Adaptive tail-length evolution in deer mice is associated with differential Hoxd13 expression in early development.

Variation in the size and number of axial segments underlies much of the diversity in animal body plans. Here we investigate the evolutionary, genetic and developmental mechanisms driving tail-length differences between forest and prairie ecotypes of deer mice (Peromyscus maniculatus). We first show that long-tailed forest mice perform better in an arboreal locomotion assay, consistent with tails being important for balance during climbing. We then identify six genomic regions that contribute to differences in tail length, three of which associate with caudal vertebra length and the other three with vertebra number. For all six loci, the forest allele increases tail length, indicative of the cumulative effect of natural selection. Two of the genomic regions associated with variation in vertebra number contain Hox gene clusters. Of those, we find an allele-specific decrease in Hoxd13 expression in the embryonic tail bud of long-tailed forest mice, consistent with its role in axial elongation. Additionally, we find that forest embryos have more presomitic mesoderm than prairie embryos and that this correlates with an increase in the number of neuromesodermal progenitors, which are modulated by Hox13 paralogues. Together, these results suggest a role for Hoxd13 in the development of natural variation in adaptive morphology on a microevolutionary timescale.

Feasibility of Low-Load Resistance Training Using Blood Flow Restriction for People With Advanced Multiple Sclerosis: A Prospective Cohort Study.

OBJECTIVE: The objective of this study was to determine the feasibility of low-load resistance training with blood flow restriction (BFR) for people with advanced disability due to multiple sclerosis (MS). METHODS: In this prospective cohort study, 14 participants with MS (Expanded Disability Status Scale [EDSS] score = 6.0 to 7.0; mean age = 55.4 [SD = 6.2] years; 71% women) were asked to perform 3 lower extremity resistance exercises (leg press, calf press, and hip abduction) bilaterally twice weekly for 8 weeks using BFR. Feasibility criteria were as follows: enrollment of 20 participants, ≥80% retention and adherence, ≥90% satisfaction, and no serious adverse events related to the intervention. Other outcomes included knee extensor, ankle plantar flexor, and hip abductor muscle strength, 30-Second Sit-to-Stand Test, Berg Balance Scale, Timed 25-Foot Walk Test, 12-Item MS Walking Scale, Modified Fatigue Impact Scale, Patient-Specific Functional Scale, and daily step count. RESULTS: Sixteen participants consented, and 14 completed the intervention, with 93% adherence overall. All participants were satisfied with the intervention. A minor hip muscle strain was the only intervention-related adverse event. There were muscle strength improvements on the more-involved (16%-28%) and less-involved (12%-19%) sides. There were also changes in the 30-Second Sit-to-Stand Test (1.9 repetitions; 95% CI = 1.0 to 2.8), Berg Balance Scale (5.3 points; 95% CI = 3.2 to 7.4), Timed 25-Foot Walk Test (-3.3 seconds; 95% CI = -7.9 to 1.3), Modified Fatigue Impact Scale (-8.8 points; 95% CI = -16.5 to -1.1), 12-Item MS Walking Scale (-3.6 points; 95% CI = -11.5 to 4.4), Patient-Specific Functional Scale (2.9 points; 95% CI = 1.9 to 3.8), and daily step count (333 steps; 95% CI = -191 to 857). CONCLUSION: Low-load resistance training using BFR in people with MS and EDSS scores of 6.0 to 7.0 appears feasible, and subsequent investigation into its efficacy is warranted. IMPACT: Although efficacy data are needed, combining BFR with low-load resistance training may be a viable alternative for people who have MS and who do not tolerate conventional moderate- to high-intensity training because of more severe symptoms, such as fatigue and weakness. LAY SUMMARY: Low-load strength training with BFR was feasible in people who have advanced disability due to MS. Using BFR may provide an alternative for people with MS who do not tolerate higher intensity training due to more severe symptoms, such as fatigue and weakness.

Self-cleaving peptides for expression of multiple genes in Dictyostelium discoideum.

The social amoeba Dictyostelium discoideum is a model for a wide range of biological processes including chemotaxis, cell-cell communication, phagocytosis, and development. Interrogating these processes with modern genetic tools often requires the expression of multiple transgenes. While it is possible to transfect multiple transcriptional units, the use of separate promoters and terminators for each gene leads to large plasmid sizes and possible interference between units. In many eukaryotic systems this challenge has been addressed through polycistronic expression mediated by 2A viral peptides, permitting efficient, co-regulated gene expression. Here, we screen the most commonly used 2A peptides, porcine teschovirus-1 2A (P2A), Thosea asigna virus 2A (T2A), equine rhinitis A virus 2A (E2A), and foot-and-mouth disease virus 2A (F2A), for activity in D. discoideum and find that all the screened 2A sequences are effective. However, combining the coding sequences of two proteins into a single transcript leads to notable strain-dependent decreases in expression level, suggesting additional factors regulate gene expression in D. discoideum that merit further investigation. Our results show that P2A is the optimal sequence for polycistronic expression in D. discoideum, opening up new possibilities for genetic engineering in this model system.

Improving shared decision-making for prosthetic care: A qualitative needs assessment of prosthetists and new lower-limb prosthesis users.

BACKGROUND: Prosthesis design is complex and multiple appropriate options exist for any individual with lower-limb amputation. However, there is insufficient evidence for guiding decision-making. Shared decision-making (SDM) offers an opportunity to incorporate patient-specific values and preferences where evidence is lacking for prosthesis design decisions. To develop resources to facilitate SDM, and consistent with the International Patient Decision Aid Standards, it is necessary to identify the decisional needs of prosthetists and prosthesis users for prosthesis design decisions. OBJECTIVES: To assess the needs of prosthetists and new prosthesis users for SDM about the first prosthesis design. STUDY DESIGN: Qualitative descriptive design. METHODS: Six focus groups were conducted with 38 prosthetists. Individual semistructured interviews were conducted with 17 new prosthesis users. Transcripts were analyzed using directed content analysis, with codes defined a priori using existing frameworks for SDM: the Three Talk Model for SDM and the Ottawa Decision Support Framework. RESULTS: Four main themes were identified among prosthetists and prosthesis users: acknowledging complexity in communication, clarifying values, recognizing the role of experience to inform preferences , and understanding the prosthetic journey . CONCLUSIONS: Resources that support SDM for the first prosthesis design should consider methods for identifying individual communication needs, support with clarifying values, and resources such as experience for achieving informed preferences, within the context of the overall course of rehabilitation and recovery following lower-limb amputation. The themes identified in this work can inform SDM to promote collaborative discussion between prosthetists and new prosthesis users when making prosthesis design decisions.

A chromosomal inversion contributes to divergence in multiple traits between deer mouse ecotypes.

How locally adapted ecotypes are established and maintained within a species is a long-standing question in evolutionary biology. Using forest and prairie ecotypes of deer mice (Peromyscus maniculatus), we characterized the genetic basis of variation in two defining traits-tail length and coat color-and discovered a 41-megabase chromosomal inversion linked to both. The inversion frequency is 90% in the dark, long-tailed forest ecotype; decreases across a habitat transition; and is absent from the light, short-tailed prairie ecotype. We implicate divergent selection in maintaining the inversion at frequencies observed in the wild, despite high levels of gene flow, and explore fitness benefits that arise from suppressed recombination within the inversion. We uncover a key role for a large, previously uncharacterized inversion in the evolution and maintenance of classic mammalian ecotypes.

Leveraging the model-experiment loop: Examples from cellular slime mold chemotaxis.

Interplay between models and experimental data advances discovery and understanding in biology, particularly when models generate predictions that allow well-designed experiments to distinguish between alternative mechanisms. To illustrate how this feedback between models and experiments can lead to key insights into biological mechanisms, we explore three examples from cellular slime mold chemotaxis. These examples include studies that identified chemotaxis as the primary mechanism behind slime mold aggregation, discovered that cells likely measure chemoattractant gradients by sensing concentration differences across cell length, and tested the role of cell-associated chemoattractant degradation in shaping chemotactic fields. Although each study used a different model class appropriate to their hypotheses - qualitative, mathematical, or simulation-based - these examples all highlight the utility of modeling to formalize assumptions and generate testable predictions. A central element of this framework is the iterative use of models and experiments, specifically: matching experimental designs to the models, revising models based on mismatches with experimental data, and validating critical model assumptions and predictions with experiments. We advocate for continued use of this interplay between models and experiments to advance biological discovery.

Clinical use of blood flow restriction in people with neurologic conditions: a cross-sectional survey.

[Purpose] There is little evidence for blood flow restriction (BFR), or Kaatsu, training in people with neurologic conditions. This study's purpose was to survey clinicians on BFR use in people with neurologic conditions. [Participants and Methods] One-hundred twelve physical therapists and other healthcare professionals who reported using BFR in the past 5 years completed an anonymous, online survey. [Results] Eighty-nine percent of respondents thought BFR was safe in people with neurologic conditions. Meanwhile, 38% reported BFR use in people with neurologic conditions. The most common intervention used with BFR was resistance training (n=33) and the most commonly reported benefit was improved strength (n=27). The most common side-effect causing treatment to stop was intolerance to pressure (n=6). No side-effects requiring medical attention were reported. In order to support future BFR use in neurologic populations, the most common response was the need for more research (n=63). [Conclusion] Despite the lack of evidence, clinical use of BFR in people with neurologic conditions may be somewhat common. Although this study had a relatively small sample size and collected data retrospectively, the results support the potential clinical feasibility and safety of BFR use in patients with neurologic conditions and suggest that more research is needed.

The Impact of COVID-19 on Community-Based Exercise Classes for People With Parkinson Disease.

OBJECTIVE: he purpose of the study was to determine the impact of novel coronavirus 2019 (COVID-19) restrictions on community-based exercise classes for people with Parkinson disease (PD) and their instructors. METHODS: Data were collected via custom-designed electronic surveys for people with PD and class instructors who reported attending or teaching PD-specific exercise class ≥1 time/week for ≥3 months prior to pandemic restrictions (March 2020). The PD group also completed the Godin Leisure-Time Questionnaire, Self-Efficacy for Exercise scale, Schwab-England scale, and Parkinson's Disease Questionnaire 8. RESULTS: Eighty-seven people with PD (mean = 70 [7.3] years old) and 43 instructors (51 [12.1] years old) from the United States completed surveys (October 2020 to February 2021). Mean Schwab-England (84 [16]) and Parkinson's Disease Questionnaire 8 (21 [15]) scores indicated low-to-moderate disability in the PD group. Ninety-five percent of the PD group had COVID-19 exposure concerns, and 54% reported leaving home ≤1 time/week. Although 77% of the PD group scored "active" on the Godin Leisure-Time Questionnaire, the mean Self-Efficacy for Exercise Scale score (55 [24]) indicated only moderate exercise self-efficacy, and >50% reported decreased exercise quantity/intensity compared with pre-COVID. There was decreased in-person and increased virtual class participation for both groups. The top in-person class barrier for the PD (63%) and instructor (51%) groups was fear of participant COVID-19 exposure. The top virtual class barriers were lack of socialization (20% of PD group) and technology problems (74% of instructor group). CONCLUSION: During COVID-19, there has been less in-person and more virtual exercise class participation in people with PD and decreased exercise quantity and intensity. Virtual classes may not fully meet the needs of people with PD, and primary barriers include technology and lack of socialization. IMPACT: As COVID-19 restrictions wane, it is imperative to help people with PD increase exercise and activity. The barriers, needs, and facilitators identified in this study might help inform approaches to increase participation in exercise and activity for people with PD. LAY SUMMARY: During COVID-19, there has been less in-person and more virtual exercise class participation in people with PD and a decrease in exercise quantity and intensity. If you have PD, virtual classes might not fully meet your needs. Primary barriers may include technology problems and lack of social interaction.

Movement compensations during a step ascent task are associated with stair climbing performance in people with multiple sclerosis.

BACKGROUND: The biomechanical mechanisms underlying stair climbing limitations are poorly understood in people with multiple sclerosis (MS). RESEARCH QUESTIONS: Are trunk and pelvis motion and lower extremity joint moments during step ascent different between MS and control groups? Are step ascent biomechanics and stair climbing performance associated in people with MS? METHODS: 20 people with MS (49 ±â€¯12 years, EDSS range: 1.5-5.5) and ten control participants (48 ±â€¯12 years) underwent three-dimensional motion analysis while ascending a 15.2-cm step and also completed a timed Functional Stair Test. Main effects of group (MS vs Control) and limb (Stronger/Dominant vs Weaker/Non-dominant) and interactions were assessed using two-way analyses of variance. Associations between movement patterns during the step ascent and Functional Stair Test performance were performed using Pearson's correlations and backward stepwise linear regression. RESULTS: Significant group main effects were observed in greater sagittal pelvis excursion (p < 0.001), greater sagittal (p = 0.013) and frontal (p = 0.001) trunk excursion, and lower trail limb peak ankle plantar flexion moment (p < 0.001) of the MS group. Significant limb main effects were observed with greater sagittal trunk excursion (p = 0.037) and peak trail limb ankle plantar flexion moment (p = 0.037) in the stronger/dominant limb. A significant interaction was observed in peak knee extensor moment (p = .002). Stair climbing performance in the MS group correlated with sagittal (r = .607, p=<0.001) and frontal pelvis excursions (r = 0.385, p = 0.014), sagittal trunk excursion (r = .411, p = 0.008), and ankle plantar flexion moments (r=-0.415, p = 0.008). Sagittal and frontal pelvis excursion and bilateral handrail use explained a significant amount of variability in stair climbing performance (Adj R2 = 0.775). SIGNIFICANCE: In conclusion, despite the presence of proximal and distal lower extremity movement pattern compensations during a step ascent task, larger pelvis angular excursions are associated with impaired stair climbing performance in people with MS and may serve as targets for future rehabilitation interventions.

Tail Length Evolution in Deer Mice: Linking Morphology, Behavior, and Function.

Determining how variation in morphology affects animal performance (and ultimately fitness) is key to understanding the complete process of evolutionary adaptation. Long tails have evolved many times in arboreal and semi-arboreal rodents; in deer mice, long tails have evolved repeatedly in populations occupying forested habitat even within a single species (Peromyscus maniculatus). Here, we use a combination of functional modeling, laboratory studies, and museum records to test hypotheses about the function of tail-length variation in deer mice. First, we use computational models, informed by museum records documenting natural variation in tail length, to test whether differences in tail morphology between forest and prairie subspecies can influence performance in behavioral contexts relevant for tail use. We find that the deer- mouse tail plays little role in statically adjusting center of mass or in correcting body pitch and yaw, but rather it can affect body roll during arboreal locomotion. In this context, we find that even intraspecific tail-length variation could result in substantial differences in how much body rotation results from equivalent tail motions (i.e., tail effectiveness), but the relationship between commonly-used metrics of tail-length variation and effectiveness is non-linear. We further test whether caudal vertebra length, number, and shape are associated with differences in how much the tail can bend to curve around narrow substrates (i.e., tail curvature) and find that, as predicted, the shape of the caudal vertebrae is associated with intervertebral bending angle across taxa. However, although forest and prairie mice typically differ in both the length and number of caudal vertebrae, we do not find evidence that this pattern is the result of a functional trade-off related to tail curvature. Together, these results highlight how even simple models can both generate and exclude hypotheses about the functional consequences of trait variation for organismal-level performance.