Locomotor adaptation to a powered ankle-foot orthosis depends on control method

<p>Abstract</p> <p>Background</p> <p>We studied human locomotor adaptation to powered ankle-foot orthoses with the intent of identifying differences between two different orthosis control methods. The first orthosis control method used a footswitch to provide bang-bang control (a kinematic control) and the second orthosis control method used a proportional myoelectric signal from the soleus (a physiological control). Both controllers activated an artificial pneumatic muscle providing plantar flexion torque.</p> <p>Methods</p> <p>Subjects walked on a treadmill for two thirty-minute sessions spaced three days apart under either footswitch control (n = 6) or myoelectric control (n = 6). We recorded lower limb electromyography (EMG), joint kinematics, and orthosis kinetics. We compared stance phase EMG amplitudes, correlation of joint angle patterns, and mechanical work performed by the powered orthosis between the two controllers over time.</p> <p>Results</p> <p>During steady state at the end of the second session, subjects using proportional myoelectric control had much lower soleus and gastrocnemius activation than the subjects using footswitch control. The substantial decrease in triceps surae recruitment allowed the proportional myoelectric control subjects to walk with ankle kinematics close to normal and reduce negative work performed by the orthosis. The footswitch control subjects walked with substantially perturbed ankle kinematics and performed more negative work with the orthosis.</p> <p>Conclusion</p> <p>These results provide evidence that the choice of orthosis control method can greatly alter how humans adapt to powered orthosis assistance during walking. Specifically, proportional myoelectric control results in larger reductions in muscle activation and gait kinematics more similar to normal compared to footswitch control.</p

The exoskeletons are here

It is a fantastic time for the field of robotic exoskeletons. Recent advances in actuators, sensors, materials, batteries, and computer processors have given new hope to creating the exoskeletons of yesteryear's science fiction. While the most common goal of an exoskeleton is to provide superhuman strength or endurance, scientists and engineers around the world are building exoskeletons with a wide range of diverse purposes. Exoskeletons can help patients with neurological disabilities improve their motor performance by providing task specific practice. Exoskeletons can help physiologists better understand how the human body works by providing a novel experimental perturbation. Exoskeletons can even help power mobile phones, music players, and other portable electronic devices by siphoning mechanical work performed during human locomotion. This special thematic series on robotic lower limb exoskeletons and orthoses includes eight papers presenting novel contributions to the field. The collective message of the papers is that robotic exoskeletons will contribute in many ways to the future benefit of humankind, and that future is not that distant

Unexpected decline in tuberculosis cases coincident with economic recession -- United States, 2009

<p>Abstract</p> <p>Background</p> <p>Since 1953, through the cooperation of state and local health departments, the U.S. Centers for Disease Control and Prevention (CDC) has collected information on incident cases of tuberculosis (TB) disease in the United States. In 2009, TB case rates declined -11.4%, compared to an average annual -3.8% decline since 2000. The unexpectedly large decline raised concerns that TB cases may have gone unreported. To address the unexpected decline, we examined trends from multiple sources on TB treatment initiation, medication sales, and laboratory and genotyping data on culture-positive TB.</p> <p>Methods</p> <p>We analyzed 142,174 incident TB cases reported to the U. S. National Tuberculosis Surveillance System (NTSS) during January 1, 2000-December 31, 2009; TB control program data from 59 public health reporting areas; self-reported data from 50 CDC-funded public health laboratories; monthly electronic prescription claims for new TB therapy prescriptions; and complete genotyping results available for NTSS cases. Accounting for prior trends using regression and time-series analyses, we calculated the deviation between observed and expected TB cases in 2009 according to patient and clinical characteristics, and assessed at what point in time the deviation occurred.</p> <p>Results</p> <p>The overall deviation in TB cases in 2009 was -7.9%, with -994 fewer cases reported than expected (<it>P </it>< .001). We ruled out evidence of surveillance underreporting since declines were seen in states that used new software for case reporting in 2009 as well as states that did not, and we found no cases unreported to CDC in our examination of over 5400 individual line-listed reports in 11 areas. TB cases decreased substantially among both foreign-born and U.S.-born persons. The unexpected decline began in late 2008 or early 2009, and may have begun to reverse in late 2009. The decline was greater in terms of case counts among foreign-born than U.S.-born persons; among the foreign-born, the declines were greatest in terms of percentage deviation from expected among persons who had been in the United States less than 2 years. Among U.S.-born persons, the declines in percentage deviation from expected were greatest among homeless persons and substance users. Independent information systems (NTSS, TB prescription claims, and public health laboratories) reported similar patterns of declines. Genotyping data did not suggest sudden decreases in recent transmission.</p> <p>Conclusions</p> <p>Our assessments show that the decline in reported TB was not an artifact of changes in surveillance methods; rather, similar declines were found through multiple data sources. While the steady decline of TB cases before 2009 suggests ongoing improvement in TB control, we were not able to identify any substantial change in TB control activities or TB transmission that would account for the abrupt decline in 2009. It is possible that other multiple causes coincident with economic recession in the United States, including decreased immigration and delayed access to medical care, could be related to TB declines. Our findings underscore important needs in addressing health disparities as we move towards TB elimination in the United States.</p

The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus

This is the author accepted manuscript. the final version is available from the Society for Neuroscience via the DOI in this recordData availability: RNAseq data (fastq files) were deposited at the Gene Expression Omnibus (GEO) archive under the accession number GSE240887 and made freely available upon publicationThe histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b ΔARID allele that lacks demethylase activity. Kdm5b ΔARID/ΔARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon learning stimulus compared to wildtype mice. A number of other learning-associated genes was also significantly dysregulated in the Kdm5b ΔARID/ΔARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, wildtype mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms. Significance statement The histone lysine demethylase KDM5B has been implicated in cognitive performance and intellectual disability conditions in the human population. In the present manuscript we show that mice expressing a demethylase-deficient KDM5B and mice with a specific knockdown of KDM5B in the adult hippocampus exhibit hippocampus-dependent learning and memory phenotypes. Molecular analyses suggest a key role for KDM5B in regulating the dynamic expression of activity-regulated genes during memory consolidation. Deficits in LTP are present in mice with KDM5B knockdown. Together, these findings provide the first evidence for a direct function for KDM5B in memory consolidation in the hippocampus.Medical Research Council (MRC)National Institute of AgingWellcome Trus

The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5bΔARID allele that lacks demethylase activity. Kdm5bΔARID/ΔARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon learning stimulus compared to wildtype mice. A number of other learning-associated genes was also significantly dysregulated in the Kdm5bΔARID/ΔARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, wildtype mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms. Significance statement The histone lysine demethylase KDM5B has been implicated in cognitive performance and intellectual disability conditions in the human population. In the present manuscript we show that mice expressing a demethylase-deficient KDM5B and mice with a specific knockdown of KDM5B in the adult hippocampus exhibit hippocampus-dependent learning and memory phenotypes. Molecular analyses suggest a key role for KDM5B in regulating the dynamic expression of activity-regulated genes during memory consolidation. Deficits in LTP are present in mice with KDM5B knockdown. Together, these findings provide the first evidence for a direct function for KDM5B in memory consolidation in the hippocampus

p53 Amino-Terminus Region (1–125) Stabilizes and Restores Heat Denatured p53 Wild Phenotype

BACKGROUND:The intrinsically disordered N-ter domain (NTD) of p53 encompasses approximately hundred amino acids that contain a transactivation domain (1-73) and a proline-rich domain (64-92) and is responsible for transactivation function and apoptosis. It also possesses an auto-inhibitory function as its removal results in remarkable reduction in dissociation of p53 from DNA. PRINCIPAL FINDINGS/METHODOLOGY:In this report, we have discovered that p53-NTD spanning amino acid residues 1-125 (NTD125) interacted with WT p53 and stabilized its wild type conformation under physiological and elevated temperatures, both in vitro and in cellular systems. NTD125 prevented irreversible thermal aggregation of heat denatured p53, enhanced p21-5'-DBS binding and further restored DBS binding activity of heat-denatured p53, in vitro, in a dose-dependent manner. In vivo ELISA and immunoprecipitation analysis of NTD125-transfected cells revealed that NTD125 shifted equilibrium from p53 mutant to wild type under heat stress conditions. Further, NTD125 initiated nuclear translocation of cytoplasmic p53 in transcriptionally active state in order to activate p53 downstream genes such as p21, Bax, PUMA, Noxa and SUMO. CONCLUSION/SIGNIFICANCE:Here, we showed that a novel chaperone-like activity resides in p53-N-ter region. This study might have significance in understanding the role of p53-NTD in p53 stabilization, conformational activation and apoptosis under heat-stress conditions

Deletion of Fibroblast Growth Factor Receptor 2 from the Peri-Wolffian Duct Stroma Leads to Ureteric Induction Abnormalities and Vesicoureteral Reflux

Purpose: Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity. Methods: We conditionally deleted Fgfr2 in ST (Fgfr2 ST-/- ) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects. Results: We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2 ST-/- mice at embryonic day (E) 10.5. E11.5 Fgfr2 ST-/- mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2 ST-/- mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2 ST-/- mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes. Conclusion: Mutations in FGFR2 could possibly cause VUR in humans. © 2013 Walker et al

The many possible climates from the Paris Agreement’s aim of 1.5 °C warming

The United Nations’ Paris Agreement includes the aim of pursuing efforts to limit global warming to only 1.5 °C above pre-industrial levels. However, it is not clear what the resulting climate would look like across the globe and over time. Here we show that trajectories towards a ‘1.5 °C warmer world’ may result in vastly different outcomes at regional scales, owing to variations in the pace and location of climate change and their interactions with society’s mitigation, adaptation and vulnerabilities to climate change. Pursuing policies that are considered to be consistent with the 1.5 °C aim will not completely remove the risk of global temperatures being much higher or of some regional extremes reaching dangerous levels for ecosystems and societies over the coming decades

Inducible cAMP Early Repressor (ICER) and Brain Functions

The inducible cAMP early repressor (ICER) is an endogenous repressor of cAMP-responsive element (CRE)-mediated gene transcription and belongs to the CRE-binding protein (CREB)/CRE modulator (CREM)/activating transcription factor 1 (ATF-1) gene family. ICER plays an important role in regulating the neuroendocrine system and the circadian rhythm. Other aspects of ICER function have recently attracted heightened attention. Being a natural inducible CREB antagonist, and more broadly, an inducible repressor of CRE-mediated gene transcription, ICER regulates long-lasting plastic changes that occur in the brain in response to incoming stimulation. This review will bring together data on ICER and its functions in the brain, with a special emphasis on recent findings highlighting the involvement of ICER in the regulation of long-term plasticity underlying learning and memory

Shared Pattern of Endocranial Shape Asymmetries among Great Apes, Anatomically Modern Humans, and Fossil Hominins

Anatomical asymmetries of the human brain are a topic of major interest because of their link with handedness and cognitive functions. Their emergence and occurrence have been extensively explored in human fossil records to document the evolution of brain capacities and behaviour. We quantified for the first time antero-posterior endocranial shape asymmetries in large samples of great apes, modern humans and fossil hominins through analysis of “virtual” 3D models of skull and endocranial cavity and we statistically test for departures from symmetry. Once based on continuous variables, we show that the analysis of these brain asymmetries gives original results that build upon previous analysis based on discrete traits. In particular, it emerges that the degree of petalial asymmetries differs between great apes and hominins without modification of their pattern. We indeed demonstrate the presence of shape asymmetries in great apes, with a pattern similar to modern humans but with a lower variation and a lower degree of fluctuating asymmetry. More importantly, variations in the position of the frontal and occipital poles on the right and left hemispheres would be expected to show some degree of antisymmetry when population distribution is considered, but the observed pattern of variation among the samples is related to fluctuating asymmetry for most of the components of the petalias. Moreover, the presence of a common pattern of significant directional asymmetry for two components of the petalias in hominids implicates that the observed traits were probably inherited from the last common ancestor of extant African great apes and Homo sapiens