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Introduction: Dietary intervention is the cornerstone in the management of disorders of amino acid metabolism (AAMDs). Therefore, a MyProteinGuideTM web-based application was developed to assist the caregivers of AAMDs in self-monitoring their nutritional status especially the dietary intake. Materials and methods: A cross-sectional study was conducted to evaluate the usability of the MyProteinGuideTM web-based application among caregivers of patients diagnosed with AAMDs including aminoacidopathies (AA), Organic Aciduria (OA) and Urea Cycle Disorders (UCD) aged between 6 months to 18-year-old who are receiving treatment in the genetic clinic, Hospital Kuala Lumpur (HKL) and Hospital Pulau Pinang (HPP). A total of 30 caregivers participated in this study, out of most of the caregivers had children with AA (43.3%), followed by OA (30.0%) and UCD (26.7%). The Malay version of mHealth application usability questionnaire (MAUQ) and System Usability Scale (SUS) were used as the assessment tools to assess the application usability. Results: An overall usability mean (SD) score of 5.88 (0.76) out of a maximum score of seven as rated by MAUQ while SUS score was 78.17 (15.70), indicating good usability. In term of domain breakdown, the highest scoring domain being Domain 3: Usefulness 5.99 (0.79) followed by Domain 2: User Interface and Satisfaction 5.94 (0.73) and Domain 1: Ease of Use 5.69 (0.91). Suggestions to improve the application include to make it into a responsive web application or mobile application which are user-friendly to both mobile phone user. Conclusion: In conclusion, the usability results showed that MyProteinGuideTM had a good usability. [ABSTRACT FROM AUTHOR]

The bone marrow microenvironment is a critical regulator of haematopoietic stem cell self-renewal and fate 1 . Although it is appreciated that ageing, chronic inflammation and other insults compromise bone marrow function and thereby negatively affect haematopoiesis 2 , it is not known whether different bone compartments exhibit distinct microenvironmental properties and functional resilience. Here we use imaging, pharmacological approaches and mouse genetics to uncover specialized properties of bone marrow in adult and ageing skull. Specifically, we show that the skull bone marrow undergoes lifelong expansion involving vascular growth, which results in an increasing contribution to total haematopoietic output. Furthermore, skull is largely protected against major hallmarks of ageing, including upregulation of pro-inflammatory cytokines, adipogenesis and loss of vascular integrity. Conspicuous rapid and dynamic changes to the skull vasculature and bone marrow are induced by physiological alterations, namely pregnancy, but also pathological challenges, such as stroke and experimental chronic myeloid leukaemia. These responses are highly distinct from femur, the most extensively studied bone marrow compartment. We propose that skull harbours a protected and dynamically expanding bone marrow microenvironment, which is relevant for experimental studies and, potentially, for clinical treatments in humans., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Demyelination due to autoreactive T cells and inflammation in the central nervous system are principal features of multiple sclerosis (MS), a chronic and highly disabling human disease affecting brain and spinal cord. Here, we show that treatment with apelin, a secreted peptide ligand for the G protein-coupled receptor APJ/Aplnr, is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Apelin reduces immune cell entry into the brain, delays the onset and reduces the severity of EAE. Apelin affects the trafficking of leukocytes through the lung by modulating the expression of cell adhesion molecules that mediate leukocyte recruitment. In addition, apelin induces the internalization and desensitization of its receptor in endothelial cells (ECs). Accordingly, protection against EAE major outcomes of apelin treatment are phenocopied by loss of APJ/Aplnr function, achieved by EC-specific gene inactivation in mice or knockdown experiments in cultured primary endothelial cells. Our findings highlight the importance of the lung-brain axis in neuroinflammation and indicate that apelin targets the transendothelial migration of immune cells into the lung during acute inflammation., (© 2024. The Author(s).)

Bone regeneration requires a well-orchestrated cellular and molecular response including robust vascularization and recruitment of mesenchymal and osteogenic cells. In femoral fractures, angiogenesis and osteogenesis are closely coupled during the complex healing process. Here, we show with advanced longitudinal intravital multiphoton microscopy that early vascular sprouting is not directly coupled to osteoprogenitor invasion during calvarial bone regeneration. Early osteoprogenitors emerging from the periosteum give rise to bone-forming osteoblasts at the injured calvarial bone edge. Microvessels growing inside the lesions are not associated with osteoprogenitors. Subsequently, osteogenic cells collectively invade the vascularized and perfused lesion as a multicellular layer, thereby advancing regenerative ossification. Vascular sprouting and remodeling result in dynamic blood flow alterations to accommodate the growing bone. Single cell profiling of injured calvarial bones demonstrates mesenchymal stromal cell heterogeneity comparable to femoral fractures with increase in cell types promoting bone regeneration. Expression of angiogenesis and hypoxia-related genes are slightly elevated reflecting ossification of a vascularized lesion site. Endothelial Notch and VEGF signaling alter vascular growth in calvarial bone repair without affecting the ossification progress. Our findings may have clinical implications for bone regeneration and bioengineering approaches., (© 2024. The Author(s).)

Hematopoietic stem cell transplantation (HSCT) is commonly used to treat patients with various blood disorders, genetic and immunological diseases, and solid tumors. Several systemic complications following HSCT are critical limiting factors for achieving a successful outcome. These systemic complications are mainly due to the lack of initial engraftment after transplantation. However, the detailed underlying cellular dynamics of early engraftment have not been fully characterized yet. We performed in vivo longitudinal visualization of early engraftment characteristics of transplanted hematopoietic stem and progenitor cells (HSPCs) in the mouse calvarial bone marrow (BM). To achieve this, we utilized an in vivo laser-scanning confocal microscopy imaging system with a cranial BM imaging window and stereotaxic device. We observed two distinct cellular behaviors of HSPCs in vivo, cluster formation and cluster dissociation, early after transplantation. Furthermore, we successfully identified three cellular phases of engraftment with distinct cellular distances which are coordinated with cell proliferation and cell migration dynamics during initial engraftment., Competing Interests: P.K. is a founder and the major stock holder of IVIM Technology, and S.A. is the employee of IVIM Technology. The other authors declare no competing or financial interests., (© 2022 The Authors. FASEB BioAdvances published by Wiley Periodicals LLC on behalf of The Federation of American Societies for Experimental Biology.)

In adult mammalian bone marrow (BM), vascular endothelial cells and perivascular reticular cells control the function of haematopoietic stem and progenitor cells (HSPCs). During fetal development, the mechanisms regulating the de novo haematopoietic cell colonization of BM remain largely unknown. Here, we show that fetal and adult BM exhibit fundamental differences in cellular composition and molecular interactions by single cell RNA sequencing. While fetal femur is largely devoid of leptin receptor-expressing cells, arterial endothelial cells (AECs) provide Wnt ligand to control the initial HSPC expansion. Haematopoietic stem cells and c-Kit +  HSPCs are reduced when Wnt secretion by AECs is genetically blocked. We identify Wnt2 as AEC-derived signal that activates β-catenin-dependent proliferation of fetal HSPCs. Treatment of HSPCs with Wnt2 promotes their proliferation and improves engraftment after transplantation. Our work reveals a fundamental switch in the cellular organization and molecular regulation of BM niches in the embryonic and adult organism., (© 2022. The Author(s).)

Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRβ and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.

Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER - breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.

Isolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα + Flk1 - cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. This novel population of actively proliferating cells is cardiac lineage-committed but in a morphologically and functionally immature state compared to mature cardiomyocytes. Most important, most of CsAYTE-induced PCBs spontaneously differentiated into functional αMHC + cardiomyocytes (M + CMs) and could be a potential cellular resource for cardiac regeneration., Competing Interests: The authors declare no competing financial interests.

Rationale: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined., Objective: To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling., Methods and Results: Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF., Conclusions: Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling., (© 2016 American Heart Association, Inc.)

Several bone marrow-derived cells have been shown to promote tumour growth and progression. These cells can home to the primary tumour and become active components of the tumour microenvironment. Recent studies have also identified bone marrow-derived cells—such as mesenchymal stem cells and regulatory T cells—as contributors to cancer metastasis. The innate versatility of these cells provides diverse functional aid to promote malignancy, ranging from structural support to signal-mediated suppression of the host immune response. Here, we review the role of mesenchymal stem cells and regulatory T cells in cancer metastasis. A better understanding of the bipolar nature of these bone marrow-derived cells in physiological and malignant contexts could pave the way for new therapeutics against metastatic disease.

Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have entered clinical application despite little definition of their function in residence. Here, we report genetic pulse-chase experiments that define osteoblastic cells as short-lived and nonreplicative, requiring replenishment from bone-marrow-derived, Mx1(+) stromal cells with "MSC" features. These cells respond to tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing. Single cell transplantation yielded progeny that both preserve progenitor function and differentiate into osteoblasts, producing new bone. They are capable of local and systemic translocation and serial transplantation. While these cells meet current definitions of MSCs in vitro, they are osteolineage restricted in vivo in growing and adult animals. Therefore, bone-marrow-derived MSCs may be a heterogeneous population with the Mx1(+) population, representing a highly dynamic and stress responsive stem/progenitor cell population of fate-restricted potential that feeds the high cell replacement demands of the adult skeleton., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Tremendous efforts have been made to establish effective therapeutic neovascularization using adipose tissue-derived stromal vascular fraction (SVF), but the efficiency is low, and underlying mechanisms and their interaction with the host in a new microenvironment are poorly understood., Methods and Results: Here we demonstrate that direct implantation of SVF derived from donor adipose tissue can create a profound vascular network through the disassembly and reassembly of blood endothelial cells at the site of implantation. This neovasculature successfully established connection with recipient blood vessels to form a functionally perfused circuit. Addition of vascular growth factors to the SVF implant improved the efficiency of functional neovasculature formation. In contrast, spheroid culture of SVF before implantation reduced the capacity of vasculature formation, possibly because of cellular alteration. Implanting SVF into the mouse ischemic hindlimb induced the robust formation of a local neovascular network and salvaged the limb. Moreover, the coimplantation of SVF prevented fat absorption in the subcutaneous adipose tissue graft model., Conclusions: Freshly isolated SVF can effectively induce new vessel formation through the dynamic reassembly of blood endothelial cells and could be applied to achieve therapeutic neovascularization for relieving ischemia and preventing fat absorption in an autologous manner.

Lymph node lymphatic vessels (LNLVs) serve as a conduit to drain antigens from peripheral tissues to within the lymph nodes. LNLV density is known to be positively regulated by vascular endothelial growth factors secreted by B cells, macrophages, and dendritic cells (DCs). Here, we show that LNLV formation was negatively regulated by T cells. In both steady and inflammatory states, the density of LNLVs was increased in the absence of T cells but decreased when T cells were restored. Interferon-γ secretion by T cells suppressed lymphatic-specific genes in lymphatic endothelial cells and consequently caused marked reduction in LNLV formation. When T cells were depleted, recruitment of antigen-carrying DCs to LNs was augmented, reflecting a compensatory mechanism for antigen presentation to T cells through increased LNLVs. Thus, T cells maintain the homeostatic balance of LNLV density through a negative paracrine action of interferon-γ., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Highly metastatic and chemotherapy-resistant properties of malignant melanomas stand as challenging barriers to successful treatment; yet, the mechanisms responsible for their aggressive characteristics are not fully defined. We show that a distinct population expressing CD133 (Prominin-1), which is highly enriched after administration of a chemotherapeutic drug, dacarbazine, has enhanced metastatic potential in vivo. CD133(+) tumor cells are located close to tumor-associated lymphatic vessels in metastatic organs such as the regional lymph nodes and lung. Lymphatic endothelial cells promote the migratory activity of a CD133(+) subset to target organs and regulation of lymphatic growth efficiently modulates the metastasis of CD133(+) tumor cells. We found that lymphatic vessels in metastatic tissues stimulate chemokine receptor 4 (CXCR4)(+)/CD133(+) cell metastasis to target organs by secretion of stromal cell-derived factor-1 (SDF-1). The CXCR4(+)/CD133(+) cells exhibited higher metastatic activity compared with CXCR4(-)/CD133(+) cells and, importantly, blockade of CXCR4 coupled with dacarbazine efficiently inhibited both tumor growth and metastasis; dacarbazine alone could not attenuate tumor metastasis. The current study demonstrates a previously unidentified role of the lymphatic microenvironment in facilitating metastasis of chemoresistant melanoma cells via a specific chemotactic axis, SDF-1/CXCR4. Our findings suggest that targeting the SDF-1/CXCR4 axis in addition to dacarbazine treatment could therapeutically block chemoresistant CD133(+) cell metastasis toward a lymphatic metastatic niche., (©2010 AACR.)

Global optimization algorithms (e.g., simulated annealing, genetic, and particle swarm) have been gaining popularity in biomechanics research, in part due to advances in parallel computing. To date, such algorithms have only been applied to small- or medium-scale optimization problems (<100 design variables). This study evaluates the applicability of a parallel particle swarm global optimization algorithm to large-scale human movement problems. The evaluation was performed using two large-scale (660 design variables) optimization problems that utilized a dynamic, 27 degree-of-freedom, full-body gait model to predict new gait motions from a nominal gait motion. Both cost functions minimized a quantity that reduced the external knee adduction torque. The first one minimized footpath errors corresponding to an increased toe out angle of 15 degrees, while the second one minimized the knee adduction torque directly without changing the footpath. Constraints on allowable changes in trunk orientation, joint angles, joint torques, centers of pressure, and ground reactions were handled using a penalty method. For both problems, a single run with a gradient-based nonlinear least squares algorithm found a significantly better solution than did 10 runs with the global particle swarm algorithm. Due to the penalty terms, the physically realistic gradient-based solutions were located within a narrow "channel" in design space that was difficult to enter without gradient information. Researchers should exercise caution when extrapolating the performance of parallel global optimizers to human movement problems with hundreds of design variables, especially when penalty terms are included in the cost function.

The high computational cost of complex engineering optimization problems has motivated the development of parallel optimization algorithms. A recent example is the parallel particle swarm optimization (PSO) algorithm, which is valuable due to its global search capabilities. Unfortunately, because existing parallel implementations are synchronous (PSPSO), they do not make efficient use of computational resources when a load imbalance exists. In this study, we introduce a parallel asynchronous PSO (PAPSO) algorithm to enhance computational efficiency. The performance of the PAPSO algorithm was compared to that of a PSPSO algorithm in homogeneous and heterogeneous computing environments for small- to medium-scale analytical test problems and a medium-scale biomechanical test problem. For all problems, the robustness and convergence rate of PAPSO were comparable to those of PSPSO. However, the parallel performance of PAPSO was significantly better than that of PSPSO for heterogeneous computing environments or heterogeneous computational tasks. For example, PAPSO was 3.5 times faster than was PSPSO for the biomechanical test problem executed on a heterogeneous cluster with 20 processors. Overall, PAPSO exhibits excellent parallel performance when a large number of processors (more than about 15) is utilized and either (1) heterogeneity exists in the computational task or environment, or (2) the computation-to-communication time ratio is relatively small.

Optimization is frequently employed in biomechanics research to solve system identification problems, predict human movement, or estimate muscle or other internal forces that cannot be measured directly. Unfortunately, biomechanical optimization problems often possess multiple local minima, making it difficult to find the best solution. Furthermore, convergence in gradient-based algorithms can be affected by scaling to account for design variables with different length scales or units. In this study we evaluate a recently-developed version of the particle swarm optimization (PSO) algorithm to address these problems. The algorithm's global search capabilities were investigated using a suite of difficult analytical test problems, while its scale-independent nature was proven mathematically and verified using a biomechanical test problem. For comparison, all test problems were also solved with three off-the-shelf optimization algorithms--a global genetic algorithm (GA) and multistart gradient-based sequential quadratic programming (SQP) and quasi-Newton (BFGS) algorithms. For the analytical test problems, only the PSO algorithm was successful on the majority of the problems. When compared to previously published results for the same problems, PSO was more robust than a global simulated annealing algorithm but less robust than a different, more complex genetic algorithm. For the biomechanical test problem, only the PSO algorithm was insensitive to design variable scaling, with the GA algorithm being mildly sensitive and the SQP and BFGS algorithms being highly sensitive. The proposed PSO algorithm provides a new off-the-shelf global optimization option for difficult biomechanical problems, especially those utilizing design variables with different length scales or units.

Dynamic patient-specific musculoskeletal models have great potential for addressing clinical problems in orthopedics and rehabilitation. However, their predictive capability is limited by how well the underlying kinematic model matches the patient's structure. This study presents a general two-level optimization procedure for tuning any multi-joint kinematic model to a patient's experimental movement data. An outer level optimization modifies the model's parameters (joint position and orientations) while repeated inner level optimizations modify the model's degrees of freedom given the current parameters, with the goal of minimizing errors between model and experimental marker trajectories. The approach is demonstrated by fitting a 27 parameter, three-dimensional, 12 degree-of-freedom lower-extremity kinematic model to synthetic and experimental movement data for isolated joint (hip, knee, and ankle) and gait (full leg) motions. For noiseless synthetic data, the approach successfully recovered the known joint parameters to within an arbitrarily tight tolerance. When noise was added to the synthetic data, root-mean-square (RMS) errors between known and recovered joint parameters were within 10.4 degrees and 10 mm. For experimental data, RMS marker distance errors were reduced by up to 62% compared to methods that estimate joint parameters from anatomical landmarks. Optimized joint parameters found using a loaded full-leg gait motion differed significantly from those found using unloaded individual joint motions. In the future, this approach may facilitate the creation of dynamic patient-specific musculoskeletal models for predictive clinical applications.

As the complexity of musculoskeletal models continues to increase, so will the computational demands of biomechanical optimizations. For this reason, parallel biomechanical optimizations are becoming more common. Most implementations parallelize the optimizer. In this study, an alternate approach is investigated that parallelizes the analysis function (i.e., a kinematic or dynamic simulation) called repeatedly by the optimizer to calculate the cost function and constraints. To evaluate this approach, a system identification problem involving a kinematic ankle joint model was solved using a gradient-based optimizer and three parallel decomposition methods: gradient calculation decomposition, analysis function decomposition, or both methods combined. For a given number of processors, analysis function decomposition exhibited the best performance despite the highest communication and synchronization overhead, while gradient calculation decomposition demonstrated the worst performance due to the fact that the necessary line searches were not performed in parallel. These findings suggest that the method of parallelization most commonly used for biomechanical optimizations may not be the most efficient, depending on the optimization algorithm used. In many applications, the best computational strategy may be to focus on parallelizing the analysis function.