmortem controls. METHODS: Prospective; clinical investigation using computed tomography, magnetic resonance imaging, video-otoscopy, myringotomy; cytological assessment of 30 and bacteriology of 28 effusions; histology and immunohistochemistry (CD3 for T-lymphocytes, Pax5 for B lymphocytes and MAC387 for macrophages) of 10 middle ear sections. RESULTS: Effusions were associated with neurological deficits in 6/16 (38%) and concurrent atopic dermatitis and otitis externa in 9/16 (56%) of live cases. Neutrophils and macrophages predominated on cytology (median 60 [range 2%-95.5%] and 27 [2%-96.5%]) whether culture of effusions was positive or not. In histology sections, the mucosa was thickened in affected dogs but submucosal gland dilatation occurred in affected and unaffected dogs. There was no bacterial growth from 22/28 (79%) of effusions. Bacteria isolated from the other 6 (21%) were predominantly Staphylococcus pseudintermedius (4/6, 67%). CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical, morphological, and cytological findings in middle ear effusions of dogs and people suggest similar pathogeneses. Middle ear effusion of dogs could be a useful model of human otitis media with effusion. Such comparisons can improve understanding and management across species.


Asunto(s)
Craneosinostosis/veterinaria , Enfermedades de los Perros/microbiología , Otitis Media con Derrame/veterinaria , Animales , Craneosinostosis/complicaciones , Dermatitis Atópica/veterinaria , Modelos Animales de Enfermedad , Perros , Oído Medio/citología , Oído Medio/patología , Exudados y Transudados/citología , Exudados y Transudados/microbiología , Imagen por Resonancia Magnética/veterinaria , Enfermedades del Sistema Nervioso/veterinaria , Otitis Media con Derrame/diagnóstico por imagen , Otitis Media con Derrame/microbiología , Otoscopía/veterinaria , Estudios Prospectivos , Staphylococcus/aislamiento & purificación , Tomografía Computarizada por Rayos X/veterinaria
15.
Urol J ; 17(4): 429-431, 2020 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-31144290

RESUMEN

Nowadays there is not any specific technique for repairing the recurrent urethral stricture with retained urethral stent. We report a 49 year-old man with history of end to end urethroplasty 11 years ago who was referred with urethral stricture. He refused to undergo urethroplasty again, so the stricture was managed by Uventa stent insertion which failed after six months. Finally the patient underwent end to end urethroplasty with complete excision of the obstructed urethra, stent and surrounding periurethral fibrosis. End to end urethroplasty post Uventa stent stricture is an available option with good postoperative outcomes.


Asunto(s)
Complicaciones Posoperatorias/cirugía , Stents , Uretra/cirugía , Estrechez Uretral/cirugía , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Urológicos Masculinos/métodos
16.
Urol J ; 17(1): 61-67, 2020 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-31836997

RESUMEN

PURPOSE: The aim of the present study was translation, cross cultural adaptation and face validity evaluation of the Persian version of Patient-Reported Outcome Measure for Urethral Stricture Surgery (USS-PROM) Questionnaire. MATERIALS AND METHODS: This study was assessed: translation, translation quality, reverse translation and comparison of the english version, Content validity, internal consistency and stability. Content validity presents by index of content validity (CVI) and the content validity ratio (CVR). Internal consistency reliability was tested by Cronbach's ?, and test-retest reliability was evaluated by Intraclass Correlation Coefficient (ICC) assessed by Guttman two way mixed absolute agreements. RESULT: Frothy males with history urethroplasty and mean age of 41.4±9.08 (range of 19 to 52) years old; enrolled.  In the case of mean scores of difficulty from the 16 translated items, 80% had easy translation. In terms of translation quality, 92% were the satisfactorily clear. In terms of similar concept, 92% were satisfactory. The overall quality of the translation was satisfactory at 88%. The translated questionnaire has a good internal consistency (Cronbach's alpha as 0.84). CVI and the CVR, test-retest ICC evaluation were appropriate/acceptable in all questions. The questionnaire ICC was .791(CI 95%, .678-.876). Two main different aspects of the questionnaire consisted of urinary symptoms (question 1-10) and Quality of life (question 11-15) Cronbach's alpha were .800 and .671 respectively. CONCLUSION: The Persian version of the questionnaire has acceptable cultural adaptation and face Validity. Further studies should be done using this translated tool to determine its applicability in the urethroplasty patients.


Asunto(s)
Medición de Resultados Informados por el Paciente , Estrechez Uretral/cirugía , Adulto , Humanos , Irán , Lenguaje , Masculino , Persona de Mediana Edad , Psicometría , Reproducibilidad de los Resultados , Traducciones , Adulto Joven
17.
J Lasers Med Sci ; 10(3): 179-184, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31749942

RESUMEN

Introduction: Transurethral lithotripsy (TUL) is an appropriate treatment for ureteral stones and is usually used for stones in the middle and lower part of the ureter. Different devices such as the Holmium laser, the stone basket, and the stone cone exist to prevent any fragments from retropulsion during TUL. The present study aims to compare the advantages and disadvantages of the Holmium laser, the stone basket, and the stone cone. Methods: A retrospective study was conducted from September 2016 to January 2018 comparing various TUL methods in 88 subjects with proximal ureteral calculi. The study participants were divided into 4 matched groups. The first one included 20 patients undergoing TUL with no device (group 1), the second group included 22 patients undergoing TUL while using the stone retrieval basket, the third group included 18 patients undergoing TUL while utilizing the stone cone and the fourth group included 28 patients undergoing TUL while using the Hol-YAG laser. Results: A residual stone ≥3 mm was recorded in 15.9% of the patients. The stone free rate was seen in 100%, 90.9, 83.3%, and 55% of the Holmium laser group, the retrieval basket group, the stone cone group and the no device group respectively (P=0.001). The lowest rate of surgery complications including ureteral perforation, post-operative fever, and mucosal damage between the 4 groups (P=0.003) and the highest time of surgery (P=0.001) belonged to the laser group. If we want to ignore the laser group, the success rate for lithotripsy was better in both groups with a stone retrieval device compared to the no device group, but no advantage existed between the stone basket and the stone cone. Conclusion: We can safely conclude that lasers significantly help to prevent stone migration during TUL. If we want to ignore the laser group, the success rate for lithotripsy was significantly better in both groups with a stone retrieval device compared to the no device group, but no advantage existed between the stone basket and the stone cone.

18.
Dis Model Mech ; 12(4)2019 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-31028034

RESUMEN

Patients with mutations in the ectodysplasin receptor signalling pathway genes - the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD - have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby (EdaTa ) and downless (Edardl-J/dl-J ) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in EdaTa mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired (swh) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh/swh than those in unaffected heterozygous Edaraddswh/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children.


Asunto(s)
Oído Medio/metabolismo , Oído Medio/patología , Displasia Ectodermal Anhidrótica Tipo 1/metabolismo , Displasia Ectodermal Anhidrótica Tipo 1/patología , Ectodisplasinas/metabolismo , Nariz/patología , Transducción de Señal , Animales , Anticuerpos/farmacología , Modelos Animales de Enfermedad , Femenino , Hialina/metabolismo , Masculino , Ratones , Nasofaringitis/complicaciones , Nasofaringitis/patología , Nasofaringe/efectos de los fármacos , Nasofaringe/patología , Otitis Media/complicaciones , Otitis Media/patología , Fenotipo , Ratas , Receptores de la Ectodisplasina/agonistas , Receptores de la Ectodisplasina/metabolismo , Rinitis/complicaciones
19.
Cell Stem Cell ; 25(1): 137-148.e6, 2019 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-31031138

RESUMEN

Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.


Asunto(s)
Leucemia Mieloide Aguda/terapia , Células Madre Neoplásicas/fisiología , Proteínas de Unión al ARN/metabolismo , Animales , Autorrenovación de las Células , Hematopoyesis , Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/genética , Células THP-1
20.
Dis Model Mech ; 12(3)2019 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-30898767

RESUMEN

Auditory bulla cavitation defects are a cause of otitis media, but the normal cellular pattern of bulla mesenchyme regression and its failure are not well understood. In mice, neural-crest-derived mesenchyme occupies the bulla from embryonic day 17.5 (E17.5) to postnatal day 11 (P11) and then regresses to form the adult air-filled bulla cavity. We report that bulla mesenchyme is bordered by a single layer of non-ciliated epithelium characterized by interdigitating cells with desmosome cell junctions and a basal lamina, and by Bpifa1 gene expression and laminin staining of the basal lamina. At P11-P12, the mesenchyme shrinks: mesenchyme-associated epithelium shortens, and mesenchymal cells and extracellular matrix collagen fibrils condense, culminating in the formation of cochlea promontory mucosa bordered by compact non-ciliated epithelial cells. FBXO11 is a candidate disease gene in human chronic otitis media with effusion and we report that a bulla cavitation defect initiates the pathogenesis of otitis media in the established mouse model Jeff (Fbxo11Jf/+ ). Persistent mesenchyme in Fbxo11Jf/+ bullae has limited mesenchymal cell condensation, fibrosis and hyperplasia of the mesenchyme-associated epithelium. Subsequent modification forms fibrous adhesions that link the mucosa and the tympanic membrane, and this is accompanied by dystrophic mineralization and accumulation of serous effusion in the bulla cavity. Mouse models of bulla cavitation defects are important because their study in humans is limited to post-mortem samples. This work indicates new diagnostic criteria for this otitis media aetiology in humans, and the prospects of studying the molecular mechanisms of murine bulla cavitation in organ culture.


Asunto(s)
Oído Medio/metabolismo , Oído Medio/patología , Proteínas F-Box/metabolismo , Otitis Media/patología , Animales , Animales Recién Nacidos , Enfermedad Crónica , Modelos Animales de Enfermedad , Oído Medio/embriología , Oído Medio/ultraestructura , Epitelio/embriología , Epitelio/ultraestructura , Femenino , Proteína del Locus del Complejo MDS1 y EV11/metabolismo , Masculino , Mesodermo/embriología , Mesodermo/ultraestructura , Ratones Endogámicos C57BL , Otitis Media/embriología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Tiempo , Adherencias Tisulares/patología
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