Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes.

Diabetes Type 1 and Type 2 are widely occurring diseases. In spite of a vast amount of biomedical literature about diabetic processes in general, links to certain biological processes are only becoming evident these days. One such area of biology is the sulfation of small molecules, such as steroid hormones or metabolites from the gastrointestinal tract, as well as larger biomolecules, such as proteins and proteoglycans. Thus, modulating the physicochemical propensities of the different sulfate acceptors, resulting in enhanced solubility, expedited circulatory transit, or enhanced macromolecular interaction. This review lists evidence for the involvement of sulfation pathways in the maintenance of functional pancreatic beta-cell mass and the implications for diabetes, grouped into various classes of sulfated biomolecule. Complex heparan sulfates might play a role in the development and maintenance of beta-cells. The sulfolipids sulfatide and sulfo-cholesterol might contribute to beta-cell health. In beta-cells, there are only very few proteins with confirmed sulfation on some tyrosine residues, with the IRS4 molecule being one of them. Sulfated steroid hormones, such as estradiol-sulfate and vitamin-D-sulfate, may facilitate downstream steroid signaling in beta-cells, following de-sulfation. Indoxyl sulfate is a metabolite from the intestine, that causes kidney damage, contributing to diabetic kidney disease. Finally, from a technological perspective, there is heparan sulfate, heparin, and chondroitin sulfate, that all might be involved in next-generation beta-cell transplantation. Sulfation pathways may play a role in pancreatic beta-cells through multiple mechanisms. A more coherent understanding of sulfation pathways in diabetes will facilitate discussion and guide future research.

Religious Involvement and Cognitive Function Among White, Black, and Hispanic Older Adults.

We examined whether religious involvement was associated with cognitive function among older adults in the 2006-2020 waves of the Health and Retirement Study. Using growth curve analysis, we found the association between religious involvement and cognition varied by facet of religious involvement and race and Hispanic ethnicity. Attending religious services with friends was associated with higher initial levels of cognitive function (b = 0.22, p < .05). For Hispanic older adults, frequent attendance at religious services was associated with a slower rate of cognitive decline (b = 0.16, p < .01). Stratified models by race and Hispanic ethnicity demonstrated that religious salience was associated with lower initial levels of cognitive function among non-Hispanic White adults (b = -0.19, p < .01). We found no association between religious involvement and cognitive function among non-Hispanic Black respondents. In sum, elements of religious involvement are positively or negatively related to cognitive function in later life and vary by race and ethnicity.

Characterizing and Modeling Ovine Hide and Costal Cartilage for Use in Modeling High-Rate Non-Penetrating Blunt Impact.

INTRODUCTION: High-rate non-penetrating blunt impacts to the thorax, such as from impacts to protective equipment, can lead to a wide range of thoracic injuries. These injuries can include rib fractures, lung contusions, and abdominal organ contusions. Ovine animals have been used to study such impacts, in a variety of ways, including in silico. To properly model these impacts in silico, it is imperative that the tissues impacted are properly characterized. The objective of this study is to characterize and validate two tissues impacted that are adjacent to the point of impact-costal cartilage and hide. Heretofore, these materials have not been characterized for use in computational models despite their nearly immediate engagement in the high-rate, non-penetrating loading environment. MATERIALS AND METHODS: Ovine costal cartilage and hide samples were procured from a local abattoir following USDA regulations. Costal cartilage samples were then cut into ASTM D638 Type V tensile coupons and compressive disks for testing. The cartilage tensile coupons were tested at 150 ε/s, and the compressive samples were tested at -150 ε/s. Identical coupons and disks were then simulated in LS-Dyna using a hyperelastic material model based on test data and experimental boundary conditions. Hide samples were shaved and cut into ASTM D638 Type V tensile coupons and validated in silico using identical boundary conditions and an Ogden rubber model based on test data. RESULTS: The structural responses of costal cartilage and hide are presented and exhibit typical behavior for biological specimens. The respective model fits in LS-Dyna were a hyperelastic- based "simplified rubber" for the costal cartilage and an Ogden rubber for the hide. The costal cartilage had a mean failure strain of 0.094 ± 0.040 in tension and -0.1755 ± 0.0642 in compression. The costal cartilage was also noted to have an order-of-magnitude difference in the stresses observed experimentally between the tensile and compressive experiments. Hide had a mean failure strain of 0.2358 ± 0.1362. The energies for all three simulations showed material stability. CONCLUSIONS: Overall, we successfully characterized the mechanical behavior of the hide and costal cartilage in an ovine model. The data are intended for use in computational analogs of the ovine model for testing non-penetrating blunt impact in silico. To improve upon these models, rate sensitivity should be included, which will require additional mechanical testing.

Corrigendum: Follicular lymphoma regulatory T-cell origin and function.

[This corrects the article DOI: 10.3389/fimmu.2024.1391404.].

Enhancing Roles: Teaching the Teachers Through EHR Documentation and Associated Quality of Care Analysis.

Electronic health records (EHR) are designed to promote patient safety, workflow efficiency, and communication (HealthIT.gov). Competency in the use of an EHR is essential for both undergraduate and graduate nursing students. Masters prepared nurse educator students may become clinical faculty in schools of nursing or clinical nurse educators in hospitals or out-patient settings after graduation. A gap exists in preparing future nurse educators to teach EHR-specific skills to their future nursing student populations and in promoting patient safety through quality improvement initiatives. The purpose of this observational study is to evaluate experiential learning activities for Master of Science in Nursing (MSN) nurse educator students aimed at preparing them to teach EHR-specific skills to undergraduate nursing students and in utilizing an EHR query activity to develop quality improvement plans.

Follicular lymphoma regulatory T-cell origin and function.

Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse. Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays. Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.

Educational Inequalities in Dual-Function Life Expectancy.

OBJECTIVES: This study investigates educational inequalities in dual functionality, a new concept that captures a combination of physical and cognitive functioning, both of which are important for independent living and quality of life. METHODS: Using data from the Health and Retirement Study and the National Health Interview Survey Linked Mortality Files, we define a measure of dual functionality based on the absence of limitations in activities of daily living and dementia. We estimate age-graded dual-function rates among adults 65+ and age-65 dual-function life expectancy across levels of education stratified by gender. RESULTS: In their mid-60s, 67% of women with less than a high school degree manifest dual functionality as compared with over 90% of women with at least a 4-year college degree. A similar pattern holds among men. These education-based gaps in dual functionality remain across later life, even as dual-function rates decline at older ages. Lower dual-function rates among older adults with less education translate into inequalities of 6.7 and 7.3 years in age-65 dual-function life expectancy between men and women, respectively, with at least a 4-year college degree compared to their counterparts with less than a high school degree. DISCUSSION: Older adults, particularly women, with less than a high school degree are estimated to live a smaller percentage of their remaining years with dual functionality compared with older adults with at least a college degree. These inequalities have implications for the distribution of caregiving resources of individuals, family members, and the broader healthcare community.

The importance of covert memory consolidation in schizophrenia: Dysfunctional network profiles of the hippocampus and the dorsolateral prefrontal cortex.

Altered brain network profiles in schizophrenia (SCZ) during memory consolidation are typically observed during task-active periods such as encoding or retrieval. However active processes are also sub served by covert periods of memory consolidation. These periods are active in that they allow memories to be recapitulated even in the absence of overt sensorimotor processing. It is plausible that regions central to memory formation like the dlPFC and the hippocampus, exert network signatures during covert periods. Are these signatures altered in patients? The question is clinically relevant because real world learning and memory is facilitated by covert processing, and may be impaired in schizophrenia. Here, we compared network signatures of the dlPFC and the hippocampus during covert periods of a learning and memory task. Because behavioral proficiency increased non-linearly, functional connectivity of the dlPFC and hippocampus [psychophysiological interaction (PPI)] was estimated for each of the Early (linear increases in performance) and Late (asymptotic performance) covert periods. During Early periods, we observed hypo-modulation by the hippocampus but hyper-modulation by dlPFC. Conversely, during Late periods, we observed hypo-modulation by both the dlPFC and the hippocampus. We stitch these results into a conceptual model of network deficits during covert periods of memory consolidation.

Social connectedness, functional capacity, and longevity: A focus on positive relations with others.

RATIONALE: A large literature links social connectedness to health, but there is growing recognition of considerable nuance in the ways social connectedness is defined, assessed, and associated with health. OBJECTIVE: This study centers on positive relations with others - a measure derived from philosophical notions of the components of a "good life" - and the extent to which it predicts functional limitations and mortality using data from the national, longitudinal Mid-Life in the United States (MIDUS) study. We also assess whether these associations are independent of two common measures of social connectedness: social integration and social support. METHODS: Data on social connectedness came from the first wave of MIDUS (1994-1996), self-reported functional limitations were from the first (MIDUS 1) and third (MIDUS 3; 2013-2014) waves, and mortality data through 2022 were obtained from the National Death Index. RESULTS: Linear regression analyses showed that higher scores on positive relations with others predicted significantly less increase in functional limitations over time, and logistic regression models showed reduced probability of onset of functional limitations between MIDUS 1 and MIDUS 3 in those scoring higher on positive relations with others. Mortality was also significantly lower in those with higher scores on positive relations with others. All models adjusted for demographic and health characteristics, and all associations were robust to the inclusion of social integration and social support in the models. CONCLUSIONS: These results show that positive relations with others, a component of a well-lived life that describes sustained investment in social relationships that are mutual and trusting, is associated with two key health outcomes in aging adults: functional limitations and longevity. That these associations are independent of social integration and social support suggests a unique role for this formulation of social connectedness in the health of aging adults.

Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding.

The propensity to develop type 2 diabetes (T2D) is known to have both environmental and hereditary components. In those with a genetic predisposition to T2D, it is widely believed that elevated concentrations of circulatory long-chain fatty acids (LC-FFA) significantly contribute towards the demise of insulin-producing pancreatic ß-cells - the fundamental feature of the development of T2D. Over 25 years of research support that LC-FFA are deleterious to ß-cells, through a process termed lipotoxicity. However, the work underpinning the theory of ß-cell lipotoxicity is mostly based on rodent studies. Doubts have been raised as to whether lipotoxicity also occurs in humans. In this review, we examine the evidence, both in vivo and in vitro, for the pathogenic effects of LC-FFA on ß-cell viability and function in humans, highlighting key species differences. In this way, we aim to uncover the role of lipotoxicity in the human pathogenesis of T2D and motivate the need for species-specific understanding.

Contrast enhanced computed tomography of small ruminants: Caprine and ovine.

The use of small ruminants, mainly sheep and goats, is increasing in biomedical research. Small ruminants are a desirable animal model due to their human-like anatomy and physiology. However, the large variability between studies and lack of baseline data on these animals creates a barrier to further research. This knowledge gap includes a lack of computed tomography (CT) scans for healthy subjects. Full body, contrast enhanced CT scans of caprine and ovine subjects were acquired for subsequent modeling studies. Scans were acquired from an ovine specimen (male, Khatadin, 30-35 kg) and caprine specimen (female, Nubian 30-35 kg). Scans were acquired with and without contrast. Contrast enhanced scans utilized 1.7 mL/kg of contrast administered at 2 mL/s and scans were acquired 20 seconds, 80 seconds, and 5 minutes post-contrast. Scans were taken at 100 kV and 400 mA. Each scan was reconstructed using a bone window and a soft tissue window. Sixteen full body image data sets are presented (2 specimens by 4 contrast levels by 2 reconstruction windows) and are available for download through the form located at: https://redcap.link/COScanData. Scans showed that the post-contrast timing and scan reconstruction method affected structural visualization. The data are intended for further biomedical research on ruminants related to computational model development, device prototyping, comparative diagnostics, intervention planning, and other forms of translational research.

The Case for the Target of Rapamycin Pathway as a Candidate Circadian Oscillator.

The molecular mechanisms that drive circadian (24 h) rhythmicity have been investigated for many decades, but we still do not have a complete picture of eukaryotic circadian systems. Although the transcription/translation feedback loop (TTFL) model has been the primary focus of research, there are many examples of circadian rhythms that persist when TTFLs are not functioning, and we lack any good candidates for the non-TTFL oscillators driving these rhythms. In this hypothesis-driven review, the author brings together several lines of evidence pointing towards the Target of Rapamycin (TOR) signalling pathway as a good candidate for a non-TTFL oscillator. TOR is a ubiquitous regulator of metabolism in eukaryotes and recent focus in circadian research on connections between metabolism and rhythms makes TOR an attractive candidate oscillator. In this paper, the evidence for a role for TOR in regulating rhythmicity is reviewed, and the advantages of TOR as a potential oscillator are discussed. Evidence for extensive feedback regulation of TOR provides potential mechanisms for a TOR-driven oscillator. Comparison with ultradian yeast metabolic cycles provides an example of a potential TOR-driven self-sustained oscillation. Unanswered questions and problems to be addressed by future research are discussed.

The role of candidate transport proteins in ß-cell long-chain fatty acid uptake: Where are we now?

Type 2 diabetes (T2D) in humans is typically preceded by elevated levels of circulatory long-chain free fatty acids (LC-FFA). These excess LC-FFA are widely thought to be taken up by pancreatic ß-cells, contributing to their dysfunction and death during the development of T2D; a process that has been termed lipotoxicity. Depending on their degree of saturation and carbon chain length, LC-FFA can exert different effects on pancreatic ß-cells viability and function in vitro. Long-chain saturated fatty acids (LC-SFA) are thought to be toxic, whereas monounsaturated fatty acids are not and may even offer protection against the toxic effects of LC-SFAs. However, the mechanism of LC-FFA uptake into pancreatic ß-cells is poorly understood, partly because it has been an understudied area of research. Determining how LC-FFA are taken up into ß-cells is crucial for later formulation of therapies to prevent potential cellular overload of LC-FFA, thereby slowing the onset of T2D. In this work, we detail more than 40 years of literature investigating the role of membrane-associated transport proteins in LC-FFA uptake. By focussing on what is known in other cell types, we highlight where we can extrapolate our current understanding of protein-mediated transport to ß-cells and uncover where further understanding is required.

Learning without contingencies: A loss of synergy between memory and reward circuits in schizophrenia.

Motivational deficits in schizophrenia may interact with foundational cognitive processes including learning and memory to induce impaired cognitive proficiency. If such a loss of synergy exists, it is likely to be underpinned by a loss of synchrony between the brains learning and reward sub-networks. Moreover, this loss should be observed even during tasks devoid of explicit reward contingencies given that such tasks are better models of real world performance than those with artificial contingencies. Here we applied undirected functional connectivity (uFC) analyses to fMRI data acquired while participants engaged in an associative learning task without contingencies or feedback. uFC was estimated and inter-group differences (between schizophrenia patients and controls, n = 54 total, n = 28 patients) were assessed within and between reward (VTA and NAcc) and learning/memory (Basal Ganglia, DPFC, Hippocampus, Parahippocampus, Occipital Lobe) sub-networks. The task paradigm itself alternated between Encoding, Consolidation, and Retrieval conditions, and uFC differences were quantified for each of the conditions. Significantly reduced uFC dominated the connectivity profiles of patients across all conditions. More pertinent to our motivations, these reductions were observed within and across classes of sub-networks (reward-related and learning/memory related). We suggest that disrupted functional connectivity between reward and learning sub-networks may drive many of the performance deficits that characterize schizophrenia. Thus, cognitive deficits in schizophrenia may in fact be underpinned by a loss of synergy between reward-sensitivity and cognitive processes.

A Time of Healing: Can Social Engagement After Bereavement Reduce Trajectories of Depression After the Death of a Child?

OBJECTIVES: We work from a stress and life-course perspective to examine the mental health of parents who experienced the death of their child. We examine whether mental health eventually returns to pre-bereavement levels and how social engagement after bereavement may shape the recovery process of depressive symptoms. METHODS: We analyze discontinuous growth curve models to assess the association between a child's death and trajectories of parents' depressive symptoms from the 1998-2016 Health and Retirement Study. The sample includes 16,182 parents aged 50 years and older. RESULTS: Those who transitioned to bereavement experienced an elevation in depressive symptoms and a relatively long recovery time (e.g., 7 years) to their pre-bereavement mental health in our findings. However, when engaging in volunteer work after their loss, depressive symptoms reduce more quickly to their pre-bereavement levels. Volunteering offsets up to 3 years of the negative consequences of child loss. DISCUSSION: The death of a child is a traumatic event with extensive health consequences, but research should more fully examine the dynamic nature and potential mitigation of these health consequences over time. Our findings expand the temporal lens to encompass healing processes after bereavement, incorporating the importance of social engagement.

The topology, stability, and instability of learning-induced brain network repertoires in schizophrenia.

There is a paucity of graph theoretic methods applied to task-based data in schizophrenia (SCZ). Tasks are useful for modulating brain network dynamics, and topology. Understanding how changes in task conditions impact inter-group differences in topology can elucidate unstable network characteristics in SCZ. Here, in a group of patients and healthy controls (n = 59 total, 32 SCZ), we used an associative learning task with four distinct conditions (Memory Formation, Post-Encoding Consolidation, Memory Retrieval, and Post-Retrieval Consolidation) to induce network dynamics. From the acquired fMRI time series data, betweenness centrality (BC), a metric of a node's integrative value was used to summarize network topology in each condition. Patients showed (a) differences in BC across multiple nodes and conditions; (b) decreased BC in more integrative nodes, but increased BC in less integrative nodes; (c) discordant node ranks in each of the conditions; and (d) complex patterns of stability and instability of node ranks across conditions. These analyses reveal that task conditions induce highly variegated patterns of network dys-organization in SCZ. We suggest that the dys-connection syndrome that is schizophrenia, is a contextually evoked process, and that the tools of network neuroscience should be oriented toward elucidating the limits of this dys-connection.

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modelling.

OBJECTIVES: Schizophrenia is characterised by deficits across multiple cognitive domains and altered glutamate related neuroplasticity. The purpose was to investigate whether glutamate deficits are related to cognition in schizophrenia, and whether glutamate-cognition relationships are different between schizophrenia and controls. METHODS: Magnetic resonance spectroscopy (MRS) at 3 Tesla was acquired from the dorsolateral prefrontal cortex (dlPFC) and hippocampus in 44 schizophrenia participants and 39 controls during passive viewing visual task. Cognitive performance (working memory, episodic memory, and processing speed) was assessed on a separate session. Group differences in neurochemistry and mediation/moderation effects using structural equation modelling (SEM) were investigated. RESULTS: Schizophrenia participants showed lower hippocampal glutamate (p = .0044) and myo-Inositol (p = .023) levels, and non-significant dlPFC levels. Schizophrenia participants also demonstrated poorer cognitive performance (p < .0032). SEM-analyses demonstrated no mediation or moderation effects, however, an opposing dlPFC glutamate-processing speed association between groups was observed. CONCLUSIONS: Hippocampal glutamate deficits in schizophrenia participants are consistent with evidence of reduced neuropil density. Moreover, SEM analyses indicated that hippocampal glutamate deficits in schizophrenia participants as measured during a passive state were not driven by poorer cognitive ability. We suggest that functional MRS may provide a better framework for investigating glutamate-cognition relationships in schizophrenia.

Dual Functionality in Later Life.

Gerontologists have long shown interest in both longevity and quality of life during later life, but considerable debate has ensued as scholars sought to integrate the two. Drawing from research on the topics of exceptional longevity, successful aging, and active life expectancy, we propose the concept of dual functionality to examine how humans reach advanced ages while maintaining physical and cognitive function. Dual functionality refers to being free of both physical and cognitive impairment. The loss of dual functionality challenges social networks to respond to the functional loss and is a harbinger of additional losses. Evidence of change in the percent of the older population maintaining dual functionality would be helpful for evaluating public health policies to aid quality of life during later life. This article is based on the first author's Robert W. Kleemeier Award Lecture at The Gerontological Society of America 2022 Annual Scientific Meeting.

Racial-Ethnic Disparities in Dual-Function Life Expectancy.

BACKGROUND: This study develops a new concept, dual functionality, that integrates physical and cognitive function. We use the concept to define a measure of dual-function life expectancy (2FLE) and assess racial-ethnic inequalities in aging. METHODS: Drawing on data from the National Health Interview Survey Linked Mortality Files and the Health and Retirement Study, we define dual functionality as having no limitations in activities of daily living and being free of dementia. We use this measure and Sullivan life tables to estimate age-50 total life expectancy and age-50 2FLE for women and men across 4 racial-ethnic and nativity groups. RESULTS: At ages 50-54, between 79.0% (95% CI: 73.5, 84.5) and 87.6% (95% CI: 84.0, 91.2) of (non-Hispanic) Black, foreign-born Hispanic, and U.S.-born Hispanic women and men remain dual functional as compared with 90.4% (95% CI: 89.3, 91.4) and 91.4% (95% CI: 90.2, 92.5) of (non-Hispanic) White women and men, respectively. These and corresponding racial-ethnic disparities in dual functionality through ages 85 and older translate into substantial inequalities in 2FLE. For instance, the Black-White gap in age-50 2FLE is 6.9 years (95% CI: -7.5, -6.4) for women and 6.0 years (95% CI: -6.6, -5.4) for men. CONCLUSIONS: Black, foreign-born Hispanic, and U.S.-born Hispanic older adults are estimated to live a smaller percentage of their remaining years with dual functionality than White older adults. These results reveal stark racial-ethnic inequalities in aging that have significant implications for quality of life, caregiving, and health needs.

Micro-CT Imaging and Mechanical Properties of Ovine Ribs.

The use of ovine animal models in the study of injury biomechanics and modeling is increasing, due to their favorable size and other physiological characteristics. Along with this increase, there has also been increased interest in the development of in silico ovine models for computational studies to compliment physical experiments. However, there remains a gap in the literature characterizing the morphological and mechanical characteristics of ovine ribs. The objective of this study therefore is to report anatomical and mechanical properties of the ovine ribs using microtomography (micro-CT) and two types of mechanical testing (quasi-static bending and dynamic tension). Using microtomography, young ovine rib samples obtained from a local abattoir were cut into approximately fourteen 38 mm sections and scanned. From these scans, the cortical bone thickness and cross-sectional area were measured, and the moment of inertia was calculated to enhance the mechanical testing data. Based on a standard least squares statistical model, the cortical bone thickness varied depending on the region of the cross-section and the position along the length of the rib (p < 0.05), whereas the cross-sectional area remained consistent (p > 0.05). Quasi-static three-point bend testing was completed on ovine rib samples, and the resulting force-displacement data was analyzed to obtain the stiffness (44.67 ± 17.65 N/mm), maximum load (170.54 ± 48.28 N) and displacement at maximum load (7.19 ± 2.75 mm), yield load (167.81 ± 48.12 N) and displacement at yield (6.10 ± 2.25 mm), and the failure load (110.90 ± 39.30 N) and displacement at failure (18.43 ± 2.10 mm). The resulting properties were not significantly affected by the rib (p > 0.05), but by the animal they originated from (p < 0.05). For the dynamic testing, samples were cut into coupons and tested in tension with an average strain rate of 18.9 strain/sec. The resulting dynamic testing properties of elastic modulus (5.16 ± 2.03 GPa), failure stress (63.29 ± 14.02 MPa), and failure strain (0.0201 ± 0.0052) did not vary based on loading rate (p > 0.05).