A Change of Pace: Record Photoresponse through Spirooxazine Confinement in a Metal-Organic Matrix.

Modern and upcoming high-speed optoelectronics as well as secure data storage or solar energy harvesting technologies integrating stimuli-responsive materials fully rely on the fundamental concept of rapid transitions between discrete states possessing different properties. Relatively slow transition kinetics between those states for commonly used classes of photochromic compounds in solution or bulk solids severely restrict the applicability of stimuli-responsive materials for device development. Herein, we report a multivariate strategy based on a photochromic spirooxazine derivative, coordinatively integrated in the solvent-free confined space of a solid-state matrix, such as a metal-organic framework (MOF), for the first time, resulting in the fastest photoresponse reported for any solid-state material to date. The photoisomerization rate for the developed photochromic material was estimated to be 126 s-1, surpassing any literature reports to the best of our knowledge. We also shed light on the fundamentals of the correlation between framework topology, the nature of organic linkers, and the presence/absence of organic solvent within the scaffold voids on the material photoresponse using a series of isoreticular frameworks. Overall, the presented conceptual approach allows for tailoring the isomerization kinetics of photochromic molecules in the solid state over a range of 4 orders of magnitude-an unprecedented span that provides a pathway for addressing challenges associated with the response rate and photoisomerization, which are key criteria in stimuli-responsive material development.

Effectiveness of a pediatric critical care pilot preceptor program: Improved confidence and competency outcomes among a cohort of professional nurses in Blantyre, Malawi.

BACKGROUND: Availability of high-level pediatric training for nurses in Malawi is limited. To address this gap, a novel pediatric critical care nurse preceptor program was developed and implemented by pediatric nurse specialists. AIM: Evaluate the effectiveness of a pediatric critical care nurse preceptor program, via change in nurses' knowledge, skills, confidence, and precepting competence. DESIGN: A 12-month pediatric critical care nurse preceptor program with assessments at baseline, end of intensive (3 months), and end of program (6 months). SETTING: Blantyre, Malawi. PARTICIPANTS: Nurses with two or more years of pediatric nursing experience (N = 20) nominated by unit managers. METHODS: Quantitative data were collected throughout program implementation. Assessments included: (1) multiple choice knowledge test, (2) Objective Structured Clinical Examinations in two areas (vital signs and airway, breathing, circulation, disability, exposure assessments; and blood gas and electrolyte analysis), (3) group simulations (cardiopulmonary resuscitation or respiratory distress), (4) Likert-scale clinical confidence survey, and (5) Likert-scale precepting competence survey. Data were analyzed using repeated measures ANOVA with pairwise comparisons. For Likert-scale surveys, median confidence scores were compared using a Friedman test with post hoc pairwise comparisons using Wilcoxon signed-rank tests. RESULTS: Participants demonstrated significant improvement in clinical knowledge (p < .001), vital signs and airway, breathing, circulation, disability, exposure assessment (p = .001), blood gas and electrolyte analysis (p = .001), CPR (p < .001) and respiratory distress (p < .001) simulations, clinical confidence (p = .002), and precepting competence (p = .041). CONCLUSION: This pediatric critical care nurse preceptor program was effective in improving participants' confidence and competence (knowledge and skills) in pediatric critical care nursing and precepting. Results suggest the program's potential to address the shortage of highly trained pediatric critical care nurses in Malawi. This lays groundwork for refining and expanding preceptorship, ultimately improving pediatric critical care nursing education in resource-limited settings.

Impact of a Quality Improvement Initiative on Medical Management of Veterans With Peripheral Artery Disease.

Guideline-directed medical therapy (GDMT) for peripheral artery disease (PAD) remains severely underused. Prevention of Amputation in Veterans Everywhere (PAVE) is a screening program designed to prevent or delay major lower extremity amputation. This study aimed to determine whether diagnosis of PAD through the PAVE program improves the prescription of GDMT in veterans with asymptomatic PAD. Patients enrolled into the PAVE program from our institution from 2020 to 2021 were included. Patients with an abnormal ankle-brachial index (ABI), defined as ABI <0.9 or >1.2, were selected for further analysis. Primary outcome was adherence to GDMT, following class I and class IIa recommendations. Secondary outcomes included changes in low-density lipoprotein (LDL), blood pressure, and hemoglobin A1c (HbA1c). A total of 6,313 patients were enrolled into the PAVE program between 2020 and 2021. Of these, 211 had abnormal ABI and were included in our analysis. With enrollment into PAVE, there was significant increase in the prescription of aspirin (74.4% vs 64.9%, p = 0.044) and statins (91.5% vs 82%, p = 0.006). The overall adherence to GDMT significantly increased (56.9% vs 38.9%, p <0.001). The number of patients needed to enroll in PAVE to improve GDMT adherence is 5.6 (95% confidence interval 3.6 to 12.3). Patients enrolled into PAVE program saw significant decreases in HbA1c, with mean decrease of 0.3 (p = 0.012) and a decrease in LDL, with a mean decrease of 6.2 (p = 0.01). In conclusion, enrollment into an amputation prevention program secondarily increased adherence to GDMT, driven by increases in the prescription of statins and aspirin, with resulting decreases in HbA1c and LDL.

Breaking the photoswitch speed limit.

The forthcoming generation of materials, including artificial muscles, recyclable and healable systems, photochromic heterogeneous catalysts, or tailorable supercapacitors, relies on the fundamental concept of rapid switching between two or more discrete forms in the solid state. Herein, we report a breakthrough in the "speed limit" of photochromic molecules on the example of sterically-demanding spiropyran derivatives through their integration within solvent-free confined space, allowing for engineering of the photoresponsive moiety environment and tailoring their photoisomerization rates. The presented conceptual approach realized through construction of the spiropyran environment results in ~1000 times switching enhancement even in the solid state compared to its behavior in solution, setting a record in the field of photochromic compounds. Moreover, integration of two distinct photochromic moieties in the same framework provided access to a dynamic range of rates as well as complementary switching in the material's optical profile, uncovering a previously inaccessible pathway for interstate rapid photoisomerization.

Cooperative and Orthogonal Switching in the Solid State Enabled by Metal-Organic Framework Confinement Leading to a Thermo-Photochromic Platform.

Cooperative behavior and orthogonal responses of two classes of coordinatively integrated photochromic molecules towards distinct external stimuli were demonstrated on the first example of a photo-thermo-responsive hierarchical platform. Synergetic and orthogonal responses to temperature and excitation wavelength are achieved by confining the stimuli-responsive moieties within a metal-organic framework (MOF), leading to the preparation of a novel photo-thermo-responsive spiropyran-diarylethene based material. Synergistic behavior of two photoswitches enables the study of stimuli-responsive resonance energy transfer as well as control of the photoinduced charge transfer processes, milestones required to advance optoelectronics development. Spectroscopic studies in combination with theoretical modeling revealed a nonlinear effect on the material electronic structure arising from the coordinative integration of photoresponsive molecules with distinct photoisomerization mechanisms. Thus, the reported work covers multivariable facets of not only fundamental aspects of photoswitch cooperativity, but also provides a pathway to modulate photophysics and electronics of multidimensional functional materials exhibiting thermo-photochromism.

Confinement-Driven Photophysics in Hydrazone-Based Hierarchical Materials.

Confinement-imposed photophysics was probed for novel stimuli-responsive hydrazone-based compounds demonstrating a conceptual difference in their behavior within 2D versus 3D porous matrices for the first time. The challenges associated with photoswitch isomerization arising from host interactions with photochromic compounds in 2D scaffolds could be overcome in 3D materials. Solution-like photoisomerization rate constants were realized for sterically demanding hydrazone derivatives in the solid state through their coordinative immobilization in 3D scaffolds. According to steady-state and time-resolved photophysical measurements and theoretical modeling, this approach provides access to hydrazone-based materials with fast photoisomerization kinetics in the solid state. Fast isomerization of integrated hydrazone derivatives allows for probing and tailoring resonance energy transfer (ET) processes as a function of excitation wavelength, providing a novel pathway for ET modulation.

Metal-Photoswitch Friendship: From Photochromic Complexes to Functional Materials.

Cooperative metal-photoswitch interfaces comprise an application-driven field which is based on strategic coupling of metal cations and organic photochromic molecules to advance the behavior of both components, resulting in dynamic molecular and material properties controlled through external stimuli. In this Perspective, we highlight the ways in which metal-photoswitch interplay can be utilized as a tool to modulate a system's physicochemical properties and performance in a variety of structural motifs, including discrete molecular complexes or cages, as well as periodic structures such as metal-organic frameworks. This Perspective starts with photochromic molecular complexes as the smallest subunit in which metal-photoswitch interactions can occur, and progresses toward functional materials. In particular, we explore the role of the metal-photoswitch relationship for gaining fundamental knowledge of switchable electronic and magnetic properties, as well as in the design of stimuli-responsive sensors, optically gated memory devices, catalysts, and photodynamic therapeutic agents. The abundance of stimuli-responsive systems in the natural world only foreshadows the creative directions that will uncover the full potential of metal-photoswitch interactions in the coming years.

Capture Instead of Release: Defect-Modulated Radionuclide Leaching Kinetics in Metal-Organic Frameworks.

Comparison of defect-controlled leaching-kinetics modulation of metal-organic frameworks (MOFs) and porous functionalized silica-based materials was performed on the example of a radionuclide and radionuclide surrogate for the first time, revealing an unprecedented readsorption phenomenon. On a series of zirconium-based MOFs as model systems, we demonstrated the ability to capture and retain >99% of the transuranic 241Am radionuclide after 1 week of storage. We report the possibility of tailoring radionuclide release kinetics in MOFs through framework defects as a function of postsynthetically installed organic ligands including cation-chelating crown ether-based linkers. Based on comprehensive analysis using spectroscopy (EXAFS, UV-vis, FTIR, and NMR), X-ray crystallography (single crystal and powder), and theoretical calculations (nine kinetics models and structure simulations), we demonstrated the synergy of radionuclide integration methods, topological restrictions, postsynthetic scaffold modification, and defect engineering. This combination is inaccessible in any other material and highlights the advantages of using well-defined frameworks for gaining fundamental knowledge necessary for the advancement of actinide-based material development, providing a pathway for addressing upcoming challenges in the nuclear waste administration sector.

Stimuli-Modulated Metal Oxidation States in Photochromic MOFs.

Tuning metal oxidation states in metal-organic framework (MOF) nodes by switching between two discrete linker photoisomers via an external stimulus was probed for the first time. On the examples of three novel photochromic copper-based frameworks, we demonstrated the capability of switching between +2 and +1 oxidation states, on demand. In addition to crystallographic methods used for material characterization, the role of the photochromic moieties for tuning the oxidation state was probed via conductivity measurements, cyclic voltammetry, and electron paramagnetic resonance, X-ray photoelectron, and diffuse reflectance spectroscopies. We confirmed the reversible photoswitching activity including photoisomerization rate determination of spiropyran- and diarylethene-containing linkers in extended frameworks, resulting in changes in metal oxidation states as a function of alternating excitation wavelengths. To elucidate the switching process between two states, the photoisomerization quantum yield of photochromic MOFs was determined for the first time. Overall, the introduced noninvasive concept of metal oxidation state modulation on the examples of stimuli-responsive MOFs foreshadows a new pathway for alternation of material properties toward targeted applications.

Addressing Organizational Barriers to Adolescent Access to High-Quality, Low-Cost, Confidential Sexual and Reproductive Health Services in a Community Health Center.

Adolescents face a number of barriers to accessing high-quality, confidential sexual and reproductive health (SRH) services. Although federally qualified health centers (FQHCs), a type of community health center (CHC), are a critical source of health care for medically underserved adolescents, they often lack the capacity and resources to provide specialized SRH services to adolescents. In this article, we describe the development and implementation of an initiative aimed at improving an FQHC's capacity to provide high-quality confidential SRH services to adolescents. For this initiative, a team of clinical and quality improvement staff developed a set of six strategies to improve adolescent SRH services at an FQHC: (1) building community relationships and galvanizing internal organizational support to improve adolescent access to confidential SRH services, (2) developing a long-acting reversible contraception (LARC) program, (3) training clinic staff on SRH and adolescent health topics, (4) adapting the adolescent patient workflow to improve SRH service delivery during appointments, (5) updating and implementing a universal adolescent health assessment tool, and (6) developing billing and registration policies that allow adolescents to receive confidential SRH services. We identified several factors that we believe were key to the successful implementation of our approach in other CHC settings, including encouraging cross-sector collaboration and community focus, providing training as a tool to engage and empower staff as agents of change, involving interdisciplinary staff, piloting on a small scale, and establishing consistent meetings with a clinic champion and improvement team.

Helping Babies Breathe (2nd edition) implementation on a shoestring budget in Zanzibar, Tanzania.

BACKGROUND: To assess the efficacy and viability of implementing Helping Babies Breathe, a neonatal resuscitation program for resource-limited environments on a small budget in two of the largest delivery centers in Zanzibar, Tanzania. The quality improvement initiative concentrated on training midwives, who directly care for neonates at birth on Helping Babies Breathe to address high rates of neonatal mortality secondary to birth asphyxia. METHODS: The convenience sample was 59 midwives working in the two delivery centers of interest in Zanzibar, Tanzania. The train-the-trainer implementation strategy with repeated measures design was used to assess knowledge and skills at three time points. Observations were completed through supportive supervision of deliveries in both facilities. A budget was kept throughout the implementation. RESULTS: Knowledge scores and resuscitation skills significantly improved and were sustained over a 6-month period of time, Ps < .001. 130 supportive supervision observations were completed. Eighteen times (14%) a baby did not cry at birth and needed intervention. All were appropriately intervened for and survived the Golden Minute. The budget for this implementation was 9015.50 USD. Considering in-kind donations and financial support by the Zanzibar Ministry of Health the bottom line cost was much lower. CONCLUSION: Results indicate that participants retained knowledge and skills over time and were able to translate these skills into clinical practice. This initiative provides an alternative approach to implementing Helping Babies Breathe, relying on a small budget, local leadership and government support. TRIAL REGISTRATION: Not applicable.

Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy.

BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1-/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1-/-, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.

Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration.

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb+, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.

TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.

BACKGROUND: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular ß-amyloid (Aß) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. RESULTS: Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. CONCLUSIONS: Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aß and tau pathologies.

Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus.

Neuropathy is a major diabetic complication. While the mechanism of this neuropathy is not well understood, it is believed to result in part from deficient nerve regeneration. Work from our laboratory established that gp130 family of cytokines are induced in animals after axonal injury and are involved in the induction of regeneration-associated genes (RAGs) and in the conditioning lesion response. Here, we examine whether a reduction of cytokine signaling occurs in diabetes. Streptozotocin (STZ) was used to destroy pancreatic ß cells, leading to chronic hyperglycemia. Mice were injected with either low doses of STZ (5×60mg/kg) or a single high dose (1×200mg/kg) and examined after three or one month, respectively. Both low and high dose STZ treatment resulted in sustained hyperglycemia and functional deficits associated with the presence of both sensory and autonomic neuropathy. Diabetic mice displayed significantly reduced intraepidermal nerve fiber density and sudomotor function. Furthermore, low and high dose diabetic mice showed significantly reduced tactile touch sensation measured with Von Frey monofilaments. To look at the regenerative and injury-induced responses in diabetic mice, neurons in both superior cervical ganglia (SCG) and the 4th and 5th lumbar dorsal root ganglia (DRG) were unilaterally axotomized. Both high and low dose diabetic mice displayed significantly less axonal regeneration in the sciatic nerve, when measured in vivo, 48h after crush injury. Significantly reduced induction of two gp130 cytokines, leukemia inhibitory factor and interleukin-6, occurred in diabetic animals in SCG 6h after injury compared to controls. Injury-induced expression of interleukin-6 was also found to be significantly reduced in the DRG at 6h after injury in low and high dose diabetic mice. These effects were accompanied by reduced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the gp130 signaling pathway. We also found decreased induction of several gp130-dependent RAGs, including galanin and vasoactive intestinal peptide. Together, these data suggest a novel mechanism for the decreased response of diabetic sympathetic and sensory neurons to injury.

Helping Babies Breathe implementation in Zanzibar, Tanzania.

AIM: To assess the efficacy and feasibility of implementing Helping Babies Breathe, a neonatal resuscitation programme for resource-limited environments. BACKGROUND: This quality improvement project focused on training midwives on Helping Babies Breathe to address high rates of neonatal mortality secondary to birth asphyxia. METHODS: The convenience sample was 33 midwives in Zanzibar, Tanzania. The train-the-trainer strategy with repeated measures design was used to assess knowledge and skills at 3 time points. Observations were completed during "real-time" deliveries, and a focused interview generated feedback regarding satisfaction and sustainability. RESULTS: Knowledge scores and resuscitation skills significantly improved and were sustained, P < .05. Of the 62 birth observations, 19% needed intervention. All were appropriately resuscitated and survived. CONCLUSION: Results indicate that participants retained knowledge and skills and used them in clinical practice. Observations demonstrated that participants took appropriate actions when presented with a baby who was not breathing.

Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer's Disease.

Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate in patients with Alzheimer's disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome-changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2-6 months of age-time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)-a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma.

Axonal transport deficits precede structural loss in glaucoma and other neurodegenerations. Impairments in structural support, including modified cytoskeletal proteins, and microtubule-destabilizing elements, could be initiating factors in glaucoma pathogenesis. We investigated the time course of changes in protein levels and post-translational modifications in the DBA/2J mouse model of glaucoma. Using anterograde tract tracing of the retinal projection, we assessed major cytoskeletal and transported elements as a function of transport integrity in different stages of pathological progression. Using capillary-based electrophoresis, single- and multiplex immunosorbent assays, and immunofluorescence, we quantified hyperphosphorylated neurofilament-heavy chain, phosphorylated tau (ptau), calpain-mediated spectrin breakdown product (145/150 kDa), ß-tubulin, and amyloid-ß42 proteins based on age and transport outcome to the superior colliculus (SC; the main retinal target in mice). Phosphorylated neurofilament-heavy chain (pNF-H) was elevated within the optic nerve (ON) and SC of 8-10 month-old DBA/2J mice, but was not evident in the retina until 12-15 months, suggesting that cytoskeletal modifications first appear in the distal retinal projection. As expected, higher pNF-H levels in the SC and retina were correlated with axonal transport deficits. Elevations in hyperphosphorylated tau (ptau) occurred in ON and SC between 3 and 8 month of age while retinal ptau accumulations occurred at 12-15 months in DBA/2J mice. In vitro co-immunoprecipitation experiments suggested increased affinity of ptau for the retrograde motor complex protein dynactin. We observed a transport-related decrease of ß-tubulin in ON of 10-12 month-old DBA/2J mice, suggesting destabilized microtubule array. Elevations in calpain-mediated spectrin breakdown product were seen in ON and SC at the earliest age examined, well before axonal transport loss is evident. Finally, transport-independent elevations of amyloid-ß42, unlike pNF-H or ptau, occurred first in the retina of DBA/2J mice, and then progressed to SC. These data demonstrate distal-to-proximal progression of cytoskeletal modifications in the progression of glaucoma, with many of these changes occurring prior to complete loss of functional transport and axon degeneration. The earliest changes, such as elevated spectrin breakdown and amyloid-ß levels, may make retinal ganglion cells susceptible to future stressors. As such, targeting modification of the axonal cytoskeleton in glaucoma may provide unique opportunities to slow disease progression.

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.