Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity.

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

Real-Space Observations of Three-Dimensional Antiskyrmions and Skyrmion Strings.

Nanometric topological spin textures, such as skyrmions (Sks) and antiskyrmions (antiSks), have attracted much attention recently. However, most studies have focused on two-dimensional spin textures in films with inherent or synthetic antisymmetric spin-exchange interaction, termed Dzyaloshinskii-Moriya interaction, although three-dimensional (3D) topological spin textures, such as antiSks composed of alternating Bloch- and Néel-type spin spirals, chiral bobbers carrying emergent magnetic monopoles, and deformed Sk strings, are ubiquitous. To elucidate these textures, we have developed a 3D nanometric magnetic imaging technique, tomographic Lorentz transmission electron microscopy (TEM). The approach enables the visualization of the 3D shape of magnetic objects and their 3D vector field mapping. Here we report 3D vector field maps of deformed Sk-strings and antiSk using the technique. This research approach will lead to discoveries and understanding of fertile 3D magnetic structures in a broad class of magnets, providing insight into 3D topological magnetism.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing.

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Molecular self-assembly of DBBA on Au(111) at room temperature.

We have investigated the self-assembly of the graphene nanoribbon molecular precursor 10,10'-dibromo-9,9'-bianthryl (DBBA) on Au(111) with frequency modulation scanning force microscopy (FM-SFM) at room temperature combined with ab initio calculations. For low molecular coverages, the molecules aggregate along the substrate herringbone reconstruction main directions while remaining mobile. At intermediate coverage, two phases coexist, zigzag stripes of monomer chains and decorated herringbones. For high coverage, the molecules assemble in a dimer-striped phase. The adsorption behaviour of DBBA molecules and their interactions are discussed and compared with the results from ab initio calculations.

Anti-gravity treadmill rehabilitation improves gait and muscle atrophy in patients with surgically treated ankle and tibial plateau fractures after one year: A randomised clinical trial.

OBJECTIVE: To compare the one-year postoperative outcomes of anti-gravity treadmill rehabilitation with those of standard rehabilitation in patients with ankle or tibial plateau fractures. DESIGN: An open-label prospective randomised study. SETTING: Three trauma centres. SUBJECTS: Patients were randomised into the intervention (anti-gravity treadmill) or control (standard protocol) rehabilitation group. MAIN MEASURES: The primary endpoint was changes in the Foot and Ankle Outcome Score for ankle fractures and Knee Injury and Osteoarthritis Outcome Score for tibial plateau fractures from baseline to 12 months after operation. Secondary endpoints were the subscores of these scores, muscle atrophy (leg circumference at 20 cm above and 10 cm below the knee joint) and the Dynamic Gait Index. RESULTS: Initially, 73 patients (37 vs 36) underwent randomisation. After 12 months, 29 patients in the intervention group and 24 patients in the control group could be analysed. No significant difference was noted in the Foot and Ankle Outcome Score (80.8 ± 18.4 and 78.4 ± 21.1) and Knee Injury and Osteoarthritis Outcome Score (84.8 ± 15.2 and 81.7 ± 17.0). The change in the Dynamic Gait Index from 12 weeks to 12 months differed significantly between the groups (P = 0.04). Patients with tibial plateau fractures had a 3 cm wider thigh circumference in the intervention group than those in the control group (95% confidence interval: -0.2 to 6.3 cm, P = 0.08). CONCLUSION: One year after surgery, patients who had undergone anti-gravity treadmill rehabilitation showed better gait than patients in the control group, and those with tibial plateau fractures had less muscle atrophy.

Predicting Perceived Exhaustion in Rehabilitation Exercises Using Facial Action Units.

Physical exercise has become an essential tool for treating various non-communicable diseases (also known as chronic diseases). Due to this, physical exercise allows to counter different symptoms and reduce some risk of death factors without medication. A solution to support people in doing exercises is to use artificial systems that monitor their exercise progress. While one crucial aspect is to monitor the correct physical motions for rehabilitative exercise, another essential element is to give encouraging feedback during workouts. A coaching system can track a user's exhaustion and give motivating feedback accordingly to boost exercise adherence. For this purpose, this research investigates whether it is possible to predict the subjective exhaustion level based on non-invasive and non-wearable technology. A novel data set was recorded with the facial record as the primary predictor and individual exhaustion levels as the predicted variable. 60 participants (30 male, 30 female) took part in the data recording. 17 facial action units (AU) were extracted as predictor variables for the perceived subjective exhaustion measured using the BORG scale. Using the predictor and the target variables, several regression and classification methods were evaluated aiming to predict exhaustion. The results showed that the decision tree and support vector methods provide reasonable prediction results. The limitation of the results, depending on participants being in the training data set and subjective variables (e.g., participants smiling during the exercises) were further discussed.

Visual processing speed is linked to functional connectivity between right frontoparietal and visual networks.

Visual information processing requires an efficient visual attention system. The neural theory of visual attention (TVA) proposes that visual processing speed depends on the coordinated activity between frontoparietal and occipital brain areas. Previous research has shown that the coordinated activity between (i.e., functional connectivity and "inter-FC") cingulo-opercular (COn) and right-frontoparietal (RFPn) networks is linked to visual processing speed. However, how inter-FC of COn and RFPn with visual networks links to visual processing speed has not been directly addressed yet. Forty-eight healthy adult participants (27 females) underwent resting-state (rs-)fMRI and performed a whole-report psychophysical task. To obtain inter-FC, we analyzed the entire frequency range available in our rs-fMRI data (i.e., 0.01-0.4 Hz) to avoid discarding neural information. Following previous approaches, we analyzed the data across frequency bins (Hz): Slow-5 (0.01-0.027), Slow-4 (0.027-0.073), Slow-3 (0.073-0.198), and Slow-2 (0.198-0.4). We used the mathematical TVA framework to estimate an individual, latent-level visual processing speed parameter. We found that visual processing speed was negatively associated with inter-FC between RFPn and visual networks in Slow-5 and Slow-2, with no corresponding significant association for inter-FC between COn and visual networks. These results provide the first empirical evidence that links inter-FC between RFPn and visual networks with the visual processing speed parameter. These findings suggest that direct connectivity between occipital and right frontoparietal, but not frontoinsular, regions support visual processing speed.

Development of a Flexible and Robust Synthesis of Tetrahydrofuro[3,4-b]furan Nucleoside Analogues.

In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31-48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC50 of 0.8 nM, a MCF-7 target engagement EC50 of 3 nM, and a Z138 cell proliferation EC50 of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.

Impact of anti-gravity treadmill rehabilitation therapy on the clinical outcomes after fixation of lower limb fractures: A randomized clinical trial.

OBJECTIVE: To compare the effects of anti-gravity treadmill rehabilitation with those of standard rehabilitation on surgically treated ankle and tibial plateau fractures. DESIGN: Open-label prospective randomized multicenter study. SETTING: Three level 1 trauma centers. SUBJECTS: Patients with tibial plateau or ankle fractures who underwent postoperative partial weight-bearing were randomized into the intervention (anti-gravity treadmill use) or control (standard rehabilitation protocol) groups. MAIN MEASURES: The primary endpoint was the change in the Foot and Ankle Outcome Score for ankle fractures and total Knee injury and Osteoarthritis Outcome Score for tibial plateau fractures (0-100 points) from baseline (T1) to six weeks after operation (T4) in both groups. Leg circumference of both legs was measured to assess thigh muscle atrophy in the operated leg. RESULTS: Thirty-seven patients constituted the intervention and 36 the control group, respectively; 14 patients dropped out during the follow-up period. Among the 59 remaining patients (mean age 42 [range, 19-65] years), no difference was noted in the Foot and Ankle Outcome Score (54.2 ± 16.1 vs. 56.0 ± 16.6) or Knee injury and Osteoarthritis Outcome Score (52.8 ± 18.3 vs 47.6 ± 17.7) between the intervention and control groups 6 weeks after operation. The change in the leg circumference from T1 to T4 was greater by 4.6 cm in the intervention group (95% confidence interval: 1.2-8.0, P = 0.005). No adverse event associated with anti-gravity treadmill rehabilitation was observed. CONCLUSION: No significant difference was noted in patient-reported outcomes between the two groups. Significant differences in muscular atrophy of the thigh were observed six weeks after operation.

Does the COVID-19 pandemic threaten global solidarity? Evidence from Germany.

The global COVID-19 pandemic poses challenges to the economy, politics and public health systems of developed and developing countries alike. However, the latter are less well placed to cope with adverse effects. In particular, important advances towards sustainable development might be reversed. Tackling the pandemic and its effects therefore requires global cooperation as well as solidarity in the form of development assistance. Yet, support for development assistance among donor publics might be dampened by individual health-related and economic worries as well as decreasing trust in government during the pandemic. Against this backdrop, we investigate the possible effect of pandemic-induced worries on public support for development assistance as well as the moderating role of moral considerations and trust in government. Drawing on literature on aid attitudes, and using survey data for Germany provided by the COVID-19 Snapshot Monitoring (COSMO) project from April 2020 (N = 1,006), our analyses show that neither health-related nor economic worries are associated with less support for providing development assistance during the first wave of the pandemic. However, we observe a marginal interaction between health-related worries and trust in government in predicting support for development assistance. For those with high levels of trust in government the effect of worry regarding the loss of friends or relatives on support for development assistance is positive, whereas it is close to zero for those with low levels of trust. We conclude that at the peak of the first wave of the pandemic there was little need for concern by policy-makers endorsing development assistance as neither form of worry correlated negatively with public support for development assistance and trust was high. However, when worries recur and trust in government simultaneously decreases, public support for global solidarity may wane.

Fine-Tuning Semiconducting Polymer Self-Aggregation and Crystallinity Enables Optimal Morphology and High-Performance Printed All-Polymer Solar Cells.

Polymer aggregation and crystallization behavior play a crucial role in the performance of all-polymer solar cells (all-PSCs). Gaining control over polymer self-assembly via molecular design to influence bulk-heterojunction active-layer morphology, however, remains challenging. Herein, we show a simple yet effective way to modulate the self-aggregation of the commonly used naphthalene diimide (NDI)-based acceptor polymer (N2200), by systematically replacing a certain amount of alkyl side-chains with compact bulky side-chains (CBS). Specifically, we have synthesized a series of random copolymer (PNDI-CBSx) with different molar fractions (x = 0-1) of the CBS units and have found that both solution-phase aggregation and solid-state crystallinity of these acceptor polymers are progressively suppressed with increasing x as evidenced by UV-vis absorption, photoluminescence (PL) spectroscopies, thermal analysis, and grazing incidence X-ray scattering (GIWAXS) techniques. Importantly, as compared to the highly self-aggregating N2200, photovoltaic results show that blending of more amorphous acceptor polymers with donor polymer (PBDB-T) can enable all-PSCs with significantly increased PCE (up to 8.5%). The higher short-circuit current density (Jsc) results from the smaller polymer phase-separation domain sizes as evidenced by PL quenching and resonant soft X-ray scattering (R-SoXS) analyses. Additionally, we show that the lower crystallinity of the active layer is less sensitive to the film deposition methods. Thus, the transition from spin-coating to solution coating can be easily achieved with no performance losses. On the other hand, decreasing aggregation and crystallinity of the acceptor polymer too much reduces the photovoltaic performance as the donor phase-separation domain sizes increases. The highly amorphous acceptor polymers appear to induce formation of larger donor polymer crystallites. These results highlight the importance of a balanced aggregation strength between the donor and acceptor polymers to achieve high-performance all-PSCs with optimal active layer film morphology.

Decreased cortical thickness mediates the relationship between premature birth and cognitive performance in adulthood.

Cortical thickness (CTh) reflects cortical properties such as dendritic complexity and synaptic density, which are not only vulnerable to developmental disturbances caused by premature birth but also highly relevant for cognitive performance. We tested the hypotheses whether CTh in young adults is altered after premature birth and whether these aberrations are relevant for general cognitive abilities. We investigated CTh based on brain structural magnetic resonance imaging and surface-based morphometry in a large and prospectively collected cohort of 101 very premature-born adults (<32 weeks of gestation and/or birth weight [BW] below 1,500 g) and 111 full-term controls at 26 years of age. Cognitive performance was assessed by full-scale intelligence quotient (IQ) using the Wechsler Adult Intelligence Scale. CTh was reduced in frontal, parietal, and temporal associative cortices predominantly in the left hemisphere in premature-born adults compared to controls. We found a significant positive association of CTh with both gestational age and BW, particularly in the left hemisphere, and a significant negative association between CTh and intensity of neonatal treatment within limited regions bilaterally. Full-scale IQ and CTh in the left hemisphere were positively correlated. Furthermore, CTh in the left hemisphere acted as a mediator on the association between premature birth and full-scale IQ. Results provide evidence that premature born adults have widespread reduced CTh that is relevant for their general cognitive performance. Data suggest lasting reductions in cortical microstructure subserving CTh after premature birth.

Hippocampal subfield volumes are nonspecifically reduced in premature-born adults.

Reduced global hippocampus volumes have been demonstrated in premature-born individuals, from newborns to adults; however, it is unknown whether hippocampus subfield (HCSF) volumes are differentially affected by premature birth and how relevant they are for cognitive performance. To address these questions, we investigated magnetic resonance imaging (MRI)-derived HCSF volumes in very premature-born adults, and related them with general cognitive performance in adulthood. We assessed 103 very premature-born (gestational age [GA] <32 weeks and/or birth weight <1,500 g) and 109 term-born individuals with cognitive testing and structural MRI at 26 years of age. HCSFs were automatically segmented based on three-dimensional T1- and T2-weighted sequences and studied both individually and grouped into three functional units, namely hippocampus proper (HP), subicular complex (SC), and dentate gyrus (DG). Cognitive performance was measured using the Wechsler-Adult-Intelligence-Scale (full-scale intelligence quotient [FS-IQ]) at 26 years. We observed bilateral volume reductions for almost all HCSF volumes in premature-born adults and associations with GA and neonatal treatment intensity but not birth weight. Left-sided HP, SC, and DG volumes were associated with adult FS-IQ. Furthermore, left DG volume was a mediator of the association between GA and adult FS-IQ in premature-born individuals. Results demonstrate nonspecifically reduced HCSF volumes in premature-born adults; but specific associations with cognitive outcome highlight the importance of the left DG. Data suggest that specific interventions toward hippocampus function might be promising to lower adverse cognitive effects of prematurity.

Sulfate is transported at significant rates through the symbiosome membrane and is crucial for nitrogenase biosynthesis.

Legume-rhizobia symbioses play a major role in food production for an ever growing human population. In this symbiosis, dinitrogen is reduced ("fixed") to ammonia by the rhizobial nitrogenase enzyme complex and is secreted to the plant host cells, whereas dicarboxylic acids derived from photosynthetically produced sucrose are transported into the symbiosomes and serve as respiratory substrates for the bacteroids. The symbiosome membrane contains high levels of SST1 protein, a sulfate transporter. Sulfate is an essential nutrient for all living organisms, but its importance for symbiotic nitrogen fixation and nodule metabolism has long been underestimated. Using chemical imaging, we demonstrate that the bacteroids take up 20-fold more sulfate than the nodule host cells. Furthermore, we show that nitrogenase biosynthesis relies on high levels of imported sulfate, making sulfur as essential as carbon for the regulation and functioning of symbiotic nitrogen fixation. Our findings thus establish the importance of sulfate and its active transport for the plant-microbe interaction that is most relevant for agriculture and soil fertility.

Pion-Pole Contribution to Hadronic Light-By-Light Scattering in the Anomalous Magnetic Moment of the Muon.

The π^{0} pole constitutes the lowest-lying singularity of the hadronic light-by-light (HLBL) tensor, and thus, it provides the leading contribution in a dispersive approach to HLBL scattering in the anomalous magnetic moment of the muon (g-2)_{µ}. It is unambiguously defined in terms of the doubly virtual pion transition form factor, which in principle, can be accessed in its entirety by experiment. We demonstrate that, in the absence of a direct measurement, the full spacelike doubly virtual form factor can be reconstructed very accurately based on existing data for e^{+}e^{-}→3π, e^{+}e^{-}→e^{+}e^{-}π^{0}, and the π^{0}→γγ decay width. We derive a representation that incorporates all the low-lying singularities of the form factor, matches correctly onto the asymptotic behavior expected from perturbative QCD, and is suitable for the evaluation of the (g-2)_{µ} loop integral. The resulting value, a_{µ}^{π^{0}-pole}=62.6_{-2.5}^{+3.0}×10^{-11}, for the first time, represents a complete data-driven determination of the pion-pole contribution with fully controlled uncertainty estimates. In particular, we show that already improved singly virtual measurements alone would allow one to further reduce the uncertainty in a_{µ}^{π^{0}-pole}.

Monitoring of gas composition in a laboratory biogas plant using cavity enhanced Raman spectroscopy.

Biogas production from organic raw materials is a highly complex biotechnological process. The responsible anaerobic fermentation process is difficult to measure due to its multi-stage nature. Still, optimization of biogas production and the development of robust and efficient process management strategies require continually updated information about the process. Hence, the development of a comprehensive sensor system with high temporal resolution is key to further advancement in biogas technology. Here, we demonstrate a gas sensor based on cavity enhanced Raman spectroscopy for biogas monitoring. Online detection of all gas components of a biogas mixture enables a comprehensive quantification. In addition, robust calibration routines facilitate the adaptation of the sensor for biogas monitoring. A simulated concentration course of a typical fermentation process with defined gas mixtures consisting of CH4, CO2, N2, O2 and H2 showed reliable results for all relevant biogas components for varying concentration ranges from ppm to 100 vol%. The response time of 5 seconds allows online detection and - as a consequence - real time information is obtained about the biogas composition. A laboratory biogas reactor was designed to operate biogas production on a miniaturized scale and analyze it using the Raman gas sensor. The developed sensor enables the observation of methane production throughout the first 24 h of the fermentation process. The obtained results show the suitability of cavity enhanced Raman spectroscopy as a gas sensor to monitor the entire process of biogas production. As this strategy would allow the process to be manipulated and optimized according to the current state, it is of great biotechnological interest.

Intra-wire coupling in segmented Ni/Cu nanowires deposited by electrodeposition.

Segmented magnetic nanowires are a promising route for the development of three dimensional data storage techniques. Such devices require a control of the coercive field and the coupling mechanisms between individual magnetic elements. In our study, we investigate electrodeposited nanomagnets within host templates using vibrating sample magnetometry and observe a strong dependence between nanowire length and coercive field (25 nm-5 µm) and diameter (25-45 nm). A transition from a magnetization reversal through coherent rotation to domain wall propagation is observed at an aspect ratio of approximately 2. Our results are further reinforced via micromagnetic simulations and angle dependent hysteresis loops. The found behavior is exploited to create nanowires consisting of a fixed and a free segment in a spin-valve like structure. The wires are released from the membrane and electrically contacted, displaying a giant magnetoresistance effect that is attributed to individual switching of the coupled nanomagnets. We develop a simple analytical model to describe the observed switching phenomena and to predict stable and unstable regimes in coupled nanomagnets of certain geometries.

Outcome of patients after lower limb fracture with partial weight bearing postoperatively treated with or without anti-gravity treadmill (alter G®) during six weeks of rehabilitation - a protocol of a prospective randomized trial.

BACKGROUND: Partial or complete immobilization leads to different adjustment processes like higher risk of muscle atrophy or a decrease of general performance. The present study is designed to prove efficacy of the anti-gravity treadmill (alter G®) compared to a standard rehabilitation protocol in patients with tibial plateau (group 1)or ankle fractures (group 2) with six weeks of partial weight bearing of 20 kg. METHODS AND DESIGN: This prospective randomized study will include a total of 60 patients for each group according to predefined inclusion and exclusion criteria. 1:1 randomization will be performed centrally via fax supported by the Clinical Trial Centre Leipzig (ZKS Leipzig). Patients in the treatment arm will be treated with an anti-gravity treadmill (alter G®) instead of physiotherapy. The protocol is designed parallel to standard physiotherapy with a frequency of two to three times of training with the treadmill per week with duration of 20 min for six weeks. DISCUSSION: Up to date no published randomized controlled trial with an anti-gravity treadmill is available. The findings of this study can help to modify rehabilitation of patients with partial weight bearing due to their injury or postoperative protocol. It will deliver interesting results if an anti-gravity treadmill is useful in rehabilitation in those patients. Further ongoing studies will identify different indications for an anti-gravity treadmill. Thus, in connection with those studies, a more valid statement regarding safety and efficacy is possible. TRIAL REGISTRATION: NCT02790229 registered on May 29, 2016.

How Oliceridine (TRV-130) Binds and Stabilizes a µ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways.

Substantial attention has recently been devoted to G protein-biased agonism of the µ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 µs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand-receptor interactions that are expected to inform the structure-based design of improved opioid analgesics.

Reduced-Intensity Conditioning Combined with (188)Rhenium Radioimmunotherapy before Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: The Role of In Vivo T Cell Depletion.

The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome.