Antibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most ...abundant surface protein of SPZ is the leading candidate for passive (and subunit) immunization approaches against malaria. Comprehensive assessment of the parasite-inhibitory capacity of anti-CSP monoclonal antibodies (mAbs) is an important step in advancing CSP-based immunization strategies. In this study, we employed a quantitative imaging-based motility assay to quantify the effect of anti-CSP mAbs on SPZ motility, both in vitro and in human skin.Our assay provided a quantitative measure of mAb parasite-inhibitory capacity through measurement of the half-maximal motility inhibitory concentration (IC
) value for anti-CSP mAbs (IC
2A10: 24 nM, IC
3SP2: 71 nM). We found a sevenfold discrepancy between the IC
and the binding saturation concentration measured by ELISA, possibly related to the observed shedding of CSP-mAb complexes during SPZ movement. In a subset of SPZ (5%), in vitro motility was unaffected by the presence of 2A10 while 3SP2 was able to completely block movement. In our ex vivo skin explant model, SPZ proved less susceptible to anti-CSP mAbs compared to SPZ in an in vitro environment. By quantitatively assessing motility, we created a valuable tool that can be used for comprehensive assessment of anti-CSP mAb potency. Insight that will help deepen our understanding of anti-CSP mAb potency and guide selection of the most promising anti-CSP mAbs for downstream clinical development.
Natural killer (NK) cells are innate lymphocytes capable to recognize and kill virus-infected and cancer cells. In the past years, the use of allogeneic NK cells as anti-cancer therapy gained ...interest due to their ability to induce graft-versus-cancer responses without causing graft-versus-host disease and multiple protocols have been developed to produce high numbers of activated NK cells. While the ability of these cells to mediate tumor kill has been extensively studied, less is known about their capacity to influence the activity of other immune cells that may contribute to a concerted anti-tumor response in the tumor microenvironment (TME). In this study, we analyzed how an allogeneic off-the-shelf cord blood stem cell-derived NK-cell product influenced the activation of dendritic cells (DC). Crosstalk between NK cells and healthy donor monocyte-derived DC (MoDC) resulted in the release of IFNγ and TNF, MoDC activation, and the release of the T-cell-recruiting chemokines CXCL9 and CXCL10. Moreover, in the presence of prostaglandin-E2, NK cell/MoDC crosstalk antagonized the detrimental effect of IL-10 on MoDC maturation leading to higher expression of multiple (co-)stimulatory markers. The NK cells also induced activation of conventional DC2 (cDC2) and CD8+ T cells, and the release of TNF, GM-CSF, and CXCL9/10 in peripheral blood mononuclear cells of patients with metastatic colorectal cancer. The activated phenotype of MoDC/cDC2 and the increased release of pro-inflammatory cytokines and T-cell-recruiting chemokines resulting from NK cell/DC crosstalk should contribute to a more inflamed TME and may thus enhance the efficacy of T-cell-based therapies.
Summary
Functional impairment of dendritic cells (DCs) is part of a survival strategy evolved by Leishmania and Plasmodium parasites to evade host immune responses. Here, the effects of co‐exposing ...human monocyte‐derived DCs to Leishmania donovani promastigotes and Plasmodium falciparum‐infected erythrocytes were investigated. Co‐stimulation resulted in a dual, dose‐dependent effect on DC differentiation which ranged from semi‐mature cells, secreting low interleukin(‐12p70 levels to a complete lack of phenotypic maturation in the presence of high parasite amounts. The effect was mainly triggered by the Leishmania parasites, as illustrated by their ability to induce semi‐mature, interleukin‐10‐producing DCs, that poorly responded to lipopolysaccharide stimulation. Conversely, P. falciparum blood‐stage forms failed to activate DCs and only slightly interfered with lipopolysaccharide effects. Stimulation with high L. donovani concentrations triggered phosphatidylserine translocation, whose onset presented after initiating the maturation impairment process. When added in combination, the two parasites could co‐localize in the same DCs, confirming that the leading effects of Leishmania over Plasmodium may not be due to mutual exclusion. Altogether, these results suggest that in the presence of visceral leishmaniasis–malaria co‐infections, Leishmania‐driven effects may overrule the more silent response elicited by P. falciparum, shaping host immunity towards a regulatory pattern and possibly delaying disease resolution.
We report observations of waveforms in surface pressure made over several years by a network of ground‐level barometers in the eastern United States. The waveforms can be reconstructed by ...superimposing the 4th through 10th subharmonics of the solar day. Some of these solar harmonics are likely generated by the temperature and pressure gradients across the solar terminators. The measurements presented here enable a wave detection analysis which indicates that some waveforms are coherent between stations with a median speed of 49.7 m/s to the southeast. We interpret these propagating signals, which are interference patterns created by internal gravity waves with periods that are subharmonics of a solar day, as a previously undiscovered type of terminator wave. The waveforms appear predominantly postsunrise during winter and postsunset in summer. Their quasi‐eastward propagation direction suggests an analogy with “stern” waves left behind by the faster, westward‐moving terminator.
Plain Language Summary
The pressure of Earth's atmosphere at any point is a measure of the weight of the air above that location. Air pressure changes constantly due to many factors such as the weather and solar heating. Lesser‐known gravity waves (also known as buoyancy waves) play a key role in the dynamics of the atmosphere as their movement redistributes energy from one part of the atmosphere to another and temporarily changes air pressure locally. Air pressure measurements have been used for centuries to forecast weather conditions. In addition to practical interest, air pressure has also been the subject of much research over this time span as we seek a better understanding of how the dynamic atmosphere functions. In this paper, we present results from a new, large, network of pressure sensors in the United States which record air pressure continuously at many points. Gravity waves are observed that appear to be due to heating and cooling that occurs at sunrise and sunset. The waves, known as terminator waves, have never before been observed at Earth's surface. This is important because it provides further insight into how the atmosphere functions under the influence of the Sun.
Key Points
Surface pressure oscillations are observed in the 2 to 6‐hr passband in a temporal pattern that is linked with the solar terminator
Array analysis reveals that most of these oscillations propagate with a median phase velocity of 49.7 ms−1 to the east‐southeast
These signals are interpreted as evidence of a previously undiscovered type of terminator wave
Botulinum toxin (BoNT) injections in the dystonic muscles is the preferred treatment for Cervical Dystonia (CD), but the proper identification of the dystonic muscles remains a challenge. Previous ...studies showed decreased 8-14 Hz autospectral power in the electromyography (EMG) of splenius muscles in CD patients. Cumulative distribution functions (CDF's) of dystonic muscles showed increased CDF
values, representing increased autospectral powers between 3 and 10 Hz, relative to power between 3 and 32 Hz. In this study, we evaluated both methods and investigated the effects of botulinum toxin. Intramuscular EMG recordings were obtained from the splenius, semispinalis, and sternocleidomastoid muscles during standardized isometric tasks in 4 BoNT-naïve CD patients, 12 BoNT-treated patients, and 8 healthy controls. BoNT-treated patients were measured 4-7 weeks after their last BoNT injections and again after 11-15 weeks. We found significantly decreased 8-14 Hz autospectral power in splenius muscles, but not in the semispinalis and sternocleidomastoid muscles of CD patients when compared to healthy controls. CDF
analysis was superior in demonstrating subtle autospectral changes, and showed increased CDF
values in all studied muscles of CD patients. These results did not change significantly after BoNT injections. Further studies are needed to investigate the origin of these autospectral changes in dystonia patients, and to assess their potential in muscle selection for BoNT treatment.
•Dystonic muscles displayed increased 3–10Hz power with reduced 10–30Hz power.•Similar shifts were detected in head forces and moments in cervical dystonia patients.•We associate these shifts with ...prokinetic sensorimotor control.
To identify effects of a deviant motor drive in the autospectral power of dystonic muscles during voluntary contraction in cervical dystonia patients.
Submaximal (20%) isometric head-neck tasks were performed with the head fixed, measuring surface EMG of the sternocleidomastoid, splenius capitis and semispinalis capitis in CD patients and controls. Autospectral power of muscle activity, and head forces was analyzed using cumulative distribution functions (CDF). A downward shift between the theta/low alpha-band (3–10Hz) and the high alpha/beta-band (10–30Hz) was detected using the CDF10, defined as the cumulative power from 3 to 10Hz relative to power from 3 to 30Hz.
CDF10 was increased in dystonic muscles compared to controls and patient muscles unaffected by dystonia, due to a 3–10Hz power increase and a 10–30Hz decrease. CDF10 also increased in patient head forces.
Submaximal isometric contractions with the head fixed provided a well-defined test condition minimizing effects of reflexive feedback and tremor. We associate shifts in autospectral power with prokinetic sensorimotor control.
Analysis of autospectral power in isometric tasks with the head fixed is a promising approach in research and diagnostics of cervical dystonia.
Abstract Objective Botulinum toxin injections in the dystonic muscles are the preferred treatment for cervical dystonia (CD), but proper selection of the dystonic muscles remains a challenge. We ...investigated the use of EMG coherence and autospectral analysis as discriminative tools to identify dystonic muscles in CD patients. Methods We compared the occurrence of 8–14 Hz autospectral peaks and 4–7 Hz intermuscular coherences between 10 CD patients and 10 healthy controls. Secondly, we compared the muscles with significant 4–7 Hz coherences with the muscles that were selected clinically for botulinum toxin treatment. Results Autospectral peaks between 8 and 14 Hz were significantly more often absent in the splenius capitis (SPL) muscles of CD patients compared to controls (p < 0.01). Contrary to previous findings, there was no significant difference in the occurrence of 4–7 Hz intermuscular coherences between patients and controls and the diagnostic accuracy of coherence analysis to identify the clinically dystonic muscles was low. Conclusion Intermuscular EMG coherence analysis cannot reliably discriminate patients from controls. Autospectral changes in the SPL muscles are a more discriminative feature of CD. In patients, coherence analysis does not seem to be a reliable method to identify dystonic muscles. The clinical relevance and the origin of the autospectral changes need further study.
Abstract Background The preferred treatment for cervical dystonia (CD) is injection of botulinum toxin in the dystonic muscles. Unfortunately, in the absence of reliable diagnostic methods it can be ...difficult to discriminate dystonic muscles from healthy muscles acting in compensation. We investigated if dystonic muscle activation patterns could be identified in cervical dystonia patients during a harmonized isometric contraction task. Furthermore, we investigated whether dystonia worsens at higher levels of voluntary contraction, which might further improve the identification of dystonic muscle activity. Methods An isometric device was used to investigate muscle activation during voluntary contraction tasks in 10 controls and 10 CD patients. Surface electromyography (EMG) of the sternocleidomastoidus, splenius capitis, and semispinalis capitis muscles was evaluated during a rest task and when performing submaximal (20%) and maximal voluntary contractions for eight head transversal force directions and for head twist. Two measures were developed to identify dystonic activation: 1) Muscle activity in the contraction direction in which the contribution of the muscle was lowest (Minimum EMG), and 2) the average muscle activity over all contraction directions (Total Mean EMG). Results Patients showed increased dystonic activity in the rest task and during submaximal contractions relative to controls, but not during maximal contractions. Increases in Minimum EMG indicated an inability of patients to deactivate dystonic muscles counteracting the task. Increases in Total Mean EMG indicated dystonic activity in all task directions. During maximal contractions these effects were absent in dystonic muscles. Dystonia is therefore found not to worsen at higher levels of isometric voluntary contraction. The activity of dystonic muscles modulated with different loading directions similar to controls. Using Minimum EMG 54% of the muscles clinically diagnosed as dystonic and 91% of non-dystonic muscles were predicted correctly. Conclusions Dystonic muscle activity was found in cervical dystonia patients during submaximal contractions in all task directions using a harmonized isometric task, but no differences were found during maximal contractions. With some adaptation this method may prove useful to identify dystonic muscles.
Abstract Background Effective sensorimotor integration is essential to modulate (adapt) neck stabilization strategies in response to varying tasks and disturbances. This study evaluates the ...hypothesis that relative to healthy controls cervical dystonia patients have an impaired ability to modulate afferent feedback for neck stabilization with changes in the frequency content of mechanical perturbations. Methods We applied anterior-posterior displacement perturbations (110 s) on the torso of seated subjects, while recording head-neck kinematics and muscular activity. We compared low bandwidth (0.2
–
1.2 Hz) and high bandwidth (0.2
–
8 Hz) perturbations where our previous research showed a profound modulation of stabilization strategies in healthy subjects. Cervical dystonia patients and age matched controls performed two tasks: (1) maintain head forward posture and (2) allow dystonia to dictate head posture. Findings Patients and controls demonstrated similar kinematic and muscular responses. Patient modulation was similar to that of healthy controls (P > 0.05); neck stiffness and afferent feedback decreased with high bandwidth perturbations. During the head forward task patients had an increased neck stiffness relative to controls (P < 0.05), due to increased afferent feedback. Interpretation The unaffected modulation of head-neck stabilization (both kinematic and muscular) in patients with cervical dystonia does not support the hypothesis of impaired afferent feedback modulation for neck stabilization.
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