ABSTRACT
The Variational Monte Carlo (VMC) method has recently seen important advances through the use of neural network quantum states. While more and more sophisticated ansatze have been designed to tackle a wide variety of quantum many-body problems, modest progress has been made on the associated optimization algorithms. In this work, we revisit the Kronecker-Factored Approximate Curvature (KFAC), an optimizer that has been used extensively in a variety of simulations. We suggest improvements in the scaling and the direction of this optimizer and find that they substantially increase its performance at a negligible additional cost. We also reformulate the VMC approach in a game theory framework, to propose a novel optimizer based on decision geometry. We find that on a practical test case for continuous systems, this new optimizer consistently outperforms any of the KFAC improvements in terms of stability, accuracy and speed of convergence. Beyond VMC, the versatility of this approach suggests that decision geometry could provide a solid foundation for accelerating a broad class of machine learning algorithms. This article is part of the theme issue 'The liminal position of Nuclear Physics: from hadrons to neutron stars'.
ABSTRACT
Environmental conditions, including temperature, humidity, and light, can impact the quality of drugs. Microwave-based approaches offer a fast and cost-effective way to detect quality variations, providing an alternative to traditional techniques in the pharmaceutical and cosmetic industries. This article proposes the use of a microwave sensor for monitoring the quality of pharmaceutical drugs at distinct temperature levels. A small planar sensor based on three hexagonal split ring resonators (TH-SRR) is fabricated. The design is manufactured on an FR-4 dielectric substrate. The sensor is tested on a 1000 mg paracetamol tablet, at temperatures ranging from 40 to 80 [Formula: see text]C. The Variation in the permittivity that characterizes product degradation is translated into a shift in the frequency of the scattering matrix elements. To validate the microwave approach, drug quality is examined with the laser-induced breakdown spectroscopy (LIBS) technique, an optical emission laser used for both qualitative and quantitative investigations of elements contained in a sample. The existing elements are classified using the National Institute of Standards and Technology (NIST) database and categorized according to their spectral line wavelengths. The experiments show the presence of optimal wavelength values for carbon (C), hydrogen (H), nitrogen (N), and oxygen (O) at 247.92 nm, 656.49 nm, 244.23 nm, and 777.48 nm, respectively. The microwave experimental results show a shift frequency of approximately 1 MHz on average when the tablet is heated at 80 [Formula: see text]C for 15 min. Meanwhile, the LIBS measurement shows a remarkable shift in terms of intensity of approximately 8884 and 812 for carbon and hydrogen, respectively. Understanding how paracetamol dries under high temperatures and improving the process settings of the microwave sensor are investigated and assessed in this work.
ABSTRACT
AIM: The aim of our study was to identify predictors for prolonged ICU stay following elective adult cardiac surgery under cardiopulmonary bypass. PATIENTS AND METHODS: A retrospective study was conducted during 5 years and a half period. Were included, patients age≥18 years old, underwent elective cardiac surgery under cardiopulmonary bypass. Patients who died within 48hours of surgery were excluded. Prolonged ICU stay was defined as stay in the ICU for 48hours or more. RESULTS: During the review period, 610 patients were included. One hundred and sixty-four patients have required a prolonged ICU stay (26.9 %). In multivariate analysis, 5 predictors were identified: ejection fraction<30 % (OR 19.991, IC 95 % [1.382-289.1], P=0.028], pulmonary hypertension (OR 2.293, IC 95 % [1.058-4.973], P=0.036), prolonged ventilation (≥12hours) (OR 4.026, IC 95 % [2.407-6.733], P<0.001). Number of blood units transfused (OR 1.568, IC 95 % [1.073-2.291], and postoperative acute renal failure (OR 2.620, IC 95 % [1.026-6.690], P=0.044]. Prolonged ICU stay is significantly associated with prolonged hospital stay (17 days vs 13 days ; P<0.001) and higher in hospital mortality (22 % vs. 3 %, P<0.001). CONCLUSION: The identification of these patients at risk of prolonged ICU stay is crucial. It will aid to plan prophylactic measures to optimize their support.
Subject(s)
Cardiopulmonary Bypass , Heart Valve Diseases/surgery , Heart Valve Prosthesis Implantation , Hospital Mortality , Intensive Care Units , Length of Stay , Adult , Cardiopulmonary Bypass/mortality , Elective Surgical Procedures/mortality , Female , Heart Valve Diseases/mortality , Heart Valve Prosthesis Implantation/mortality , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
The aneurysms of digestive arteries are a rare pathological entity, with a risk of rupture associated to a high mortality rate, often asymptomatic, then they are discovered incidentally during a exam for other diagnostic purposes. We report three cases of digestive aneurysms, one of celiac trunk, one of mesenteric artery on behçet disease, and one of splenic artery, which were treated surgically with success.
Subject(s)
Aneurysm , Celiac Artery , Mesenteric Arteries , Splenic Artery , Adult , Aneurysm/complications , Aneurysm/diagnostic imaging , Aneurysm/surgery , Behcet Syndrome/complications , Celiac Artery/diagnostic imaging , Celiac Artery/surgery , Female , Humans , Hypertension/complications , Incidental Findings , Male , Mesenteric Arteries/diagnostic imaging , Mesenteric Arteries/surgery , Middle Aged , Risk Factors , Splenectomy , Splenic Artery/diagnostic imaging , Splenic Artery/surgery , Tomography, X-Ray Computed , Treatment Outcome , Vascular Surgical Procedures/methods , beta-Thalassemia/complicationsABSTRACT
BACKGROUND & AIMS: Weight loss and malnutrition are frequent problems in oncology patients. The aim of this study was to get a perspective of the current practice of parenteral nutrition (PN) care in an outpatient setting and to improve patient-centered nutritional care. METHODS: Fifty-three outpatient oncology centers participated in this observational study performed between July 2010 and March 2011. All participating centers entered data online into a web-based documentation form, containing a number of oncology patients, diagnoses, and detailed data about oncology patients receiving PN. RESULTS: Two cohorts were analyzed. First cohort consisted of all oncology patients in quarter 04/2010. Second cohort consisted of patients with PN during the whole studying period. In the first cohort 2.46% (n = 626) of 25,424 oncology patients received PN. Most frequent diagnoses of patients receiving PN were gastric cancer (n = 119) and colorectal cancer (n = 104), however most stated diagnosis was "other" (n = 163). In the second cohort (n = 1137), a common indication for PN was impaired gastrointestinal passage (n = 177), although here again most stated reason was "other" (n = 924). In the course of the PN treatment, patients (n = 1137) showed a stable or slowly increasing body mass index (from 21.6 ± 3.8 kg/m(2) to 21.8 ± 3.5 kg/m(2)). CONCLUSION: This is the largest study outlining the characteristics of oncology patients in the context of PN in German ambulatory centers. They confirm the important role of PN in the care of gastrointestinal cancer. Further studies have to be performed to identify if other indications than those mentioned in relevant guidelines can trigger initiation of PN.
Subject(s)
Gastrointestinal Neoplasms/diet therapy , Medical Oncology/methods , Nutrition Therapy/methods , Parenteral Nutrition/methods , Patient Care/methods , Aged , Body Mass Index , Female , Gastrointestinal Neoplasms/physiopathology , Humans , Male , Middle Aged , Nutrition Therapy/standards , Nutrition Therapy/trends , Observation , Parenteral Nutrition/adverse effects , Practice Guidelines as Topic , Retrospective Studies , Treatment OutcomeABSTRACT
Gram-negative carbapenem-resistant bacteria, in particular those producing New Delhi Metallo-betalactamase-1 (NDM-1), are a major global health problem. To inform the scientific and medical community in real time about worldwide dissemination of isolates of NDM-1-producing bacteria, we used the PubMed database to review all available publications from the first description in 2009 up to 31 December 2012, and created a regularly updated worldwide dissemination map using a web-based mapping application. We retrieved 33 reviews, and 136 case reports describing 950 isolates of NDM-1-producing bacteria. Klebsiella pneumoniae (n= 359) and Escherichia coli (n=268) were the most commonly reported bacteria producing NDM-1 enzyme. Several case reports of infections due to imported NDM-1 producing bacteria have been reported in a number of countries, including the United Kingdom, Italy, and Oman. In most cases (132/153, 86.3%), patients had connections with the Indian subcontinent or Balkan countries. Those infected were originally from these areas, had either spent time and/or been hospitalised there, or were potentially linked to other patients who had been hospitalised in these regions. By using Google Maps, we were able to trace spread of NDM-1-producing bacteria. We strongly encourage epidemiologists to use these types of interactive tools for surveillance purposes and use the information to prevent the spread and outbreaks of such bacteria.
Subject(s)
Disease Outbreaks/prevention & control , Gram-Negative Bacteria/enzymology , beta-Lactamases , Animals , HumansABSTRACT
OBJECTIVES: Enterobacter cloacae is a major nosocomial bacterium causing severe infections. A multicenter retrospective cohort study was conducted to collect baseline information on the molecular characteristics of ß-lactamase producing Enterobacter cloacae in the west of Algeria. MATERIALS AND METHODS: We report a series of 42 extended-spectrum ß-lactamase (ESBL) producing non-repetitive Enterobacter cloacae strains, collected in 3 university hospital (Tlemcen, Oran, and Sidi Bel Abbes). Antibiotic susceptibility testing (antibiogram and MIC) and screening for ESBL were performed according to the French Society for Microbiology guidelines. PFGE typing was used to characterize the clonality of all the strains. ß-lactamase genes (blaTEM, blaSHV, blaCTX-M, blaECB, and blaCMY-2) were amplified by PCR with specific primers. Plasmid isolation, electroporation, and conjugation experiments were carried out using standard methods. RESULTS: Sequence analysis revealed that most strains produced CTX-M type ESBLs (CTX-M-15 and CTX-M-3), whereas only 5 produced SHV-type ESBLs (SHV-12). The blaTEM gene was identified in all strains of Enterobacter cloacae. Several epidemic clones were determined. One strain was found to produce plasmid-mediated AmpC ß-lactamase (CMY-2); this gene was transferred from E. cloacae by electroporation. Conjugation experiments showed that blaCTX-M, blaTEM, and blaSHV were carried by conjugative plasmids of high molecular weight (≥70kb). CONCLUSION: The emergence of resistance genes is a public health problem.
Subject(s)
Enterobacter cloacae/classification , Enterobacter cloacae/enzymology , beta-Lactamases/metabolism , Algeria , Cohort Studies , Enterobacter cloacae/isolation & purification , Hospitals , Humans , Molecular Typing , Retrospective StudiesABSTRACT
Aneurysm of the superior mesenteric artery is a rare finding. The risk of rupture is difficult to predict and manage. We report the case of a young woman who developed an aneurysm of the superior mesenteric artery in a context of bacterial endocarditis. Surgical resection without revascularization was successful.
Subject(s)
Aneurysm, Infected/pathology , Endocarditis, Bacterial/complications , Mesenteric Artery, Superior/pathology , Amoxicillin/therapeutic use , Aneurysm, Infected/drug therapy , Aneurysm, Infected/microbiology , Aneurysm, Infected/surgery , Angiography , Anti-Bacterial Agents/therapeutic use , Combined Modality Therapy , Endocarditis, Bacterial/drug therapy , Endocarditis, Bacterial/surgery , Female , Fistula/etiology , Heart Diseases/etiology , Humans , Mesenteric Artery, Superior/microbiology , Mesenteric Artery, Superior/surgery , Mitral Valve Insufficiency/complications , Periodontitis/complications , Tomography, X-Ray Computed , Young AdultABSTRACT
BACKGROUND: Aortic valve replacement improves clinical symptoms and left ventricular systolic function in patients with chronic aortic regurgitation despite a higher surgical risk. The objective of this study is to determine if left ventricular function will be normalized after surgery. PATIENTS AND METHOD: This retrospective study included 40 patients (nine females and 31 males) with chronic aortic regurgitation and left ventricular systolic dysfunction who were evaluated by echocardiography Doppler. Were included patients with left ventricular ejection fraction less or equal to 45%. Ages ranged from 18 to 77 years (mean = 46.4 ± 12.6 years). Preoperatively, six patients (15%) were asymptomatic, ten (25%) were in NYHA II, half (50%) in NYHA III and four (10%) in NYHA IV. The mean preoperative ejection fraction (EF) was 36.2 ± 2%. The mean end systolic and diastolic dimensions were 61.7 ± 8.5 mm and 78.9 ± 9.7 mm respectively. Aortic regurgitation was quantified grade III in sixteen patients (40%) and grade IV in twenty-four (60%). RESULTS: Thirty-seven patients underwent aortic valve replacement and three Bentall operations. Hospital mortality was 7.5% (3/40). The mean follow-up period was 69.7 months. All survivor patients were investigated. Out of these, five were lost and 32 were controlled. Symptomatic improvement was noted in most of the survivors. Sixty percent (24/40) were severely symptomatic before and only 6.25% (2/32) during follow-up. The ejection fraction increased significantly after surgery (36.2 ± 2% in preoperative period vs. 55.2 ± 10% in postoperative period, P < 0.02). Left ventricular diameters decreased significantly also. Survival rates were 3-year 94%, 5-year 91% and 7-year 89%. CONCLUSION: Despite reduced left ventricular systolic function, aortic valve replacement in chronic aortic regurgitation was associated with acceptable operative risk. Surgery improves functional status, symptoms and ejection fraction in most patients.
Subject(s)
Aortic Valve Insufficiency/physiopathology , Aortic Valve Insufficiency/surgery , Aortic Valve/surgery , Heart Valve Prosthesis Implantation , Ventricular Dysfunction, Left/surgery , Adolescent , Adult , Aged , Aortic Valve Insufficiency/complications , Aortic Valve Insufficiency/diagnosis , Aortic Valve Insufficiency/mortality , Female , Follow-Up Studies , Hospital Mortality , Humans , Male , Middle Aged , Postoperative Period , Preoperative Period , Retrospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Ventricular Dysfunction, Left/complications , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/mortality , Ventricular Dysfunction, Left/physiopathologyABSTRACT
BACKGROUND: The aim of this study was to compare the results of myocardial revascularisation with or without cardiopulmonary bypass in patients with impaired left ventricular function. PATIENTS AND METHODS: Five hundred and sixteen consecutive patients who underwent coronary artery bypass grafting from January 2000 through December 2007 were analyzed retrospectively. One hundred and eight cases had a left ventricular EF (ejection fraction) of 45% or less. Of these patients, 78 underwent conventional coronary artery bypass (CCABG) and 30 underwent off-pump procedure (OCABG). The CCABG group received 300IU/kg of heparin while the OCABG received 100IU/kg. The off-pump coronary surgery was carried out using a tissue stabilizer Octopus II. Different pre-, per- and postoperative variables were evaluated among both groups. Statistical analysis was performed by SPSS 11.5. The variables were compared between these two groups using univariate analysis (Chi(2) test, Fisher's test exact) for qualitative variable and (Student's t test, Mann-Whitney's test) for quantitative variable. RESULTS: Patients profiles and risk factors were similar among both groups except for age (CCABG: 57.8±9.2 year vs OCABG: 52±9.9 year; P=0.004) and left ventricular EF (CCABG: 37.4±6.3% vs OCABG: 34±7.8%; P=0.02). The number of grafts performed per patient was significantly more among patients who underwent extracorporeal circulation (CCABG: 2.53±0.7 graft/patient vs OCABG: 1.77±0.8 graft/patient; P<0.0001). The hospital mortality was more among CCABG group 9% vs 3.3% in OCABG but the difference was not significant (P=0.3). However, the operative time and the operative room stay were long in CCABG (252±61min vs 175±38min; P<0.0001 - 389±70min vs 298±54min; P<0.0001). The ventilation time was also long in CCABG (32.3±67hour vs 10.4±5.9hour; P=0.15). There was more postoperative myocardial infarction in CCABG (P=0.008), but the EF increased and was better in CCABG. CONCLUSION: Off-pump coronary artery bypass surgery provides satisfactory operative results for most patients with reduced left ventricular function. Prospective and randomly study will be necessary before concluding.
Subject(s)
Coronary Artery Bypass, Off-Pump , Coronary Artery Bypass/methods , Myocardial Infarction/surgery , Ventricular Dysfunction, Left/surgery , Adult , Aged , Coronary Artery Bypass/mortality , Coronary Artery Bypass, Off-Pump/methods , Female , Humans , Male , Middle Aged , Morocco/epidemiology , Myocardial Infarction/diagnosis , Myocardial Infarction/mortality , Myocardial Infarction/physiopathology , Prevalence , Retrospective Studies , Risk Factors , Sex Distribution , Statistics, Nonparametric , Survival Rate , Treatment Outcome , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/mortality , Ventricular Dysfunction, Left/physiopathologyABSTRACT
The aim of this study was to detect extended-spectrum beta-lactamases (ESBL) in Enterobacteriaceae isolates in the intensive care unit (ICU) of Tlemcen hospital in north-western Algeria. Antimicrobial susceptibility testing, molecular typing, characterization of ESBL-encoding genes and the genetic environment, conjugation experiments and plasmid analysis were carried out. In all, 28 Enterobacteriaceae isolates were isolated from specimens recovered from patients in the ICU and 2 from surfaces of the unit. Of these, 11 isolates (4 Escherichia coli, 5 Klebsiella pneumoniae and 2 Enterobacter cloacae) produced ESBL of the CT-X-M-15 type. Molecular typing of the isolates showed the clonal nature of 4 K. pneumoniae isolates. The bla(CTXM-15) gene was genetically linked to insertion sequence lSEcp1B and was transferable by conjugation from 3 isolates. Regular monitoring of resistance mechanisms, the establishment of a prevention strategy, and more rational and appropriate use of antibiotics are needed.
Subject(s)
Anti-Infective Agents/therapeutic use , Cross Infection/drug therapy , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae/isolation & purification , beta-Lactamases/metabolism , Algeria , Anti-Infective Agents/pharmacology , Bacteremia/drug therapy , Bacteremia/microbiology , Bacterial Typing Techniques , Cluster Analysis , Cross Infection/epidemiology , Cross Infection/microbiology , DNA Fingerprinting , Drug Resistance, Bacterial , Electrophoresis, Gel, Pulsed-Field , Enterobacteriaceae/classification , Enterobacteriaceae Infections/epidemiology , Humans , Intensive Care Units , Microbial Sensitivity Tests , Polymerase Chain Reaction , beta-Lactamases/drug effectsABSTRACT
PURPOSE: To investigate of predictor's factors of difficult venous access device in the operating room in elective surgery. METHODS: In a prospective study in central operating room, were included all patients scheduled for a surgical or diagnostic intervention. Were excluded all patients admitted with functional venous access. For each, were recorded patient's demographic characteristics (age, gender, ASA class, BMI), history (chemotherapy, prolonged ICU stay, hospitalization for more than five days), data from the clinical examination (presence of skin lesions, arteriovenous fistulas, burns, neurological deficits) and the type of operator (trainee, nurse, resident, senior). The difficulty was judged on the number of attempts required for successful venous access. Puncture was considered easier for a number of attempts to one to two and difficult if the number of attempts was greater than two. Predictor's factors were identified after univariate and multivariate analysis. RESULTS: During one year (March 2008 to February 2009), form returns in 1500 were met, 1325 were usable. Venous catheterization was successful in 50.9% at the first attempt in 24.2% of patients at the second attempt and after three attempts in 18% of patients. Only 6.8% of patients required more than three attempts. A central venous catheter was required in seven patients. In multivariate analysis, chemotherapy (OR=4.54, 95% CI [2.92 to 7.03]; P<0.001), a nurse in training (OR=2.27, 95% CI [1.40 to 3.63]; P=0.001), a resident in training (OR=2.14, 95% CI [1.29 to 3.58]; P=0.003) and the presence of burns (OR=3.59, 95% CI [2.44 to 5.27]; P<0.001) were identified as independent predictors of difficulty of peripheral venous access. DISCUSSION: The optimization of venous access devices in the operating room through the search for predictors of difficulty.
Subject(s)
Catheterization, Peripheral/statistics & numerical data , Intraoperative Care/statistics & numerical data , Operating Rooms , Preoperative Care/statistics & numerical data , Arteriovenous Shunt, Surgical/statistics & numerical data , Burns/epidemiology , Catheterization, Peripheral/instrumentation , Catheterization, Peripheral/nursing , Diagnosis-Related Groups , Drug Therapy/statistics & numerical data , Equipment Design , Hospitals, Military/statistics & numerical data , Humans , Internship and Residency , Morocco , Operating Room Nursing , Operating Room Technicians , Physicians , Prospective Studies , Risk Factors , Socioeconomic FactorsABSTRACT
The aim of this study was to detect extended-spectrum beta-lactamases [ESBL] in Enterobacteriaceae isolates in the intensive care unit [ICU] of Tlemcen hospital in north-western Algeria. Antimicrobial susceptibility testing, molecular typing, characterization of ESBL-encoding genes and the genetic environment, conjugation experiments and plasmid analysis were carried out. In all, 28 Enterobacteriaceae isolates were isolated from specimens recovered from patients in the ICU and 2 from surfaces of the unit. Of these, 11 isolates [4 Escherichia coti, 5 Klebsiellapneumoniae and 2 Enterobacter cloacae] produced ESBL of the CT-X-M-15 type. Molecular typing of the isolates showed the clonal nature of 4 K, pneumonlae isolates. The bla[CTMX-15] gene was genetically linked to insertion sequence ISEcp1B and was transferable by conjugation from 3 isolates. Regular monitoring of resistance mechanisms, the establishment of a prevention strategy, and more rational and appropriate use of antibiotics are needed
Subject(s)
Enterobacteriaceae , Intensive Care Units , Microbial Sensitivity Tests , beta-LactamasesABSTRACT
Evidence from various in vitro gain and loss of function studies indicate that the bHLH transcription factor Twist1 negatively regulates chondrocyte differentiation; however limited information regarding Twist1 function in postnatal cartilage development and maintenance is available. Twist1 expression within the postnatal growth plate is restricted to immature, proliferating chondrocytes, and is significantly decreased or absent in hypertrophic chondrocytes. In order to examine the effect of maintaining the expression of Twist1 at later stages of chondocyte differentiation, we used type II collagen Cre (Col2-Cre) mice to activate a Cre-inducible Twist1 transgene specifically in chondrocytes (Col2-Twist1). At two weeks, postnatal growth was inhibited in Col2-Twist1 mice, as evidenced by limb shortening. Histological examination revealed abnormal growth plate structure, characterized by poor columnar organization of proliferating cartilaginous cells, decreased cellularity, and expansion of the hypertrophic zone. Moreover, structural defects within the growth plates of Col2-Twist1 transgenic mice included abnormal vascular invasion and focal regions of bony formation. Quantitative analysis of endochondral bone formation via micro-computed topography revealed impaired trabecular bone formation in the hindlimbs of Col2-Twist1 transgenic mice at various timepoints of postnatal development. Taken together, these findings indicate that regulated Twist1 expression contributes to growth plate organization and endochondral ossification to modulate postnatal longitudinal bone growth.
Subject(s)
Chondrocytes/metabolism , Dwarfism/metabolism , Growth Plate/abnormalities , Nuclear Proteins/biosynthesis , Twist-Related Protein 1/biosynthesis , Animals , Bone Development/genetics , Cell Differentiation , Chondrogenesis , Collagen Type II , Dwarfism/genetics , Female , Gene Expression Regulation, Developmental , Gene Knockout Techniques , Genotype , Growth Plate/growth & development , Growth Plate/metabolism , Male , Mice , Mice, Transgenic , Nuclear Proteins/genetics , Osteogenesis , Twist-Related Protein 1/geneticsABSTRACT
Although genetic evidence has demonstrated a role for Wnt5b during cartilage and limb development, little is known about the mechanisms underlying Wnt5b-regulated chondrocyte differentiation. We observed that Wnt5b inhibited chondrocyte hypertrophy and expression of type X collagen. In addition, Wnt5b regulated the overall size of chondrogenic cultures, suggesting that Wnt5b regulates other processes involved in cartilage development. We therefore investigated the signaling pathways by which Wnt5b influences differentiation. Wnt5b activated known calcium-dependent signaling pathways and JNK, a component of the planar cell polarity pathway. Since the planar cell polarity pathway regulates process such as cell migration and cell aggregation that are involved in limb development, we assayed for effects of Wnt5b on these processes. We observed a marked increase chondroprogenitor cell migration with Wnt5b expression. This effect was blocked by inhibition of JNK, but not by inhibition of other Wnt5b-responsive factors. Expression of Wnt5b also disrupted the cellular aggregation associated with mesenchymal condensation. Decreased aggregation was associated with reduced cadherin expression as well as increased cadherin receptor turnover. This increase in cadherin receptor turnover was associated with an increase in Src-dependent beta-catenin phosphorylation downstream of Wnt5b. Our data demonstrate that not only does Wnt5b inhibit chondrocyte hypertrophy, but document a novel role for Wnt5b in modulating cellular migration through the JNK-dependent and cell adhesion through an activation of Src and subsequent cadherin receptor turnover.
Subject(s)
Cell Differentiation , Cell Polarity , Chondrocytes/cytology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Signal Transduction , Wnt Proteins/metabolism , Animals , Cell Adhesion , Cell Aggregation , Cell Movement , Cell Size , Chondrocytes/enzymology , Limb Buds/cytology , Limb Buds/metabolism , Mice , Protein Stability , Receptors, Cell Surface/metabolism , Stem Cells/cytology , Stem Cells/metabolism , src-Family Kinases/metabolismSubject(s)
Acinetobacter baumannii/drug effects , Acinetobacter baumannii/enzymology , Bacterial Proteins/biosynthesis , Carbapenems/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , beta-Lactamases/biosynthesis , Acinetobacter Infections/microbiology , Acinetobacter baumannii/genetics , Acinetobacter baumannii/isolation & purification , Algeria , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , DNA Transposable Elements , Hospitals, University , Humans , Intensive Care Units , Microbial Sensitivity Tests , beta-Lactamases/geneticsABSTRACT
Although genetic evidence demonstrated a requirement for Wnt5a during cartilage development, little is known about the mechanisms underlying Wnt5a-regulated chondrocyte growth and differentiation. We therefore investigated the signaling pathways by which Wnt5a influences chondrogenesis and differentiation to hypertrophy. Wnt5a treatment of chondroprogenitor cells increased chondrocyte hypertrophy and was associated with an increase in nuclear factor of activated T cells (NFAT) and a decrease in nuclear factor-kappaB (NF-kappaB) activation. In contrast, Wnt5a inhibited chondrocyte hypertrophy. This inhibition of hypertrophy occurred with the reciprocal signaling activation, in that a decrease in NFAT and an increase in NF-kappaB activation was observed. Furthermore, the increase in chondroprogenitor cell differentiation with Wnt5a treatment was blocked by calmodulin kinase or NFAT loss of function. In addition, the repression of chondrocyte hypertrophy observed was abrogated by NF-kappaB loss of function. Activation of the NFAT pathway downstream of Wnt5a also negatively regulated NF-kappaB activity, providing evidence of antagonism between these two pathways. Mechanistically, Wnt5a acts to increase chondrocyte differentiation at an early stage through calmodulin kinase /NFAT-dependent induction of Sox9. Conversely, Wnt5a represses chondrocyte hypertrophy via NF-kappaB-dependent inhibition of Runx2 expression. These data indicate that Wnt5a regulates chondrogenesis and chondrocyte hypertrophy in a stage-dependent manner through differential utilization of NFAT- and NF-kappaB-dependent signal transduction.