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1.
PLoS Biol ; 21(2): e3002000, 2023 02.
Article in English | MEDLINE | ID: mdl-36787309

ABSTRACT

Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR's precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.


Subject(s)
Autoimmune Diseases , Multiple Sclerosis , Mice , Animals , Autoimmunity , T-Lymphocytes , Neuroinflammatory Diseases , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism
2.
FASEB J ; 38(15): e23872, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39126272

ABSTRACT

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.


Subject(s)
Fingolimod Hydrochloride , Neuralgia , Paclitaxel , Animals , Fingolimod Hydrochloride/pharmacology , Paclitaxel/pharmacology , Neuralgia/chemically induced , Neuralgia/drug therapy , Neuralgia/metabolism , Neuralgia/pathology , Mice , Female , Calcium-Binding Proteins/metabolism , Calcium-Binding Proteins/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Astrocytes/metabolism , Astrocytes/drug effects , Extracellular Matrix Proteins/metabolism , Extracellular Matrix Proteins/genetics , Cell Line, Tumor , Sphingosine-1-Phosphate Receptors/metabolism , Humans , Disease Progression , Antineoplastic Agents, Phytogenic/pharmacology , Glial Fibrillary Acidic Protein/metabolism , Glial Fibrillary Acidic Protein/genetics
3.
J Lipid Res ; 65(6): 100556, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38719150

ABSTRACT

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative cholesterol and sphingolipid storage disorder primarily due to mutations in the cholesterol-trafficking protein NPC1. In addition to catabolic-derived sphingolipids, NPC1 dysfunction also leads to an increase in de novo sphingolipid biosynthesis, yet little is known about the cellular mechanism involved. Although deletion of NPC1 or inhibition of the NPC1 sterol binding domain enhanced de novo sphingolipid biosynthesis, surprisingly levels of the ORMDLs, the regulatory subunits of serine palmitoyltransferase (SPT), the rate-limiting step in sphingolipid biosynthesis, were also greatly increased. Nevertheless, less ORMDL was bound in the SPT-ORMDL complex despite elevated ceramide levels. Instead, ORMDL colocalized with p62, the selective autophagy receptor, and accumulated in stalled autophagosomes due to defective autophagy in NPC1 disease cells. Restoration of autophagic flux with N-acetyl-L-leucine in NPC1 deleted cells decreased ORMDL accumulation in autophagosomes and reduced de novo sphingolipid biosynthesis and their accumulation. This study revealed a previously unknown link between de novo sphingolipid biosynthesis, ORMDL, and autophagic defects present in NCP1 disease. In addition, we provide further evidence and mechanistic insight for the beneficial role of N-acetyl-L-leucine treatment for NPC1 disease which is presently awaiting approval from the Food and Drug Administration and the European Medicines Agency.


Subject(s)
Autophagy , Niemann-Pick Disease, Type C , Sphingolipids , Sphingolipids/metabolism , Sphingolipids/biosynthesis , Niemann-Pick Disease, Type C/metabolism , Niemann-Pick Disease, Type C/pathology , Niemann-Pick Disease, Type C/genetics , Humans , Membrane Proteins/metabolism , Membrane Proteins/genetics , Animals , Niemann-Pick C1 Protein , Serine C-Palmitoyltransferase/metabolism , Serine C-Palmitoyltransferase/genetics , Serine C-Palmitoyltransferase/antagonists & inhibitors
4.
J Am Chem Soc ; 146(19): 13391-13398, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38691098

ABSTRACT

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

5.
Magn Reson Med ; 91(5): 2188-2199, 2024 May.
Article in English | MEDLINE | ID: mdl-38116692

ABSTRACT

PURPOSE: The purpose of this work was to design and build a coil for quadri-nuclear MRI of the human brain at 7 T. METHODS: We built a transmit/receive triple-tuned (45.6 MHz for 2 $$ {}^2 $$ H, 78.6 MHz for 23 $$ {}^{23} $$ Na, and 120.3 MHz for 31 $$ {}^{31} $$ P) quadrature four-rod birdcage that was geometrically interleaved with a transmit/receive four-channel dipole array (297.2 MHz for 1 $$ {}^1 $$ H). The birdcage rods contained passive, two-pole resonant circuits that emulated capacitors required for single-tuning at three frequencies. The birdcage assembly also included triple-tuned matching networks, baluns, and transmit/receive switches. We assessed the performance of the coil with quality factor (Q) and signal-to-noise ratio (SNR) measurements, and performed in vivo multinuclear MRI and MR spectroscopic imaging (MRSI). RESULTS: Q measurements showed that the triple-tuned birdcage efficiency was within 33% of that of single-tuned baseline birdcages at all three frequencies. The quadri-tuned coil SNR was 78%, 59%, 44%, and 48% lower than that of single or dual-tuned reference coils for 1 $$ {}^1 $$ H, 2 $$ {}^2 $$ H, 23 $$ {}^{23} $$ Na, and 31 $$ {}^{31} $$ P, respectively. Quadri-nuclear MRI and MRSI was demonstrated in brain in vivo in about 30 min. CONCLUSION: While the SNR of the quadruple tuned coil was significantly lower than dual- and single-tuned reference coils, it represents a step toward truly simultaneous quadri-nuclear measurements.


Subject(s)
Magnetic Resonance Imaging , Pyrimidines , Sodium , Strobilurins , Humans , Phantoms, Imaging , Equipment Design , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy , Sodium/chemistry
6.
Psychosom Med ; 86(7): 615-624, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-38787553

ABSTRACT

OBJECTIVE: American Indian/Alaska Native (AI/AN) people have high rates of physical pain. Pain is understudied in urban-dwelling, AI/AN emerging adults, a group with unique sociocultural risk and protective factors. We explore associations between socioeconomic disadvantage, additional sociocultural factors, and pain among urban AI/AN emerging adults. METHODS: AI/AN participants aged 18-25 years ( N = 417) were recruited via social media. Regression models tested associations between socioeconomic disadvantage (income and ability to afford health care) and pain as well as additional sociocultural factors (discrimination, historical loss, cultural pride and belonging, visiting tribal lands) and pain. Multigroup regression models tested whether associations between sociocultural factors and pain differed between participants who were socioeconomically disadvantaged and those who were less disadvantaged. RESULTS: In the full sample, lower income ( b = 1.00-1.48, p < .05), inability to afford health care ( b = 1.00, p = .011), discrimination ( b = 0.12, p = .001), and historical loss ( b = 0.24, p = .006) were positively associated with pain, whereas visiting tribal lands was negatively associated with pain ( b = -0.86 to -0.42, p < .05). In the multigroup model, visiting tribal lands 31+ days was negatively associated with pain only among the less socioeconomically disadvantaged group ( b = -1.48, p < .001). CONCLUSIONS: Socioeconomic disadvantage may, in part, drive pain disparities among AI/AN emerging adults and act as a barrier to benefitting from visiting tribal lands. Results support a biopsychosocial approach to targeting pain in this population, including addressing socioeconomic challenges and developing culturally informed, strengths-based interventions.


Subject(s)
American Indian or Alaska Native , Pain , Protective Factors , Adolescent , Adult , Female , Humans , Male , Young Adult , American Indian or Alaska Native/statistics & numerical data , Pain/ethnology , Pain/epidemiology , Risk Factors , Socioeconomic Factors , Urban Population/statistics & numerical data
7.
Psychosom Med ; 86(4): 349-358, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38446714

ABSTRACT

OBJECTIVE: Sleep quality is an important health-protective factor. Psychosocial factors, including attachment orientation, may be valuable for understanding who is at risk of poor sleep quality and associated adverse health outcomes. High attachment anxiety is reliably associated with adverse health outcomes, whereas high attachment avoidance is associated with adverse health outcomes when co-occurring with poor self-regulatory capacity, indexed by heart rate variability (HRV). We examined the associations between attachment anxiety, attachment avoidance, HRV, and sleep quality. METHODS: Using longitudinal data from a sample of 171 older adults measured four times over 1 year ( M = 66.18 years old; 67.83% women), we separated the between-person variance (which we call "trait") and within-person variance (which we call "state") for attachment anxiety, attachment avoidance, and HRV (via the root mean square of successive differences). Sleep quality was measured with the Pittsburgh Sleep Quality Index. RESULTS: Higher trait attachment anxiety was associated with poorer global sleep quality ( B = 0.22, p = .005). Higher state attachment avoidance was associated with poorer sleep quality ( B = -0.13, p = .01), except for those with higher trait HRV. Higher state attachment anxiety was associated with poorer sleep quality ( B = -0.15, p = .002), except for those with higher or mean trait HRV. Higher trait attachment anxiety was associated with poorer sleep quality ( B = -0.31, p = .02), except for those with higher trait HRV. CONCLUSIONS: High trait HRV mitigated the adverse effects of attachment insecurity on sleep quality. Our results suggest that people with high trait HRV had greater self-regulation capacity, which may enable them to enact emotion regulation strategies effectively.


Subject(s)
Anxiety , Heart Rate , Object Attachment , Sleep Quality , Humans , Female , Heart Rate/physiology , Male , Aged , Anxiety/physiopathology , Middle Aged , Longitudinal Studies
8.
FASEB J ; 37(3): e22799, 2023 03.
Article in English | MEDLINE | ID: mdl-36753412

ABSTRACT

Genome-wide association studies have linked the ORM (yeast)-like protein isoform 3 (ORMDL3) to asthma severity. Although ORMDL3 is a member of a family that negatively regulates serine palmitoyltransferase (SPT) and thus biosynthesis of sphingolipids, it is still unclear whether ORMDL3 and altered sphingolipid synthesis are causally related to non-Th2 severe asthma associated with a predominant neutrophil inflammation and high interleukin-17 (IL-17) levels. Here, we examined the effects of ORMDL3 overexpression in a preclinical mouse model of allergic lung inflammation that is predominantly neutrophilic and recapitulates many of the clinical features of severe human asthma. ORMDL3 overexpression reduced lung and circulating levels of dihydrosphingosine, the product of SPT. However, the most prominent effect on sphingolipid levels was reduction of circulating S1P. The LPS/OVA challenge increased markers of Th17 inflammation with a predominant infiltration of neutrophils into the lung. A significant decrease of neutrophil infiltration was observed in the Ormdl3 transgenic mice challenged with LPS/OVA compared to the wild type and concomitant decrease in IL-17, that plays a key role in the pathogenesis of neutrophilic asthma. LPS decreased survival of murine neutrophils, which was prevented by co-treatment with S1P. Moreover, S1P potentiated LPS-induced chemotaxis of neutrophil, suggesting that S1P can regulate neutrophil survival and recruitment following LPS airway inflammation. Our findings reveal a novel connection between ORMDL3 overexpression, circulating levels of S1P, IL-17 and neutrophil recruitment into the lung, and questions the potential involvement of ORMDL3 in the pathology, leading to development of severe neutrophilic asthma.


Subject(s)
Asthma , Interleukin-17 , Membrane Proteins , Animals , Humans , Mice , Asthma/metabolism , Genome-Wide Association Study , Inflammation/metabolism , Interleukin-17/genetics , Interleukin-17/therapeutic use , Lipopolysaccharides , Membrane Proteins/metabolism , Mice, Transgenic , Sphingolipids/metabolism
9.
Brain Behav Immun ; 115: 458-469, 2024 01.
Article in English | MEDLINE | ID: mdl-37924959

ABSTRACT

The gut microbiome consists of trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea, has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea: L. intestinalis and L. murinus. Using this microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFNγ levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and provide novel methods to study potential therapies to treat mood disorders.


Subject(s)
Gastrointestinal Microbiome , Lactobacillus , Probiotics , Resilience, Psychological , Animals , Mice , Gastrointestinal Tract/microbiology , Homeostasis , Probiotics/pharmacology
10.
Brain Behav Immun ; 119: 665-680, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38579936

ABSTRACT

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression.


Subject(s)
Depression , Dysbiosis , Gastrointestinal Microbiome , Stress, Psychological , Animals , Male , Mice , Behavior, Animal/physiology , Depression/metabolism , Depression/microbiology , Dysbiosis/metabolism , Dysbiosis/microbiology , Gastrointestinal Microbiome/physiology , Hepatocyte Nuclear Factor 4/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mucins/metabolism , Stress, Psychological/metabolism , Stress, Psychological/microbiology
11.
Prev Sci ; 25(2): 330-346, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37923885

ABSTRACT

American Indian/Alaska Native (AI/AN) communities are disproportionately affected by the opioid epidemic. AI/AN emerging adults (ages 18-25) in urban areas are at particularly high risk, with the overdose death rate among urban-dwelling AI/AN people 1.4 times higher than rural-dwelling AI/AN people. Despite these challenges, there are no evidence-based culturally tailored prevention or intervention programs to address opioid, alcohol and other drug use among urban AI/AN emerging adults. This study focused on understanding AI/AN emerging adults' experiences with two culturally tailored programs addressing opioid, cannabis, and alcohol use as part of the randomized controlled trial for Traditions and Connections for Urban Native Americans (TACUNA) in order to enhance feasibility of this intervention. Using a convergent mixed methods design at 3-month follow-up, we collected satisfaction and experience ratings and written narratives (total n = 162; intervention n = 77; control n = 85) from a sample of urban-dwelling AI/AN emerging adults who participated in both programs. We analyzed data through simultaneous examination of qualitative and quantitative data. The quantitative ratings show that both programs were rated highly. The qualitative data contextualized these ratings, illustrating pathways through which specific components were perceived to cause desired or observed behavioral change in participants. Among the elements that mattered most to these participants were the convenience of the virtual format, having a comfortable and safe space to share personal stories, and learning new information about their social networks. Negative comments focused on workshop length and inconvenient scheduling. This is one of the first studies to explore participant satisfaction and experience with culturally tailored substance use programming among a historically marginalized and understudied population. It is important to consider the voices of urban-dwelling AI/AN people in program development because hidden factors, such as limited financial resources, limited time, and misalignment with cultural values may prevent existing programs from being feasible.


Subject(s)
American Indian or Alaska Native , Patient Satisfaction , Substance-Related Disorders , Adolescent , Adult , Humans , Young Adult , Analgesics, Opioid , Substance-Related Disorders/prevention & control
12.
J Adolesc ; 96(6): 1316-1327, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38757459

ABSTRACT

BACKGROUND: Urban American Indian/Alaska Native (AI/AN) adolescents are vulnerable to sleep and other health-related disparities due to numerous social drivers, including historical trauma and relocation to urban areas. This study aims to identify strategies to increase protective factors and culturally tailor sleep health interventions for this population. METHODS: Using community-based participatory research, the NAYSHAW study conducted in-depth interviews with urban AI/AN adolescents aged 12-19 years to understand critical components needed for developing a culturally sensitive sleep health intervention. Data from two qualitative subsamples (N = 46) and parent surveys (N = 110) were analyzed, focusing on factors that affect sleep health behaviors, including parental involvement, technology, and traditional practices. RESULTS: Key findings include the detrimental impact of electronics use at night and protective effects of traditional practices on sleep. Parental involvement in sleep routines varied by adolescent's age. Adolescents desired sleep health education in interactive formats, whereas parents preferred workshops and digital applications for sleep health strategies. Findings suggest that interventions need to address electronics use and should also be culturally tailored to address the unique experiences of urban AI/AN adolescents. CONCLUSIONS: Results underscore the importance of utilizing community-based strategies to develop culturally tailored sleep interventions for underserved populations, specifically urban AI/AN adolescents. Integrating traditional practices with evidence-based sleep health strategies can provide a holistic approach to improving sleep and overall well-being. Parental education and involvement will be critical to the success of such interventions.


Subject(s)
Alaska Natives , Indians, North American , Urban Population , Humans , Adolescent , Female , Male , Alaska Natives/psychology , Child , Young Adult , Indians, North American/psychology , Community-Based Participatory Research , Sleep
13.
Sensors (Basel) ; 24(12)2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38931494

ABSTRACT

Due to limitations in current motion tracking technologies and increasing interest in alternative sensors for motion tracking both inside and outside the MRI system, in this study we share our preliminary experience with three alternative sensors utilizing diverse technologies and interactions with tissue to monitor motion of the body surface, respiratory-related motion of major organs, and non-respiratory motion of deep-seated organs. These consist of (1) a Pilot-Tone RF transmitter combined with deep learning algorithms for tracking liver motion, (2) a single-channel ultrasound transducer with deep learning for monitoring bladder motion, and (3) a 3D Time-of-Flight camera for observing the motion of the anterior torso surface. Additionally, we demonstrate the capability of these sensors to simultaneously capture motion data outside the MRI environment, which is particularly relevant for procedures like radiation therapy, where motion status could be related to previously characterized cyclical anatomical data. Our findings indicate that the ultrasound sensor can track motion in deep-seated organs (bladder) as well as respiratory-related motion. The Time-of-Flight camera offers ease of interpretation and performs well in detecting surface motion (respiration). The Pilot-Tone demonstrates efficacy in tracking bulk respiratory motion and motion of major organs (liver). Simultaneous use of all three sensors could provide complementary motion information outside the MRI bore, providing potential value for motion tracking during position-sensitive treatments such as radiation therapy.


Subject(s)
Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Respiration , Liver/diagnostic imaging , Liver/physiology , Movement/physiology , Urinary Bladder/diagnostic imaging , Urinary Bladder/physiology , Algorithms , Deep Learning , Motion , Ultrasonography/methods
14.
Am J Physiol Heart Circ Physiol ; 325(1): H149-H162, 2023 07 01.
Article in English | MEDLINE | ID: mdl-37204873

ABSTRACT

Patients with two congenital heart diseases (CHDs), Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.R237C) in the gene encoding Kelch-like protein 26 (KLHL26) by differentiating induced pluripotent stem cells (iPSCs) generated from affected and unaffected family members into cardiomyocytes (iPSC-CMs) and assessing iPSC-CM morphology, function, gene expression, and protein abundance. Compared with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo(sarco)plasmic reticulum (ER/SR) and dysmorphic mitochondria and aberrant function that included decreased contractions per minute, altered calcium transients, and increased proliferation. Pathway enrichment analyses based on RNASeq data indicated that the "structural constituent of muscle" pathway was suppressed, whereas the "ER lumen" pathway was activated. Taken together, these findings suggest that iPSC-CMs containing this KLHL26 (p.R237C) variant develop dysregulated ER/SR, calcium signaling, contractility, and proliferation.NEW & NOTEWORTHY We demonstrate here that iPSCs derived from patients with Ebstein's anomaly and left ventricular noncompaction, when differentiated into cardiomyocytes, display significant structural and functional changes that offer insight into disease pathogenesis, including altered ER/SR and mitochondrial morphology, contractility, and calcium signaling.


Subject(s)
Ebstein Anomaly , Induced Pluripotent Stem Cells , Humans , Ebstein Anomaly/genetics , Ebstein Anomaly/metabolism , Ebstein Anomaly/pathology , Induced Pluripotent Stem Cells/metabolism , Myocytes, Cardiac/metabolism , Cell Differentiation , Calcium Signaling
15.
FASEB J ; 36(7): e22372, 2022 07.
Article in English | MEDLINE | ID: mdl-35639028

ABSTRACT

Non-alcoholic steatohepatitis (NASH) results from the accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well-characterized clinical and histological pathology for NASH-driven HCC in humans, its etiology remains unclear and there is a deficiency in pre-clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high-fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on the chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC-related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH-driven HCC that can be utilized for future molecular mechanistic studies of this disease.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Animals , Carcinoma, Hepatocellular/metabolism , Diet, Western/adverse effects , Fibrosis , Inflammation/complications , Liver Neoplasms/metabolism , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/metabolism
16.
Am J Hum Biol ; 35(7): e23886, 2023 07.
Article in English | MEDLINE | ID: mdl-36862016

ABSTRACT

OBJECTIVE: Research regarding ongoing epidemic or pandemic events is often proximate, focusing on the immediate need to understand the epidemiology of the outbreak and the populations at highest risk for negative outcomes. There are other characteristics of pandemics that can only be uncovered after time has passed, and some long-lasting health consequences may not be directly linked to infection with or disease from the pandemic pathogen itself. METHODS: We discuss the emerging literature on observations delayed care during the COVID-19 pandemic and the potential population health consequences of this phenomenon in postpandemic years, especially for conditions such as cardiovascular disease, cancer, and reproductive health. RESULTS: Delayed care has occurred for various conditions since the beginning of the COVID-19 pandemic, but the drivers for those delays have yet to be thoroughly investigated. While delayed care can be either voluntary or involuntary, the determinants of delayed care often intersect with systemic inequalities that are important to understand for pandemic responses and future preparedness. CONCLUSION: Human biologists and anthropologists are well poised to lead the research on postpandemic population health consequences of delayed care.


Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Pandemics , Health Personnel
17.
Acta Radiol ; 64(9): 2570-2577, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37470466

ABSTRACT

BACKGROUND: Wrist pain in the extended or extended weightbearing positions may be incompletely evaluated using standard magnetic resonance imaging (MRI) with standard rigid clamshell coils in the neutral position. PURPOSE: To evaluate a flexible 24-channel glove coil and harness when imaging the wrist in neutral, dorsally extended, and weightbearing positions. MATERIAL AND METHODS: Ten wrists in 10 asymptomatic volunteers (mean age = 29 years) were scanned. Participants underwent 3-T MRI using the harness and flexible glove coil, acquiring sagittal turbo spin echo (TSE) and half-Fourier acquisition single-shot turbo spin echo (HASTE) pulse sequences. Static TSE images were obtained in neutral, extended, and weightbearing positions using proton density parameters and independently evaluated by two radiologists for: dorsal radiocarpal ligament thickness; radiocapitate, radiolunate, and capitatolunate angles; palmar translation of the lunate on the radius; angulation of the extensor tendons; and distance from the distal extensor retinaculum to Lister's tubercle. Cine HASTE images were dynamically acquired between neutral-maximum extension to measure the radiocapitate angle. RESULTS: Good reader agreement was observed (r > 0.73) for all measurements except palmar translation in the neutral position (r = 0.27). Significant increases in dorsal radiocarpal ligament thickness; radiocapitate, radiolunate and capitolunate angulation; and extensor tendon angulation were observed between the neutral and extended positions (P < 0.001). A further significant increase in these metrics between extended and weightbearing positions was also seen (P < 0.01). CONCLUSION: Significant increases in dorsal radiocarpal ligament thickness, articular and tendon angulations occur during wrist extension, that further increase with dorsal weightbearing.


Subject(s)
Wrist Joint , Wrist , Humans , Adult , Wrist/diagnostic imaging , Pilot Projects , Biomechanical Phenomena , Wrist Joint/diagnostic imaging , Magnetic Resonance Imaging/methods , Volunteers , Ligaments, Articular , Weight-Bearing
18.
J Pers Assess ; : 1-10, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-38084881

ABSTRACT

Researchers have developed numerous individual differences measures to assess people's endorsement of honor ideology (i.e., beliefs regarding the importance of honor and reputation) with most ranging from 12-36 items in length. Despite having great utility, the length of these measures magnifies the costs associated with survey research, especially in research contexts that use large, representative samples (e.g., health surveys). The present study aimed to develop and validate single-item measures that assess participants' agreement with gender-specific honor prototypes, as well as short-form versions of the honor ideology for manhood (HIM) and honor ideology for womanhood (HIW) scales. An initial sample of participants (N = 879) completed single-item honor prototype measures, a battery of previously validated honor measures (including the HIM and HIW), and measures of constructs previously shown to be related to the dynamics of honor (e.g., aggression, firearm ownership). A second sample of participants (N = 100) completed the new measures, as well as an abbreviated battery of honor measures, to examine test-retest reliability. Results indicated that the new, brief measures were strongly correlated with both the original HIM and HIW as well as several other established honor measures. Moreover, the associations between these new measures and honor-related outcomes were nearly identical to those found with the original HIM and HIW. Our new measures also demonstrated acceptable test-retest reliability, despite being single-item scales. Overall, the present work provides preliminary support for several brief measures of honor endorsement that researchers can use when longer scales are not feasible.

19.
J Emerg Nurs ; 49(2): 210-221, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36411149

ABSTRACT

INTRODUCTION: To understand the experiences of emergency nurses who have returned to work after parental leave, specifically relating to the return to work transition, work-life balance, work engagement, and opportunities to continue human milk expression. METHODS: Nurses (N = 19) were recruited from 5 emergency departments within 1 hospital system in the United States Midwest. Nurses (n = 11) were eligible to participate in a one-on-one interview if they had returned from parental leave within 6 months of the interview date. Nurses (n = 8) were eligible to participate in a focus group if they had returned from parental leave within 2 years of the interview date. Interviews were structured and data collection concluded when researchers believed data saturation was reached. Interviews were audio recorded and transcribed verbatim. Data were analyzed using Braun and Clarke's qualitative thematic analysis 6-phase framework. RESULTS: Three major themes from the data were identified: (1) work engagement, (2) lactation, and (3) childcare. Work engagement was broken down into the subthemes: lack of communication, perceived engagement expectations, and actual engagement. Lactation was broken down into the subthemes: the act of pumping, lactation breaks, and lactation rooms. The coronavirus disease 2019 pandemic impact on return-to-work is described under each major theme. DISCUSSION: Our findings provide insight into the unique challenges and experiences of nurses navigating parental leave and return-to-work in the emergency department. Strategies such as provision of managerial check-ins, return to work reorientation, lactation break coverage, enhanced supplementary lactation support, and leadership-provided accommodation may lighten the burden of these challenges and improve the returning nurse's job satisfaction.


Subject(s)
COVID-19 , Nurses , Female , Humans , Return to Work , Parental Leave , Parents , Qualitative Research
20.
Healthc Manage Forum ; 36(6): 378-381, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37671740

ABSTRACT

Physicians and governments work collaboratively to determine optimal healthcare policy options. Physicians are also engaged by health researchers to participate in studies. Physician engagement can be impeded by limits on physician time and remuneration for engagement, and the impact of physician burnout (exacerbated by COVID-19). Doctors Nova Scotia engaged physicians on various research and policy items throughout the pandemic. Strategies included integrating physicians into research teams, remunerating engagement activities, and leveraging existing tools and networks. Health researchers and policy-makers can improve physician engagement through physician champions, reduction of research duplication, valuing of physician contributions, and integrating networks.


Subject(s)
Burnout, Professional , COVID-19 , Physicians , Humans , COVID-19/epidemiology , Burnout, Professional/prevention & control , Health Policy , Policy Making
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