Long-Dose Intensive Therapy Is Necessary for Strong, Clinically Significant, Upper Limb Functional Gains and Retained Gains in Severe/Moderate Chronic Stroke

Background. Effective treatment methods are needed for moderate/severely impairment chronic stroke. Objective. The questions were the following: (1) Is there need for long-dose therapy or is there a mid-treatment plateau? (2) Are the observed gains from the prior-studied protocol retained after treatment? Methods. Single-blind, stratified/randomized design, with 3 applied technology treatment groups, combined with motor learning, for long-duration treatment (300 hours of treatment). Measures were Arm Motor Ability Test time and coordination-function (AMAT-T, AMAT-F, respectively), acquired pre-/posttreatment and 3-month follow-up (3moF/U); Fugl-Meyer (FM), acquired similarly with addition of mid-treatment. Findings. There was no group difference in treatment response (P ≥ .16), therefore data were combined for remaining analyses (n = 31; except for FM pre/mid/post, n = 36). Pre-to-Mid-treatment and Mid-to-Posttreatment gains of FM were statistically and clinically significant (P \u3c .0001; 4.7 points and P \u3c .001; 5.1 points, respectively), indicating no plateau at 150 hours and benefit of second half of treatment. From baseline to 3moF/U: (1) FM gains were twice the clinically significant benchmark, (2) AMAT-F gains were greater than clinically significant benchmark, and (3) there was statistically significant improvement in FM (P \u3c .0001); AMAT-F (P \u3c .0001); AMAT-T (P \u3c .0001). These gains indicate retained clinically and statistically significant gains at 3moFU. From posttreatment to 3moF/U, gains on FM were maintained. There were statistically significant gains in AMAT-F (P = .0379) and AMAT-T P = .003

A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive

Development and Testing of The Gait Assessment and Intervention Tool (G.A.I.T.): A Measure of Coordinated Gait Components

Recent neuroscience methods have provided the basis upon which to develop effective gait training methods for recovery of the coordinated components of gait after neural injury. We determined that there was not an existing observational measure that was, at once, adequately comprehensive, scored in an objectively-based manner, and capable of assessing incremental improvements in the coordinated components of gait. Therefore, the purpose of this work was to use content valid procedures in order to develop a relatively inexpensive, more comprehensive measure, scored with an objectively-based system, capable of incrementally scoring improvements in given items, and that was both reliable and capable of discriminating treatment response for those who had a stroke. Eight neurorehabilitation specialists developed criteria for the gait measure, item content, and scoring method. In subjects following stroke (\u3e12 months), the new measure was tested for intra- and inter-rater reliability using the Intraclass Correlation Coefficient; capability to detect treatment response using Wilcoxon Signed Ranks Test; and discrimination between treatment groups, using the Plum Ordinal Regression. The Gait Assessment and Intervention Tool (G.A.I.T.) is a 31-item measure of the coordinated movement components of gait and associated gait deficits. It exhibited the following advantages: comprehensive, objective-based scoring method, incremental measurement of improvement within given items. The G.A.I.T. had good intra- and inter-rater reliability (ICC = .98, p = .0001, 95% CI = .95, .99; ICC = .83, p = .007, 95% CI = .32, .96, respectively. The inexperienced clinician who had training, had an inter-rater reliability with an experienced rater of ICC = .99 (p = .0001, CI = .97, .999). The G.A.I.T. detected improvement in response to gait training for two types of interventions: comprehensive gait training (z = −2.93, p = .003); and comprehensive gait training plus functional electrical stimulation (FES; z = −3.3, p = .001). The G.A.I.T. was capable of discriminating between two gait training interventions, showing an additive advantage of FES to otherwise comparable comprehensive gait training (parameter estimate = 1.72, p = .021; CI, .25, 3.1)

Development and Testing of The Gait Assessment and Intervention Tool (G.A.I.T.): A Measure of Coordinated Gait Components

Recent neuroscience methods have provided the basis upon which to develop effective gait training methods for recovery of the coordinated components of gait after neural injury. We determined that there was not an existing observational measure that was, at once, adequately comprehensive, scored in an objectively-based manner, and capable of assessing incremental improvements in the coordinated components of gait. Therefore, the purpose of this work was to use content valid procedures in order to develop a relatively inexpensive, more comprehensive measure, scored with an objectively-based system, capable of incrementally scoring improvements in given items, and that was both reliable and capable of discriminating treatment response for those who had a stroke. Eight neurorehabilitation specialists developed criteria for the gait measure, item content, and scoring method. In subjects following stroke (\u3e12 months), the new measure was tested for intra- and inter-rater reliability using the Intraclass Correlation Coefficient; capability to detect treatment response using Wilcoxon Signed Ranks Test; and discrimination between treatment groups, using the Plum Ordinal Regression. The Gait Assessment and Intervention Tool (G.A.I.T.) is a 31-item measure of the coordinated movement components of gait and associated gait deficits. It exhibited the following advantages: comprehensive, objective-based scoring method, incremental measurement of improvement within given items. The G.A.I.T. had good intra- and inter-rater reliability (ICC = .98, p = .0001, 95% CI = .95, .99; ICC = .83, p = .007, 95% CI = .32, .96, respectively. The inexperienced clinician who had training, had an inter-rater reliability with an experienced rater of ICC = .99 (p = .0001, CI = .97, .999). The G.A.I.T. detected improvement in response to gait training for two types of interventions: comprehensive gait training (z = −2.93, p = .003); and comprehensive gait training plus functional electrical stimulation (FES; z = −3.3, p = .001). The G.A.I.T. was capable of discriminating between two gait training interventions, showing an additive advantage of FES to otherwise comparable comprehensive gait training (parameter estimate = 1.72, p = .021; CI, .25, 3.1)

An avalanche-photodiode-based photon-number-resolving detector

Avalanche photodiodes are widely used as practical detectors of single photons.1 Although conventional devices respond to one or more photons, they cannot resolve the number in the incident pulse or short time interval. However, such photon number resolving detectors are urgently needed for applications in quantum computing,2-4 communications5 and interferometry,6 as well as for extending the applicability of quantum detection generally. Here we show that, contrary to current belief,3,4 avalanche photodiodes are capable of detecting photon number, using a technique to measure very weak avalanches at the early stage of their development. Under such conditions the output signal from the avalanche photodiode is proportional to the number of photons in the incident pulse. As a compact, mass-manufactured device, operating without cryogens and at telecom wavelengths, it offers a practical solution for photon number detection.Comment: 12 pages, 4 figure

Long-Dose Intensive Therapy Is Necessary for Strong, Clinically Significant, Upper Limb Functional Gains and Retained Gains in Severe/Moderate Chronic Stroke

Background. Effective treatment methods are needed for moderate/severely impairment chronic stroke. Objective. The questions were the following: (1) Is there need for long-dose therapy or is there a mid-treatment plateau? (2) Are the observed gains from the prior-studied protocol retained after treatment? Methods. Single-blind, stratified/randomized design, with 3 applied technology treatment groups, combined with motor learning, for long-duration treatment (300 hours of treatment). Measures were Arm Motor Ability Test time and coordination-function (AMAT-T, AMAT-F, respectively), acquired pre-/posttreatment and 3-month follow-up (3moF/U); Fugl-Meyer (FM), acquired similarly with addition of mid-treatment. Findings. There was no group difference in treatment response (P ≥ .16), therefore data were combined for remaining analyses (n = 31; except for FM pre/mid/post, n = 36). Pre-to-Mid-treatment and Mid-to-Posttreatment gains of FM were statistically and clinically significant (P \u3c .0001; 4.7 points and P \u3c .001; 5.1 points, respectively), indicating no plateau at 150 hours and benefit of second half of treatment. From baseline to 3moF/U: (1) FM gains were twice the clinically significant benchmark, (2) AMAT-F gains were greater than clinically significant benchmark, and (3) there was statistically significant improvement in FM (P \u3c .0001); AMAT-F (P \u3c .0001); AMAT-T (P \u3c .0001). These gains indicate retained clinically and statistically significant gains at 3moFU. From posttreatment to 3moF/U, gains on FM were maintained. There were statistically significant gains in AMAT-F (P = .0379) and AMAT-T P = .003

A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila.

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive

Single-molecule multiparameter fluorescence spectroscopy reveals directional MutS binding to mismatched bases in DNA

Mismatch repair (MMR) corrects replication errors such as mismatched bases and loops in DNA. The evolutionarily conserved dimeric MMR protein MutS recognizes mismatches by stacking a phenylalanine of one subunit against one base of the mismatched pair. In all crystal structures of G:T mismatch-bound MutS, phenylalanine is stacked against thymine. To explore whether these structures reflect directional mismatch recognition by MutS, we monitored the orientation of Escherichia coli MutS binding to mismatches by FRET and anisotropy with steady state, pre-steady state and single-molecule multiparameter fluorescence measurements in a solution. The results confirm that specifically bound MutS bends DNA at the mismatch. We found additional MutS–mismatch complexes with distinct conformations that may have functional relevance in MMR. The analysis of individual binding events reveal significant bias in MutS orientation on asymmetric mismatches (G:T versus T:G, A:C versus C:A), but not on symmetric mismatches (G:G). When MutS is blocked from binding a mismatch in the preferred orientation by positioning asymmetric mismatches near the ends of linear DNA substrates, its ability to authorize subsequent steps of MMR, such as MutH endonuclease activation, is almost abolished. These findings shed light on prerequisites for MutS interactions with other MMR proteins for repairing the appropriate DNA strand

D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders

The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful

Nucleosomes in gene regulation: theoretical approaches

This work reviews current theoretical approaches of biophysics and bioinformatics for the description of nucleosome arrangements in chromatin and transcription factor binding to nucleosomal organized DNA. The role of nucleosomes in gene regulation is discussed from molecular-mechanistic and biological point of view. In addition to classical problems of this field, actual questions of epigenetic regulation are discussed. The authors selected for discussion what seem to be the most interesting concepts and hypotheses. Mathematical approaches are described in a simplified language to attract attention to the most important directions of this field