A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders

A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11and Gi/oto stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-functionCASRmutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+iresponses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680Gin HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+iresponses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11and Gi/oand was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767salt bridge in mediating signaling bias

Chromatic techniques for in vivo monitoring jaundice in neonate tissues

Objective: A chromatic method is described for providing a preliminary indication of unacceptable bilirubin levels in a newly born baby in order to avoid the development of serious mental deficiencies. The aim was to investigate the reliability of a new chromatic approach using a novel template unit for a preliminary, non-invasive monitoring of the skin tissue of newly born babies with jaundice and its capability for use with different mobile phone cameras. Approach: A description of the monitoring system is given along with an explanation of the monitoring technique used. Preliminary tests have been performed on 48 different neonates each being addressed by one of six different mobile phone cameras, which were randomly available to the operating clinicians. Main results: The test results have a correlation (R 2) of 0.81, a sensitivity (Sn) of 0.97, a specificity (Sp) of 0.82, a positive predictive value (PPV) of 0.95 and a negative predictive value (NPV) of 0.9. Significance: The significance of the results obtained is that they show the approach to have a high level of fail-safe reliability in indicating the bilirubin levels when compared with blood test results. The results also show that the approach can be used with a few different mobile phone cameras and that because of its non-invasive nature and its cost effectiveness, has the potential for remote use from a medical hospital to provide an immediate preliminary diagnosis

Structural Insights into Notum Covalent Inhibition

The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer’s disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors

Cmos Programmable Time Control Circuit Design For Phased Array Uwb Ground Penetrating Radar Antenna Beamforming

Phased array radar systems employ multiple antennas to create a radar beam that can be steered electronically. By manipulating the relative phase values of feeding signals among different antennas, the effective radiation pattern of the array can be synthesized to enhance the main lobe in a desired direction while suppressing the undesired side lobes in other directions. Hence the radar scanning angles can be electronically controlled without employing the bulky mechanical gimbal structure, which can significantly reduce radar system size, weight and power consumption. In recent years, phased array technologies have received great attentions and are explored in developing many new applications, such as smart communication systems, military radars, vehicular radar, etc. Most of these systems are narrow band systems, where the phase delays are realized with narrow band phase shifter circuits. For the impulse ground penetrating radar however, its operating frequency spans an ultrawide bandwidth. Therefore the traditional phase shifters are not applicable due to their narrow band nature. To resolve the issue, in this study, a true time delay approach is explored which can precisely control time delays for the feeding pulse signals among different antennas in the array. In the design, an on chip programmable delay generator is being developed using Global Foundry 0.18 µm 7 HV high voltage CMOS process. The time delay control is realized by designing a programmable phase locked loop (PLL) circuit which can generate true time delays ranging from 100 ps (picoseconds) to 500 ps with the step size of 25 ps. The PLL oscillator\u27s frequency is programmable from 100MHz to 500MHz through two reconfigurable frequency dividers in the feedback loop. As a result, the antenna beam angle can be synthesized to change from 9.59° to 56.4° with a step of 2.75°, and the 3dB beamwidth is 10°. The power consumption of the time delay circuit is very low, where the supply voltage is 1.8V and the average current is as low as 472uA

Micro-Flow Imaging: Flow Microscopy Applied to Sub-visible Particulate Analysis in Protein Formulations

The need to monitor, measure, and control sub-visible proteinaceous particulates in biopharmaceutical formulations has been emphasized in recent publications and commentaries. Some of these particulates can be highly transparent, fragile, and unstable. In addition, for much of the size range of concern, no practical measurement method with adequate sensitivity and repeatability has been available. A complication in measuring protein particulates in many formulations is the simultaneous presence of other particle types such as silicone micro-droplets, air bubbles, and extrinsic contaminants. The need has therefore been identified for new analytical methods which can accurately measure and characterize sub-visible particulates in formulations. Micro-flow imaging has been shown to provide high sensitivity in detecting and imaging transparent protein particles and a unique capability to independently analyze such populations even when other particle types are present

Functional Leadership in Interteam Contexts: Understanding ‘What’ in the Context of Why? Where? When? and Who?

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordResearch on team leadership has primarily focused on leadership processes targeted within teams, in support of team objectives. Yet, teams are open systems that interact with other teams to achieve proximal as well as distal goals. This review clarifies that defining ‘what’ constitutes functionally effective leadership in interteam contexts requires greater precision with regard to where (within teams, across teams) and why (team goals, system goals) leadership processes are enacted, as well as greater consideration of when and among whom leadership processes arise. We begin by synthesizing findings from empirical studies published over the past 30 years that shed light on questions of what, where, why, when, and who related to interteam leadership and end by providing three overarching recommendations for how research should proceed in order to provide a more comprehensive picture of leadership in interteam contexts

P16-23. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

International audienc

The Surface Waters Acidification Project Palaeolimnology Programme: modern diatom/lake-water chemistry data-set

In 1983, when the Surface Waters Acidification Programme (SWAP) was announced, we were asked to design and implement a palaeolimnology sub-project involving scientists from Sweden, Norway, and the UK. Our aim was to reconstruct the acidification history of a range of sites in the three countries and to identify and evaluate the various alternative causes of lake acidification. The results of the project have been published recently (Battarbee et al. 1990, Renberg and Battarbee 1990). Although a comprehensive range of palaeolimnological methods and approaches was used in the study we recognised diatom analysis as central to the entire project. We consequently committed considerable effort to improving our diatom methodology and we were especially concerned with the pursuit of a common approach to diatom taxonomy and pH reconstruction. This effort centred on the creation and analysis of a large data-set of surface-sediment diatom assemblages and associated environmental variables from 170 sites representing the full range of lake types in the acid-sensitive and acidified regions of the three countries