Reduction of freezing of gait in Parkinson's disease by repetitive robot-assisted treadmill training: a pilot study

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease is a chronic, neurodegenerative disease characterized by gait abnormalities. Freezing of gait (FOG), an episodic inability to generate effective stepping, is reported as one of the most disabling and distressing parkinsonian symptoms. While there are no specific therapies to treat FOG, some external physical cues may alleviate these types of motor disruptions. The purpose of this study was to examine the potential effect of continuous physical cueing using robot-assisted sensorimotor gait training on reducing FOG episodes and improving gait.</p> <p>Methods</p> <p>Four individuals with Parkinson's disease and FOG symptoms received ten 30-minute sessions of robot-assisted gait training (Lokomat) to facilitate repetitive, rhythmic, and alternating bilateral lower extremity movements. Outcomes included the FOG-Questionnaire, a clinician-rated video FOG score, spatiotemporal measures of gait, and the Parkinson's Disease Questionnaire-39 quality of life measure.</p> <p>Results</p> <p>All participants showed a reduction in FOG both by self-report and clinician-rated scoring upon completion of training. Improvements were also observed in gait velocity, stride length, rhythmicity, and coordination.</p> <p>Conclusions</p> <p>This pilot study suggests that robot-assisted gait training may be a feasible and effective method of reducing FOG and improving gait. Videotaped scoring of FOG has the potential advantage of providing additional data to complement FOG self-report.</p

Notch Initiates the Endothelial-to-Mesenchymal Transition in the Atrioventricular Canal through Autocrine Activation of Soluble Guanylyl Cyclase

SummaryThe heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC)

High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

About one-third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below-normal Elmo1 expression in mice ameliorates the albuminuria and glomerular histological changes resulting from long-standing type 1 diabetes, whereas above-normal Elmo1 expression makes both worse. Increasing Elmo1 expression leads to aggravation of oxidative stress markers and enhances the expression of fibrogenic genes. Suppressing Elmo1 action in human patients could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes

Optogenetic stimulation probes with single-neuron resolution based on organic LEDs monolithically integrated on CMOS

Funding: This work was supported in part by the Defense Advanced Research Projects Agency (DARPA) under contract N6600117C4012, by the National Institutes of Health under grant U01NS090596, by the Leverhulme Trust (RPG-2017-231) and by the Alexander von Humboldt Stiftung (Humboldt-Professorship to M.C.G.). This work was performed in part at the Columbia Nano Initiative cleanroom facility, at the CUNY Advanced Science Research Center Nanofabrication Facility, and at the Singh Center for Nanotechnology, part of the National Nanotechnology Coordinated Infrastructure Program, which is supported by the National Science Foundation grant NNCI-2025608. C.-K.M. acknowledges funding from the European Commission through a Marie-Skłodowska Curie Individual Fellowship (101029807).The use of optogenetic stimulation to evoke neuronal activity in targeted neural populations—enabled by opsins with fast kinetics, high sensitivity and cell-type and subcellular specificity—is a powerful tool in neuroscience. However, to interface with the opsins, deep-brain light delivery systems are required that match the scale of the spatial and temporal control offered by the molecular actuators. Here we show that organic light-emitting diodes can be combined with complementary metal–oxide–semiconductor technology to create bright, actively multiplexed emissive elements. We create implantable shanks in which 1,024 individually addressable organic light-emitting diode pixels with a 24.5 µm pitch are integrated with active complementary metal–oxide–semiconductor drive and control circuitry. This integration is enabled by controlled electrode conditioning, monolithic deposition of the organic light-emitting diodes and optimized thin-film encapsulation. The resulting probes can be used to access brain regions as deep as 5 mm and selectively activate individual neurons with millisecond-level precision in mice.Publisher PDFPeer reviewe

AMP-Activated Protein Kinase Directly Phosphorylates and Destabilizes Hedgehog Pathway Transcription Factor GLI1 in Medulloblastoma

The Hedgehog (Hh) pathway regulates cell differen- tiation and proliferation during development by controlling the Gli transcription factors. Cell fate de- cisions and progression toward organ and tissue maturity must be coordinated, and how an energy sensor regulates the Hh pathway is not clear. AMP- activated protein kinase (AMPK) is an important sensor of energy stores and controls protein synthe- sis and other energy-intensive processes. AMPK is directly responsive to intracellular AMP levels, inhib- iting a wide range of cell activities if ATP is low and AMP is high. Thus, AMPK can affect development by influencing protein synthesis and other processes needed for growth and differentiation. Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcrip- tional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency

Baryon Number in Warped GUTs : Model Building and (Dark Matter Related) Phenomenology

In the past year, a new non-supersymmetric framework for electroweak symmetry breaking (with or without Higgs) involving SU(2)_L * SU(2)_R * U(1)_{B-L} in higher dimensional warped geometry has been suggested. In this work, we embed this gauge structure into a GUT such as SO(10) or Pati-Salam. We showed recently (in hep-ph/0403143) that in a warped GUT, a stable Kaluza-Klein fermion can arise as a consequence of imposing proton stability. Here, we specify a complete realistic model where this particle is a weakly interacting right-handed neutrino, and present a detailed study of this new dark matter candidate, providing relic density and detection predictions. We discuss phenomenological aspects associated with the existence of other light (<~ TeV) KK fermions (related to the neutrino), whose lightness is a direct consequence of the top quark's heaviness. The AdS/CFT interpretation of this construction is also presented. Most of our qualitative results do not depend on the nature of the breaking of the electroweak symmetry provided that it happens near the TeV brane.Comment: 61 pages, 12 figures; v2: minor changes; v3: Two additional diagrams in Fig. 10; a numerical factor corrected in section 16.1 (baryogenesis section), corresponding discussion slightly modified but qualitative results unchange

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Low-Energy Probes of a Warped Extra Dimension

We investigate a natural realization of a light Abelian hidden sector in an extended Randall-Sundrum (RS) model. In addition to the usual RS bulk we consider a second warped space containing a bulk U(1)_x gauge theory with a characteristic IR scale of order a GeV. This Abelian hidden sector can couple to the standard model via gauge kinetic mixing on a common UV brane. We show that if such a coupling induces significant mixing between the lightest U(1)_x gauge mode and the standard model photon and Z, it can also induce significant mixing with the heavier U(1)_x Kaluza-Klein (KK) modes. As a result it might be possible to probe several KK modes in upcoming fixed-target experiments and meson factories, thereby offering a new way to investigate the structure of an extra spacetime dimension.Comment: 26 pages, 1 figure, added references, corrected minor typos, same as journal versio

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: a study protocol (LUANA trial)

AbstractAnorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]

Low-Energy Signals from Kinetic Mixing with a Warped Abelian Hidden Sector

We investigate the detailed phenomenology of a light Abelian hidden sector in the Randall-Sundrum framework. Relative to other works with light hidden sectors, the main new feature is a tower of hidden Kaluza-Klein vectors that kinetically mix with the Standard Model photon and Z. We investigate the decay properties of the hidden sector fields in some detail, and develop an approach for calculating processes initiated on the ultraviolet brane of a warped space with large injection momentum relative to the infrared scale. Using these results, we determine the detailed bounds on the light warped hidden sector from precision electroweak measurements and low-energy experiments. We find viable regions of parameter space that lead to significant production rates for several of the hidden Kaluza-Klein vectors in meson factories and fixed-target experiments. This offers the possibility of exploring the structure of an extra spacetime dimension with lower-energy probes.Comment: (1+32) Pages, 13 Figures. v2: JHEP version (minor modifications, results unchanged