Activity of leg motoneurons during single leg walking of the stick insect: From synaptic inputs to motor performance

In the single middle leg preparation of the stick insect, leg motoneurons were recorded intracellularly during stepping movements on a treadmill. This preparation allows investigating the synaptic drive from local sense organs and central pattern generating networks to motoneurons. The synaptic drive comprises rhythmic (�phasic�) excitation and inhibition and a sustained (�tonic�) depolarization. This general scheme was found to be true for all motoneurons innervating the muscles of the three major leg joints. A comparison e.g. with results obtained from deafferented and pharmacologically activated preparations of the stick insect suggests that both tonic depolarization and phasic inhibition originate from central networks, while the phasic excitation is mainly generated by local sense organs. Recruitment of motoneurons was studied on the flexor tibiae muscle as an example of a complexly innervated muscle. It is innervated by ~14 slow, semifast and fast motoneurons that are firing action potentials during the stance phase of the step cycle. During slow steps or steps under small load, less motoneurons are recruited than during fast steps or steps under high load. Fast flexor motoneurons are recruited later during stance phase than slow motoneurons. All motoneurons receive substantial common synaptic drive during walking. They are recruited in an orderly fashion due to the more negative resting membrane potential of the fast motoneurons, which thus require a larger and longer lasting depolarization to reach the threshold for the generation of action potentials. Because walking is not invariable but needs to be adjusted to the behavioral requirements, it was investigated how these adjustments are implemented at the motoneuronal level. The activity of flexor and extensor tibiae motoneurons was analyzed during steps with different velocities. Extensor motoneuron activity during the extension phase of the step cycle (i.e. swing phase) is rather stereotypic and invariant with stance velocity. Flexor motoneurons show two distinct periods of depolarization at the beginning of stance. The initial depolarization is also stereotypic and most likely generated by a release from inhibition that allows the underlying tonic excitation to depolarize the neuron. The subsequent depolarization is larger and faster during fast steps than during slow steps. This indicates that in the single insect leg during walking, mechanisms for altering stepping velocity are becoming effective only during already ongoing stance phase motor output. Since a large portion of the phasic excitation arises from sense organs, it is conceivable that for the generation of different stepping velocities the effectiveness of these pathways are centrally modulated, for example by variations in the degree of presynaptic inhibition

Type Ia Supernova Distances at z > 1.5 from the Hubble Space Telescope Multi-Cycle Treasury Programs: The Early Expansion Rate

We present an analysis of 15 Type Ia supernovae (SNe Ia) at redshift z > 1 (9 at 1.5 < z < 2.3) recently discovered in the CANDELS and CLASH Multi-Cycle Treasury programs using WFC3 on the Hubble Space Telescope. We combine these SNe Ia with a new compilation of 1050 SNe Ia, jointly calibrated and corrected for simulated survey biases to produce accurate distance measurements. We present unbiased constraints on the expansion rate at six redshifts in the range 0.07 < z < 1.5 based only on this combined SN Ia sample. The added leverage of our new sample at z > 1.5 leads to a factor of ~3 improvement in the determination of the expansion rate at z = 1.5, reducing its uncertainty to ~20%, a measurement of H(z=1.5)/H0=2.67 (+0.83,-0.52). We then demonstrate that these six measurements alone provide a nearly identical characterization of dark energy as the full SN sample, making them an efficient compression of the SN Ia data. The new sample of SNe Ia at z > 1 usefully distinguishes between alternative cosmological models and unmodeled evolution of the SN Ia distance indicators, placing empirical limits on the latter. Finally, employing a realistic simulation of a potential WFIRST SN survey observing strategy, we forecast optimistic future constraints on the expansion rate from SNe Ia.Comment: 14 pages, 5 figures, 7 tables; submitted to Ap

Association Between Intravenous Thrombolysis and Clinical Outcomes Among Patients With Ischemic Stroke and Unsuccessful Mechanical Reperfusion.

IMPORTANCE Clinical evidence of the potential treatment benefit of intravenous thrombolysis preceding unsuccessful mechanical thrombectomy (MT) is scarce. OBJECTIVE To determine whether intravenous thrombolysis (IVT) prior to unsuccessful MT improves functional outcomes in patients with acute ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS Patients were enrolled in this retrospective cohort study from the prospective, observational, multicenter German Stroke Registry-Endovascular Treatment between May 1, 2015, and December 31, 2021. This study compared IVT plus MT vs MT alone in patients with acute ischemic stroke due to anterior circulation large-vessel occlusion in whom mechanical reperfusion was unsuccessful. Unsuccessful mechanical reperfusion was defined as failed (final modified Thrombolysis in Cerebral Infarction grade of 0 or 1) or partial (grade 2a). Patients meeting the inclusion criteria were matched by treatment group using 1:1 propensity score matching. INTERVENTIONS Mechanical thrombectomy with or without IVT. MAIN OUTCOMES AND MEASURES Primary outcome was functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2. Safety outcomes were the occurrence of symptomatic intracranial hemorrhage and death. RESULTS After matching, 746 patients were compared by treatment arms (median age, 78 [IQR, 68-84] years; 438 women [58.7%]). The proportion of patients who were functionally independent at 90 days was 68 of 373 (18.2%) in the IVT plus MT and 42 of 373 (11.3%) in the MT alone group (adjusted odds ratio [AOR], 2.63 [95% CI, 1.41-5.11]; P = .003). There was a shift toward better functional outcomes on the modified Rankin Scale favoring IVT plus MT (adjusted common OR, 1.98 [95% CI, 1.35-2.92]; P < .001). The treatment benefit of IVT was greater in patients with partial reperfusion compared with failed reperfusion. There was no difference in symptomatic intracranial hemorrhages between treatment groups (AOR, 0.71 [95% CI, 0.29-1.81]; P = .45), while the death rate was lower after IVT plus MT (AOR, 0.54 [95% CI, 0.34-0.86]; P = .01). CONCLUSIONS AND RELEVANCE These findings suggest that prior IVT was safe and improved functional outcomes at 90 days. Partial reperfusion was associated with a greater treatment benefit of IVT, indicating a positive interaction between IVT and MT. These results support current guidelines that all eligible patients with stroke should receive IVT before MT and add a new perspective to the debate on noninferiority of combined stroke treatment

One, two, three: portable sample size in agricultural research

Determination of sample size (the number of replications) is a key step in the design of an observational study or randomized experiment. Statistical procedures for this purpose are readily available. Their treatment in textbooks is often somewhat marginal, however, and frequently the focus is on just one particular method of inference (significance test, confidence interval). Here, we provide a unified review of approaches and explain their close interrelationships, emphasizing that all approaches rely on the standard error of the quantity of interest, most often a pairwise difference of two means. The focus is on methods that are easy to compute, even without a computer. Our main recommendation based on standard errors is summarized as what we call the 1-2-3 rule for a difference of two treatment means

Connectivity and Synchronisation of Lake Ecosystems in Space and Time - CONNECT

Within the project CONNECT we are establishing a collaborative network between experts in remote sensing (RS) and freshwater ecology to study connectivity and coherence of lake ecosystems in a regional context at unprecedented temporal and spatial resolution. The overall aim is to understand the yet unexplained variation in phytoplankton dynamics among river-connected German lowland lakes, many of which are presently classified as in poor to bad ecological status. These lakes often face a high risk of eutrophication, mass development of harmful algal blooms, and high production of greenhouse gases. We suggest if measured on adequate temporal and spatial scales much of the among-lake variation in phytoplankton dynamics to be explained by the strength of hydrological lake-to-lake and lake-to-catchment connectivity as modulated by lake depth and mixing regime. This may have profound implications for the maximum intensity, spatial range and regional-scale magnitude of eutrophication impacts. We will use (i) a large-scale experimental manipulation of lake connectivity, and (ii) an observational field campaign contrasting deep and shallow river-connected lakes, to challenge this research frontier by an innovative combination of automatic high- frequency in situ measurements with state of the art near-to-far RS technology. Climate change is expected to alter the hydrology, and thus the connectivity of lake-river systems. However, it is also predicted to increase extreme weather events leading to an increased input of nutrients as well as colored dissolved organic matter (cDOM). By providing data of high spatio-temporal coverage, CONNECT will provide basic high quality data to better understand mechanisms of eutrophication at the local and regional scale. Our data, thus, provide a valuable basis to improve current management of such river-connected lake ecosystems under future climate scenarios. To reach this ambitious goal, the project will (i) build a cross- disciplinary collaborative network of excellence, (ii) develop a mechanistic understanding of lake ecosystem functioning at local and regional scale, (iii) improve future environmental monitoring and interpretation of available data from inland waters, and (iv) support more effective integrated management of river-connected lakes to mitigate eutrophication impacts

Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A-) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A- individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A- groups. After classifying this matched sample for phospho-tau pathology (T-/T+), individuals with A+/T+ were significantly more memory-impaired than A-/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer's disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer's disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

BACKGROUND AND OBJECTIVES: We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. METHODS: We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. RESULTS: In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers. DISCUSSION: Novelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity