Helmetless Tackling Training Intervention and Preseason Self-efficacy Effects on Head Impacts in Hawai'i High School Football.

OBJECTIVE: To determine how football head impacts are influenced by self-efficacy (SE), helmetless tackling intervention participation (IP), and years of experience (YE) playing football. DESIGN: Cross-sectional. SETTING: Three high schools. PARTICIPANTS: 120 (male; n = 118, female; n = 2, 15.57 ± 1.23 years) participants were recruited from 5 high school teams (3 varsity and 2 junior-varsity). INDEPENDENT VARIABLES: SE, days of IP, and YE playing tackle football. MAIN OUTCOME MEASURES: SE was measured using a 53-question survey and categorized into 5 subscales. The accumulation of total head impacts (THI) was measured using Riddell InSite Speedflex helmets (Elyria, OH) throughout the season. Head impact exposure (HIE) was standardized as a ratio of impacts per session (games, scrimmages, and practices). Multiple regression analyses tested the relationship between THI or HIE with the predictor variables. RESULTS: For THI, 22.1% was explained by the predictors (r = 0.470, r2 = 0.221). Intervention participation had a negative correlation (B = -4.480, P = 0.019), whereas confidence in performing proper tackling and blocking (SE1) (B = 3.133, P = 0.010) and >8 YE (B = 135.9, P = 0.009) positively correlated with THI. For HIE, 25.4% was explained by the predictors (r = 0.504, r2 = 0.254). Intervention participation negatively correlated (B = -0.077, P = 0.007), whereas SE1 (B = 3.133, P = 0.010) and >8 YE (B = 2.735, P ≤ 0.001) correlated positively with HIE. CONCLUSIONS: Increased head impacts were associated with less helmetless tackling participation, more than 8 YE, and more self-confidence in tackling ability. Increasing the amount of time athletes spend practicing proper tackling and blocking techniques to reduce head first and risky play is warranted to reduce the amount of head impacts received over time.

Regulatory T cells differ from conventional CD4+ T cells in their recirculatory behavior and lymph node transit times.

Regulatory T cells (Tregs) continuously suppress autoreactive immune responses within tissues to prevent autoimmunity, yet the recirculatory behavior of Tregs between and within tissues enabling the maintenance of peripheral tolerance remains incompletely defined. Here, we quantified homing efficiency to and the dwell time of Tregs within secondary lymphoid organs (SLOs) and used intravital two-photon microscopy to measure Treg surveillance behavior of dendritic cells. Tregs homed substantially less efficiently to SLOs compared with conventional CD4+ T cells (Tconvs), despite similar expression of homing receptors. Tregs remained on average 2-3 times longer within the LN than Tconvs before exiting, and retained Tregs differed from recirculating Tregs in phenotype, motility and interaction duration with dendritic cells. Taken together, these data revealed fundamental differences in Treg versus conventional T cell in vivo recirculation and migration behaviors, identified a Treg population with prolonged LN dwell time, and provided quantitative insight into their spatiotemporal behavior within LNs.

Transient Surface CCR5 Expression by Naive CD8+ T Cells within Inflamed Lymph Nodes Is Dependent on High Endothelial Venule Interaction and Augments Th Cell-Dependent Memory Response.

In inflamed lymph nodes, Ag-specific CD4(+) and CD8(+) T cells encounter Ag-bearing dendritic cells and, together, this complex enhances the release of CCL3 and CCL4, which facilitate additional interaction with naive CD8(+) T cells. Although blocking CCL3 and CCL4 has no effect on primary CD8(+) T cell responses, it dramatically impairs the development of memory CD8(+) T cells upon Ag rechallenge. Despite the absence of detectable surface CCR5 expression on circulating native CD8(+) T cells, these data imply that naive CD8(+) T cells are capable of expressing surface CCR5 prior to cognate Ag-induced TCR signaling in inflamed lymph nodes; however, the molecular mechanisms have not been characterized to date. In this study, we show that CCR5, the receptor for CCL3 and CCL4, can be transiently upregulated on a subset of naive CD8(+) T cells and that this upregulation is dependent on direct contact with the high endothelial venule in inflamed lymph node. Binding of CD62L and CD11a on T cells to their ligands CD34 and CD54 on the high endothelial venule can be enhanced during inflammation. This enhanced binding and subsequent signaling promote the translocation of CCR5 molecules from intracellular vesicles to the surface of the CD8(+) T cell. The upregulation of CCR5 on the surface of the CD8(+) T cells increases the number of contacts with Ag-bearing dendritic cells, which ultimately results in increased CD8(+) T cell response to Ag rechallenge.

Notch2 blockade enhances hematopoietic stem cell mobilization and homing.

Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers of hematopoietic progenitor cells (HPCs) into blood, precluding use of the procedure, or being placed at increased risk of complications due to slow hematopoietic reconstitution. Developing more efficacious HPC mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is not essential for homeostasis of adult hematopoietic stem cells (HSCs), Notch-ligand adhesive interaction maintains HSC quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade, but not Notch1 blockade, sensitizes hematopoietic stem cells and progenitors (HSPCs) to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting HSC homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor lead to decreased CXCR4 expression by HSC but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow HSPCs show an increased homing to the marrow, while mobilized Notch2-blocked, but not Notch2-deficient stem cells and progenitors, displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance HPC mobilization and improve engraftment during HCT.

Polyphenol administration impairs T-cell proliferation by imprinting a distinct dendritic cell maturational profile.

Currently little is known as to how nutritionally derived compounds may affect dendritic cell (DC) maturation and potentially prevent inappropriate inflammatory responses that are characteristic of chronic inflammatory syndromes. Previous observations have demonstrated that two polyphenols quercetin and piperine delivered through reconstituted oil bodies (ROBs-QP) can influence DC maturation in response to LPS leading to a modulated inflammatory response. In the present study, we examined the molecular effects of ROBs-QP exposure on DC differentiation in mice and identified a unique molecular signature in response to LPS administration that potentially modulates DC maturation and activity in inflammatory conditions. Following LPS administration, ROBs-QP-exposed DCs expressed an altered molecular profile as compared with control DCs, including cytokine and chemokine production, chemokine receptor repertoire, and antigen presentation ability. In vivo ROBs-QP administration suppresses antigen-specific T-cell division in the draining lymph nodes resulting from a reduced ability to create stable immunological synapse. Our data demonstrate that polyphenols exposure can drive DCs toward a new anti-inflammatory molecular profile capable of dampening the inflammatory response, highlighting their potential as complementary nutritional approaches in the treatment of chronic inflammatory syndromes.

Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention.

Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here, we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK -mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK -independent HSPC egress and enhanced HSPC mobilization. We, therefore, conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch.

Head Impact Exposure in Hawaiian High School Football: Influence of Adherence Rates on a Helmetless Tackling and Blocking Training Intervention.

CONTEXT: High school football remains a popular, physically demanding sport despite the known risks for acute brain and neck injury. Impacts to the head also raise concerns about their cumulative effects and long-term health consequences. OBJECTIVE: To examine the effectiveness of a helmetless tackling training program to reduce head impact exposure in football participants. DESIGN: A three-year, quasi-experimental, prospective cohort (clinicaltrials.gov #NCTXXX) study. SETTING: Honolulu (XXX, XXX) area public and private secondary schools with varsity and junior varsity football. PATIENTS OR OTHER PARTICIPANTS: Football participants (n=496) ages 14 to 18 years old. Intervention(s) Participants wore new football helmets furnished with head impact sensor technology. Teams employed a season-long helmetless tackling and blocking intervention in Years 2 and 3 consisting of a 3-phase, systematic progression of 10 instructional drills. MAIN OUTCOME MEASURE(S): Head impact frequency per athlete exposure (ImpAE), location, and impact magnitude per participant intervention adherence levels (60% and 80%). RESULTS: An overall regression analysis revealed a significant negative association between ImpAE and adherence (p=0.003, beta=-1.21, SE=0.41). In year 3, a longitudinal data analysis of weekly ImpAE data resulted in an overall difference between the adherent and non-adherent groups (p=0.040 at 80%; p=0.004 at 60%), mainly due to decreases in top and side impacts. Mean cumulative impact burden for the adherent group (n=131: 2,105.84g ± 219.76,) was significantly (p=0.020) less than the non-adherent group (n=90: 3,158.25g ± 434.80) at the 60% adherence level. CONCLUSIONS: Participants adhering to the intervention on at least a 60% level experienced a 34% to 37% significant reduction in the number of head impacts (per exposure) through the season. These results provide additional evidence that a helmetless tackling and blocking training intervention (utilizing the HuTT® program) reduces head impact exposure in high school football players. Adherence to an intervention is crucial for achieving intended outcomes.

Extravascular CX3CR1+ cells extend intravascular dendritic processes into intact central nervous system vessel lumen.

Within the central nervous system (CNS), antigen-presenting cells (APCs) play a critical role in orchestrating inflammatory responses where they present CNS-derived antigens to immune cells that are recruited from the circulation to the cerebrospinal fluid, parenchyma, and perivascular space. Available data indicate that APCs do so indirectly from outside of CNS vessels without direct access to luminal contents. Here, we applied high-resolution, dynamic intravital two-photon laser scanning microscopy to directly visualize extravascular CX3CR1+ APC behavior deep within undisrupted CNS tissues in two distinct anatomical sites under three different inflammatory stimuli. Surprisingly, we observed that CNS-resident APCs dynamically extend their cellular processes across an intact vessel wall into the vascular lumen with preservation of vessel integrity. While only a small number of APCs displayed intravascular extensions in intact, noninflamed vessels in the brain and the spinal cord, the frequency of projections increased over days in an experimental autoimmune encephalomyelitis model, whereas the number of projections remained stable compared to baseline days after tissue injury such as CNS tumor infiltration and aseptic spinal cord trauma. Our observation of this unique behavior by parenchyma CX3CR1+ cells in the CNS argues for further exploration into their functional role in antigen sampling and immune cell recruitment.

Oral TGF-ßR1 inhibitor Vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity.

Osteosarcoma (OS) is an aggressive malignant bone cancer, with refractory and metastatic disease remaining a significant challenge. Transforming growth factor-ß1 (TGF-ß) is a potent immune suppressive cytokine in OS and the TGF-ß is increased in the sera of OS patients and this increase is associated with high-grade OS and lung metastases. Therefore, blocking TGF-ß1 signaling may be a novel therapy for OS treatment. Here we show that blocking TGF-ß1 signaling using TGF-ßR1 inhibitor, Vactosertib, significantly inhibited OS proliferation in vitro and in vivo. Notably, Vactosertib inhibits c-Myc expression in the OS cells. Vactosertib increased immune effectors (IFNγ+CD8+ cells and NK cells) and inhibited immune suppressors (M2-like TAM, MDSC) in the OS tumor microenvironment. Our results suggest that inhibition of TGF-ß1 signaling is an effective therapeutic strategy against OS through a multi-pronged approach that targets tumor intrinsic and extrinsic factors to achieve optimal immune-effector functions and maximal clinical response.

Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation.

BACKGROUND: Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood. METHODS: The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9STINGwt or RMS 76-9STING-/-, along with other murine tumor models, in C57BL/6 or STING-/- (TMEM173-/- ) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME). RESULTS: The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components. CONCLUSIONS: Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches.

Piezo1 facilitates optimal T cell activation during tumor challenge.

Functional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. T cell anti-tumor function is dependent on their ability to differentiate from a naïve state, infiltrate into the tumor site, and exert cytotoxic functions. The factors dictating whether a particular T cell can successfully undergo these processes during tumor challenge are not yet completely understood. Piezo1 is a mechanosensitive cation channel with high expression on both CD4+ and CD8+ T cells. Previous studies have demonstrated that Piezo1 optimizes T cell activation and restrains the CD4+ regulatory T cell (Treg) pool in vitro and under inflammatory conditions in vivo. However, little is known about the role Piezo1 plays on CD4+ and CD8+ T cells in cancer. We hypothesized that disruption of Piezo1 on T cells impairs anti-tumor immunity in vivo by hindering inflammatory T cell responses. We challenged mice with T cell Piezo1 deletion (P1KO) with tumor models dependent on T cells for immune rejection. P1KO mice had the more aggressive tumors, higher tumor growth rates and were unresponsive to immune-mediated therapeutic interventions. We observed a decreased CD4:CD8 ratio in both the secondary lymphoid organs and TME of P1KO mice that correlated inversely with tumor size. Poor CD4+ helper T cell responses underpinned the immunodeficient phenotype of P1KO mice. Wild type CD8+ T cells are sub-optimally activated in vivo with P1KO CD4+ T cells, taking on a CD25loPD-1hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.

National Athletic Trainers' Association Position Statement: Reducing Intentional Head-First Contact Behavior in American Football Players.

OBJECTIVE: To provide evidence-based recommendations for reducing the prevalence of head-first contact behavior in American football players with the aim of reducing the risk of head and neck injuries. BACKGROUND: In American football, using the head as the point of contact is a persistent, well-documented, and direct cause of catastrophic head and cervical spine injury. Equally concerning is that repeated head-impact exposures are likely to result from head-first contact behavior and may be associated with long-term neurocognitive conditions such as dementia, depression, and chronic traumatic encephalopathy. CONCLUSIONS: The National Athletic Trainers' Association proposes 14 recommendations to help the certified athletic trainer, allied health care provider, coach, player, parent, and broader community implement strategies for reducing the prevalence of head-first contact in American football.

Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche.

The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). Methods: in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL. We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis. We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4. We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function. Results: we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche. The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration. Further, targeting endothelial PERK significantly improved T-ALL outcome. EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival. Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia. Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts. Conclusion: our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.

A targetable pathway in neutrophils mitigates both arterial and venous thrombosis.

Arterial and venous thrombosis constitutes a major source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that arterial and venous thrombosis can occur in the same populations, suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, antithrombotic therapies targeting the immune system for therapeutics gain are lacking. Here, we show that neutrophils are key effectors of both arterial and venous thrombosis and can be targeted through immunoregulatory nanoparticles. Using antiphospholipid antibody syndrome (APS) as a model for arterial and venous thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation through genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils clustered P-selectin glycoprotein ligand 1 (PSGL-1) by cortical actin remodeling, thereby increasing adhesion potential at sites of thrombosis. Targeting clustered PSGL-1 using nanoparticles attenuated neutrophil-mediated thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutrophils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis.

O-fucose modulates Notch-controlled blood lineage commitment.

Notch receptors are cell surface molecules essential for cell fate determination. Notch signaling is subject to tight regulation at multiple levels, including the posttranslational modification of Notch receptors by O-linked fucosylation, a reaction that is catalyzed by protein O-fucosyltransferase-1 (Pofut1). Our previous studies identified a myeloproliferative phenotype in mice conditionally deficient in cellular fucosylation that is attributable to a loss of Notch-dependent suppression of myelopoiesis. Here, we report that hematopoietic stem cells deficient in cellular fucosylation display decreased frequency and defective repopulating ability as well as decreased lymphoid but increased myeloid developmental potential. This phenotype may be attributed to suppressed Notch ligand binding and reduced downstream signaling of Notch activity in hematopoietic stem cells. Consistent with this finding, we further demonstrate that mouse embryonic stem cells deficient in Notch1 (Notch1(-/-)) or Pofut1 (Pofut1(-/-)) fail to generate T lymphocytes but differentiate into myeloid cells while coculturing with Notch ligand-expressing bone marrow stromal cells in vitro. Moreover, in vivo hematopoietic reconstitution of CD34(+) progenitor cells derived from either Notch1(-/-) or Pofut1(-/-) embryonic stem cells show enhanced granulopoiesis with depressed lymphoid lineage development. Together, these results indicate that Notch signaling maintains hematopoietic lineage homeostasis by promoting lymphoid development and suppressing overt myelopoiesis, in part through processes controlled by O-linked fucosylation of Notch receptors.

Notch-Regulated Dendritic Cells Restrain Inflammation-Associated Colorectal Carcinogenesis.

Conventional dendritic cells (cDC) play a central role in T-cell antitumor responses. We studied the significance of Notch-regulated DC immune responses in a mouse model of colitis-associated colorectal cancer in which there is epithelial downregulation of Notch/Hes1 signaling. This defect phenocopies that caused by GMDS (GDP-mannose 4,6-dehydratase) mutation in human colorectal cancers. We found that, although wild-type immune cells restrained dysplasia progression and decreased the incidence of adenocarcinoma in chimeric mice, the immune system with Notch2 deleted in all blood lineages or in only DCs promoted inflammation-associated transformation. Notch2 signaling deficiency not only impaired cDC terminal differentiation, but also downregulated CCR7 expression, reduced DC migration, and suppressed antigen cross-presentation to CD8+ T cells. Transfer of Notch-primed DCs restrained inflammation-associated dysplasia progression. Consistent with the mouse data, we observed a correlation between infiltrating cDC1 and Notch2 signaling in human colorectal cancers and found that GMDS-mutant colorectal cancers showed decreased CCR7 expression and suppressed cDC1 signature gene expression. Suppressed cDC1 gene signature expression in human colorectal cancer was associated with a poor prognosis. In summary, our study supports an important role for Notch2 signaling in cDC1-mediated antitumor immunity and indicates that Notch2-controlled DCs restrain inflammation-associated colon cancer development in mice.

Fucose-deficient hematopoietic stem cells have decreased self-renewal and aberrant marrow niche occupancy.

BACKGROUND: Modification of Notch receptors by O-linked fucose and its further elongation by the Fringe family of glycosyltransferase has been shown to be important for Notch signaling activation. Our recent studies disclose a myeloproliferative phenotype, hematopoietic stem cell (HSC) dysfunction, and abnormal Notch signaling in mice deficient in FX, which is required for fucosylation of a number of proteins including Notch. The purpose of this study was to assess the self-renewal and stem cell niche features of fucose-deficient HSCs. STUDY DESIGN AND METHODS: Homeostasis and maintenance of HSCs derived from FX(-/-) mice were studied by serial bone marrow transplantation, homing assay, and cell cycle analysis. Two-photon intravital microscopy was performed to visualize and compare the in vivo marrow niche occupancy by fucose-deficient and wild-type (WT) HSCs. RESULTS: Marrow progenitors from FX(-/-) mice had mild homing defects that could be partially prevented by exogenous fucose supplementation. Fucose-deficient HSCs from FX(-/-) mice displayed decreased self-renewal capability compared with the WT controls. This is accompanied with their increased cell cycling activity and suppressed Notch ligand binding. When tracked in vivo by two-photon intravital imaging, the fucose-deficient HSCs were found localized farther from the endosteum of the calvarium marrow than the WT HSCs. CONCLUSIONS: The current reported aberrant niche occupancy by HSCs from FX(-/-) mice, in the context of a faulty blood lineage homeostasis and HSC dysfunction in mice expressing Notch receptors deficient in O-fucosylation, suggests that fucosylation-modified Notch receptor may represent a novel extrinsic regulator for HSC engraftment and HSC niche maintenance.

Relationships among balance, visual search, and lacrosse-shot accuracy.

The purpose of this study was to examine variables that may contribute to shot accuracy in women's college lacrosse. A convenience sample of 15 healthy women's National Collegiate Athletic Association Division III College lacrosse players aged 18-23 (mean+/-SD, 20.27+/-1.67) participated in the study. Four experimental variables were examined: balance, visual search, hand grip strength, and shoulder joint position sense. Balance was measured by the Biodex Stability System (BSS), and visual search was measured by the Trail-Making Test Part A (TMTA) and Trail-Making Test Part B (TMTB). Hand-grip strength was measured by a standard hand dynamometer, and shoulder joint position sense was measured using a modified inclinometer. All measures were taken in an indoor setting. These experimental variables were then compared with lacrosse-shot error that was measured indoors using a high-speed video camera recorder and a specialized L-shaped apparatus. A Stalker radar gun measured lacrosse-shot velocity. The mean lacrosse-shot error was 15.17 cm with a mean lacrosse-shot velocity of 17.14 m.s (38.35 mph). Lower scores on the BSS level 8 eyes open (BSS L8 E/O) test and TMTB were positively related to less lacrosse-shot error (r=0.760, p=0.011) and (r=0.519, p=0.048), respectively. Relations were not significant between lacrosse-shot error and grip strength (r=0.191, p = 0.496), lacrosse-shot error and BSS level 8 eyes closed (BSS L8 E/C) (r=0.501, p=0.102), lacrosse-shot error and BSS level 4 eyes open (BSS L4 E/O) (r=0.313, p=0.378), lacrosse-shot error and BSS level 4 eyes closed (BSS L4 E/C) (r=-0.029, p=0.936) lacrosse-shot error and shoulder joint position sense (r=-0.509, p=0.055) and between lacrosse-shot error and TMTA (r=0.375, p=0.168). The results reveal that greater levels of shot accuracy may be related to greater levels of visual search and balance ability in women college lacrosse athletes.

Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus.

Glycoprotein fucosylation enables fringe-dependent modulation of signal transduction by Notch transmembrane receptors, contributes to selectin-dependent leukocyte trafficking, and is faulty in leukocyte adhesion deficiency (LAD) type II, also known as congenital disorder of glycosylation (CDG)-IIc, a rare human disorder characterized by psychomotor defects, developmental abnormalities, and leukocyte adhesion defects. We report here that mice with an induced null mutation in the FX locus, which encodes an enzyme in the de novo pathway for GDP-fucose synthesis, exhibit a virtually complete deficiency of cellular fucosylation, and variable frequency of intrauterine demise determined by parental FX genotype. Live-born FX(-/-) mice exhibit postnatal failure to thrive that is suppressed with a fucose-supplemented diet. FX(-/-) adults suffer from an extreme neutrophilia, myeloproliferation, and absence of leukocyte selectin ligand expression reminiscent of LAD-II/CDG-IIc. Contingent restoration of leukocyte and endothelial selectin ligand expression, general cellular fucosylation, and normal postnatal physiology is achieved by modulating dietary fucose to supply a salvage pathway for GDP-fucose synthesis. Conditional control of fucosylation in FX(-/-) mice identifies cellular fucosylation events as essential concomitants to fertility, early growth and development, and leukocyte adhesion.

A helmetless-tackling intervention in American football for decreasing head impact exposure: A randomized controlled trial.

OBJECTIVES: To evaluate a behavioral intervention to reduce head impact exposure in youth playing American football. DESIGN: Nested randomized controlled trial. METHODS: Participants, ages 14-17 years, wore head impact sensors (SIM-G™) during two seasons of play. Those randomized to the intervention group underwent weekly tackling/blocking drills performed without helmets (WoH) and shoulder pads while the control group trained as normal, matching frequency and duration. Research personnel provided daily oversight to maintain fidelity. Head impact frequency (≥10g) per athlete exposure (ImpAE) was analyzed over time (two 11-week seasons) using mixed effect models or ANCOVA. Secondary outcomes included exposure-type (training, game) and participation level (entry-level versus upper-level secondary education). RESULTS: One-hundred fifteen participants (59 WoH, 56 control) met compliance criteria, contributing 47,382 head impacts and 10,751 athlete exposures for analysis. WoH had fewer ImpAE during games compared to control participants at weeks 4 (p=0.0001 season 1, p=0.0005 season 2) and 7 (p=0.0001 both seasons). Upper-level WoH participants had less ImpAE during games than their matched controls at weeks 4 (p=0.017 and p=0.026) and 7 (p=0.037 and p=0.014) in both seasons, respectively. Upper-level WoH also had fewer ImpAE during training at week 7 (p=0.015) in season one. CONCLUSIONS: Tackling and blocking drills performed without a helmet during training reduced the frequency of head impacts during play, especially during games. However, these differences disappeared by the end of the season. Future research should explore the frequency of behavioral intervention and a dose-response relationship considering years of player experience. TRIAL REGISTRATION: ClinicalTrials.gov # NCT02519478.