Modulation and lack of cross-talk between signal transducer and activator of transcription 5 and suppressor of cytokine signaling-3 in insulin and growth hormone signaling in 3T3-L1 adipocytes

Objective: To examine the role of signal transducer and activator of transcription (STAT) 5 and suppressor of cytokine signaling (SOCS)-3 in the cross-talk between growth hormone and insulin (INS) signaling in fat cells. Research Methods and Procedures: Fully differentiated 3T3-L1 adipocytes were exposed to INS, growth hormone (GH), or both of these growth factors, and the activation of STAT5 proteins and mitogen-activated protein kinase was examined using phospho-specific antibodies. The induction of SOCS-3 mRNA was assessed by Northern blot analysis. INS-stimulated glucose transport was also measured. Results: We observed that GH, not INS, induced STAT5 activation in adipocytes in a manner that was independent of extracellular signal-regulated kinase (ERK) activation or new protein synthesis. GH strongly induced SOCS-3 mRNA expression, whereas INS had a much less potent effect on SOCS-3 mRNA expression. Because SOCS-3 has been implicated in the attenuation of GH and INS signaling, we examined the cross-talk between these signaling pathways. GH pretreatment of adipocytes inhibited GH signaling. Similarly, INS pretreatment inhibited INS signaling. However, INS did not block the GH-induced activation of STAT5, and GH did not block the INS induction of ERK activity or of increased glucose uptake. We observed that neither new protein synthesis nor activation of ERKs 1 and 2 were required for the inhibition of GH signaling. Discussion: These results demonstrate that blocking the induction of the SOCS-3 protein has no effect on the attenuation of GH signaling and support recent studies suggesting that SOCS proteins have additional functions. In addition, these studies demonstrate that GH-induced SOCS-3 expression is insufficient to inhibit INS-induced glucose uptake in adipocytes. Copyright © 2006 NAASO

A Topological Deep Learning Framework for Neural Spike Decoding

The brain's spatial orientation system uses different neuron ensembles to aid in environment-based navigation. One of the ways brains encode spatial information is through grid cells, layers of decked neurons that overlay to provide environment-based navigation. These neurons fire in ensembles where several neurons fire at once to activate a single grid. We want to capture this firing structure and use it to decode grid cell data. Understanding, representing, and decoding these neural structures require models that encompass higher order connectivity than traditional graph-based models may provide. To that end, in this work, we develop a topological deep learning framework for neural spike train decoding. Our framework combines unsupervised simplicial complex discovery with the power of deep learning via a new architecture we develop herein called a simplicial convolutional recurrent neural network (SCRNN). Simplicial complexes, topological spaces that use not only vertices and edges but also higher-dimensional objects, naturally generalize graphs and capture more than just pairwise relationships. Additionally, this approach does not require prior knowledge of the neural activity beyond spike counts, which removes the need for similarity measurements. The effectiveness and versatility of the SCRNN is demonstrated on head direction data to test its performance and then applied to grid cell datasets with the task to automatically predict trajectories

Importance of Preserved Tricuspid Valve Function for Effective Soft Robotic Augmentation of the Right Ventricle in Cases of Elevated Pulmonary Artery Pressure

Purpose: In clinical practice, many patients with right heart failure (RHF) have elevated pulmonary artery pressures and increased afterload on the right ventricle (RV). In this study, we evaluated the feasibility of RV augmentation using a soft robotic right ventricular assist device (SRVAD), in cases of increased RV afterload. Methods: In nine Yorkshire swine of 65-80 kg, a pulmonary artery band was placed to cause RHF and maintained in place to simulate an ongoing elevated afterload on the RV. The SRVAD was actuated in synchrony with the ventricle to augment native RV output for up to one hour. Hemodynamic parameters during SRVAD actuation were compared to baseline and RHF levels. Results: Median RV cardiac index (CI) was 1.43 (IQR, 1.37-1.80) L/min/m(2) and 1.26 (IQR 1.05-1.57) L/min/m(2) at first and second baseline. Upon PA banding RV CI fell to a median of 0.79 (IQR 0.63-1.04) L/min/m(2). Device actuation improved RV CI to a median of 0.87 (IQR 0.78-1.01), 0.85 (IQR 0.64-1.59) and 1.11 (IQR 0.67-1.48) L/min/m(2) at 5 min (p = 0.114), 30 min (p = 0.013) and 60 (p = 0.033) minutes respectively. Statistical GEE analysis showed that lower grade of tricuspid regurgitation at time of RHF (p = 0.046), a lower diastolic pressure at RHF (p = 0.019) and lower mean arterial pressure at RHF (p = 0.024) were significantly associated with higher SRVAD effectiveness. Conclusions: Short-term augmentation of RV function using SRVAD is feasible even in cases of elevated RV afterload. Moderate or severe tricuspid regurgitation were associated with reduced device effectiveness

iPSC-derived myelinoids to study myelin biology of humans

Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids (“myelinoids”) and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination—both at the level of individual oligodendrocytes and globally across whole myelinoids—and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination

CRAFT (Cerclage after full dilatation caesarean section): protocol of a mixed methods study investigating the role of previous in-labour caesarean section in preterm birth risk

BACKGROUND: Full dilatation caesarean sections are associated with recurrent early spontaneous preterm birth and late miscarriage. The risk following first stage caesarean sections, are less well defined, but appears to be increased in late-first stage of labour. The mechanism for this increased risk of late miscarriage and early spontaneous preterm birth in these women is unknown and there are uncertainties with regards to clinical management. Current predictive models of preterm birth (based on transvaginal ultrasound and quantitative fetal fibronectin) have not been validated in these women and it is unknown whether the threshold to define a short cervix (≤25 mm) is reliable in predicting the risk of preterm birth. In addition the efficacy of standard treatments or whether benefit may be derived from prophylactic interventions such as a cervical cerclage is unknown. METHODS: There are three distinct components to the CRAFT project (CRAFT-OBS, CRAFT-RCT and CRAFT-IMG). CRAFT-OBS: Observational Study; To evaluate subsequent pregnancy risk of preterm birth in women with a prior caesarean section in established labour. This prospective study of cervical length and quantitative fetal fibronectin data will establish a predictive model of preterm birth. CRAFT-RCT: Randomised controlled trial arm; To assess treatment for short cervix in women at high risk of preterm birth following a fully dilated caesarean section. CRAFT-IMG: Imaging sub-study; To evaluate the use of MRI and transvaginal ultrasound imaging of micro and macrostructural cervical features which may predispose to preterm birth in women with a previous fully dilated caesarean section, such as scar position and niche. DISCUSSION: The CRAFT project will quantify the risk of preterm birth or late miscarriage in women with previous in-labour caesarean section, define the best management and shed light on pathological mechanisms so as to improve the care we offer to women and their babies. TRIAL REGISTRATION: CRAFT was prospectively registered on 25th November 2019 with the ISRCTN registry ( https://doi.org/10.1186/ISRCTN15068651 )

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

ARM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. JMG is funded by a starter grant for clinical lecturers from the Academy of Medical Sciences. CS is supported by a Medical Research Council grant (MR/L016400/1). NMM was funded by a Wellcome Trust New Investigator Award (100981/Z/13/Z). RNC and NMM are funded by a Diabetes UK grant (17/0005697). The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the MRC, Alzheimer's Society and Alzheimer's Research UK. SC also acknowledges funding from the ARRNC, My Name’5 Doddie Foundation, and an MRC Dementias Platform UK Stem Cell Partnership grant (MR/N013255/1). BTS is a Rowling-DRI Fellow.Peer reviewedPublisher PD

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNA-binding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALS-causing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival. We then performed coculture experiments to evaluate the effects of M337V astrocytes on the survival of wild-type and M337V TDP-43 motor neurons, showing that mutant TDP-43 astrocytes do not adversely affect survival of cocultured neurons. These observations reveal a significant and previously unrecognized glial cell-autonomous pathological phenotype associated with a pathogenic mutation in TDP-43 and show that TDP-43 proteinopathies do not display an astrocyte non-cell-autonomous component in cell culture, as previously described for SOD1 ALS. This study highlights the utility of induced pluripotent stem cell-based in vitro disease models to investigate mechanisms of disease in ALS and other TDP-43 proteinopathies

CMB-S4 Science Book, First Edition

This book lays out the scientific goals to be addressed by the next-generation ground-based cosmic microwave background experiment, CMB-S4, envisioned to consist of dedicated telescopes at the South Pole, the high Chilean Atacama plateau and possibly a northern hemisphere site, all equipped with new superconducting cameras. CMB-S4 will dramatically advance cosmological studies by crossing critical thresholds in the search for the B-mode polarization signature of primordial gravitational waves, in the determination of the number and masses of the neutrinos, in the search for evidence of new light relics, in constraining the nature of dark energy, and in testing general relativity on large scales