The cJUN NH2-terminal kinase (JNK) pathway contributes to mouse mammary gland remodeling during involution

Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK has a key role in mammary gland involution post lactation

A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear. We now find that inactivation of NHE9 in mice reproduces behavioral features of ASD including impaired social interaction, repetitive behaviors, and altered sensory processing. Physiological characterization reveals hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9

The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor suppressive function was not mediated by a role of JNK in the growth of established tumors, but by a requirement of JNK to prevent tumor initiation. Together, these data identify JNK pathway defects as \u27driver\u27 mutations that promote genome instability and tumor initiation

Randomized Controlled Study of a Remote Flipped Classroom Neuro-otology Curriculum

CONTEXT: Medical Education can be delivered in the traditional classroom or via novel technology including an online classroom. OBJECTIVE: To test the hypothesis that learning in an online classroom would result in similar outcomes as learning in the traditional classroom when using a flipped classroom pedagogy. DESIGN: Randomized controlled trial. A total of 274 subjects enrolled in a Neuro-otology training program for non-Neuro-otologists of 25 h held over a 3-day period. Subjects were randomized into a control group attending a traditional classroom and a trial group of equal numbers participating in an online synchronous Internet streaming classroom using the Adobe Connect e-learning platform. INTERVENTIONS: Subjects were randomized into a control group attending a traditional classroom and a treatment group of equal numbers participating in an online synchronous Internet streaming classroom. MAIN OUTCOME MEASURES: Pre- and post-multiple choice examinations of VOR, Movement, Head Turns, Head Tremor, Neurodegeneration, Inferior Olivary Complex, Collateral Projections, Eye Movement Training, Visual Saccades, Head Saccades, Visual Impairment, Walking Speed, Neuroprotection, Autophagy, Hyperkinetic Movement, Eye and Head Stability, Oscilllatory Head Movements, Gaze Stability, Leaky Neural Integrator, Cervical Dystonia, INC and Head Tilts, Visual Pursuits, Optokinetic Stimulation, and Vestibular Rehabilitation. METHODS: All candidates took a pretest examination of the subject material. The 2-9 h and 1-8 h sessions over three consecutive days were given live in the classroom and synchronously in the online classroom using the Adobe Connect e-learning platform. Subjects randomized to the online classroom attended the lectures in a location of their choice and viewed the sessions live on the Internet. A posttest examination was given to all candidates after completion of the course. Two sample unpaired t tests with equal variances were calculated for all pretests and posttests for all groups including gender differences. RESULTS: All 274 subjects demonstrated statistically significant learning by comparison of their pre- and posttest scores. There were no statistically significant differences in the test scores between the two groups of 137 subjects each (0.8%, 95% CI 85.45917-86.67952; P = 0.9195). A total of 101 males in the traditional classroom arm had statistically significant lower scores than 72 females (0.8%, 95% CI 84.65716-86.53096; P = 0.0377) but not in the online arm (0.8%, 95% CI 85.46172-87.23135; P = 0.2176) with a moderate effect size (Cohen\u27s d = -0.407). CONCLUSION: The use of a synchronous online classroom in neuro-otology clinical training has demonstrated similar outcomes to the traditional classroom. The online classroom is a low cost and effective complement to medical specialty training in Neuro-Otology. The significant difference in outcomes between males and females who attended the traditional classroom suggests that women may do better than males in this learning environment, although the effect size is moderate. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT03079349

Hydrophilic 2,9-bis-triazolyl-1,10-phenanthroline ligands enable selective Am(iii) separation: a step further towards sustainable nuclear energy

The first hydrophilic, 1,10-phenanthroline derived ligands consisting of only C, H, O and N atoms for the selective extraction of Am(iii) from spent nuclear fuel are reported herein. One of these 2,9-bis-triazolyl-1,10-phenanthroline (BTrzPhen) ligands combined with a non-selective extracting agent, was found to exhibit process-suitable selectivity for Am(iii) over Eu(iii) and Cm(iii), providing a clear step forward

Transition metal-free, visible-light mediated synthesis of 1,10-phenanthroline derived ligand systems

A broad range of 1,10-phenanthroline substrates was efficiently C-H functionalised, providing rapid, gram-scale access to substituted heteroaromatic cores of broad utility. Furthermore, this C-H functionalisation pathway was extended to the synthesis of previously inaccessible, ultra-soluble, 2,9-bis-triazinyl-1,10-phenanthroline (BTPhen) ligands for advanced nuclear fuel cycles

Modeling dimethylsulphide production in the upper ocean

Dimethylsulphide (DMS) is produced by upper ocean ecosystems and emitted to the atmosphere, where it may have an important role in climate regulation. Several attempts to quantify the role of DMS in climate change have been undertaken in modeling studies. We examine a model of biogenic DMS production and describe its endogenous dynamics and sensitivities. We extend the model to develop a one-dimensional version that more accurately resolves the important processes of the mixed layer in determining the ecosystem dynamics. Comparisons of the results of the one-dimensional model with an empirical relationship that describes the global distribution of DMS, and also with vertical profiles of DMS in the upper ocean measured at the Bermuda Atlantic Time Series, suggest that the model represents the interaction between the biological and physical processes well on local and global scales. Our analysis of the model confirms its veracity and provides insights into the important processes determining DMS concentration in the oceans

Nutrition training in medical and other health professional schools in West Africa: the need to improve current approaches and enhance training effectiveness

Background: Health professionals play a key role in the delivery of nutrition interventions. Improving the quality of nutrition training in health professional schools is vital for building the necessary human resource capacity to implement effective interventions for reducing malnutrition in West Africa. This study was undertaken to assess the current status of nutrition training in medical, nursing and midwifery schools in West Africa. Design: Data were collected from 127 training programs organized by 52 medical, nursing, and midwifery schools. Using a semi-structured questionnaire, we collected information on the content and distribution of nutrition instruction throughout the curriculum, the number of hours devoted to nutrition, the years of the curriculum in which nutrition was taught, and the prevailing teaching methods. Simple descriptive and bivariate analyses were performed. Results: Nutrition instruction occurred mostly during the first 2 years for the nursing (84%), midwifery (87%), and nursing assistant (77%) programs and clinical years in medical schools (64%). The total amount of time devoted to nutrition was on average 57, 56, 48, and 28 hours in the medical, nursing, midwifery, and nursing assistant programs, respectively. Nutrition instruction was mostly provided within the framework of a dedicated nutrition course in nursing (78%), midwifery (87%), and nursing assistant programs (100%), whereas it was mainly embedded in other courses in medical schools (46%). Training content was heavily weighted to basic nutrition in the nursing (69%), midwifery (77%), and nursing assistant (100%) programs, while it was oriented toward clinical practice in the medical programs (64%). For all the programs, there was little focus (<6 hours contact time) on public health nutrition. The teaching methods on nutrition training were mostly didactic in all the surveyed schools; however, we found an integrated model in some medical schools (12%). None of the surveyed institutions had a dedicated nutrition faculty. The majority (55%) of the respondents rated nutrition instruction in their institutions as insufficient. Conclusions: The results of our study reveal important gaps in current approaches to nutrition training in health professional schools in West Africa. Addressing these gaps is critical for the development of a skilled nutrition workforce in the region. Nutrition curricula that provide opportunities to obtain more insights about the basic principles of human nutrition and their application to public health and clinical practice are recommended

Prediction of early clinical response in patients receiving tofacitinib in the OCTAVE Induction 1 and 2 studies

INTRODUCTION: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Outcome prediction based on early treatment response, along with clinical and laboratory variables, would be very useful for clinical practice. The aim of this study was to determine early variables predictive of responder status in patients with UC treated with tofacitinib. METHODS: Data were collected from patients treated with tofacitinib 10 mg twice daily in the OCTAVE Induction 1 and 2 studies (NCT01465763 and NCT01458951). Logistic regression and random forest analyses were performed to determine the power of clinical and/or laboratory variables to predict 2- and 3-point partial Mayo score responder status of patients at Weeks 4 or 8 after baseline. RESULTS: From a complete list of variables measured in OCTAVE Induction 1 and 2, analyses identified partial Mayo score, partial Mayo subscore (stool frequency, rectal bleeding, and Physician Global Assessment), cholesterol level, and C-reactive protein level as sufficient variables to predict responder status. Using these variables at baseline and Week 2 predicted responder status at Week 4 with 84–87% accuracy and Week 8 with 74–79% accuracy. Variables at baseline, Weeks 2 and 4 could predict responder status at Week 8 with 85–87% accuracy. CONCLUSION: Using a limited set of time-dependent variables, statistical and machine learning models enabled early and clinically meaningful predictions of tofacitinib treatment outcomes in patients with moderately to severely active UC