Non-genetic adaptation by collective migration.

Collective behaviors require coordination of individuals. Thus, a population must adjust its phenotypic distribution to adapt to changing environments. How can a population regulate its phenotypic distribution? One strategy is to utilize specialized networks for gene regulation and maintaining distinct phenotypic subsets. Another involves genetic mutations, which can be augmented by stress-response pathways. Here, we studied how a migrating bacterial population regulates its phenotypic distribution to traverse across diverse environments. We generated isogenic Escherichia coli populations with varying distributions of swimming behaviors and observed their phenotype distributions during migration in liquid and porous environments. Surprisingly, we found that during collective migration, the distributions of swimming phenotypes adapt to the environment without mutations or gene regulation. Instead, adaptation is caused by the dynamic and reversible enrichment of high-performing swimming phenotypes within each environment. This adaptation mechanism is supported by a recent theoretical study, which proposed that the phenotypic composition of a migrating population results from a balance between cell growth generating diversity and collective migration eliminating the phenotypes that are unable to keep up with the migrating group. Furthermore, by examining chemoreceptor abundance distributions during migration towards different attractants, we found that this mechanism acts on multiple chemotaxis-related traits simultaneously. Our findings reveal that collective migration itself can enable cell populations with continuous, multi-dimensional phenotypes to flexibly and rapidly adapt their phenotypic composition to diverse environmental conditions. Significance statement: Conventional cell adaptation mechanisms, like gene regulation and random phenotypic switching, act swiftly but are limited to a few traits, while mutation-driven adaptations unfold slowly. By quantifying phenotypic diversity during bacterial collective migration, we discovered an adaptation mechanism that rapidly and reversibly adjusts multiple traits simultaneously. By dynamically balancing the elimination of phenotypes unable to keep pace with generation of diversity through growth, this process enables populations to tune their phenotypic composition based on the environment, without the need for gene regulation or mutations. Given the prevalence of collective migration in microbes, cancers, and embryonic development, non-genetic adaptation through collective migration may be a universal mechanism for populations to navigate diverse environments, offering insights into broader applications across various fields.

Identification of cell-type specific alternative transcripts in the multicellular alga Volvox carteri.

BACKGROUND: Cell type specialization is a hallmark of complex multicellular organisms and is usually established through implementation of cell-type-specific gene expression programs. The multicellular green alga Volvox carteri has just two cell types, germ and soma, that have previously been shown to have very different transcriptome compositions which match their specialized roles. Here we interrogated another potential mechanism for differentiation in V. carteri, cell type specific alternative transcript isoforms (CTSAI). METHODS: We used pre-existing predictions of alternative transcripts and de novo transcript assembly with HISAT2 and Ballgown software to compile a list of loci with two or more transcript isoforms, identified a small subset that were candidates for CTSAI, and manually curated this subset of genes to remove false positives. We experimentally verified three candidates using semi-quantitative RT-PCR to assess relative isoform abundance in each cell type. RESULTS: Of the 1978 loci with two or more predicted transcript isoforms 67 of these also showed cell type isoform expression biases. After curation 15 strong candidates for CTSAI were identified, three of which were experimentally verified, and their predicted gene product functions were evaluated in light of potential cell type specific roles. A comparison of genes with predicted alternative splicing from Chlamydomonas reinhardtii, a unicellular relative of V. carteri, identified little overlap between ortholog pairs with alternative splicing in both species. Finally, we interrogated cell type expression patterns of 126 V. carteri predicted RNA binding protein (RBP) encoding genes and found 40 that showed either somatic or germ cell expression bias. These RBPs are potential mediators of CTSAI in V. carteri and suggest possible pre-adaptation for cell type specific RNA processing and a potential path for generating CTSAI in the early ancestors of metazoans and plants. CONCLUSIONS: We predicted numerous instances of alternative transcript isoforms in Volvox, only a small subset of which showed cell type specific isoform expression bias. However, the validated examples of CTSAI supported existing hypotheses about cell type specialization in V. carteri, and also suggested new hypotheses about mechanisms of functional specialization for their gene products. Our data imply that CTSAI operates as a minor but important component of V. carteri cellular differentiation and could be used as a model for how alternative isoforms emerge and co-evolve with cell type specialization.

Force-amplifying implant to improve key pinch strength in tendon transfer surgery: Cadaver model proof-of-concept.

The brachioradialis (BR) to flexor pollicis longus (FPL) tendon transfer surgery is a common procedure used to restore key pinch grip for incomplete spinal cord injury patients. However, the procedure only restores 22% of the physiological grip strength, which is important for successfully grasping objects and minimizing fatigue. The purpose of this study was to evaluate the efficacy of using a novel force-amplifying pulley implant to modify the standard BR to FPL tendon transfer surgery to improve key pinch grip strength in a human cadaver forearm model. A total of eight cadaveric specimens were mounted onto a custom testbed where a torque-controlled motor actuated the BR tendon to produce key pinch grip. In each cadaver, two experimental groups were examined: a standard and an implant-modified BR to FPL tendon transfer surgery. A force sensor mounted to the thumb recorded isometric key pinch grip forces over a range of input BR forces (2 N-25 N) applied in a ramp-and-hold protocol. Across the range of input BR forces, the average improvement in key pinch grip strength in the implant-modified surgery compared to the standard surgery was 58 ± 7.1% (ranging from 41% to 64% improvement). Throughout the experiments, we observed that the implant did not hinder the movement of the BR or FPL tendons. These results suggest that a BR to FPL tendon transfer surgery utilizing a force-amplifying pulley implant to augment force transmission can provide additional functional strength restoration over the standard procedure that directly sutures two tendons together.

A novel implantable mechanism-based tendon transfer surgery for adult acquired flatfoot deformity: Evaluating feasibility in biomechanical simulation.

Adult acquired flatfoot deformity becomes permanent with stage III posterior tibialis tendon dysfunction and results in foot pain and difficulty walking and balancing. To prevent progression to stage III posterior tibialis tendon dysfunction when conservative treatment fails, a flexor digitorum longus to posterior tibialis tendon transfer is often conducted. However, since the flexor digitorum longus only has one-third the force-capability of the posterior tibialis, an osteotomy is typically also required. We propose the use of a novel implantable mechanism to replace the direct attachment of the tendon transfer with a sliding pulley to amplify the force transferred from the donor flexor digitorum longus to the foot arch. In this work, we created four OpenSim models of an arched foot, a flatfoot, a flatfoot with traditional tendon transfer, and a flatfoot with implant-modified tendon transfer. Paired with these models, we developed a forward dynamic simulation of the stance phase of gait that reproduces the medial/lateral distribution of vertical ground reaction forces. The simulation couples the use of a fixed tibia, moving ground plane methodology with simultaneous activation of nine extrinsic lower limb muscles. The arched foot and flatfoot models produced vertical ground reaction forces with the characteristic double-peak profile of gait, and the medial/lateral distribution of these forces compared well with the literature. The flatfoot model with implant-modified tendon transfer produced a 94.2% restoration of the medial/lateral distribution of vertical ground reaction forces generated by our arched foot model, which also represents a 2.1X improvement upon our tendon transfer model. This result demonstrates the feasibility of a pulley-like implant to improve functional outcomes for surgical treatment of adult acquired flatfoot deformity with ideal biomechanics in simulation. The real-world efficacy and feasibility of such a device will require further exploration of factors such as surgical variability, soft tissue interactions and healing response.

Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology.

Dynamic loading is a shared feature of tendon tissue homeostasis and pathology. Tendon cells have the inherent ability to sense mechanical loads that initiate molecular-level mechanotransduction pathways. While mature tendons require physiological mechanical loading in order to maintain and fine tune their extracellular matrix architecture, pathological loading initiates an inflammatory-mediated tissue repair pathway that may ultimately result in extracellular matrix dysregulation and tendon degeneration. The exact loading and inflammatory mechanisms involved in tendon healing and pathology is unclear although a precise understanding is imperative to improving therapeutic outcomes of tendon pathologies. Thus, various model systems have been designed to help elucidate the underlying mechanisms of tendon mechanobiology via mimicry of the in vivo tendon architecture and biomechanics. Recent development of model systems has focused on identifying mechanoresponses to various mechanical loading platforms. Less effort has been placed on identifying inflammatory pathways involved in tendon pathology etiology, though inflammation has been implicated in the onset of such chronic injuries. The focus of this work is to highlight the latest discoveries in tendon mechanobiology platforms and specifically identify the gaps for future work. An interdisciplinary approach is necessary to reveal the complex molecular interplay that leads to tendon pathologies and will ultimately identify potential regenerative therapeutic targets.

Genetic Algorithm-Based Optimization for the Geometric Design of a Novel Orthopedic Implant.

OBJECTIVE: A tendon-transfer is a reconstructive orthopedic surgery where tendons are re-routed from a non-functioning muscle and attached a functioning muscle. Prior work has shown that using a passive implanted device in the ECRL-to-FDP tendon-transfer surgery significantly improves hand grasping function. However, it is still unclear how hand-function improvement, measured by finger joint range of motion and torque, is dependent on the implant's geometry and location within the tendon network. This paper presents a genetic algorithm that determines the device's optimal geometry and location. METHODS: Hand biomechanical simulation platform was developed to model hand function and also model the tendon-transfer surgery with and without the implant. Finger kinematics and joint torque were used to develop three unique objective functions to optimize the implant's parameters. RESULTS: The optimized device resulted in an 11X increase in finger kinematics with only a 0.9% decrease in joint torque when compared with the biomechanical function enabled by the current suture-based surgery. CONCLUSION: Designing implantable devices that modify musculoskeletal function is challenging. Factors like tendon routing and joint kinematics create a complex nonlinear system when considering biomechanical function. A genetic algorithm is an effective tool to tackle these nonlinear landscapes to produce optimized designs. SIGNIFICANCE: The state-of-the-art surgical procedure to repair high median-ulnar nerve palsy leads to poor hand function and severely limits the patient's ability to perform activities of daily life. This work provides a method for defining relevant objective functions for hand biomechanical function and then uses those objective functions with genetic algorithms to optimize the geometry of an orthopedic implant across multiple variables. The achieved biomechanical function is significantly better than hand function enabled by current surgical procedure.

Volvox barberi (Chlorophyceae) actively forms two-dimensional flocks in culture.

Volvox barberi is a multicellular green alga forming spherical colonies of 10,000-50,000 differentiated somatic and germ cells. We observed that in culture, these colonies actively self-organized in just a few minutes into "flocks" that contained as many as 100 colonies moving and rotating collectively for hours. The colonies in flocks formed two-dimensional, irregular, active crystals, that is, geometric lattices within which individual colonies rotated separately. These groupings sometimes disassembled back into individual colonies just as quickly, but in some cases, flocks persisted over several hours. Close inspection of flock formation in the presence of a tracer dye suggested that colony and flock rotations were producing vortices in the fluid medium over a range spanning multiple flock diameters, perhaps providing a physical mechanism for aggregation.

An Investigation of a Novel Tendon Transfer Surgery for High Median-Ulnar Nerve Palsy in a Chicken Model.

PURPOSE: The state-of-the-art tendon transfer surgery for high median-ulnar nerve palsy involves directly suturing four finger flexor tendons to one wrist extensor muscle. This couples finger flexion limiting the patient's ability to grasp objects. Therefore, we propose a new approach to attach a novel passive implant to the extensor digitorum longus tendon in order to create a differential mechanism in situ. The implant is expected to enable the fingers to adapt to an object's shape during grasping. Chickens have been used as a model in tendon research, but studies have primarily focused on the digital flexor tendon mechanism. Thus, the aim of this study was to explore the feasibility of the chicken model for extensor tendon research and to validate the surgical technique for a new approach to tendon transfer surgery. MATERIALS AND METHODS: Twenty-nine chickens were randomly divided into three groups: implant (n = 12), sham (n = 10), and control (n = 7). Postoperative healing and complications were documented. RESULTS: Surgery was successful in all chickens. All animals healed appropriately by Day 16 postoperatively. Chickens in the implant group experienced significantly more intermittent toe-knuckling gait than the sham group (p = 0.001). CONCLUSIONS: The described surgical technique allowed for successful application of a novel implantable passive mechanism in a live chicken model. In combination with previous work, findings from the present study further validated a novel tendon-transfer surgery for high median-ulnar nerve palsy. Based on the degree of intermittent abnormal gait experienced by the implant group, refinement to the implant design is warranted in future studies.

Passive engineering mechanism enhancement of a flexor digitorum longus tendon transfer procedure.

Standard treatments of adult acquired flatfoot deformity (AAFD) fail to correct associated dysfunction of the posterior tibial tendon (PTT). This study aimed to determine if a novel passive engineering mechanism (PEM) enhanced flexor digitorum longus (FDL) tendon transfer procedure would better restore physiologic PTT function to improve AAFD gait parameters compared to standard treatment. We evaluated the kinetic, pedobarographic, and kinematic effects of a pulley-based PEM-enhancement system utilizing a cadaveric flatfoot model and robotic gait simulator. FDL tendon force, FDL tendon excursion, regional peak plantar pressures, center of pressure, and foot bone/joint motions were quantified. Throughout the stance phase of gait, PEM-enhancement significantly increased FDL tendon forces, resulting in gait cycle medial column unloading, lateral column loading, forefoot adduction, hindfoot inversion, and increased plantar flexion (p < 0.05). This proof-of-concept study demonstrated that an innovative PEM-enhanced FDL tendon transfer procedure better restored physiologic PTT function, resulting in improved correction of the distinctive AAFD gait characteristics-medial column collapse, hindfoot eversion, and forefoot abduction. Clinical significance: Novel PEM-enhancement of a FDL tendon transfer procedure holds promise as a method for improved treatment of AAFD. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3033-3042, 2018.

MicroRNA-7a2 suppression causes hypogonadotropism and uncovers signaling pathways in gonadotropes.

MicroRNAs (miRNAs) have emerged as important regulators of a variety of biological processes and pathways. In this issue of the JCI, Ahmed et al. reveal that miR-7a2 is a critical regulator of sexual maturation and reproductive function, as mice lacking miR-7a2 develop hypogonadotropic hypogonadism and infertility. Using a bioinformatics approach, the authors identified several miR-7a2 target genes and pathways that have not been previously associated with gonadotropin biosynthesis and/or secretion. Together, these results identify miR-7a2-regulated genes involved in reproductive hormone biosynthesis pathways and provide a framework for future studies aimed at understanding rare reproductive conditions.

Modeling Implantable Passive Mechanisms for Modifying the Transmission of Forces and Movements Between Muscle and Tendons.

This paper explores the development of biomechanical models for evaluating a new class of passive mechanical implants for orthopedic surgery. The proposed implants take the form of passive engineered mechanisms, and will be used to improve the functional attachment of muscles to tendons and bone by modifying the transmission of forces and movement inside the body. Specifically, we present how two types of implantable mechanisms may be modeled in the open-source biomechanical software OpenSim. The first implant, which is proposed for hand tendon-transfer surgery, differentially distributes the forces and movement from one muscle across multiple tendons. The second implant, which is proposed for knee-replacement surgery, scales up the forces applied to the knee joint by the quadriceps muscle. This paper's key innovation is that such mechanisms have never been considered before in biomechanical simulation modeling and in surgery. When compared with joint function enabled by the current surgical practice of using sutures to make the attachment, biomechanical simulations show that the surgery with 1) the differential mechanism (tendon network) implant improves the fingers' ability to passively adapt to an object's shape significantly during grasping tasks (2.74× as measured by the extent of finger flexion) for the same muscle force, and 2) the force-scaling implant increases knee-joint torque by 84% for the same muscle force. The critical significance of this study is to provide a methodology for the design and inclusion of the implants into biomechanical models and validating the improvement in joint function they enable when compared with current surgical practice.

Implanted passive engineering mechanism improves hand function after tendon transfer surgery: a cadaver-based study.

PURPOSE: The purpose of this study was to investigate if a new tendon transfer surgical procedure that uses an implanted passive engineering mechanism for attaching multiple tendons to a single donor muscle in place of directly suturing the tendons to the muscle improves hand function in physical interaction tasks such as grasping. METHODS: The tendon transfer surgery for high median ulnar palsy was used as an exemplar, where all four flexor digitorum profundus (FDP) tendons are directly sutured to the extensor carpi radialis longus (ECRL) muscle to restore flexion. The new procedure used a passive hierarchical artificial pulley system to connect the muscle to the tendons. Both the suture-based and pulley-based procedures were conducted on N = 6 cadaver hands. The fingers' ability to close around four objects when the ECRL tendon was pulled was tested. Post-surgery hand function was evaluated based on the actuation force required to create a grasp and the slip between the fingers and the object after the grasp was created. RESULTS: When compared with the suture-based procedure, the pulley-based procedure (i) reduced the actuation force required to close all four fingers around the object by 45 % and (ii) improved the fingers' individual adaptation to the object's shape during the grasping process and reduced slip by 52 % after object contact (2.99° ± 0.28° versus 6.22° ± 0.66°). CONCLUSIONS: The cadaver study showed that the implanted engineering mechanism for attaching multiple tendons to one muscle significantly improved hand function in grasping tasks when compared with the current procedure.

Acquiring variable moment arms for index finger using a robotic testbed.

Human level of dexterity has not been duplicated in a robotic form to date. Dexterity is achieved in part due to the biomechanical structure of the human body and in part due to the neural control of movement. We have developed an anatomically correct testbed (ACT) hand to investigate the importance and behavioral consequences of anatomical features and neural control strategies of the human hand. One of the critical aspects of understanding dexterity is the analysis of the relationships between the hand muscle movements and joint movements, defined by the moment arms of the muscles. It is known that the moment arms for the hand muscles are configuration-dependent and vary substantially with change in posture. This paper presents a methodology for determining continuous variations in the moment arms with respect to multiple joints moving simultaneously. To determine variations in the moment arms of the ACT hand index finger muscles, we employed a nonparametric regression method called Gaussian processes (GPs). GPs give a functional mapping between the joint angles and muscle excursions, and the gradients of these mappings are the muscle moment arms. We compared the moment arm relationships of the ACT hand with those determined from the available cadaver data. We present the implications of the determination of variable moment arms toward understanding of the biomechanical properties of the human hand and for the neuromuscular control for the ACT hand index finger movements.

Task performance is prioritized over energy reduction.

The objective of this study was to characterize the temporal relationship between hand stiffness and task performance during adaptation to a brief contact task that required precision at the time of contact. The experiment required subjects to control the vertical position of a paddle on a computer display by grasping a robot's instrumented handle, with the goal of intercepting a virtual ball within 1 mm from the paddle center. A force transient was applied to the hand immediately after the ball-paddle impact to estimate the intrinsic hand impedance. There were two main results: 1) more trials were required for a brief contact task to find a low-energy strategy when compared with tasks that received feedback through the entire movement trajectory and 2) when the whole course of adaptation is long for brief contact tasks, viscoelastic forces were increased to achieve the task goal before the energy reduction initiated. Also, as the accuracy requirement was increased by changing the gain between handle and paddle motion through visual amplification, peak stiffness increased and occurred later, indicating that higher energy strategies are used for longer when the task's accuracy requirements were increased. These results indicated that task performance may be prioritized over energy reduction for a brief contact task.