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The distribution, pharmacology and function of the arginine vasopressin (Avp) 1b receptor subtype (Avpr1b) has proved more challenging to investigate compared to other members of the Avp receptor family. Avp is increasingly recognised as an important modulator of the hypothalamic-pituitary-adrenal (HPA) axis, an action mediated by the Avpr1b present on anterior pituitary corticotrophs. The Avpr1b is also expressed in some peripheral tissues including pancreas and adrenal, and in the hippocampus (HIP), paraventricular nucleus and olfactory bulb of the rodent brain where its function is unknown. The central distribution of Avpr1bs is far more restricted than that of the Avpr1a, the main Avp receptor subtype found in the brain. Whether Avpr1b expression in rodent tissues is dependent on differences in the length of microsatellite dinucleotide repeats present in the 5′ promoter region of the Avpr1b gene remains to be determined. One difficulty of functional studies on the Avpr1b, especially its involvement in the HPA axis response to stress, which prompted the generation of Avpr1b knockout (KO) mouse models, was the shortage of commercially available Avpr1b ligands, particularly antagonists. Research on mice lacking functional Avpr1bs has highlighted behavioural deficits in social memory and aggression. The Avpr1b KO also appears to be an excellent model to study the contribution of the Avpr1b in the HPA axis response to acute and perhaps some chronic (repeated) stressors where corticotrophin-releasing hormone and other genes involved in the HPA axis response to stress do not appear to compensate for the loss of the Avpr1b. [ABSTRACT FROM AUTHOR]

Abstract Background Appetite and energy expenditure are regulated in part by ghrelin and leptin produced in the gastric mucosa, which may be modified by H. pylori colonization. We prospectively evaluated the effect of H. pylori eradication on meal-associated changes in serum ghrelin and leptin levels, and body weight. Methods Veterans referred for upper GI endoscopy were evaluated at baseline and ≥8 weeks after endoscopy, and H. pylori status and body weight were ascertained. During the first visit in all subjects, and during subsequent visits in the initially H. pylori-positive subjects and controls, blood was collected after an overnight fast and 1 h after a standard high protein meal, and levels of eight hormones determined. Results Of 92 enrolled subjects, 38 were H. pylori-negative, 44 H. pylori-positive, and 10 were indeterminate. Among 23 H. pylori-positive subjects who completed evaluation after treatment, 21 were eradicated, and 2 failed eradication. After a median of seven months following eradication, six hormones related to energy homeostasis showed no significant differences, but post-prandial acylated ghrelin levels were nearly six-fold higher than pre-eradication (p = 0.005), and median integrated leptin levels also increased (20%) significantly (p < 0.001). BMI significantly increased (5 ± 2%; p = 0.008) over 18 months in the initially H. pylori-positive individuals, but was not significantly changed in those who were H. pylori-negative or indeterminant at baseline. Conclusions Circulating meal-associated leptin and ghrelin levels and BMI changed significantly after H. pylori eradication, providing direct evidence that H. pylori colonization is involved in ghrelin and leptin regulation, with consequent effects on body morphometry.

Objective: Stereotactic radiosurgery (SRS) is an effective treatment for refractory tremor. However, the lack of reliable patient-specific targeting biomarkers leads to varying outcomes. Although connectomic-based targeting is commonly used in deep brain stimulation, its application in SRS is limited. This study aimed to develop a new targeting approach by using patient-specific structural connectivity to improve outcomes after SRS., Methods: The authors performed a retrospective study of patients in a prospective trial for frameless virtual-cone SRS on a linear accelerator for essential tremor or tremor-dominant Parkinson disease. The primary endpoint was percentage improvement in Fahn-Tolosa-Marin tremor rating scale scores contralateral to the treatment side. Probabilistic tractography assessed connectivity from each thalamic voxel to the primary motor cortex (M1), primary sensory cortex (S1), and supplemental motor area/premotor cortex (SMA/PMC). Group-level comparisons were conducted to evaluate the relationship between the sweet spot for maximum contralateral tremor improvement and areas maximally connected to M1, S1, and SMA/PMC. Multiple regression analysis assessed the relationship between the lesion centerpoint coordinates and the maximally connected voxel to M1, S1, and SMA/PMC at the individual level., Results: The analysis included 27 patients with a mean follow-up of 17.9 ± 11.1 months. The sweet spot for maximal contralateral tremor improvement at the group level was in the region most connected to M1 cortex. Smaller y-distances (anterior-posterior) from the lesion center to the M1 maximally connected voxel significantly correlated with tremor improvement at the single-subject level (p < 0.001). However, the authors found no significant correlation between the lesion y-coordinate and the maximally connected voxel to SMA/PMC and S1, nor between the x-distances from the lesions to the SMA/PMC, M1, and S1 voxels (p > 0.07)., Conclusions: This study demonstrates that patient-specific connectivity between the treatment target and M1 correlates with treatment outcomes. The authors' approach provides a practical targeting method for SRS thalamotomy for tremor.

Introduction: Galectin-1 (Gal-1) is a lectin that has been shown to be involved in a number of pro-tumorigenic mechanisms and has also been shown to be immune-suppressive. Therefore, pharmacological blockade of Gal-1 has the potential to be therapeutically beneficial in cancers that overexpress this lectin where it is hypothesized to be driving cancer progression., Methods: GB1908 is a novel, selective and high affinity inhibitor of the Gal-1 carbohydrate recognition domain and in this study we have pharmacologically characterized this small molecule in a range of in vitro and in vivo systems in the context of cancer therapy. In addition, we used a data-driven approach to identify the cancer types which may benefit from Gal-1 inhibitor therapy., Results: The selectivity of GB1908 for Gal-1 compared with galectin-3 (Gal-3) was confirmed in biophysical and cellular assays. GB1908 attenuated Gal-1-induced T cell (Jurkat) apoptosis and reduced the production of immunosuppressive cytokines in a stromal non-small cell lung cancer (NSCLC) tumor microenvironment model. Breast carcinoma and metastatic skin cutaneous melanoma were identified as cancers in which high Gal-1 expression correlated with poorer survival outcomes in patients. Treatment with GB1908 slowed tumor growth in syngeneic mouse models of these cancers., Conclusion: The inhibition of both tumor growth and immune-suppressive cytokines, in cancers in which high Gal-1 is associated with poorer survival outcomes, suggests a potential therapeutic benefit for Gal-1 inhibitors such as GB1908., (S. Karger AG, Basel.)

The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor, GB1211 (h-galectin-3 K d = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including GB1211 (m-galectin-3 K d = 0.77 μM). Pharmacokinetic experiments in mouse dosing GB1211 up to 100 mg/kg results in free plasma levels below m-galectin-3 K d , which is not comparable to the data observed in humans. To better support translation into clinical studies, a new improved mouse galectin-3 tool compound, GB2095 , was developed. Dosing this new compound in in vivo syngeneic mouse models of cancer resulted in reduction of the growth of breast and melanoma cancers.

Upon injury, fibroblasts in the surrounding tissue become activated, migrating into the wound in a controlled manner. Once they arrive, they contract the wound and remodel the stroma. While certain cell surface receptors promote fibroblast migration, others cause repulsion between fibroblasts upon contact, seemingly opposing their clustering within the wound bed. Eph receptor-ephrin interactions on colliding cells trigger this repulsion, but how fibroblasts transition to clustering behaviour during healing remains unclear. Syndecan-4 modulates transmembrane receptors involved in wound healing, including receptors for the extracellular matrix and growth factors. As a result, Sdc4-/- mice experience delayed healing due to impaired fibroblast recruitment. In this study, we report that syndecan-4 also regulates fibroblast repulsion during wound healing. We discover that syndecan-4 inhibits the expression and signalling of EphA2 by activating PKCα. Changes in syndecan-4 expression, such as those observed during wound healing, alter fibroblast behaviour from repulsion to adhesion upon cell collision by modulating EphA2 levels. Moreover, we find that EphA2 expression is suppressed in wound bed fibroblasts in a syndecan-4-dependent manner, explaining how fibroblast clustering is achieved during wound healing., (© The Author(s) 2024. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.)

Background and Purpose: Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. GB1107 is a novel orally active Gal-3 small molecule inhibitor that has high affinity for Gal-3 >1000-fold selectively over other galectins. The aim of this study was to characterise GB1107 and galectin-3 in vitro and in vivo in the context of fibrosis signalling and liver disease., Experimental Approach: Liver fibrosis was induced by administration of CCl 4 twice weekly by intraperitoneal injection in mice for 8 weeks. GB1107 was orally administered once daily (10 mg/kg) for the last 4 weeks of CCl 4 treatment. Fibrosis was assessed by picrosirius red staining of FFPE sections. Liver enzymes, Gal-3 and downstream biomarkers were assessed in liver and plasma. Paired-end sequencing was performed on the Nextseq 2000 platform. Pathway enrichment analysis was performed to determine enrichment of differentially expressed genes (DEGs) within Reactome pathways and Gene Ontology (GO) terms., Key Results: GB1107 significantly reduced plasma transaminases and liver Gal-3 and reduced liver fibrosis. RNAseq analysis of whole liver showed that 1659 DEGs were identified with CCl 4 treatment compared to control. Pathways enriched in up-regulated genes in the CCl 4 group included those related to the extracellular matrix, collagen biosynthesis and assembly, cell cycle and the immune system. Comparing GB1107 treatment with CCl 4 control 1147 DEGs were identified. GB1107 effectively reversed the majority of the CCl 4 induced gene changes., Conclusions and Implications: GB1107 attenuated liver fibrosis and highlights Gal-3 as a therapeutic target for hepatic fibrosis., Competing Interests: Declaration of competing interest Conflict of interest disclosure: DH, JR, IH, JM, RJS, ACM, AP, FZ, HS: employees, personal fees – Galecto Biotech AB, UJN, HL: shareholders, personal fees – Galecto Biotech AB., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Essential tremor (ET) is a prevalent movement disorder that impairs gait function, including gait speed - a critical marker of mobility disability and adverse outcomes. This meta-analysis aimed to quantify differences in gait speed between individuals diagnosed with ET compared to people without a movement disorder diagnosis. Electronic databases were searched for studies comparing gait speed in ET patients and controls. Effect sizes were calculated using standardized mean differences (Hedges' g) and pooled using a random-effects model. Eight studies (390 ET, 227 controls) were included. ET patients exhibited significantly slower gait speeds than controls. The effect size (Hedges' g = -1.06, 95% CI -1.47 to -0.65, p < .001) indicates a large, clinically significant difference. Substantial study heterogeneity was observed (I 2  = 76.9%). These findings suggest that gait speed deficits are a significant feature of ET, potentially reflecting cerebellar dysfunction. This highlights the need for gait assessment and targeted interventions in ET management to reduce fall risk and improve quality of life. Understanding the moderating factors such as medication type and state, disorder severity, and age could provide significant benefits in the treatment and management of ET., Competing Interests: Declarations. Ethical Approval: Not Applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Gait adaptability is crucial for meeting environmental demands, and impaired gait adaptation increases fall risk, particularly in older adults. While prior research exists on older adults' gait adaptation, particularly in perturbation studies, the specific contributions of temporal and spatial adaptation strategies to step length asymmetry (SLA) during split-belt treadmill walking require further examination. This study fills this gap by evaluating how distinct adaptation strategies contribute to SLA in healthy young and older adults. 19 healthy young adults (20.4 ± 1.1 years) and 19 healthy older adults (68.3 ± 8.1 years) walked on a split-belt treadmill requiring their non-dominant leg to move twice as fast as their dominant leg. Repeated measures ANOVA investigated (1) spatial and temporal contributions to SLA, (2) SLA across gait adaptation epochs, and (3) rates of adaptation and deadaptation. Older adults displayed reduced temporal contributions to SLA compared to younger adults (F 1,36  = 6.42, p = .02, ŋ 2  = .15), but no group differences were observed in spatial contributions to SLA (F 1,36  = 3.23, p = .08, ŋ 2  = .082). SLA during adaptation and deadaptation did not differ by age group, nor did the rate of adaptation (F 1,34.7  = 0.594, p = .45) or deadaptation F 1,33.6  = 2.886, p = .09). These findings suggest that while older adults rely less on temporal strategies for gait adaptation, but maintain overall adaptability comparable to younger adults. Findings enhance our understanding of age-related changes in gait adaptation mechanisms and may inform targeted interventions to improve gait adaptability in older populations., Competing Interests: Declarations Informed consent All participants completed written informed consent prior to study participation. Research involving human participants and/or animals All procedures performed in in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board at Auburn University (18–418 MR 1811)., (© 2024. The Author(s).)

Gait adaptation during bipedal walking allows people to adjust their walking patterns to maintain balance, avoid obstacles and avoid injury. Adaptation involves complex processes that function to maintain stability and reduce energy expenditure. However, the processes that influence walking patterns during different points in the adaptation period remain to be investigated. We assessed split-belt adaptation in 17 young adults aged 19-35. We also assessed individual aerobic capacity to understand how aerobic capacity influences adaptation. We analyzed step lengths, step length asymmetry (SLA), mediolateral margins of stability, positive, negative and net mechanical work rates, as well as metabolic rate during adaptation. Dual-rate exponential mixed-effects regressions estimated the adaptation of each measure over two timescales; results indicate that mediolateral stability adapts over a single timescale in under 1 min, whereas mechanical work rates, metabolic rate, step lengths and SLA adapt over two distinct timescales (3.5-11.2 min). We then regressed mediolateral margins of stability, net mechanical work rate and metabolic rate on SLA during early and late adaptation phases to determine whether stability drives early adaptation and energetic cost drives late adaptation. Stability predicted SLA during the initial rapid onset of adaptation, and mechanical work rate predicted SLA during the latter part of adaptation. Findings suggest that stability optimization may contribute to early gait changes and that mechanical work contributes to later changes during adaptation. A final sub-analysis showed that aerobic capacity levels <36 and >43 ml kg-1 min-1 resulted in greater SLA adaptation, underscoring the metabolic influences on gait adaptation. This study illuminates the complex interplay between biomechanical and metabolic factors in gait adaptation, shedding light on fundamental mechanisms underlying human locomotion., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The α v β 6 integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β 1 , a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable α v β 6 inhibitors has proven challenging due to the zwitterionic pharmacophore required to bind to the RGD binding site. This work describes the design and development of a novel, orally bioavailable series of α v β 6 inhibitors, developing on two previously published α v β 6 inhibitors, GSK3008348 and GSK3335103. Strategies to reduce the basicity of the central ring nitrogen present in GSK3008348 were employed, while avoiding the synthetic complexity of the chiral, fluorine-containing quaternary carbon center contained in GSK3335103. Following initial PK studies, this series was optimized, aided by analysis of the physicochemical and in vitro PK properties, to deliver lead molecules ( S )- 20 and 28 as potent and orally bioavailable α v β 6 inhibitors with improved synthetic tractability.

Galectin-1 is implicated in several pro-tumourigenic mechanisms and is considered immune-suppressive. The pharmacological inhibition of galectin-1 may be beneficial in cancers in which galectin-1 is overexpressed and driving cancer progression. This study aimed to further characterise the immunosuppressive cytokines influenced by galectin-1 in in vitro immune cell cultures and an in vivo inflammatory model using a recently discovered selective inhibitor of galectin-1, GB1908. To enable a translational approach and link mouse and human pharmacology, anti-CD3/anti-CD28 stimulated T cells cultured from human whole blood and mouse spleens were compared. For in vivo studies of T cell-mediated inflammation, the concanavalin-A (Con-A) mouse model was used to induce a T lymphocyte-driven acute liver injury phenotype. The inhibition of galectin-1 with GB1908 reduced IL-17A, IFNγ and TNFα in a concentration-dependent manner in both mouse and human T cells in vitro. The immunosuppressive cytokines measured in Con-A-treated mice were all upregulated compared to naïve mice. Subsequently, mice treated with GB1908 demonstrated a significant reduction in IL-17A, IFNγ, IL-6 and TNFα compared to vehicle-treated mice. In conclusion, galectin-1 induced the production of several important immune-suppressive cytokines from T cells in vitro and in vivo. This result suggests that, in the context of cancer therapy, a selective galectin-1 could be a viable approach as a monotherapy, or in combination with chemotherapeutic agents and/or checkpoint inhibitors, to enhance the numbers and activity of cytotoxic T cells in the tumour microenvironment of high galectin-1 expressing cancers.

Osteoarthritis (OA) is a highly prevalent joint disorder that is emerging as a global threat to health. OA is associated with low-grade chronic systemic inflammation that can affect overall health, leading to a sedentary lifestyle and potentially increased risk of neurological disorders (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). A meta-analysis was conducted following the Preferred Reporting Items for 2020 Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE, Web of Science, and Embase databases were searched to identify records. The inclusion criteria for this analysis were original research articles reporting on OA and neurological disorder diagnoses (AD, PD, or MS) with non-OA comparator groups. Logarithmic odds ratios (LORs) were calculated and input into a random-effects meta-analysis using the restricted maximum-likelihood estimator. Subgroup analyses examined the associations between OA, AD, PD, and MS. A subsequent meta-regression analysis was performed to explore potential sources of heterogeneity, focusing on comorbidities and demographic factors. Publication bias was evaluated using funnel plots, Egger's test, and trim-and-fill analysis. Nine studies were included in this meta-analysis (six case-control designs, two cross-sectional designs, and one population-based cohort design) of 1,837,716 cases. The pooled odds ratio (OR) indicated a significant association between OA and ND diagnosis (OR = 1.246; confidence interval (CI): 1.01-1.53). Subsequent subgroup analyses were not statistically significant but indicated an association with PD (OR = 1.31, CI: 0.80-2.12), MS (OR = 1.12, CI: 0.80-2.81), and AD (OR = 1.50, CI: 0.80-2.81). This meta-analysis revealed that individuals with OA have approximately 25% higher odds of an accompanying ND diagnosis compared to those without OA. Importantly, these findings represent statistical associations only and do not imply causation or directionality but provide insight into factors, including shared risk factors, overlapping symptoms, or other underlying mechanisms that may influence the observed relationships., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Peoples et al.)

Adapting to different environments throughout daily activities requires flexibility in allocating attention. Compromised dual-tasking can hinder mobility, increase fall risk, and decrease functional independence in patients with essential tremor, who exhibit both mobility and cognitive impairments. We evaluated motor and cognitive dual-task effects and task prioritization in 15 people with Essential Tremor (ET) and 15 age-matched people without ET during a standard and more challenging water-carry TUG. Task-specific interference was evaluated by calculating motor and cognitive dual-task effects, whereas task prioritization was assessed by contrasting the cognitive dual-task effect with the motor dual-task effect. The simultaneous performance of two tasks did not differentially impact motor or cognitive performance in either group, and both groups prioritized cognitive task performance in standard and water-carry TUG assessments. This study enhances our understanding of motor-cognitive interactions in individuals with essential tremor. These insights could lead to patient-centered approaches to therapy to improve functional performance in dynamic daily environments., (© 2024. The Author(s).)

Objective: The aim of this study was to characterize the relationship between prosthetic device and service satisfaction, health-related quality of life (HRQOL), and functional movement in a diverse population of lower limb prosthesis users., Methods: An online survey was conducted on individuals with lower limb amputation between September and October 2021. Sample validated questionnaires assessing demographic and clinical features, satisfaction, functional outcomes, and quality of life were analyzed using path analysis., Results: Participants were 1736 individuals with lower limb amputation. Overall, 44% of participants reported dissatisfaction with prosthetic device, whereas 37% were dissatisfied with prosthetic service. Low functional mobility was reported by 58% of participants and 61% reported low HRQOL. Lower extremity functional status (β = 0.55), HRQOL (β = 0.08), Activities-specific Balance Scale (β = 0.22), and modified fall efficacy scale (β = -0.07) are significantly associated with prosthetic device satisfaction ( P < 0.0005, R 2 = 0.47). Satisfaction with provider service was significantly associated with lower extremity functional status (β = 0.44) and balance confidence (β = 0.18) ( P < 0.0005, R 2 = 0.34)., Conclusion and Clinical Relevance: Civilians, veterans, and service members reported low functional mobility, low quality of life, and moderate levels of dissatisfaction with their lower extremity prosthetic device and provider service. Improvements in mobility, balance, quality of life, and fall efficacy may enhance device satisfaction. Functional mobility and balance improvements may increase ratings of provider service. This study provides feedback that may improve clinical decisions on lower limb prosthesis patient care., (Copyright © 2023 The Authors. Published by Wolters Kluwer incorporated on behalf of The International Society for Prosthetics and Orthotics.)

Objective: To investigate the relationship between patient perception of lower extremity function and a home-based virtual clinician assessment of mobility in lower limb prosthesis clients., Design: Descriptive observational study using a clinician-administered functional mobility survey and timed Up and Go test to assess lower extremity function under supervision., Setting: Health Insurance Portability and Accountability Act-compliant online virtual platform., Participants: Twelve lower limb loss clients currently using prostheses, aged ≥19 years, not pregnant, and with no stroke, seizure disorder, or cancer., Interventions: Not applicable., Main Outcome Measures: Main outcomes were mobility survey scores and mean timed Up and Go duration., Results: Most participants reported significant ease of completing basic indoor ambulation and toileting tasks (66%-75%) and significant difficulty in running or prolonged ambulation activities (83%) requiring use of lower limb prosthesis. Timed Up and Go test was faster (11.0±2.9 s) than the reference range for transtibial prosthesis users and negatively associated with self-reported lower extremity functional status ( r =-.70, P =.02)., Conclusions: Self-reported movement with lower limb prostheses at home and evaluation of mobility via a virtual platform is a feasible assessment modality that may reduce the frequency of therapy visits, defray some rehabilitation costs, and minimize the travel burden to distant prosthetic clinics., Competing Interests: None., (© 2024 The Authors.)

Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was the hemagglutination of red blood cells. Although it is insightful, this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study, we aimed to validate a more precise and quantitative method to enable the further investigation of differences between galectins in respect to agglutination induction in different blood groups, as well as the characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat-bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer, a more comparable effect was observed between blood group B and O, but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration responses and expected selectivity profiles for a set of small-molecule glycomimetics, confirming the historical profiles obtained in biochemical binding and functional cellular assays.

The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), to various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors, it has been shown to have a pleiotropic effect across many cell types and mechanisms, resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we used fluorescence polarization (FP) assays to determine K D values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study, surface plasmon resonance (SPR) was used to compare human and mouse galectin-1 affinity measures with FP, as SPR has not been applied for compound screening against this galectin. Binding affinities for a selection of mono- and di-saccharides covering a 1000-fold range correlated well between FP and SPR assay formats for both human and mouse galectin-1. It was shown that slower dissociation drove the increased affinity at human galectin-1, whilst faster association was responsible for the effects in mouse galectin-1. This study demonstrates that SPR is a sound alternative to FP for early drug discovery screening and determining affinity estimates. Consequently, it also allows association and dissociation constants to be measured in a high-throughput manner for small molecule galectin-1 inhibitors.

We have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 ( K d galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC 50 = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over galectin-1 K d for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.

As age increases, a decline in lower extremity strength leads to reduced mobility and increased fall risks. This decline outpaces the age-related reduction in muscle mass, resulting in mobility limitations. Older adults with varying degrees of mobility-disability use different stepping strategies. However, the link between functional lower extremity strength and stepping strategy is unknown. Therefore, understanding how age-related reductions in functional lower extremity strength influence stepping strategy is vital to unraveling mobility limitations. Twenty participants (17F, 72 ± 6 years) were recruited and tested at a local community event. Participants were outfitted with inertial measurement units (IMU) and walked across a pressurized walkway under single and dual motor task conditions (walking with and without carrying a tray with water) at their usual and fast speeds. Participants were dichotomized into normal (11) or low functional strength groups (9) based on age-specific normative cutoffs using the instrumented 5-repetition Sit-to-Stand test duration. Our study reveals that older adults with normal strength prefer adjusting their step time during walking tasks, while those with reduced strength do not exhibit a preferred stepping strategy. This study provides valuable insights into the influence of functional lower extremity strength on stepping strategy in community-dwelling older adults during simple and complex walking tasks. These findings could aid in diagnosing gait deviations and developing appropriate treatment or management plans for mobility disability in older adults., (© 2024. The Author(s).)

Flexibility in performing various movements like standing, walking, and turning is crucial for navigating dynamic environments in daily life. Individuals with essential tremor often experience movement difficulties that can affect these postural transitions, limiting mobility and independence. Yet, little research has examined the performance of postural transitions in people with essential tremor. Therefore, we assessed postural transition performance using two versions of the timed up and go test: the standard version and a more complex water-carry version. We examined the total duration of the standard and water-carry timed up and go in 15 people with and 15 people without essential tremor. We also compared the time taken for each phase (sit-to-stand phase, straight-line walk phase, stand-to-sit phase) and the turning velocity between groups. Our findings revealed decreased performance across all phases of standard and water-carry timed up and go assessments. Further, both ET and non-ET groups exhibited reduced performance during the water-carry timed up and go compared to the standard timed up and go. Evaluating specific phases of the timed up and go offers valuable insights into functional movement performance in essential tremor, permitting more tailored therapeutic interventions to improve functional performance during activities of daily living.

A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 K d galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 ( K d galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability ( F % > 99%).

Individuals with an anterior cruciate ligament reconstruction (ACLR) commonly exhibit altered gait patterns, potentially contributing to an increased risk of osteoarthritis (OA). Joint moment contributions (JMCs) and support moments during incline and decline running are unknown in healthy young adults and individuals with an ACLR. Understanding these conditional joint-level changes could explain the increased incidence of OA that develops in the long term. Therefore, this knowledge may provide insight into the rehabilitation and prevention of OA development. We aimed to identify the interlimb and between-group differences in peak support moments and subsequent peak ankle, knee, and hip JMCs between individuals with an ACLR and matched controls during different sloped running conditions. A total of 17 individuals with unilateral ACLR and 17 healthy individuals who were matched based on sex, height, and mass participated in this study. The participants ran on an instrumented treadmill at an incline of 4°, decline of 4°, incline of 10°, and decline of 10°. The last 10 strides of each condition were used to compare the whole-stance phase support moments and JMCs between limbs, ACLR, and control groups and across conditions. No differences in JMCs were identified between limbs or between the ACLR and healthy control groups across all conditions. Support moments did not change among the different sloped conditions, but JMCs significantly changed. Specifically, ankle and knee JMCs decreased and increased by 30% and 33% from an incline of 10° to a decline of 10° running. Here, the lower extremities can redistribute mechanics across the ankle, knee, and hip while maintaining consistent support moments during incline and decline running. Our data provide evidence that those with an ACLR do not exhibit significant alterations in joint contributions while running on sloped conditions compared to the matched controls. Our findings inform future research interested in understanding the relationship between sloped running mechanics and the incidence of deleterious acute or chronic problems in people with an ACLR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Harrison, Holmes, Finley, Guzman, Kimbrough and Roper.)

Background: Galectin-3 (Gal-3) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and has been suggested to predict a poor response to immune checkpoint therapy with the anti-PD-1 monoclonal antibody pembrolizumab. We aimed to assess if the effect of Gal-3 was a result of direct interaction with the immune checkpoint receptor., Methods: The ability of Gal-3 to interact with the PD-1/PD-L1 complex in the absence and presence of blocking antibodies was assessed in in vitro biochemical and cellular assays as well as in an in vivo syngeneic mouse cancer model., Results: Gal-3 reduced the binding of the checkpoint inhibitors pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1), by potentiating the interaction between the PD-1/PD-L1 complex. In the presence of a highly selective Gal-3 small molecule inhibitor (GB1211) the binding of the anti-PD-1/anti-PD-L1 therapeutics was restored to control levels. This was observed in both a surface plasmon resonance assay measuring protein-protein interactions and via flow cytometry. Combination therapy with GB1211 and an anti-PD-L1 blocking antibody reduced tumor growth in an in vivo syngeneic model and increased the percentage of tumor infiltrating T lymphocytes., Conclusion: Our study suggests that Gal-3 can potentiate the PD-1/PD-L1 immune axis and potentially contribute to the immunosuppressive signalling mechanisms within the tumor microenvironment. In addition, Gal-3 prevents atezolizumab and pembrolizumab target engagement with their respective immune checkpoint receptors. Reversal of this effect with the clinical candidate GB1211 offers a potential enhancing combination therapeutic with anti-PD-1 and -PD-L1 blocking antibodies., Competing Interests: UN, FZ, RS, JR, IH, and AM have ownership interest including stock, patents, etc. in Galecto Biotech AB. AP is the COO at Galecto Biotech and has ownership interest including stock, patents, etc. in Galecto Biotech. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mabbitt, Holyer, Roper, Nilsson, Zetterberg, Vuong, Mackinnon, Pedersen and Slack.)

Introduction: The purpose of this study was to explore relationships between patient-specific characteristics and initial ankle-foot prosthesis prescription patterns among U.S. Service members with unilateral transtibial limb loss., Methods: A retrospective review of health records identified 174 individuals with unilateral transtibial limb loss who received care at Walter Reed National Military Medical Center between 2001 and 2019. We examined patient-specific factors such as demographics, participant duty status at injury and amputation, amputation etiology, and timing between injury, amputation, and initial prescription. The type of first prescribed ankle-foot prosthesis was categorized as energy storing and return - nonarticulating, energy storing and return - articulating, or computer controlled., Results: Sex, amputation etiology, time from injury to initial prescription, and time from amputation to initial prescription differed by type of initial ankle-foot prosthesis prescription. Service members with shorter intervals between injury-initial prescription and amputation-initial prescription, and those injured by combat blast, were more likely to receive a non-articulating device. Incorporating sex, time from injury-initial prescription, time from amputation-initial prescription, and amputation etiology as predictors of prosthesis type, we were able to correctly classify 72% of all first prostheses prescribed., Discussion: Patient-specific characteristics such as sex, the time between injury-initial prescription, time from amputation-initial prescription and amputation etiology are essential characteristics that influence initial ankle-foot prosthesis prescription patterns in U.S. Service members., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Monaghan, Knight, Brinkerhoff, Harrison, Dearth, Hendershot, Sefton, Zabala, Vazquez, Shannon, Crumbley and Roper.)

Galectin-3 is a beta-galactoside-binding mammalian lectin that is one of a 15-member galectin family that can bind several cell surface glycoproteins via its carbohydrate recognition domain (CRD). As a result, it can influence a range of cellular processes including cell activation, adhesion and apoptosis. Galectin-3 has been implicated in various diseases, including fibrotic disorders and cancer, and is now being therapeutically targeted by both small and large molecules. Historically, the screening and triaging of small molecule glycomimetics that bind to the galectin-3 CRD has been completed in fluorescence polarisation (FP) assays to determine K D values. Surface plasmon resonance (SPR) has not been widely used for compound screening and in this study it was used to compare human and mouse galectin-3 affinity measures between FP and SPR, as well as investigate compound kinetics. The K D estimates for a set of compounds selected from mono- and di-saccharides with affinities across a 550-fold range, correlated well between FP and SPR assay formats for both human and mouse galectin-3. Increases in affinity for compounds binding to human galectin-3 were driven by changes in both k on and k off whilst for mouse galectin-3 this was primarily due to k on . The reduction in affinity observed between human to mouse galectin-3 was also comparable between assay formats. SPR has been shown to be a viable alternative to FP for early drug discovery screening and determining K D values. In addition, it can also provide early kinetic characterisation of small molecule galectin-3 glycomimetics with robust k on and k off values generated in a high throughput manner., Competing Interests: Declaration of Competing Interest The authors have been, or are currently, employees of Galecto Biotech AB or NovAliX., (Copyright © 2023 Galecto Biotech. Published by Elsevier Inc. All rights reserved.)

Changing movement patterns in response to environmental perturbations is a critical aspect of gait and is related to reducing the energetic cost of the movement. Exercise improves energetic capacity for submaximal exercise and may affect how people adapt movement to reach an energetic minimum. The purpose of this study was to determine whether self-reported exercise behavior influences gait adaptation in young adults. Young adults who met the optimal volume of exercise according to the Physical Activity Guidelines for Americans (MOVE; n = 19) and young adults who did not meet the optimal volume of exercise (notMOVE; n = 13) walked on a split-belt treadmill with one belt moving twice the speed of the other belt for 10 minutes. Step length asymmetry (SLA) and mechanical work done by each leg were measured. Nonlinear mixed effects models compared the time course of adaptation between MOVE and notMOVE, and t-tests compared net work at the end of adaptation between MOVE and notMOVE. Compared to notMOVE, MOVE had a faster initial response to the split belt treadmill, and continued to adapt over the duration of split-belt treadmill walking. Young adults who engage in sufficient amounts of exercise responded more quickly to the onset of a perturbation, and throughout the perturbation they continued to explore movement strategies, which might be related to reduction of energetic cost. Our findings provide insights into the multisystem positive effects of exercise, including walking adaptation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Brinkerhoff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mediolateral stability during walking requires active control and is complex. Step width, a proxy for stability, follows a curvilinear relationship as gait speeds increase. However, despite the complexity of maintenance for stability, no study has yet investigated the variation across individuals of the relationship between speed and step width. The purpose of this study was to determine if variation between adults affects the estimation of the relationship between speed and step width. Participants walked on a pressurized walkway 72 times. Gait speed and step width were measured within each trial. Mixed effects models assessed the relationship between gait speed and step width, and the variability in the relationship across participants. The relationship between speed and step width followed a reverse J-curve on average, but the relationship was moderated by participants' preferred speed. Step width response as speed increases is not homogenous in adults. This finding suggests that "appropriate" stability moderation (tested across a range of speeds) differs as a function of an individual's preferred speed. Mediolateral stability is complex, and further research to elucidate individual factors contributing to variation is needed., (© 2023. The Author(s).)

Background: Environmental hazards (e.g., pedestrian traffic) cause falls and testing environment impacts gait in older adults. However, most fall risk evaluations do not assess real-world moving hazard avoidance., Aims: This study examined the effect of fall history in older adults on acceleration profiles before, during, and after a near collision with a moving hazard, in laboratory and real-world settings., Methods: Older adults with (n = 14) and without a fall history (n = 15) performed a collision avoidance walking task with a sudden moving hazard in real-world and laboratory settings. Gait acceleration and video data of participants' first-person views were recorded. Four mixed effects multilevel models analyzed the magnitude and variability of mean and peak anteroposterior and mediolateral acceleration while walking before, during, and after the moving hazard in both environments., Results: In the real-world environment, older adults without a fall history increased their mean anteroposterior acceleration after the moving hazard (p = 0.046), but those with a fall history did not (p > 0.05). Older adults without a fall history exhibited more intersubject variability than those with a fall history in mean (p < 0.001) and peak anteroposterior (p = 0.015) acceleration across environments and epochs. Older adults without a fall history exhibited a slower peak mediolateral reaction during the moving hazard (p = 0.014) than those with a fall history., Conclusions: These results suggest that compared to older adults with a fall history, older adults without a fall history are more adaptable and able to respond last-minute to unexpected hazards. Older adults with a fall history exhibited more homogenous responses., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Purpose: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy., Materials and Methods: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps., Results: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement ( r = 0.52; P  = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement ( r = 0.50; P  = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices., Conclusions: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy., (© 2023 by American Journal of Neuroradiology.)

Introduction: The purpose of the present study was to investigate core exercise training and whole-body vibration (WBV) as a training method to improve performance and recovery from an 8-km military foot march in novice trainees., Materials and Methods: A 3 × 5 repeated measures randomized control trial was used to evaluate the effects of core exercise training and WBV on performance and recovery from an 8-km foot march. Thirty-nine participants were randomized into three groups: core exercise (Ex), WBV with core exercise (WBVEx), and control. Each participant completed two 8-km foot marches (FM1 and FM2) with a 35 pound rucksack, separated by 4 weeks. Participants in the Ex and WBVEx groups completed 3 weeks of core exercise training, three times per week in between FM1 and FM2. Performance time, creatine kinase (CK), and interleukin-6 (IL-6) were measured. The Auburn University Institutional Review Board approved all aspects of this study (protocol number: 19-211 MR 1907)., Results: Performance time (P < .001) and CK (P = .005) were significantly improved during FM2 as compared to FM1. The Ex (d = -0.295) and WBVEx (d = -0.645) treatments had a large effect on performance time. CK (P < .001) and IL-6 (P < .001) were significantly elevated at the completion of the foot march regardless of group. Only CK remained elevated for 2 days (P < .001) following the foot march., Conclusions: Core exercise training with or without WBV improved 8-km foot march performance time by 5-6 minutes. The improvements are likely because of an increase in trunk stability. Additionally, this study showed that completing two identical foot marches a month apart increases performance and improves recovery., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Holmes, HH, Downs Talmage, JL, Neely, KA, and Roper, JA. Cognitive demands influence drop jump performance and relationships with leg stiffness in healthy young adults. J Strength Cond Res 37(1): 74-83, 2023-Sports-relevant cognition influences neuromuscular control and sports performance. This study assessed the influence of cognition on (a) drop jump performance and (b) commonly researched relationships between lower extremity stiffness, ground contact time (GCT), peak vertical ground reaction force (vGRF), and leg deformation. Active adults (n = 33, 13 men, 20 women, 21 ± 2 years, height = 1.71 ± 0.81 m, body mass = 70.5 ± 10.6 kg) participated in decisions to perform drop jumps or lands of a 30-cm box in 4 conditions: (a) standard, explicit instructions; (b) choice, internally driven decisions; and (c and d) visual and audio, external visual or audio cues reducing time for motor planning. Significance was set at p < 0.05. Ground contact time with audio (M ± SD: 0.62 ± 0.14 seconds) and visual cues (0.59 ± 0.10 seconds) was longer than standard instructions (0.54 ± 0.10 seconds). Standard condition jump height was higher (0.49 ± 0.10 m) than audio (0.435 ± 0.10 m) and choice (0.44 ± 0.09 m). Standard condition reactive strength index was higher (1.03 ± 0.35) than audio (0.76 ± 0.23), visual (0.82 ± 0.27), and choice (0.84 ± 0.33). Visual and audio conditions did not demonstrate significant relationships between leg stiffness and GCT, and relationships between vGRF and leg deformation were not significant with visual cues (p > 0.05). Cognition did not significantly change stiffness and vGRF, indicating alternative force strategies. Understanding how cognition influences performance can positively affect coaching practices, sports-specific assessments, and rehabilitation applications., (Copyright © 2021 National Strength and Conditioning Association.)

Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene expression in liver myofibroblasts and displayed antifibrotic activity in CCl 4 -induced liver fibrosis and bleomycin-induced lung fibrosis mouse models. On the basis of the overall pharmacokinetic, pharmacodynamic, and safety profile, GB1211 was selected as the clinical candidate and is currently in phase IIa clinical trials as a potential therapy for liver cirrhosis and cancer.

Sleep loss is a common phenomenon with consequences to physical and mental health. While the effects of sleep restriction on working memory are well documented, it is unknown how sleep restriction affects continuous force control. The purpose of this study was to determine the effects of sleep restriction on visually and memory-guided force production magnitude and variability. We hypothesized that both visually and memory-guided force production would be impaired after sleep restriction. Fourteen men participated in an eleven-day inpatient sleep study and completed a grip force task after two nights of ten hours' time in bed (baseline); four nights of five hours' time in bed (sleep restriction); and one night of ten hours' time in bed (recovery). The force task entailed four 20-second trials of isometric force production with the thumb and index finger targeting 25% of the participant's maximum voluntary contraction. During visually guided trials, participants had continuous visual feedback of their force production. During memory-guided trials, visual feedback was removed for the last 12 seconds of each trial. During both conditions, participants were told to maintain the target force production. After sleep restriction, participants decreased the magnitude of visually guided, but not memory-guided, force production, suggesting that visual attention tasks are more affected by sleep loss than memory-guided tasks. Participants who reported feeling more alert after sleep restriction and recovery sleep produced higher force during memory-guided, but not visually guided, force production, suggesting that the perception of decreased alertness may lead to more attention to the task during memory-guided visual tasks., Competing Interests: The authors have declared that no competing interests exist.

Background: The maintenance of stability during walking is critical for successful locomotion. While targeted balance training can improve stability, it is unclear how simply meeting recommended physical activity guidelines may impact dynamic stability in healthy young adults., Research Question: Examining the differences in the mediolateral margin of stability (ML-MOS) and the variability of the ML-MOS in physically active and inactive young adults across a range of stability-challenging walking tasks METHOD: Twenty-one physically active and twenty inactive young adults completed four experimental walking conditions: (1) Overground Walking, (2) Tandem Walking, (3) Beam Walking, and (4) Stepping-Stones. The ML-MOS and coefficient of variation of the ML-MOS were calculated at each heel strike while participants walked at their preferred walking speed. A two-way mixed-effects ANOVA was conducted to examine the effects of group and condition and their interaction on ML-MOS and ML-MOS variability RESULTS: Neither the ML-MOS nor the variability of the ML-MOS was significantly different between physically active and physically inactive young adults during any experimental walking conditions. A significant main effect of the experimental walking condition was observed, with the ML-MOS decreasing from overground walking to the tandem and beam walking conditions. The ML-MOS also became more variable in the tandem, beam, and stepping-stones conditions than in overground gait., Significance: Physical activity status did not influence frontal plane dynamic balance in healthy young adults, even in stability-challenging environments. Conditions that constrain step width, such as tandem and beam walking, are adequate for challenging frontal plane dynamic balance and indicate that trunk kinematics may be adjusted when step width is constrained., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Variability in gait speed is influenced by age and health status. However, no study has investigated the effects of different instructions on gait speed., Research Question: This study investigated how walking prompts contributed to variability in gait speed., Methods: Participants walked on a pressurized walkway. Gait speed variability was assessed using multilevel modeling., Results: 61% of the variance in gait speed was due to instruction, while 14% was due to individual differences., Significance: Reference values for gait speed across a number of prompts will be highly useful for assessing gait performance in young adults. Further, the instruction given produces a large amount of variability in selected walking speed. This finding urges researchers to maintain consistency when delivering walking instructions., (Copyright © 2019. Published by Elsevier B.V.)

It is not well understood how older adults meet the combined locomotor demands of obstacle avoidance at fast speeds as compared to obstacle avoidance under cognitive loads. The purpose of this study was to quantify changes in locomotor stability (margin of stability, MOS) from walking to crossing obstacles at fast speeds versus with added cognitive demands in older adults. Community-dwelling older adults walked on an unobstructed and obstructed path at their preferred speed (preferred); during a dualtask (verbal fluency); and at their 'fastest comfortable' speed (fast). We used motion capture to calculate MOS in the anteroposterior direction, and compared minimum MOS between crossing foot and support phase (lead single support, lead double support, trail single support, trail double support) and tested for within subject changes using a linear mixed effect regression model [Condition (preferred, fluency, fast) x Walkway (unobstructed, obstructed) x Phase (single support, double support) x Foot (lead, trail)]. We examined crossing kinematics (approach distance, toe clearance, and recovery distance) between conditions. A significant omnibus effect partially supported our predictions. A Condition x Walkway x Phase interaction supported that older adults increased stability under a cognitive load and prioritized stability, demonstrated by not changing MOS from walking to obstacle crossing. During fast obstacle crossing they decreased stability during double support and exhibit more stability in single support, when vulnerable to external perturbations (contacting the obstacle). During a dual-task, older adults took shorter and higher steps over the obstacle to ensure they cleared it safely, but at fast speeds they increased the length of their crossing step without higher toe clearance. The results suggest older adults attempt to preserve stability when crossing obstacles under both cognitive and speed demands, but may be unable to ensure a safer limb elevation to avoid obstacles at fast speeds as they do under cognitive demands., (Copyright © 2022 Elsevier Inc. All rights reserved.)

As the worldwide prevalence of chronic liver diseases is high and continuing to increase, there is an urgent need for treatment to prevent cirrhosis-related morbidity and mortality. Integrins are heterodimeric cell-surface proteins that are promising targets for therapeutic intervention. αv integrins are central in the development of fibrosis as they activate latent TGFβ, a known profibrogenic cytokine. The αv subunit can form heterodimers with β1, β3, β5, β6 or β8 subunits and one or more of these integrins are central to the development of liver fibrosis, however, their relative importance is not understood. This review summarises the current knowledge of αv integrins and their respective β subunits in different organs, with a focus on liver fibrosis and the emerging preclinical and clinical data with regards to αv integrin inhibitors., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins., (© 2021. Springer Nature Limited.)

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvβ6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvβ6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvβ6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvβ6 integrin and inhibit the activation of TGFβ in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvβ6 engagement, TGFβ signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvβ6 inhibitor that attenuates TGFβ signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Split-belt treadmills have become an increasingly popular means of quantifying ambulation adaptability. Multiple sensory feedback mechanisms, including vision, contribute to task execution and adaptation success. No studies have yet explored visual feedback effects on locomotor adaptability across a spectrum of available visual information. In this study, we sought to better understand the effects of visual information on locomotor adaptation and retention by directly comparing incremental levels of visual occlusion. Sixty healthy young adults completed a split-belt adaptation protocol, including a baseline, asymmetric walking condition (adapt), a symmetric walking condition (de-adapt), and another asymmetric walking condition (re-adapt). We randomly assigned participants into conditions with varied visual occlusion (i.e., complete and lower visual field occlusion, or normal vision). We captured kinematic data, and outcome measures included magnitude of asymmetry, spatial and temporal contributions to step length asymmetry, variability of the final adapted pattern, and magnitude of adaptation. We used repeated measures and four-way MANOVAs to examine the influence of visual occlusion and walking condition. Participants with complete, compared to lower visual field visual occlusion displayed less consistency in their walking pattern, evident via increased step length standard deviation ( p  = .007, d  = 0.89), and compared to normal vision groups ( p  = .003 d  = 0.81). We found no other group differences, indicating that varying levels of visual occlusion did not significantly affect locomotor adaptation or retention. This study offers insight into the role vision plays in locomotor adaptation and retention with clinical utility for improving variability in step control.

Background: The ability to walk at various speeds is essential to independence for older adults. Maintaining fast walking requires changes in spatial-temporal measures, increasing step length and/or decreasing step time. It is unknown how mobility affects the parameters that change between preferred and fast walking., Research Question: How does preferred walking performance and measures of strength and mobility relate to the approach (decreasing step time or increasing step length) older adults at risk for mobility disability use to maintain fast walking speeds?., Methods: Peak isokinetic dynamometry of knee and ankle and several mobility evaluations, including the Timed Up-and-Go, Short Physical Performance Battery, and Dynamic Gait Index, assessed mobility and strength in 57 participants, aged 65-80. Biomechanical gait analysis was used to analyze step length, step time, gait speed at preferred and fast gait speeds and ground reaction force during preferred walking. A score combining the differences between step length and time at fast and preferred speeds (Length-Time Difference) separated participants into two groups: (1) Length, representing a predominant increase in step length to walk fast and (2) Time, a predominant decrease in step time., Results: Those who decreased step time to produce increased speed performed worse during repeated chair stands (p = .006) with no difference in isokinetic strength (p ≥ .15). During preferred walking, the Time group displayed increased propulsive impulse compared to the Length group (p = .007), despite no differences in preferred speed, step length, or time (p ≥ .50)., Significance: While kinetics of preferred walking differed between groups separated by Length-Time Difference, basic spatial-temporals of preferred walking did not in this homogenous population. Length-Time Difference relates to a common mobility assessment and could be easily calculated by clinicians to provide a quantitative and more sensitive measure of ambulatory performance., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Gait and balance deficits are significant concerns for people with multiple sclerosis (MS). Shoe cushioning can influence mobility and balance, but its effect on walking and balance remains unknown in MS. This study aimed to determine how shoe cushioning affects gait and balance in females with MS (FwMS). We hypothesized that extra cushioning would improve gait but reduce balance performance. FwMS performed gait (n = 18) and balance (n = 17) assessments instrumented using inertial sensors in two different shoe conditions: a standard-cushioned and an extra-cushioned shoe. Care was taken to ensure minimal differences between shoe types other than midsole cushioning, but shoe construction was not identical between conditions. Spatiotemporal gait parameters were assessed during a 2-min walk test, while postural sway measures were evaluated using the modified Clinical Test of Sensory Interaction and Balance. In the extra-cushioned shoe, FwMS spent less time in the double support and stance phase with more time in the single support and swing phase. No differences in stride length, gait speed, or elevation at midswing were observed between shoe conditions. Decreased path length, RMS sway, and sway velocity were observed in the extra-cushioned shoe. No differences were observed in the gait cycle's spatial composition between shoe conditions, but FwMS demonstrated improvements in the gait cycle's temporal parameters and postural sway in the extra-cushioned shoe. This may suggest a less cautious walking strategy and improved balance when wearing a shoe with extra cushioning., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The primary purpose of this study was to examine how the type and magnitude of changes in running behavior, as a consequence of COVID-19 pandemic restrictions, influence running-related injuries. Secondarily, we aimed to examine how lifestyle and psychosocial well-being measures may influence running behavior change. An online survey was advertised to individuals over the age of 18 that currently run or have previously participated in running for exercise. The survey questions examined injury history and new injuries sustained during COVID-19 restrictions, as well as changes related to training behavior changes, training environment changes, social behaviors, and psychosocial well-being. Changes reflected differences in running behaviors prior to COVID-19 restrictions (1 month prior to COVID-19 restrictions being imposed) and during COVID-19 restrictions (May 5 to June 10, 2020). A total of 1,035 runners were included in the analysis. Current injuries sustained during COVID-19 occurred in 9.5% of the runners. Injured runners made a greater number of total changes ( p = 0.031) as well as training-related ( p = 0.042) and environment-related ( p = 0.017) changes compared with uninjured runners. A significant relationship was found between injury and those that reported less time to exercise to changes in work environment ( p = 0017). This study highlights the multi-dimensional nature of running-related injuries and the need to consider the interaction of multiple changes in running behavior, rather than isolating single factors. Greater understanding of the underlying causes of running-related injuries can help reduce the risk of future injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Holmes, Monaghan, Strunk, Paquette and Roper.)