Use of the improved tug-of-war acupuncture for promoting cartilage repair by inducing macrophage polarization in knee osteoarthritis.

Introduction: Knee osteoarthritis (KOA) is a type of joint disease causing degenerative changes that are challenging to treat. The improved tug-of-war acupuncture (BHZF) can improve joint pain in KOA. However, the associated mechanism has not been validated. Methods: The KOA rabbit model was established. After the surgery, the improved BHZF was provided as an intervention, and the animals were euthanized after 2 weeks. Histopathological changes in the synovium and cartilage were observed on hematoxylin & eosin staining and Safranin O-Fast Green staining. Synovial fluid and serum samples were collected to assess the presence of cytokines using the enzyme-linked immunosorbent assay. The expression of M1 macrophage (CD86) and M2 macrophage (ARG1) markers in the cartilage and synovium was detected via immunohistochemistry and immunofluorescence assays. Results: The improved BHZF could reduce KOA-related pain and inhibit joint swelling. Further, it significantly maintained the morphology of articular chondrocytes in KOA and reduced the decomposition of the cartilage matrix. Then, it significantly reduced the expression of CD86-positive cells (P < 0.05), and increased the expression of ARG1-positive cells in the cartilage and synovium (P < 0.05). Moreover, it significantly decreased the expression of inflammatory factors interleukin (IL)-1 beta and tumor necrosis factor-alpha in the serum and synovial fluid (P < 0.05), and significantly increased the expression levels of anti-inflammatory cytokines IL-4 and IL-10 (P < 0.05). Conclusions: The improved BHZF can relieve pain and improve cartilage damage by regulating macrophage polarization in KOA.

A Countable-Type Branching Process Model for the Tug-of-War Cancer Cell Dynamics.

We consider a time-continuous Markov branching process of proliferating cells with a countable collection of types. Among-type transitions are inspired by the Tug-of-War process introduced by McFarland et al. (Proc Natl Acad Sci 111(42):15138-15143, 2014) as a mathematical model for competition of advantageous driver mutations and deleterious passenger mutations in cancer cells. We introduce a version of the model in which a driver mutation pushes the type of the cell L-units up, while a passenger mutation pulls it 1-unit down. The distribution of time to divisions depends on the type (fitness) of cell, which is an integer. The extinction probability given any initial cell type is strictly less than 1, which allows us to investigate the transition between types (type transition) in an infinitely long cell lineage of cells. The analysis leads to the result that under driver dominance, the type transition process escapes to infinity, while under passenger dominance, it leads to a limit distribution. Implications in cancer cell dynamics and population genetics are discussed.

A quantitative model for virus uncoating predicts influenza A infectivity.

For virus infection of new host cells, the disassembly of the protective outer protein shell (capsid) is a critical step, but the mechanisms and host-virus interactions underlying the dynamic, active, and regulated uncoating process are largely unknown. Here, we develop an experimentally supported, multiscale kinetics model that elucidates mechanisms of influenza A virus (IAV) uncoating in cells. Biophysical modeling demonstrates that interactions between capsid M1 proteins, host histone deacetylase 6 (HDAC6), and molecular motors can physically break the capsid in a tug-of-war mechanism. Biochemical analysis and biochemical-biophysical modeling identify unanchored ubiquitin chains as essential and allow robust prediction of uncoating efficiency in cells. Remarkably, the different infectivity of two clinical strains can be ascribed to a single amino acid variation in M1 that affects binding to HDAC6. By identifying crucial modules of viral infection kinetics, the mechanisms and models presented here could help formulate novel strategies for broad-range antiviral treatment.

Tug-of-War between Two Distinct Catalytic Sites Enables Fast and Selective Ring-Opening Copolymerizations.

Ring-opening copolymerizations have emerged as a powerful approach towards the creation of sustainable polymers. Typical H-bonding catalysts for ring-opening are subject to a single catalytic site. Here we describe a H-bond-donor/Lewis-acidic-boron organocatalyst featuring two distinct catalytic sites in one molecule. The ring-opening copolymerization of epoxides with anhydride mediated by these modular, and tunable catalysts achieves high selectivity (>99 % polyester selectivity) and markedly higher activity compared to either of the di-thiourea analogues or any combinations of them. Calculations and experimental studies reveal that the superior catalytic performance arises from tug-of-war between two differentiated catalytic sites: thiourea pulls off the propagating chain-end from boron center, simultaneously enhancing the role of monomer activation and also nucleophilicity of the propagation intermediates.

Impact of noise on the regulation of intracellular transport of intermediate filaments.

Noise affects all biological processes from molecules to cells, organisms and populations. Although the effect of noise on these processes is highly variable, evidence is accumulating which shows natural stochastic fluctuations (noise) can facilitate biological functions. Herein, we investigate the effect of noise on the transport of intermediate filaments in cells by comparing the stochastic and deterministic formalizations of the bidirectional transport of intermediate filaments, long elastic polymers transported along microtubules by antagonistic motor proteins (Dallon et al., 2019; Portet et al., 2019). By numerically exploring discrepancies in timescales and attractors between both formalizations, we characterize the impact of stochastic fluctuations on the individual and ensemble transport. Biologically, we find that noise promotes the collective movement of intermediate filaments and increases the efficiency of its regulation by the biochemical properties of motor-cargo interactions. While stochastic fluctuations reduce the impact of the initial distributions of motor proteins in cells, the number of binding sites and the affinity of motor-cargo interactions are the key parameters controlling transport efficiency and efficacy.

Analysis of Physical Demands in Four Tug of War World Indoor Championships (2010-2016).

Background: Tug-of-war (TOW) is one of the oldest sports in current existence and is an internationally played activity that includes professional and amateur sport athletes, played according to the rules laid out by the Tug of War International Federation (TWIF). In this type of competition, the two teams of eight members each pull against one another on a rope. The team that pulls the opposing team towards a centerline for a distance of 4 m in two pulls out of three is considered the winning team in an international competition. To the best of the authors' knowledge, no previous scientific articles have described data during a follow-up period of Championships in TOW. Therefore, the main aim of this study was to analyze the duration of the matches, differentiating between the first (T1) and second pull (T2) of each match. Methods: The pulls were compared in the qualification point phase and the final phase, as well as in each weight category. In addition, any differences between the statistics for each of the four World Championships studied were analyzed. Finally, the total volume of pulls in each weight category was studied, both in the open club competition and in the national team competition. Data were collected from four World Indoor Championships (2010−2016). A total of 1862 matches were registered (3724 pulls), differentiating the first (T1) and second (T2) pull. The data were expressed as means (M) ± standard deviations (SD). Results: (1) The second pull is shorter than the first: T1 < T2, p < 0.001, (Es = 0.452; small effect); (2) T1 and T2 times were longer in the final phase than the qualifying phase: T1 phase2 > T1 phase1, p < 0.05 (ES = 0.469; small effect) and T2 phase2 > T2 phase1, (p < 0.05), (ES = 0.486; small effect); (3) there are statistical differences (p < 0.005) in T1 and T2 at all weights, except for T1 at 500 kg and T2 at 640 kg; (4) the comparison among World Championships does not present significant changes in the duration of the pulls; (5) however, in females, significant differences (p < 0.05) between the 2010 World Championships and the remainder in T1 are observed; (6) the volumes that we should take into account when designing the preparation should be those obtained when 11 teams compete against each other, considering the maximum volume that we could find in the competition. Conclusion: This first aspect of the reality of TOW indoor competitions, specifically the duration of the matches, leads to a better understanding of the demands of the sport and the type of effort required. These ideas may help coaches in the design of training plans, maximizing their specificity and their effectiveness.

Tug-of-War between Covalent Binding and Electrostatic Interaction Effectively Killing E. coli without Detectable Resistance.

Antimicrobial resistance in Gram-negative bacteria has become one of the leading causes of morbidity and mortality and a serious worldwide public health concern due to the fact that Gram-negative bacteria have an additional outer membrane protecting them from an unwanted compound invading. It is still very difficult for antimicrobials to reach intracellular targets and very challenging to treat Gram-negative bacteria with the current strategies. Here, we found that (o-(bromomethyl)phenyl)boronic acid was incorporated into poly((2-N,N-diethyl)aminoethyl acrylate) (PDEA), forming a copolymer (poly(o-Bn-DEA)) having both phenylboronic acid (B) and ((2-N,N-diethyl)amino) (DEA) units. Poly(o-Bn-DEA) exhibits very strong intramolecular B-N coordination, which could highly promote the covalent binding of phenylboronic acid with lipopolysaccharide (LPS) on the outer membrane of E. coli and lodge poly(o-Bn-DEA) on the LPS layer on the surface of E. coli. Meanwhile, the strong electrostatic interaction between poly(o-Bn-DEA) and the negatively charged lipid preferred tugging the poly(o-Bn-DEA) into the lipid bilayer of E. coli. The combating interactions between covalent binding and electrostatic interaction form a tug-of-war action, which could trigger the lysis of the outer membrane, thereby killing Gram-negative E. coli effectively without detectable resistance.

Analysis of Tug of War Competition: A Narrative Complete Review.

Tug-of-war (TOW) is an internationally played activity including professional and amateur athletes, defined as early as 4000 years ago (as a rope-less version) in the artwork on Egyptian tomb engravings, and is played as per the rules laid out by TWIF, which has 73 member countries and administrative headquarters in the USA. Typically, two teams of "pullers" participate and apply enormous contra directional forces on the pulling rope. Originally, two types of competition are used: knockout and points. This narrative review describes the scientific state of the art of TOW. To the best of the authors' knowledge, no previous information has been published on this topic. Anthropometric parameters for competitors are near 83.6, lean body mass 69.4, and body fat 16. The VO2MAX is 55.8 mL/kg/min. In terms of relative strength, the dynamic leg power is 4659.8 N. Endurance TOW elicits minimal muscle damage. Injured strains and sprains comprised over half of all injuries: back (42%), shoulder-upper limb (23%) and knee (17%). Pulling movement in TOW contests can be divided into three phases, namely the "drop", "hold" and "drive" phases. The maximal pulling force was 1041.6 ± 123.9 N. The percentage of dynamic pulling force in the static maximal pulling force was 75.5 ± 14.4% and the dynamic ranged from 106.4 to 182.5%. There are two gripping styles: indoor and outdoor. The friction characteristics between surface and shoe in TOW is important in determining a suitable shoe for indoor TOW. A waist belt might be a useful piece of equipment for TOW sport. The EMG technique in TOW entails a high degree of dorsal muscle activity during the pulling. The factor of force vanishing was the coordination among athletes. The force vanishing percentage goes from 8.82 ± 5.59 for two contenders to 19.74 ± 2.22 for eight athletes, 6.4% in the sum of two pullers. However, in the drop phase, for female elite TOW team, only the 0.5% of the pulling force was wasted. Future studies are need in order to understand better this historical sport activity.

Stable tug-of-war between kinesin-1 and cytoplasmic dynein upon different ATP and roadblock concentrations.

The maintenance of intracellular processes, like organelle transport and cell division, depend on bidirectional movement along microtubules. These processes typically require kinesin and dynein motor proteins, which move with opposite directionality. Because both types of motors are often simultaneously bound to the cargo, regulatory mechanisms are required to ensure controlled directional transport. Recently, it has been shown that parameters like mechanical motor activation, ATP concentration and roadblocks on the microtubule surface differentially influence the activity of kinesin and dynein motors in distinct manners. However, how these parameters affect bidirectional transport systems has not been studied. Here, we investigate the regulatory influence of these three parameters using in vitro gliding motility assays and stochastic simulations. We find that the number of active kinesin and dynein motors determines the transport direction and velocity, but that variations in ATP concentration and roadblock density have no significant effect. Thus, factors influencing the force balance between opposite motors appear to be important, whereas the detailed stepping kinetics and bypassing capabilities of the motors only have a small effect.

Tug of war: A bimanual technique for anterior circumferential proliferative vitreoretinopathy in recurrent retinal detachment.

Purpose: To describe a bimanual technique, "tug of war" for managing anterior circumferential proliferative vitreoretinopathy (PVR) in eyes with recurrent retinal detachment (RRD). Methods: We retrospectively analyzed outcomes from eyes with RRD that underwent reattachment surgery using this maneuver and had a minimum of 6 months follow-up. A chandelier light was inserted for endo-illumination and the circumferential anterior PVR was tackled with two 25-gauge forceps stretching circumferential tractional membranes in opposite direction (tug of war) till they snapped. Results: Eleven eyes of 11 patients with a mean age of 38.2 ± 19.7 years underwent surgery. All eyes had advanced PVR of Grade C A Type 4 (Circumferential). The median duration of RD from the time of first surgery was 6 months (interquartile range = 3-8 months). The tug of war maneuver was successful in relieving the anterior retinal traction leading to retinal reattachment in all eyes without the need for relaxing retinotomies or retinectomies. Small iatrogenic retina tears occurred at the time of tug of war maneuver in 3 (27%) eyes at the site of maximum traction. The mean best-corrected visual acuity (BCVA) improved from 1.87 ± 0.2 logarithm of minimum angle of resolution (logMAR) to 1.3 ± 0.4 logMAR at 6-months follow-up (P = 0.04). Conclusion: The 'tug of war' maneuver is useful for relieving circumferential anterior traction and reattaching the retina in eyes with RRD without having to resort to large relaxing retinotomies or retinectomies.

The joint evolution of cooperation and competition.

In nature, cooperation among individuals is often accompanied by competition among the same individuals for the cooperatively produced rewards. In such a situation, the evolution of cooperative and competitive investments influences each other, but previous theoretical studies mostly focused on either cooperation or competition. Here we consider a generic situation in which individuals cooperatively produce rewards according to the continuous snowdrift game, and then rewards are divided among cooperating individuals according to a generalized tug-of-war game. Using adaptive dynamics and numerical simulations, we investigated the joint evolution of two continuous traits, the investment in cooperation and in competition, respectively. We found that competition for the division of rewards promotes evolutionary branching, and hence polymorphism in both the cooperative and the competitive traits. In polymorphic populations, cooperation levels are positively correlated with competition levels among strains, so that cooperators tend to benefit disproportionately from the benefits produced. We also found that the mean cooperation level within the population is promoted by the competition. Our results show that coevolution of cooperation and competition has qualitatively different outcomes compared to the evolution of only cooperation or only competition, and suggest that it is important to simultaneously consider multiple aspects of social interactions.

Controlling DNA Tug-of-War in a Dual Nanopore Device.

Methods for reducing and directly controlling the speed of DNA through a nanopore are needed to enhance sensing performance for direct strand sequencing and detection/mapping of sequence-specific features. A method is created for reducing and controlling the speed of DNA that uses two independently controllable nanopores operated with an active control logic. The pores are positioned sufficiently close to permit cocapture of a single DNA by both pores. Once cocapture occurs, control logic turns on constant competing voltages at the pores leading to a "tug-of-war" whereby opposing forces are applied to regions of the molecules threading through the pores. These forces exert both conformational and speed control over the cocaptured molecule, removing folds and reducing the translocation rate. When the voltages are tuned so that the electrophoretic force applied to both pores comes into balance, the life time of the tug-of-war state is limited purely by diffusive sliding of the DNA between the pores. A tug-of-war state is produced on 76.8% of molecules that are captured with a maximum two-order of magnitude increase in average pore translocation time relative to the average time for single-pore translocation. Moreover, the translocation slow-down is quantified as a function of voltage tuning and it is shown that the slow-down is well described by a first passage analysis for a 1D subdiffusive process. The ionic current of each nanopore provides an independent sensor that synchronously measures a different region of the same molecule, enabling sequential detection of physical labels, such as monostreptavidin tags. With advances in devices and control logic, future dual-pore applications include genome mapping and enzyme-free sequencing.

Bidirectional sliding of two parallel microtubules generated by multiple identical motors.

It is often assumed in biophysical studies that when multiple identical molecular motors interact with two parallel microtubules, the microtubules will be crosslinked and locked together. The aim of this study is to examine this assumption mathematically. We model the forces and movements generated by motors with a time-continuous Markov process and find that, counter-intuitively, a tug-of-war results from opposing actions of identical motors bound to different microtubules. The model shows that many motors bound to the same microtubule generate a great force applied to a smaller number of motors bound to another microtubule, which increases detachment rate for the motors in minority, stabilizing the directional sliding. However, stochastic effects cause occasional changes of the sliding direction, which has a profound effect on the character of the long-term microtubule motility, making it effectively diffusion-like. Here, we estimate the time between the rare events of switching direction and use them to estimate the effective diffusion coefficient for the microtubule pair. Our main result is that parallel microtubules interacting with multiple identical motors are not locked together, but rather slide bidirectionally. We find explicit formulae for the time between directional switching for various motor numbers.

Microbial Siderophore Enterobactin Promotes Mitochondrial Iron Uptake and Development of the Host via Interaction with ATP Synthase.

Elucidating the benefits of individual microbiota-derived molecules in host animals is important for understanding the symbiosis between humans and their microbiota. The bacteria-secreted enterobactin (Ent) is an iron scavenging siderophore with presumed negative effects on hosts. However, the high prevalence of Ent-producing commensal bacteria in the human gut raises the intriguing question regarding a potential host mechanism to beneficially use Ent. We discovered an unexpected and striking role of Ent in supporting growth and the labile iron pool in C. elegans. We show that Ent promotes mitochondrial iron uptake and does so, surprisingly, by binding to the ATP synthase α subunit, which acts inside of mitochondria and independently of ATP synthase. We also demonstrated the conservation of this mechanism in mammalian cells. This study reveals a distinct paradigm for the "iron tug of war" between commensal bacteria and their hosts and an important mechanism for mitochondrial iron uptake and homeostasis.

Proofreading of Peptide-MHC Complexes through Dynamic Multivalent Interactions.

The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome. A crucial element of MHC I antigen presentation is the peptide-loading complex (PLC), a multisubunit machinery, which contains as key constituents the transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). While TAP recognizes and shuttles the cytosolic antigenic peptides into the endoplasmic reticulum (ER), Tsn samples peptides in the ER for their ability to form stable complexes with MHC I, a process called peptide proofreading or peptide editing. Through its selection of peptides that improve MHC I stability, Tsn contributes to the hierarchy of immunodominant peptide epitopes. Despite the fact that it concerns a key event in adaptive immunity, insights into the catalytic mechanism of peptide proofreading carried out by Tsn have only lately been gained via biochemical, biophysical, and structural studies. Furthermore, a Tsn homolog called TAP-binding protein-related (TAPBPR) has only recently been demonstrated to function as a second MHC I-specific chaperone and peptide proofreader. Although TAPBPR is PLC-independent and has a distinct allomorph specificity, it is likely to share a common catalytic mechanism with Tsn. This review focuses on the current knowledge of the multivalent protein-protein interactions and the concomitant dynamic molecular processes underlying peptide-proofreading catalysis. We do not only derive a model that highlights the common mechanistic principles shared by the MHC I editors Tsn and TAPBPR, and the MHC II editor HLA-DM, but also illustrate the distinct quality control strategies employed by these chaperones to sample epitopes. Unraveling the mechanistic underpinnings of catalyzed peptide proofreading will be crucial for a thorough understanding of many aspects of immune recognition, from infection control and tumor immunity to autoimmune diseases and transplant rejection.

Optical disassembly of cellular clusters by tunable 'tug-of-war' tweezers.

Bacterial biofilms underlie many persistent infections, posing major hurdles in antibiotic treatment. Here we design and demonstrate 'tug-of-war' optical tweezers that can facilitate the assessment of cell-cell adhesion-a key contributing factor to biofilm development, thanks to the combined actions of optical scattering and gradient forces. With a customized optical landscape distinct from that of conventional tweezers, not only can such 'tug-of-war' tweezers stably trap and stretch a rod-shaped bacterium in the observing plane, but, more importantly, they can also impose a tunable lateral force that pulls apart cellular clusters without any tethering or mechanical movement. As a proof of principle, we examined a Sinorhizobium meliloti strain that forms robust biofilms and found that the strength of intercellular adhesion depends on the growth medium. This technique may herald new photonic tools for optical manipulation and biofilm study, as well as other biological applications.

Evolutionary routes to stable ownership.

Ownership can evolve in potentially any species. Drawing on insights from across disciplines, we distinguish between possession and ownership and present species-neutral criteria for ownership, defined as respect for possession. We use a variant of the tug-of-war evolutionary game to demonstrate how ownership can evolve in the form of a new, biologically realistic strategy, Restraint With Retaliation (RWR). In our game, resource holding potential (RHP) is assumed to be equal between interactants, and resource holding asymmetry determines whether ownership is adaptive. RWR will be evolutionarily stable when the ratio of resource holdings between interactants is relatively low, but not when this ratio is sufficiently high. We offer RWR as one evolutionary route to ownership among many, and discuss how ownership unites previously described behavioural phenomena across taxa. We propose that some but not all mechanisms of territory formation and maintenance can be considered ownership, and show that territories are not the only resources that can be owned. We argue that ownership can be a powerful cooperative solution to tragedies of the commons and problems of collective action throughout the biological world. We advance recent scholarship that has begun to investigate the biological importance of ownership, and we call for a comprehensive account of its evolutionary logic and taxonomic distribution. We propose that ownership should be considered a fundamental, unifying biological phenomenon.

Asymmetry within social groups: division of labour and intergroup competition.

Social animals vary in their ability to compete with group members over shared resources and also vary in their cooperative efforts to produce these resources. Competition among groups can promote within-group cooperation, but many existing models of intergroup cooperation do not explicitly account for observations that group members invest differentially in cooperation and that there are often within-group competitive or power asymmetries. We present a game theoretic model of intergroup competition that investigates how such asymmetries affect within-group cooperation. In this model, group members adopt one of two roles, with relative competitive efficiency and the number of individuals varying between roles. Players in each role make simultaneous, coevolving decisions. The model predicts that although intergroup competition increases cooperative contributions to group resources by both roles, contributions are predominantly from individuals in the less competitively efficient role, whereas individuals in the more competitively efficient role generally gain the larger share of these resources. When asymmetry in relative competitive efficiency is greater, a group's per capita cooperation (averaged across both roles) is higher, due to increased cooperation from the competitively inferior individuals. For extreme asymmetry in relative competitive efficiency, per capita cooperation is highest in groups with a single competitively superior individual and many competitively inferior individuals, because the latter acquiesce and invest in cooperation rather than within-group competition. These predictions are consistent with observed features of many societies, such as monogynous Hymenoptera with many workers and caste dimorphism.

Using social parasitism to test reproductive skew models in a primitively eusocial wasp.

Remarkable variation exists in the distribution of reproduction (skew) among members of cooperatively breeding groups, both within and between species. Reproductive skew theory has provided an important framework for understanding this variation. In the primitively eusocial Hymenoptera, two models have been routinely tested: concessions models, which assume complete control of reproduction by a dominant individual, and tug-of-war models, which assume on-going competition among group members over reproduction. Current data provide little support for either model, but uncertainty about the ability of individuals to detect genetic relatedness and difficulties in identifying traits conferring competitive ability mean that the relative importance of concessions versus tug-of-war remains unresolved. Here, we suggest that the use of social parasitism to generate meaningful variation in key social variables represents a valuable opportunity to explore the mechanisms underpinning reproductive skew within the social Hymenoptera. We present a direct test of concessions and tug-of-war models in the paper wasp Polistes dominulus by exploiting pronounced changes in relatedness and power structures that occur following replacement of the dominant by a congeneric social parasite. Comparisons of skew in parasitized and unparasitized colonies are consistent with a tug-of-war over reproduction within P. dominulus groups, but provide no evidence for reproductive concessions.