Ferroptosis of Microglia in Aging Human White Matter Injury.

OBJECTIVE: Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia. METHODS: We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM. RESULTS: We found that DM, which accumulated myelin debris were selectively enriched in the iron-binding protein light chain ferritin, and accumulated PLIN2-labeled lipid droplets. DM displayed lipid peroxidation injury and enhanced expression for TOM20, a mitochondrial translocase, and a sensor of oxidative stress. DM also displayed enhanced expression of the DNA fragmentation marker phospho-histone H2A.X. We identified a unique set of ferroptosis-related genes involving iron-mediated lipid dysmetabolism and oxidative stress that were preferentially expressed in WM injury relative to gray matter neurodegeneration. INTERPRETATION: Ferroptosis appears to be a major mechanism of WM injury in Alzheimer's disease and vascular dementia. WM DM are a novel therapeutic target to potentially reduce the impact of WM injury and myelin loss on the progression of cognitive impairment. ANN NEUROL 2023;94:1048-1066.

Reversible Switch in Charge Storage Enabled by Selective Ion Transport in Solid Electrolyte Interphase.

Solid-electrolyte interphases (SEIs) in advanced rechargeable batteries ensure reversible electrode reactions at extreme potentials beyond the thermodynamic stability limits of electrolytes by insulating electrons while allowing the transport of working ions. Such selective ion transport occurs naturally in biological cell membranes as a ubiquitous prerequisite of many life processes and a foundation of biodiversity. In addition, cell membranes can selectively open and close the ion channels in response to external stimuli (e.g., electrical, chemical, mechanical, and thermal), giving rise to "gating" mechanisms that help manage intracellular reactions. We wondered whether the chemistry and structure of SEIs can mimic those of cell membranes, such that ion gating can be replicated. That is, can SEIs realize a reversible switching between two electrochemical behaviors, i.e., the ion intercalation chemistry of batteries and the ion adsorption of capacitors? Herein, we report such SEIs that result in thermally activated selective ion transport. The function of open/close gate switches is governed by the chemical and structural dynamics of SEIs under different thermal conditions, with precise behaviors as conducting and insulating interphases that enable battery and capacitive processes within a finite temperature window. Such an ion gating function is synergistically contributed by Arrhenius-activated ion transport and SEI dissolution/regrowth. Following the understanding of this new mechanism, we then develop an electrochemical method to heal the SEI layer in situ. The knowledge acquired in this work reveals the possibility of hitherto unknown biomimetic properties of SEIs, which will guide us to leverage such complexities to design better SEIs for future battery chemistries.

Radiation effects on materials for electrochemical energy storage systems.

Batteries and electrochemical capacitors (ECs) are of critical importance for applications such as electric vehicles, electric grids, and mobile devices. However, the performance of existing battery and EC technologies falls short of meeting the requirements of high energy/high power and long durability for increasing markets such as the automotive industry, aerospace, and grid-storage utilizing renewable energies. Therefore, improving energy storage materials performance metrics is imperative. In the past two decades, radiation has emerged as a new means to modify functionalities in energy storage materials. There exists a common misconception that radiation with energetic ions and electrons will always cause radiation damage to target materials, which might potentially prevent its applications in electrochemical energy storage systems. But in this review, we summarize recent progress in radiation effects on materials for electrochemical energy storage systems to show that radiation can have both beneficial and detrimental effects on various types of energy materials. Prior work suggests that fundamental understanding toward the energy loss mechanisms that govern the resulting microstructure, defect generation, interfacial properties, mechanical properties, and eventual electrochemical properties is critical. We discuss radiation effects in the following categories: (1) defect engineering, (2) interface engineering, (3) radiation-induced degradation, and (4) radiation-assisted synthesis. We analyze the significant trends and provide our perspectives and outlook on current research and future directions in research seeking to harness radiation as a method for enhancing the synthesis and performance of battery materials.

Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall.

Pharmacotherapy for major depressive disorder (MDD) typically consists of trial-and-error and clinician preference approaches, where patients often fail one or more antidepressants before finding an optimal regimen. Pharmacogenomics (PGx) can assist in prescribing appropriate antidepressants, thereby reducing the time to MDD remission and occurrence of adverse drug events. Since many antidepressants are metabolized by and/or inhibit cytochrome P450 enzymes (e.g., CYP2C19 or CYP2D6), drug-induced phenoconversion is common in patients on antidepressant combinations. This condition influences the interpretation of a patient's PGx results, overall risk of ineffective/adverse medication response due to multi-drug interactions, and the recommendations. This complex case describes a patient with MDD, generalized anxiety disorder, and chronic pain who experienced a fall due to excessive sedation following a prescribing cascade of fluoxetine, bupropion, and doxepin. These antidepressants delivered a significant additive sedative effect and interacted with the patient's hydrocodone, potentially contributing to uncontrolled pain, upward dose titration of hydrocodone, and a higher overall sedative burden. The PGx results and drug-induced phenoconversion described in this case report explain the patient's excessive sedation and possibly ineffective/toxic antidepressant and opioid treatment. This case report also illustrates how a more timely multi-drug interaction assessment (preferably in conjunction with preemptive PGx testing) may have informed a different prescribing pattern, reduced/avoided a prescribing cascade, and potentially prevented a drug-related fall.

A Comparison of Solid Electrolyte Interphase Formation and Evolution on Highly Oriented Pyrolytic and Disordered Graphite Negative Electrodes in Lithium-Ion Batteries.

The presence and stability of solid electrolyte interphase (SEI) on graphitic electrodes is vital to the performance of lithium-ion batteries (LIBs). However, the formation and evolution of SEI remain the least understood area in LIBs due to its dynamic nature, complexity in chemical composition, heterogeneity in morphology, as well as lack of reliable in situ/operando techniques for accurate characterization. In addition, chemical composition and morphology of SEI are not only affected by the choice of electrolyte, but also by the nature of the electrode surface. While introduction of defects into graphitic electrodes has promoted their electrochemical properties, how such structural defects influence SEI formation and evolution remains an open question. Here, utilizing nondestructive operando electrochemical atomic force microscopy (EChem-AFM) the dynamic SEI formation and evolution on a pair of representative graphitic materials with and without defects, namely, highly oriented pyrolytic and disordered graphite electrodes, are systematically monitored and compared. Complementary to the characterization of SEI topographical and mechanical changes during electrochemical cycling by EChem-AFM, chemical analysis and theoretical calculations are conducted to provide mechanistic insights underlying SEI formation and evolution. The results provide guidance to engineer functional SEIs through design of carbon materials with defects for LIBs and beyond.

Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans.

Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.

Humidity sensation requires both mechanosensory and thermosensory pathways in Caenorhabditis elegans.

All terrestrial animals must find a proper level of moisture to ensure their health and survival. The cellular-molecular basis for sensing humidity is unknown in most animals, however. We used the model nematode Caenorhabditis elegans to uncover a mechanism for sensing humidity. We found that whereas C. elegans showed no obvious preference for humidity levels under standard culture conditions, worms displayed a strong preference after pairing starvation with different humidity levels, orienting to gradients as shallow as 0.03% relative humidity per millimeter. Cell-specific ablation and rescue experiments demonstrate that orientation to humidity in C. elegans requires the obligatory combination of distinct mechanosensitive and thermosensitive pathways. The mechanosensitive pathway requires a conserved DEG/ENaC/ASIC mechanoreceptor complex in the FLP neuron pair. Because humidity levels influence the hydration of the worm's cuticle, our results suggest that FLP may convey humidity information by reporting the degree that subcuticular dendritic sensory branches of FLP neurons are stretched by hydration. The thermosensitive pathway requires cGMP-gated channels in the AFD neuron pair. Because humidity levels affect evaporative cooling, AFD may convey humidity information by reporting thermal flux. Thus, humidity sensation arises as a metamodality in C. elegans that requires the integration of parallel mechanosensory and thermosensory pathways. This hygrosensation strategy, first proposed by Thunberg more than 100 y ago, may be conserved because the underlying pathways have cellular and molecular equivalents across a wide range of species, including insects and humans.

Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci. METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aß proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aß toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex. DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

Chronic Pain Management in a CYP2D6 Poor Metabolizer: A Case Report for Oxycodone.

The objective of this case report is to illustrate pharmacogenomics (PGx)-guided oxycodone treatment, given the conflicting data on the analgesic response from oxycodone in Cytochrome P450 (CYP)2D6 poor metabolizers (PMs). PGx-guided therapy can help improve treatment outcomes. This case report describes a 58-year-old patient who was prescribed oxycodone for chronic pain management. The patient presented with a history of inadequate pain control despite analgesic treatment with oxycodone (morphine milliequivalent [MME] = 22.5). Pharmacogenetic testing revealed that the patient was a CYP2D6 Poor Metabolizer (PM), which may shed light on the observed lack of analgesic response to oxycodone. The clinical pharmacist recommended switching to an alternative opioid not metabolized via the CYP2D6 pathway. The patient was subsequently switched to hydromorphone (MME = 16), resulting in improved pain control and fewer side effects. The newer hydromorphone dose accounted for a 30% MME dose reduction. The patient's initial average and worst pain score were 7 and 9 out of 10, respectively, per the numeric rating scale (NRS). Upon follow-up with the patient in two weeks, her average and worst pain scores improved to 3 and 3.5 out of 10, respectively, per the NRS. Further PGx testing results led to an overall positive outcome, such as her willingness to participate in physical therapy as a result of improved pain scores. This case highlights the importance of considering individual variability in drug metabolism when prescribing medications, particularly opioids such as oxycodone, to ensure optimal therapeutic outcomes and minimize the risk of adverse events in CYP2D6 PMs.

Hatchery supplementation provides a demographic boost but alters age composition of sockeye salmon in Auke Lake, Southeast Alaska.

Evaluating salmon hatchery supplementation programs requires assessing not only program objectives but identifying potential risks to wild populations as well. Such evaluations can be hampered by difficulty in distinguishing between hatchery- and wild-born returning adults. Here, we conducted 3 years (2011-2013) of experimental hatchery supplementation of sockeye salmon in Auke Lake, Juneau, Alaska where a permanent weir allows sampling and genotyping of every returning adult (2008-2019). We identified both hatchery- and wild-born returning adults with parentage assignment, quantified the productivity (adult offspring/spawner) of hatchery spawners relative to that of wild spawners, and compared run timing, age, and size at age between hatchery- and wild-born adults. Hatchery-spawning females produced from approximately six to 50 times more returning adults than did naturally spawning females. Supplementation had no discernable effect on run timing and limited consequences for size at age, but we observed a distinct shift to younger age at maturity in the hatchery-born individuals in all three brood years. The shift appeared to be driven by hatchery-born fish being more likely to emigrate after one, rather than two, years in the lake but the cause is unknown. In cases when spawning or incubation habitat is limiting sockeye salmon production, hatchery supplementation can be effective for enhancing the number of returning adult fish but not without the risk of phenotypic change in the recipient population, which can be an undesired outcome of hatchery supplementation. This study adds to a growing body of evidence suggesting that phenotypic change within a single generation of captive spawning might be widespread in salmon hatchery programs.

Alterations in mast cell frequency and relationship to angiogenesis in the rat mammary gland during windows of physiologic tissue remodeling.

BACKGROUND: The mammary epithelium undergoes proliferation and regression accompanied by remodeling of the fibrocellular and vascular stroma. Mast cells are abundant in these compartments and have been implicated in remodeling during wound healing and cancer progression. The purpose of this study was to test the hypothesis that mast cell abundance correlates with physiologic mammary tissue remodeling during estrous cycling, lactogenesis (pregnancy and lactation) and involution. RESULTS: Mast cell and capillary frequency were quantified in the stroma surrounding ducts and lobules from mammary glands of rats. During estrous cycling, periductal mast cell numbers were unchanged, but lobule-associated mast cells significantly increased in the regressive phase of diestrus II. During lactogenesis, lobular stroma mast cells peaked early in pregnancy, at D2, followed by a significant decrease throughout lactation. Involution was associated with a rapid return in mast cell numbers, similar to diestrus II. Lobular vascularization peaked during the state of metestrus, when limited secretory differentiation occurs. Lobular angiogenesis peaked at D7 of pregnancy, regressed, and then returned to high levels during lactation and early involution, when secretory differentiation is high. CONCLUSIONS: These results suggest mast cells are predominantly associated with regressive lobular remodeling during cycling and involution, whereas angiogenesis is predominantly associated with secretory differentiation.

Reproductive success of jack and full-size males in a wild coho salmon population.

Despite the wealth of research on Pacific salmon Oncorhynchus spp. life histories there is limited understanding of the lifetime reproductive success of males that spend less time at sea and mature at a smaller size (jacks) than full-size males. Over half of returning male spawners can be jacks in some populations, so it is crucial to understand their contribution to population productivity. We quantified adult-to-adult reproductive success (RS) of jacks and their relative reproductive success (RRS) compared to full-size males in a wild population of coho salmon in the Auke Creek watershed, Juneau, Alaska. We used genetic data from nearly all individuals (approx. 8000) returning to spawn over a decade (2009-2019) to conduct parentage analysis and calculate individual RS. The average adult-to-adult RS of jacks (mean = 0.7 and s.e. = 0.1) was less than that of full-size males (mean = 1.1 and s.e. = 0.1). Jack RRS was consistently below 1.0 but ranged widely (0.23 to 0.96). Despite their lower average success, jacks contributed substantially to the population by siring 23% of the total returning adult offspring (1033 of 4456) produced between 2009 and 2015. Our results imply that jacks can affect evolutionary and population dynamics, and are relevant to the conservation and management of Pacific salmon.

An objective analysis of composite free flap donor site morbidity in head and neck surgery: Prospective series.

BACKGROUND: A poor evidence basis exists regarding the objective donor site morbidity associated with osseous free flap harvest. This study prospectively assessed the objective donor site morbidity associated with osseous free flap harvest for the fibula, scapula, and iliac crest (DCIA) donor sites. METHODS: A single-site, prospective cohort clinical research study was conducted. Sixty-four patients were recruited between 2017 and 2021. Patients were assessed using a donor site specific assessment tool pre-operatively, and again >12 months post-operatively. RESULTS: There was a significant reduction post-operatively in assessment tool scores compared to the pre-operative period for the fibula, scapula and DCIA. Females were more likely to report a greater reduction in Harris Hip Score post-operatively compared to males. CONCLUSIONS: The fibula, scapula, and DCIA donor sites are associated with reduced objective function post-operatively compared to patient's pre-operative baseline. The implications are least pronounced for the fibula.

Pharmacogenetic Testing in a 70-Year-Old Woman with Polypharmacy and Multiple Comorbidities: A Case Report.

BACKGROUND Comorbidities and polypharmacy are difficult to manage, as polypharmacy hinders identification and prevention of medication-related problems. Risk for adverse drug events (ADEs) can be minimized through pharmacogenomic (PGx) testing and related therapeutic adjustments. CASE REPORT A 70-year-old woman with comorbidities and medications enrolled in the Program of All-inclusive Care for the Elderly presented with left lower extremity (LLE) pain, generalized weakness, and major depressive disorder. The provider requested a medication safety review, where the clinical pharmacist-recommended PGx testing given the LLE pain and weakness while taking a statin and inconsistent INR readings taking warfarin. The pharmacist recommended switching atorvastatin to pravastatin to minimize the risk for statin-associated ADEs due to CYP3A4 inhibition and switching fluoxetine to citalopram due to uncontrolled depression/anxiety and to mitigate drug-drug interactions with carvedilol to reduce the risk of orthostatic hypotension. Recommendations were accepted and upon follow-up the patient reported minor LLE pain and improved wellbeing on citalopram. Following PGx testing, the patient had decreased function at SLCO1B1 and was an intermediate metabolizer for CYP2C9 and CYP2D6. This case demonstrates how preemptive PGx testing would have identified drug-gene interactions (DGIs) at the time of prescribing and reduced the risk of statin-associated muscular symptoms, highlighting the utility of panel-based PGx testing in older adults at high risk for ADEs and/or therapy failure. CONCLUSIONS Decreased function at SLCO1B1 increases exposure to statins, leading to statin-induced myalgias, as displayed in this case. PGx testing can help identify DGIs, choose optimal therapies in medically complex older adults, and minimize ADE risk.

Alternative life-history strategy contributions to effective population size in a naturally spawning salmon population.

Alternative life-history tactics are predicted to affect within-population genetic processes but have received little attention. For example, the impact of precocious males on effective population size (N e) has not been quantified directly in Pacific salmon Oncorhynchus spp., even though they can make up a large percentage of the total male spawners. We investigated the contribution of precocial males ("jacks") to N e in a naturally spawning population of Coho Salmon O. kisutch from the Auke Creek watershed in Juneau, Alaska. Mature adults that returned from 2009 to 2019 (~8000 individuals) were genotyped at 259 single-nucleotide polymorphism (SNP) loci for parentage analysis. We used demographic and genetic methods to estimate the effective number of breeders per year (N b). Jack contribution to N b was assessed by comparing values of N b calculated with and without jacks and their offspring. Over a range of N b values (108-406), the average jack contribution to N b from 2009 to 2015 was 12.9% (SE = 3.8%). Jacks consistently made up over 20% of the total male spawners. The presence of jacks did not seem to influence N b/N. The linkage disequilibrium N e estimate was lower than the demographic estimate, possibly due to immigration effects on population genetic processes: based on external marks and parentage data, we estimated that immigrant spawners produced 4.5% of all returning offspring. Our results demonstrate that jacks can influence N b and N e and can make a substantial contribution to population dynamics and conservation of threatened stocks.

Introduction to a Twin Dual-Axis Robotic Platform for Studies of Lower Limb Biomechanics.

This paper presents a twin dual-axis robotic platform system which is designed for the characterization of postural balance under various environmental conditions and quantification of bilateral ankle mechanics in 2 degrees-of-freedom (DOF) during standing and walking. Methods: Validation experiments were conducted to evaluate performance of the system: 1) to apply accurate position perturbations under different loading conditions; 2) to simulate a range of stiffness-defined mechanical environments; and 3) to reliably quantify the joint impedance of mechanical systems. In addition, several human experiments were performed to demonstrate the system's applicability for various lower limb biomechanics studies. The first two experiments quantified postural balance on a compliance-controlled surface (passive perturbations) and under oscillatory perturbations with various frequencies and amplitudes (active perturbations). The second two experiments quantified bilateral ankle mechanics, specifically, ankle impedance in 2-DOF during standing and walking. The validation experiments showed high accuracy of the platform system to apply position perturbations, simulate a range of mechanical environments, and quantify the joint impedance. Results of the human experiments further demonstrated that the platform system is sensitive enough to detect differences in postural balance control under challenging environmental conditions as well as bilateral differences in 2-DOF ankle mechanics. This robotic platform system will allow us to better understand lower limb biomechanics during functional tasks, while also providing invaluable knowledge for the design and control of many robotic systems including robotic exoskeletons, prostheses and robot-assisted balance training programs. Clinical and Translational Impact Statement- Our robotic platform system serves as a tool to better understand the biomechanics of both healthy and neurologically impaired individuals and to develop assistive robotics and rehabilitation training programs using this information.

Direct effects of conjugated linoleic acid isomers on P815 mast cells in vitro.

Conjugated linoleic acid (CLA) is a dietary fatty acid which causes extensive remodeling and mast cell recruitment in the mouse mammary gland. Two CLA isomers, 9,11- and 10,12-CLA, have differing effects in vivo, with only 10,12-CLA increasing mast cell number. The purpose of this project is to test the hypothesis that CLA acts directly on the mast cell. The P815 mastocytoma cell line was assayed for the effects of CLA on mast cell number, proliferation, apoptosis, and differentiation. Both CLA isomers decreased viable mast cell number, with no effect on membrane integrity, or cell cycle distribution. 10,12-CLA induced an increase in apoptosis, assessed by Annexin-FITC binding. Both isomers increased mast cell granularity, and secretion of MMP-9. The complex effects of CLA isomers on mast cells in the mammary gland are distinct from direct effects on mast cells in vitro, and may require interactions between multiple cell types present in vivo.

I'll have what she's having: the impact of model characteristics on children's food choices.

This research investigates children's use of social categories in their food selection. Across three studies, we presented preschoolers with sets of photographs that contrasted food-eating models with different characteristics, including model gender, race (Black, White), age (child or adult), and/or expression (acceptance or rejection of the food). Children were asked to pick between the photographs to choose which food they would like for snack. Results demonstrated that preschoolers prefer foods being eaten by models with positive over negative expressions, foods being eaten by child over adult models, and foods being eaten by child models of the same gender as themselves over models of the other gender. This work connects with previous research on children's understanding of social categories and also has important practical implications for how characteristics of a food-eating model can affect children's willingness to try new foods.

The Well-being and Instructional Experiences of K-12 Music Educators: Starting a New School Year During a Pandemic.

In adapting to remote emergency teaching modes during pandemic-imposed conditions, teachers' instruction has changed dramatically. Early research indicates that the well-being of music teachers has suffered during the COVID-19 pandemic and that high levels of depression are widespread. The purpose of this survey study was to assess the continued psychological well-being of music teachers working amid a global pandemic based upon previous research we conducted during the Spring 2020 semester when most teachers in the United States were forced into emergency remote teaching. A secondary purpose was to explore the ways that pandemic conditions have affected music teachers' sense of safety at work and their current teaching situations. Our questionnaire consisted of sections pertaining to (1) demographic and institutional information, (2) well-being and depression, (3) instructional format and preparedness, (4) teaching efficacy compared to the start of the pandemic, and (5) potential positive outcomes of the pandemic-imposed adjustments. In total, 1,325 music teachers responded to our survey. Overall, the participants reported poorer well-being than both published norms and the sample of participants in our previous study. In addition, 17% reported mild depression, 25% reported moderate depression, and 24% reported severe extremely severe levels of depression. Summaries of the participants instructional experiences and their implications for music education are discussed within.