Cerebrospinal fluid flow extends to peripheral nerves further unifying the nervous system.

Cerebrospinal fluid (CSF) is responsible for maintaining brain homeostasis through nutrient delivery and waste removal for the central nervous system (CNS). Here, we demonstrate extensive CSF flow throughout the peripheral nervous system (PNS) by tracing distribution of multimodal 1.9-nanometer gold nanoparticles, roughly the size of CSF circulating proteins, infused within the lateral cerebral ventricle (a primary site of CSF production). CSF-infused 1.9-nanometer gold transitions from CNS to PNS at root attachment/transition zones and distributes through the perineurium and endoneurium, with ultimate delivery to axoplasm of distal peripheral nerves. Larger 15-nanometer gold fails to transit from CNS to PNS and instead forms "dye-cuffs," as predicted by current dogma of CSF restriction within CNS, identifying size limitations in central to peripheral flow. Intravenous 1.9-nanometer gold is unable to cross the blood-brain/nerve barrier. Our findings suggest that CSF plays a consistent role in maintaining homeostasis throughout the nervous system with implications for CNS and PNS therapy and neural drug delivery.

Assessing the Acidic and Alkaline Recalcitrance of Covalently Modified Surface Amines on Ordered Mesoporous Carbon.

Ordered mesoporous carbon (OMC) scaffolds were covalently modified with primary amine groups by means of oxidation-coupling, yielding C-O-C bonds, or organometallic activation-coupling, yielding C-C bonds. The aminated OMCs were stressed by immersion in either 1 M hydrochloric acid or 1 M sodium hydroxide solutions at room temperature for 6 h and characterized by nitrogen sorption, electron microscopy, low-angle X-ray diffraction, thermogravimetric analysis, and the 4-nitrobenzaldehyde assay. Results demonstrate that aminated surfaces of OMC by butyllithium grafting are stable toward both 1 M HCl and 1 M NaOH, whereas the oxidation-aminated OMC surfaces can withstand 1 M NaOH only. This study illustrates the importance of chemical testing to supplant chemical intuition when tailoring carbon surfaces for applications where strong acids or bases are employed. This is especially emphasized for carbonaceous materials because of the surface heterogeneity among different carbon allotropes.

Family as a Pathway to Suicidal Behaviors Through Depression Symptoms and Internalized Homophobia.

Research consistently highlights how systemic and social factors can adversely impact mental health, and the potential buffering effects of family support, yet raced sexual minorities are vastly underrepresented among these studies. As rates of suicide increase among Black people and remain high among men and those in gender and sexually diverse communities, this study sought to examine to relationships between family dynamics and suicidality among young Black men who have sex with men (MSM) in young adulthood. We used an online survey to conduct a logistic regression to examine family factors (family support, open family communication, other adult support, and other adult value), depression symptoms, and internalized homophobia on suicide attempts. The conceptualization of the study's design and interpretation of the results were informed by minority stress theory and the phenomenological variant of ecological systems theory. The results indicate that higher levels of family support and open family communication were associated with lower levels of suicidality. Implications for future research and applications for healthcare providers and human services professionals who support young Black MSM in emerging adulthood are discussed.

Do syndemic conditions predict HIV medication adherence among urban African American men?

Much progress has been made in advancing antiretroviral (ART) adherence, yet disparities remain. To explore relationships of syndemic conditions - co-occurring health conditions caused by combinations of biological, social, and structural factors - to ART adherence among African American men, we used data from longitudinal assessments of 302 African American men enrolled in a study designed to increase physical activity and healthy eating. Syndemic conditions included alcohol dependency, drug dependency, depression, post-traumatic stress disorder, and unstable housing. A syndemic conditions variable was operationalized to indicate the presence of 0-5 conditions. About 55% of participants had 1 or more syndemic conditions. Age and marriage were positively associated with ART adherence, whereas number of syndemic conditions was negatively associated with adherence during the 12-month period. The interaction of being married and the syndemic conditions variable significantly predicted greater adherence. Similarly, the interaction of more education and the syndemic conditions variable predicted greater adherence. In multiple regression models, the syndemic conditions variable remained significant (-0.018) in predicting adherence; however, there was no significant interaction among the 5 conditions. This study lends evidence to syndemics literature indicating deleterious consequences of negative life experiences on health outcomes.

Cerebrospinal Fluid Flow Extends to Peripheral Nerves.

Cerebrospinal fluid (CSF) is an aqueous solution responsible for nutrient delivery and waste removal for the central nervous system (CNS). The three-layer meningeal coverings of the CNS support CSF flow. Peripheral nerves have an analogous three-layer covering consisting of the epineurium, perineurium, and endoneurium. Peripheral axons, located in the inner endoneurium, are bathed in "endoneurial fluid" similar to CSF but of undefined origin. CSF flow in the peripheral nervous system has not been demonstrated. Here we show CSF flow extends beyond the CNS to peripheral nerves in a contiguous flowing system. Utilizing gold nanoparticles, we identified that CSF is continuous with the endoneurial fluid and reveal the endoneurial space as the likely site of CSF flow in the periphery. Nanogold distribution along entire peripheral nerves and within their axoplasm suggests CSF plays a role in nutrient delivery and waste clearance, fundamental aspects of peripheral nerve health and disease. One Sentence Summary: Cerebrospinal fluid unites the nervous system by extending beyond the central nervous system into peripheral nerves.

Prioritizing ethical patient care responsibilities: A call to restructure student training practices in federally qualified health centers.

Federally Qualified Health Centers (FQHCs) are federally funded clinics that often serve medically underserved groups. Many Colleges of Pharmacy have faculty and non-faculty pharmacist preceptors who provide clinical services such as drug therapy management to FQHCs. It is critical that Colleges of Pharmacy and pharmacist preceptors reinforce and uphold the standard of providing high quality and evidenced based care when students rotate at these sites. Learners may have implicit biases and variable levels of emotional intelligence prior to a clinical rotation at an FQHC, which can affect the quality-of-care patients receive. Colleges of Pharmacy who send learners onto rotations at FQHCs should collaborate with FQHC sites to ensure learner readiness in clinical and emotional levels and mediate for any concerns that may arise.

Sustainability considerations for organic electronic products.

The development of organic electronic applications has reached a critical point. While markets, including the Internet of Things, transparent solar and flexible displays, gain momentum, organic light-emitting diode displays lead the way, with a current market size of over $25 billion, helping to create the infrastructure and ecosystem for other applications to follow. It is imperative to design built-in sustainability into the materials selection, processing and device architectures of all of these emerging applications, and to close the loop for a circular approach. In this Perspective, we evaluate the status of embedded carbon in organic electronics, as well as options for more sustainable materials and manufacturing, including engineered recycling solutions that can be applied within the product architecture and at the end of life. This emerging industry has a responsibility to ensure a 'cradle-to-cradle' approach. We highlight that ease of dismantling and recycling needs to closely relate to the product lifetime, and that regeneration should be facilitated in product design. Materials choices should consider the environmental effects of synthesis, processing and end-product recycling as well as performance.

Facing the rising sun: Political imagination in Black adolescents' sociopolitical development.

Black adolescents occupy one of the most precarious and marginalized social locations of society, yet they remain vigilant against oppression. Indeed, Black youth have a vast history of political action and activism around domestic and global issues. Existing scholarship frequently examines the sociocultural and cognitive factors associated with Black adolescents' political and civic engagement and related outcomes. Lost in these interrogations is an examination of the psychological processes that undergird adolescents' sociopolitical visions. To address this gap, this conceptual analysis examines political imagination and its role in Black adolescents' sociopolitical development. Political imagination is the cognitive space and process where people consciously distance the present moment to engage, explore, examine, and (de)construct sociopolitical worlds or realities.

Targeting Redundant ROBO1 and SDF-1 Pathways Prevents Adult Hemangioblast Derived-EPC and CEC Activity Effectively Blocking Tumor Neovascularization.

Neovascularization is a key therapeutic target for cancer treatment. However, anti-angiogenic therapies have shown modest success, as tumors develop rapid resistance to treatment owing to activation of redundant pathways that aid vascularization. We hypothesized that simultaneously targeting different pathways of neovascularization will circumvent the current issue of drug resistance and offer enhanced therapeutic benefits. To test this hypothesis, we made use of two distinct models of tumor-neovascularization, which exhibit equally dense microvasculature but show disparate sensitivity to anti-SDF-1 treatment. Lewis lung carcinoma (LLC) is primarily a vasculogenic-tumor that is associated with HSC functioning as a hemangioblast to generate circulating Endothelial Progenitor Cells contributing to formation of new blood vessels, and responds to anti-SDF-1 treatment. B16F0 melanoma is an angiogenic-tumor that derives new blood vessels from existing vasculature and is resistant to anti-SDF-1 therapy. In this study, we observed increased expression of the angiogenic-factor, Robo1 predominantly expressed on the blood vessels of B16F0 tumor. Blockade of Robo1 by the decoy receptor, RoboN, resulted in reduced microvascular-density and tumor-growth. However, this was associated with mobilization of BM-cells into the B16F0 tumor, thus switching the mode of neovascularization from angiogenic to vasculogenic. The use of a combinatorial treatment of RoboN and the monoclonal anti-SDF-1 antibody effectively attenuated tumor-growth and inhibited both angiogenic and BM-derived microvessels.

Best Practices in the Characterization of MOF@MSN Composites.

Research on permanently porous nanomaterials has gripped the attention of materials chemists for decades. Mesoporous silica nanoparticles (MSNs) and metal-organic frameworks (MOFs) are two of the most studied classes of materials in this field. Recently, explorations into embedding MOFs within the mesopores of MSNs have aimed to create composites that are greater than the sum of their parts. While initial progress has been promising, it has become clear that the characterization of these MOF@MSN composite materials represents a significant challenge that is often overlooked, leading to an unfortunate ambiguity in the field. The greatest difficulty lies in determining whether the product of a synthesis is simply a physical mixture of the two materials or truly the targeted composite, with MOF exclusively crystallized in the pores or on the surfaces of the MSN. This challenge is aggravated by the dramatically different porosity and composition of the components, often resulting in ambiguous information from common characterization techniques. This Viewpoint will address this challenge by calling attention to the mentioned issues and proposing a standardized approach to characterizing these materials. In particular, the use of powder X-ray diffraction, gas physisorption, and electron microscopy with systematic control experiments and data analysis is outlined. This approach can provide the information needed to clearly validate the architecture of an apparent MOF@MSN composite.

Mesh manipulation for local structural property tailoring of medical warp-knitted textiles.

Medical meshes are used as structural reinforcement both in clinical surgery and tissue engineering. However, complex loading conditions often found in such applications result in a non-homogenous stress distribution, for which the uniform reinforcement provided by the meshes is not optimal. This study aims to design a textile reinforcement with a spatially heterogeneous, load-tailored fiber architecture. To this end, we developed a simple method of manipulating a standard uniform mesh by stretching in warp and weft directions to various extents in order to control fiber orientation and fiber volume fraction. Subsequent thermal treatment locked the manipulated configurations allowing further use of the meshes. Firstly, samples in five uniform configurations (two manipulated longitudinally (warp direction), two manipulated transversely (weft direction), one non-manipulated) were obtained and analyzed regarding their morphology as well as their mechanical properties under cyclic uniaxial loading. Significant effects of the manipulation on key characteristics of the pores such as angles, side lengths, aspect ratios, and fiber volume fraction were shown. Tensile testing demonstrated the range of tensile properties achievable with the simple manipulation of the mesh, not only in magnitude but also in the shape of the stress-strain response curve. Finally, local manipulation combining different mesh configurations was exemplarily applied to create a spatially heterogeneous load-tailored reinforcement to match local strain directions in tissue-engineered tubular heart valves. The proposed method enables the use of well-established uniform medical meshes to produce load-tailored non-uniform mesh reinforcement for many applications in an easy-to-implement manner.

Discovery and Implications of Hidden Atomic-Scale Structure in a Metallic Meteorite.

Iron and its alloys have made modern civilization possible, with metallic meteorites providing one of the human's earliest sources of usable iron as well as providing a window into our solar system's billion-year history. Here highest-resolution tools reveal the existence of a previously hidden FeNi nanophase within the extremely slowly cooled metallic meteorite NWA 6259. This new nanophase exists alongside Ni-poor and Ni-rich nanoprecipitates within a matrix of tetrataenite, the uniaxial, chemically ordered form of FeNi. The ferromagnetic nature of the nanoprecipitates combined with the antiferromagnetic character of the FeNi nanophases gives rise to a complex magnetic state that evolves dramatically with temperature. These observations extend and possibly alter our understanding of celestial metallurgy, provide new knowledge concerning the archetypal Fe-Ni phase diagram and supply new information for the development of new types of sustainable, technologically critical high-energy magnets.

Emergency myelopoiesis contributes to immune cell exhaustion and pulmonary vascular remodelling.

BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) secondary to chronic lung disease (World Health Organization Group 3 PH) is deadly, with lung transplant being the only available long-term treatment option. Myeloid-derived cells are known to affect progression of both pulmonary fibrosis and PH, although the mechanism of action is unknown. Therefore, we investigated the effect of myeloid cell proliferation induced by emergency myelopoiesis on development of PH and therapy directed against programmed death-ligand 1 (PD-L1), expressed by myeloid cells in prevention of pulmonary vascular remodelling. EXPERIMENTAL APPROACH: LysM.Cre-DTR ("mDTR") mice were injected with bleomycin (0.018 U·g-1 , i.p.) while receiving either vehicle or diphtheria toxin (DT; 100 ng, i.p.) to induce severe PH. Approximately 4 weeks after initiation of bleomycin protocol, right ventricular pressure measurements were performed and tissue samples collected for histologic assessment. In a separate experiment, DT-treated mice were given anti-PD-L1 antibody (αPD-L1; 500 µg, i.p.) preventive treatment before bleomycin administration. KEY RESULTS: Mice undergoing induction of emergency myelopoiesis displayed more severe PH, right ventricular remodelling and pulmonary vascular muscularization compared to controls, without a change in lung fibrosis. This worsening of PH was associated with increased pulmonary myeloid-derived suppressor cell (MDSC), particularly polymorphonuclear MDSC (PMN-MDSC). Treatment with αPD-L1 normalized pulmonary pressures. PD-L1 expression was likewise found to be elevated on circulating PMN-MDSC from patients with interstitial lung disease and PH. CONCLUSIONS AND IMPLICATIONS: PD-L1 is a viable therapeutic target in PH, acting through a signalling axis involving MDSC. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

The Value of Integrating Fluorescent Imaging and Immunohistochemistry for Future Anatomical Studies in Aesthetic Surgery: Lessons From the Cerebrospinal Fluid Circulatory System of Human Nerves and Brain.

BACKGROUND: During their work on the cerebrospinal fluid (CSF) circulatory system of human nerves and brain, the authors applied imaging and tissue techniques that complemented basic anatomical dissection. OBJECTIVES: The authors sought to show how integrating fluorescent imaging and basic immunohistochemistry (IHC) with facial anatomy can address current problems in aesthetic surgery. METHODS: The authors developed an algorithm and a set of principles from their work on the CSF circulatory system and applied these to 3 problems in aesthetic surgery: the functional anatomy of the vermilion-cutaneous junction; chemosis; and the functional anatomy of periosteal fixation. RESULTS: Integrating fluorescent imaging and IHC with anatomical dissection characterizes structural and functional anatomy. Fluorescent imaging helps to identify and locate easily missed structures. IHC defines cell type and function. The vermilion-cutaneous junction is defined by a major lymphatic vessel. Lymphatic flow from the medial limbus to the lateral canthus suggests the etiology of chemosis. Periosteal sites of fixation prevent shear where dural CSF vessels drain directly to subcutaneous lymphatics. CONCLUSIONS: Integrating anatomical dissection with fluorescent imaging and basic IHC characterizes structural and functional anatomy and helps to better understand many problems encountered in aesthetic surgery.

Common biochemical properties of metabolic genes recurrently dysregulated in tumors.

BACKGROUND: Tumor initiation and progression are associated with numerous metabolic alterations. However, the biochemical drivers and constraints that contribute to metabolic gene dysregulation are unclear. METHODS: Here, we present MetOncoFit, a computational model that integrates 142 metabolic features that can impact tumor fitness, including enzyme catalytic activity, pathway association, network topology, and reaction flux. MetOncoFit uses genome-scale metabolic modeling and machine-learning to quantify the relative importance of various metabolic features in predicting cancer metabolic gene expression, copy number variation, and survival data. RESULTS: Using MetOncoFit, we performed a meta-analysis of 9 cancer types and over 4500 samples from TCGA, Prognoscan, and COSMIC tumor databases. MetOncoFit accurately predicted enzyme differential expression and its impact on patient survival using the 142 attributes of metabolic enzymes. Our analysis revealed that enzymes with high catalytic activity were frequently upregulated in many tumors and associated with poor survival. Topological analysis also identified specific metabolites that were hot spots of dysregulation. CONCLUSIONS: MetOncoFit integrates a broad range of datasets to understand how biochemical and topological features influence metabolic gene dysregulation across various cancer types. MetOncoFit was able to achieve significantly higher accuracy in predicting differential expression, copy number variation, and patient survival than traditional modeling approaches. Overall, MetOncoFit illuminates how enzyme activity and metabolic network architecture influences tumorigenesis.

Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia.

Pulmonary hypertension complicates the care of many patients with chronic lung diseases (defined as Group 3 pulmonary hypertension), yet the mechanisms that mediate the development of pulmonary vascular disease are not clearly defined. Despite being the most prevalent form of pulmonary hypertension, to date there is no approved treatment for patients with disease. Myeloid-derived suppressor cells (MDSCs) and endothelial cells in the lung express the chemokine receptor CXCR2, implicated in the evolution of both neoplastic and pulmonary vascular remodeling. However, precise cellular contribution to lung disease is unknown. Therefore, we used mice with tissue-specific deletion of CXCR2 to investigate the role of this receptor in Group 3 pulmonary hypertension. Deletion of CXCR2 in myeloid cells attenuated the recruitment of polymorphonuclear MDSCs to the lungs, inhibited vascular remodeling, and protected against pulmonary hypertension. Conversely, loss of CXCR2 in endothelial cells resulted in worsened vascular remodeling, associated with increased MDSC migratory capacity attributable to increased ligand availability, consistent with analyzed patient sample data. Taken together, these data suggest that CXCR2 regulates MDSC activation, informing potential therapeutic application of MDSC-targeted treatments.

Disrupting Inflammation-Associated CXCL8-CXCR1 Signaling Inhibits Tumorigenicity Initiated by Sporadic- and Colitis-Colon Cancer Stem Cells.

Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion. Here, we use RNA interference to target CXCL8 and its receptor, CXCR1, to establish the existence of a functional signaling pathway promoting tumor growth initiated by sporadic and colitis CCSCs. Knocking down either CXCL8 or CXCR1 had a dramatic effect on inhibiting both in vitro proliferation and angiogenesis. Likewise, tumorigenicity was significantly inhibited due to reduced levels of proliferation and angiogenesis. Decreased expression of cycle cell regulators cyclins D1 and B1 along with increased p21 levels suggested that the reduction in tumor growth is due to dysregulation of cell cycle progression. Therapeutically targeting the CXCL8-CXCR1 signaling pathway has the potential to block sustained tumorigenesis by inhibiting both CCSC- and pCCSC-induced proliferation and angiogenesis.

Interprofessional education model for geriatric falls risk assessment and prevention.

BACKGROUND: One in three people over the age of 65 fall every year, with 1/3 sustaining at least moderate injury. Falls risk reduction requires an interprofessional health team approach. The literature is lacking in effective models to teach students how to work collaboratively in interprofessional teams for geriatric falls prevention. The purpose of this paper is to describe the development, administration and outcome measures of an education programme to teach principles of interprofessional care for older adults in the context of falls prevention. METHODS: Students from three academic institutions representing 12 health disciplines took part in the education programme over 18 months (n=237). A mixed method one-group pretest and post-test experimental design was implemented to measure the impact of a multistep education model on progression in interprofessional collaboration competencies and satisfaction. RESULTS: Paired t-tests of pre-education to posteducation measures of Interprofessional Socialization and Valuing Scale scores (n=136) demonstrated statistically significant increase in subscales and total scores (p<0.001). Qualitative satisfaction results were strongly positive. DISCUSSION: Results of this study indicate that active interprofessional education can result in positive student attitude regarding interprofessional team-based care, and satisfaction with learning. Lessons learnt in a rapid cycle plan-do-study-act approach are shared to guide replication efforts for other educators. CONCLUSION: Effective models to teach falls prevention interventions and interprofessional practice are not yet established. This education model is easily replicable and can be used to teach interprofessional teamwork competency skills in falls and other geriatric syndromes.

Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) Is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension.

Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matricellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate vascular remodeling within the lung. We have previously demonstrated that vascular endothelial-cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in vascular endothelial cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of vascular endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory cells expressing CD11b or integrin αM (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of-Rho GTPase family member-cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in endothelial barrier function. These data indicate that endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.

Isotopic Dichotomy among Meteorites and Its Bearing on the Protoplanetary Disk.

Whole rock Δ17O and nucleosynthetic isotopic variations for chromium, titanium, nickel, and molybdenum in meteorites define two isotopically distinct populations: carbonaceous chondrites (CCs) and some achondrites, pallasites, and irons in one and all other chondrites and differentiated meteorites in the other. Since differentiated bodies accreted 1-3 Myr before the chondrites, the isotopic dichotomy cannot be attributed to temporal variations in the disk. Instead, the two populations were most likely separated in space, plausibly by proto-Jupiter. Formation of CCs outside Jupiter could account for their characteristic chemical and isotopic composition. The abundance of refractory inclusions in CCs can be explained if they were ejected by disk winds from near the Sun to the disk periphery where they spiraled inward due to gas drag. Once proto-Jupiter reached 10-20 M ⊕, its external pressure bump could have prevented millimeter- and centimeter-sized particles from reaching the inner disk. This scenario would account for the enrichment in CCs of refractory inclusions, refractory elements, and water. Chondrules in CCs show wide ranges in Δ17O as they formed in the presence of abundant 16O-rich refractory grains and 16O-poor ice particles. Chondrules in other chondrites (ordinary, E, R, and K groups) show relatively uniform, near-zero Δ17O values as refractory inclusions and ice were much less abundant in the inner solar system. The two populations were plausibly mixed together by the Grand Tack when Jupiter and Saturn migrated inward emptying and then repopulating the asteroid belt with roughly equal masses of planetesimals from inside and outside Jupiter's orbit (S- and C-type asteroids).