Physical Activity Interventions to Alleviate Depressive Symptoms in Children and Adolescents: A Systematic Review and Meta-analysis.

Importance: Depression is the second most prevalent mental disorder among children and adolescents, yet only a small proportion seek or receive disorder-specific treatment. Physical activity interventions hold promise as an alternative or adjunctive approach to clinical treatment for depression. Objective: To determine the association of physical activity interventions with depressive symptoms in children and adolescents. Data Sources: PubMed, CINAHL, PsycINFO, EMBASE, and SPORTDiscus were searched from inception to February 2022 for relevant studies written in English, Chinese, or Italian. Study Selection: Two independent researchers selected studies that assessed the effects of physical activity interventions on depressive symptoms in children and adolescents compared with a control condition. Data Extraction and Synthesis: A random-effects meta-analysis using Hedges g was performed. Heterogeneity, risk of bias, and publication bias were assessed independently by multiple reviewers. Meta-regressions and sensitivity analyses were conducted to substantiate the overall results. The study followed the PRISMA reporting guideline. Main Outcomes and Measures: The main outcome was depressive symptoms as measured by validated depression scales at postintervention and follow-up. Results: Twenty-one studies involving 2441 participants (1148 [47.0%] boys; 1293 [53.0%] girls; mean [SD] age, 14 [3] years) were included. Meta-analysis of the postintervention differences revealed that physical activity interventions were associated with a reduction in depressive symptoms compared with the control condition (g = -0.29; 95% CI, -0.47 to -0.10; P = .004). Analysis of the follow-up outcomes in 4 studies revealed no differences between the physical activity and control groups (g = -0.39; 95% CI, -1.01 to 0.24; P = .14). Moderate study heterogeneity was detected (Q = 53.92; df = 20; P < .001; I2 = 62.9% [95% CI, 40.7%-76.8%]). The primary moderator analysis accounting for total physical activity volume, study design, participant health status, and allocation and/or assessment concealment did not moderate the main treatment effect. Secondary analyses demonstrated that intervention (ie, <12 weeks in duration, 3 times per week, unsupervised) and participant characteristics (ie, aged ≥13 years, with a mental illness and/or depression diagnosis) may influence the overall treatment effect. Conclusions and Relevance: Physical activity interventions may be used to reduce depressive symptoms in children and adolescents. Greater reductions in depressive symptoms were derived from participants older than 13 years and with a mental illness and/or depression diagnosis. The association with physical activity parameters such as frequency, duration, and supervision of the sessions remains unclear and needs further investigation.

Physical activity and exercise for cancer-related cognitive impairment among individuals affected by childhood cancer: a systematic review and meta-analysis.

BACKGROUND: Individuals affected by childhood cancer can have cognitive dysfunction that persists into adulthood and negatively affects quality of life. In this study, we aimed to evaluate the effects of physical activity and exercise on cognitive function among individuals affected by childhood cancer. METHODS: In this systematic review and meta-analysis, we searched seven databases (CINAHL Plus, Cochrane Library, Embase, MEDLINE, PsycINFO, SPORTDiscus, and Web of Science) and two clinical trial registries (ClinicalTrials.gov and the International Clinical Trials Registry Platform) for randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) published (or registered) from database inception to Jan 30, 2022, with no language restrictions. We included studies that compared the effects of physical activity or exercise interventions with controls (no intervention or usual care) on cognitive function among individuals diagnosed with any type of cancer at age 0-19 years. Two reviewers (JDKB and FR) independently screened records for eligibility and searched references of the selected studies; extracted study-level data from published reports; and assessed study risk of bias of RCTs and NRSIs using the Cochrane risk of bias tool for randomised trials (RoB 2) and Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) tools, certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, and any adverse events. We used intention-to-treat data and unpublished data if available. Cognitive function was assessed by standardised cognitive performance measures (primary outcome) and by validated patient-reported measures (secondary outcome). A random-effects meta-analysis model using the inverse-variance and Hartung-Knapp methods was used to calculate pooled estimates (Hedges' g) and 95% CI values. We estimated the heterogeneity variance by the restricted maximum likelihood method and calculated I2 values to measure heterogeneity. We examined funnel plots and used Egger's regression test to assess for publication bias. This study is registered with PROSPERO, CRD42021261061. FINDINGS: We screened 12 425 titles and abstracts, which resulted in full-text assessment of 131 potentially relevant reports. We evaluated 22 unique studies (16 RCTs and six NRSIs) with data on 1277 individuals affected by childhood cancer and low-to-moderate risk of bias. Of the 1277 individuals, 674 [52·8%] were male and 603 [47·2%] were female; median age at study start was 12 (IQR 11-14) years, median time since the end of cancer treatment was 2·5 (IQR -1·1 to 3·0) years, and median intervention period was 12 [IQR 10-24] weeks. There was moderate-quality evidence that, compared with control, physical activity and exercise improved cognitive performance measures (five RCTs; Hedges' g 0·40 [95% CI 0·07-0·73], p=0·027; I2=18%) and patient-reported measures of cognitive function (13 RCTs; Hedges' g 0·26 [0·09-0·43], p=0·0070; I2=40%). No evidence of publication bias was found. Nine mild adverse events were reported. INTERPRETATION: There is moderate-certainty evidence that physical activity and exercise improves cognitive function among individuals affected by childhood cancer, which supports the use of physical activity for managing cancer-related cognitive impairment. FUNDING: Research Impact Fund of Research Grants Council of the Hong Kong University Grants Committee (R7024-20) and Seed Fund for Basic Research of the University of Hong Kong. COPYRIGHT: © 2022 Published by Elsevier Ltd. All rights reserved.

Tubulin acetylation promotes penetrative capacity of cells undergoing radial intercalation.

Post-translational modification of tubulin provides differential functions to microtubule networks. Here, we address the role of tubulin acetylation on the penetrative capacity of cells undergoing radial intercalation, which is the process by which cells move apically, insert between outer cells, and join an epithelium. There are opposing forces that regulate intercalation, namely, the restrictive forces of the epithelial barrier versus the penetrative forces of the intercalating cell. Positively and negatively modulating tubulin acetylation in intercalating cells alters the developmental timing such that cells with more acetylation penetrate faster. We find that intercalating cells preferentially penetrate higher-order vertices rather than the more prevalent tricellular vertices. Differential timing in the ability of cells to penetrate different vertices reveals that lower-order vertices represent more restrictive sites of insertion. We shift the accessibility of intercalating cells toward more restrictive junctions by increasing tubulin acetylation, and we provide a geometric-based mathematical model that describes our results.

Spatial distribution of B cells and lymphocyte clusters as a predictor of triple-negative breast cancer outcome.

While tumor infiltration by CD8+ T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method 'occupancy') to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.

Physics approaches to the spatial distribution of immune cells in tumors.

The goal of immunotherapy is to mobilize the immune system to kill cancer cells. Immunotherapy is more effective and, in general, the prognosis is better, when more immune cells infiltrate the tumor. We explore the question of whether the spatial distribution rather than just the density of immune cells in the tumor is important in forecasting whether cancer recurs. After reviewing previous work on this issue, we introduce a novel application of maximum entropy to quantify the spatial distribution of discrete point-like objects. We apply our approach to B and T cells in images of tumor tissue taken from triple negative breast cancer patients. We find that the immune cells are more spatially dispersed in good clinical outcome (no recurrence of cancer within at least 5 years of diagnosis) compared to poor clinical outcome (recurrence within 3 years of diagnosis). Our results highlight the importance of spatial distribution of immune cells within tumors with regard to clinical outcome, and raise new questions on their role in cancer recurrence.

Why Phonon Scattering in Glasses is Universally Small at Low Temperatures.

We present a novel view of the standard model of tunneling two level systems (TLSs) to explain the puzzling universal value of a quantity, C∼3×10^{-4}, that characterizes phonon scattering in glasses below 1 K as reflected in thermal conductivity, ultrasonic attenuation, internal friction, and the change in sound velocity. Physical considerations lead to a broad distribution of phonon-TLS couplings that (1) exponentially renormalize tunneling matrix elements, and (2) reduce the TLS density of states through TLS-TLS interactions. We find good agreement between theory and experiment for a variety of individual glasses.

The Understanding of Peak Oxygen Uptake in Children Aged 8-16.

Objective: To examine the understanding of the concept peak oxygen uptake (peak VO2) among children and adolescents at different ages from a developmental perspective. Methods: A total of 549 children and adolescents aged 8 to 16 were recruited and instructed to fill in a 20-item Peak VO 2 Understanding Inventory developed with reference to the research literature on peak VO2. We presented the participants with twenty scenarios and asked them to indicate whether peak VO2 would "remain unchanged," "increase," or "decrease," or that there was "insufficient information for a definite answer." The cross-sectional data was analyzed by employing a series of ANOVA analyses and chi-square association tests. Additional statistical analyses were performed to examine the error patterns and if there were gender differences. Results: Except for the 8-year-old group, the overall accuracy rate did not improve with age. Age-related differences in the choice of answers ("increase," "decrease," "unchanged," and "uncertain") for determining the resulting peak VO2 after a change of antecedent were observed. Error analysis by item showed that prefactual thinking that is important to understand the concept was emerging rather than fully developed in our child and adolescent samples. Conclusion: The mastery of peak VO2 is not subject to age-related maturation but might demand the acquisition of specific logical reasoning skill such as perfactual thinking. Early introduction of peak VO2 and related concepts is advocated and should be emphasized on the reasoning rather than providing model answers in physical literacy education.

Appropriate scaling approach for evaluating peak VO2 development in Southern Chinese 8 to 16 years old.

OBJECTIVE: To investigate scaling approaches for evaluating the development of peak VO2 and improving the identification of low cardiopulmonary fitness in Southern Chinese children and adolescents. METHODS: Nine hundred and twenty Chinese children and adolescents (8 to 16 years) underwent graded cardiopulmonary exercise test on a treadmill until volitional exhaustion. Peak VO2 was corrected for the effects of body mass by ratio or allometric scaling. Z score equations for predicting peak VO2 were developed. Correlations between scaled peak VO2, z scores, body size and age were tested to examine the effectiveness of the approach. RESULTS: Eight hundred and fifty-two participants (48% male) were included in the analyses. Absolute peak VO2 significantly increased with age in both sexes (both P<0.05), while ratio-scaled peak VO2 increased only in males (P<0.05). Allometrically scaled peak VO2 increased from 11 years in both sexes, plateauing by 12 years in girls and continuing to rise until 15 years in boys. Allometically scaled peak VO2 was not correlated with body mass, but remained correlated with height and age in all but the older girls. Peak VO2 z score was not correlated with body mass, height or age. CONCLUSIONS: Absolute and allometric scaled peak VO2 values are provided for Hong Kong Chinese children and adolescents by age and sex. Peak VO2 z scores improve the evaluation of cardiopulmonary fitness, allowing comparisons across ages and sex and will likely provide a better metric for tracking change over time in children and adolescents, regardless of body size and age.

Study protocol: a randomized controlled trial study on the effect of a game-based exercise training program on promoting physical fitness and mental health in children with autism spectrum disorder.

BACKGROUND: Suboptimal physical activity levels and tolerance, poor motor skills and poor physical health are demonstrated in children with Autism Spectrum Disorder (ASD). We speculate that social interaction and communication deficits in children with ASD are two major factors that hinder these children from actively participating in group physical activities. While previous studies have demonstrated that exercise intervention improves motor skills and behavioral outcomes in children with ASD, these programs tend to focus only on a single sport, which may not cater to the interests of different children with ASD. In this protocol, a game-based exercise training program designed by a multi-disciplinary team (pediatrics, physical education and psychology) will be implemented by front-line healthcare providers trained following the train-the-trainer (TTT) model and subjected to validation. METHOD: Using a randomized controlled trial design, the effectiveness of the game-based exercise program will be examined for 112 young children with ASD. These children were randomly assigned to two groups, which will be tested and trained in either one of the two arms of the waitlist conditions (control and intervention). The assessment of physical and psychological traits will be conducted at baseline (pre-test), at 16-weeks (post-treatment) and at 32-weeks (follow-up) of the program. DISCUSSION: Most of the interventions designed for ASD children target either their psychological traits or physical conditions, without bridging the two states. With the recognition of bidirectional relations between mental and physical health, the present game-based exercise program which includes multiple level of difficulties was developed to equip ASD children with the necessary skills for engaging in sustainable team sports or even professional sport training. The program, if effective, will provide an entertaining and engaging training for whole-person development among children with ASD. TRIAL REGISTRATION: This study is registered with the Chinese Clinical Trial Registry ( ChiCTR-IOR-17011898 ). Registered 6th July 2017.

Expanding signaling-molecule wavefront model of cell polarization in the Drosophila wing primordium.

In developing tissues, cell polarization and proliferation are regulated by morphogens and signaling pathways. Cells throughout the Drosophila wing primordium typically show subcellular localization of the unconventional myosin Dachs on the distal side of cells (nearest the center of the disc). Dachs localization depends on the spatial distribution of bonds between the protocadherins Fat (Ft) and Dachsous (Ds), which form heterodimers between adjacent cells; and the Golgi kinase Four-jointed (Fj), which affects the binding affinities of Ft and Ds. The Fj concentration forms a linear gradient while the Ds concentration is roughly uniform throughout most of the wing pouch with a steep transition region that propagates from the center to the edge of the pouch during the third larval instar. Although the Fj gradient is an important cue for polarization, it is unclear how the polarization is affected by cell division and the expanding Ds transition region, both of which can alter the distribution of Ft-Ds heterodimers around the cell periphery. We have developed a computational model to address these questions. In our model, the binding affinity of Ft and Ds depends on phosphorylation by Fj. We assume that the asymmetry of the Ft-Ds bond distribution around the cell periphery defines the polarization, with greater asymmetry promoting cell proliferation. Our model predicts that this asymmetry is greatest in the radially-expanding transition region that leaves polarized cells in its wake. These cells naturally retain their bond distribution asymmetry after division by rapidly replenishing Ft-Ds bonds at new cell-cell interfaces. Thus we predict that the distal localization of Dachs in cells throughout the pouch requires the movement of the Ds transition region and the simple presence, rather than any specific spatial pattern, of Fj.

Axonal Transport: A Constrained System.

Long-distance intracellular axonal transport is predominantly microtubule-based, and its impairment is linked to neurodegeneration. Here we review recent theoretical and experimental evidence that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Theoretical work suggests that this opposition to motion increases rapidly as the cargo approaches the wall. However, having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus decreases the effects due to such opposition. Experimental evidence supports this hypothesis: in small caliber axons, microtubule density is higher, increasing the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. For transport toward the minus-end of microtubules, e.g., toward the cell body in an axon, a recently discovered force adaptation system can also contribute to overcoming such opposition to motion.

Publisher's Note: Candidate Source of Flux Noise in SQUIDs: Adsorbed Oxygen Molecules [Phys. Rev. Lett. 115, 077002 (2015)].

This corrects the article DOI: 10.1103/PhysRevLett.115.077002.

Candidate Source of Flux Noise in SQUIDs: Adsorbed Oxygen Molecules.

A major obstacle to using superconducting quantum interference devices (SQUIDs) as qubits is flux noise. We propose that the heretofore mysterious spins producing flux noise could be O_{2} molecules adsorbed on the surface. Using density functional theory calculations, we find that an O_{2} molecule adsorbed on an α-alumina surface has a magnetic moment of ~1.8 µ_{B}. The spin is oriented perpendicular to the axis of the O-O bond, the barrier to spin rotations is about 10 mK. Monte Carlo simulations of ferromagnetically coupled, anisotropic XY spins on a square lattice find 1/f magnetization noise, consistent with flux noise in Al SQUIDs.

Association Between Leisure Time Physical Activity, Cardiopulmonary Fitness, Cardiovascular Risk Factors, and Cardiovascular Workload at Work in Firefighters.

BACKGROUND: Overweight, obesity, and cardiovascular disease risk factors are prevalent among firefighters in some developed countries. It is unclear whether physical activity and cardiopulmonary fitness reduce cardiovascular disease risk and the cardiovascular workload at work in firefighters. The present study investigated the relationship between leisure-time physical activity, cardiopulmonary fitness, cardiovascular disease risk factors, and cardiovascular workload at work in firefighters in Hong Kong. METHODS: Male firefighters (n = 387) were randomly selected from serving firefighters in Hong Kong (n = 5,370) for the assessment of cardiovascular disease risk factors (obesity, hypertension, diabetes mellitus, dyslipidemia, smoking, known cardiovascular diseases). One-third (Target Group) were randomly selected for the assessment of off-duty leisure-time physical activity using the short version of the International Physical Activity Questionnaire. Maximal oxygen uptake was assessed, as well as cardiovascular workload using heart rate monitoring for each firefighter for four "normal" 24-hour working shifts and during real-situation simulated scenarios. RESULTS: Overall, 33.9% of the firefighters had at least two cardiovascular disease risk factors. In the Target Group, firefighters who had higher leisure-time physical activity had a lower resting heart rate and a lower average working heart rate, and spent a smaller proportion of time working at a moderate-intensity cardiovascular workload. Firefighters who had moderate aerobic fitness and high leisure-time physical activity had a lower peak working heart rate during the mountain rescue scenario compared with firefighters who had low leisure-time physical activities. CONCLUSION: Leisure-time physical activity conferred significant benefits during job tasks of moderate cardiovascular workload in firefighters in Hong Kong.

Axonal transport: how high microtubule density can compensate for boundary effects in small-caliber axons.

Long-distance intracellular axonal transport is predominantly microtubule-based, and its impairment is linked to neurodegeneration. In this study, we present theoretical arguments that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Our theoretical analysis suggests that this opposition to motion increases rapidly as the cargo approaches the wall. We find that having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus minimizes the effects of any opposition to transport. Even if microtubules are randomly placed in axons, we find that the higher density of microtubules found in small-caliber axons increases the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. The boundary effect is not a factor in transport in large-caliber axons where the microtubule density is lower.

Filament-filament switching can be regulated by separation between filaments together with cargo motor number.

How intracellular transport controls the probability that cargos switch at intersections between filaments is not well understood. In one hypothesis some motors on the cargo attach to one filament while others attach to the intersecting filament, and the ensuing tug-of-war determines which filament is chosen. We investigate this hypothesis using 3D computer simulations, and discover that switching at intersections increases with the number of motors on the cargo, but is not strongly dependent on motor number when the filaments touch. Thus, simply controlling the number of active motors on the cargo cannot account for in vivo observations that found reduced switching with increasing motor number, suggesting additional mechanisms of regulation. We use simulations to show that one possible way to regulate switching is by simultaneously adjusting the separation between planes containing the crossing filaments and the total number of active motors on the cargo. Heretofore, the effect of filament-filament separation on switching has been unexplored. We find that the switching probability decreases with increasing filament separation. This effect is particularly strong for cargos with only a modest number of motors. As the filament separation increases past the maximum head-to-head distance of the motor, individual motors walking along a filament will be unable to reach the intersecting filament. Thus, any switching requires that other motors on the cargo attach to the intersecting filament and haul the cargo along it, while motor(s) engaged on the original filament detach. Further, if the filament separation is large enough, the cargo can have difficulty proceeding along the initial filament because the engaged motors can walk underneath the intersecting filament, but the cargo itself cannot fit between the filaments. Thus, the cargo either detaches entirely from the original filament, or must dip to the side of the initial filament and then pass below the crossing filament.

Modeling flux noise in SQUIDs due to hyperfine interactions.

Recent experiments implicate spins on the surface of metals as the source of flux noise in superconducting quantum interference devices and indicate that these spins are able to relax without conserving total magnetization. We present a model of 1/f flux noise in which electron spins on the surface of metals can relax via hyperfine interactions. Our results indicate that flux noise would be significantly reduced in superconducting materials where the most abundant isotopes do not have nuclear moments, such as zinc and lead.

Widom line and noise-power spectral analysis of a supercritical fluid.

We have performed extensive molecular dynamics simulations to study noise-power spectra of density and potential energy fluctuations of a Lennard-Jones model of a fluid in the supercritical region. Emanating from the liquid-vapor critical point, there is a locus of isobaric specific heat maxima, called the Widom line, which is often regarded as an extension of the liquid-vapor coexistence line. Our simulation results show that the noise-power spectrum of the density fluctuations on the Widom line of the liquid-vapor transition exhibits three distinct 1/f^{γ} behaviors with exponents γ=0, 1.2, and 2, depending on the frequency f. We find that the intermediate frequency region with an exponent γ∼ 1 appears as the temperature approaches the Widom temperature from above or below. On the other hand, we do not find three distinct regions of 1/f^{γ} in the power spectrum of the potential energy fluctuations on the Widom line. Furthermore, we find that the power spectra of both the density and potential energy fluctuations at low frequency have a maximum on the Widom line, suggesting that the noise power can provide an alternative signature of the Widom line.

Follow up of aerobic capacity in children affected by severe acute respiratory syndrome.

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the aerobic capacity of children 3 years after they were diagnosed with severe acute respiratory syndrome (SARS). METHODS: Twenty-seven patients who completed both pulmonary function and maximal aerobic capacity tests at 6 and 15 months after the acute illness were invited to return for reassessment. RESULTS: Twenty-one patients (median age 18.2 years, interquartile range (IQR) 16.5-19.7) completed all investigations at 36 months. Pulmonary function was normal in all patients. Maximal aerobic capacity, peak oxygen pulse (peak VO(2) ) and ventilatory anaerobic threshold showed significant improvements compared with values measured at 6 months in both boys and girls. In girls, ventilatory efficiency (ventilatory equivalents for oxygen and carbon dioxide) and perfusion of the lungs (end-tidal partial carbon dioxide pressure) had not increased further compared with the values measured at 15 months. Although peak VO(2) improved further at 36 months in patients with or without persistent radiological abnormalities, the values were 68% (IQR 50-84) and 74% (IQR 60-99), respectively, of those for normal control subjects. CONCLUSIONS: There were improvements in aerobic capacity at 36 months in children affected by SARS; however, the measured values remained suboptimal.

Mechanical stochastic tug-of-war models cannot explain bidirectional lipid-droplet transport.

Intracellular transport via the microtubule motors kinesin and dynein plays an important role in maintaining cell structure and function. Often, multiple kinesin or dynein motors move the same cargo. Their collective function depends critically on the single motors' detachment kinetics under load, which we experimentally measure here. This experimental constraint--combined with other experimentally determined parameters--is then incorporated into theoretical stochastic and mean-field models. Comparison of modeling results and in vitro data shows good agreement for the stochastic, but not mean-field, model. Many cargos in vivo move bidirectionally, frequently reversing course. Because both kinesin and dynein are present on the cargos, one popular hypothesis explaining the frequent reversals is that the opposite-polarity motors engage in unregulated stochastic tugs-of-war. Then, the cargos' motion can be explained entirely by the outcome of these opposite-motor competitions. Here, we use fully calibrated stochastic and mean-field models to test the tug-of-war hypothesis. Neither model agrees well with our in vivo data, suggesting that, in addition to inevitable tugs-of-war between opposite motors, there is an additional level of regulation not included in the models.