bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of the Liver Transplant Risk Score in Europe
Authors: Ashwat Eishan , Kaltenmeier Christof , Liu Hao , Reddy Dheera , Thompson Ann , Dharmayan Stalin , Ayloo Subhashini , Nadalin Silvio , Ciccarelli Olga , Xu Qingyong , Adam Rene , Karam Vincent , Zieniewicz Krzystof , Mirza Darius , Heneghan Michael , Romagnoli Renato , Paul Andreas , Cherqui Daniel , Pratschke Johann , Boudjema Karim , Schemmer Peter , Rodriguez Fernando San Juan , Lodge Peter , de Simone Paolo , Bachellier Phillippe , Fronek Jiri , Fondevila Constantino , Molinari Michele
Published: October 2022

The Liver Transplant Risk Score (LTRS) is a simple clinical instrument developed to predict post liver transplant outcomes based on patient characteristics measured at the time of listing. The LTRS was developed using data of adult patients transplanted in the United States. In this study, we validated the performance of the LTRS in a cohort of patients transplanted in Europe.
B cells defined by immunoglobulin isotypes
Authors: James Louisa Katherine
Published: October 2022

The ability of B cells to generate antibodies and provide long-lived protective immunity is the cornerstone of vaccination and has contributed to the success of modern medicine. The nine different antibody subclasses produced by humans have effector functions that differ according to antigen type and route of exposure. Expression of the appropriate isotype is critical for effective humoral immunity, and it is becoming clear that subclass specificity is to some extent reflected at the cellular level. Understanding the mechanisms that govern the induction, expansion, and maintenance of B cells expressing different antibody subclasses informs the strategic manipulation of responses to benefit human health. This article provides an overview of the mechanisms by which the different human antibody subclasses regulate immunity, presents an update on how antibody subclass expression is regulated at the cellular level and highlights key areas for future research.
High cortical iron is associated with the disruption of white matter tracts supporting cognitive function in healthy older adults
Authors: Zachariou Valentinos , Bauer Christopher E , Pappas Colleen , Gold Brian T
Published: October 2022

Aging is associated with brain iron accumulation, which has been linked to cognitive decline. However, how brain iron affects the structure and function of cognitive brain networks remains unclear. Here, we explored the possibility that iron load in gray matter is associated with disruption of white matter (WM) microstructure within a network supporting cognitive function, in a cohort of 95 cognitively normal older adults (age range: 60–86). Functional magnetic resonance imaging was used to localize a set of brain regions involved in working memory and diffusion tensor imaging based probabilistic tractography was used to identify a network of WM tracts connecting the functionally defined regions. Brain iron concentration within these regions was evaluated using quantitative susceptibility mapping and microstructural properties were assessed within the identified tracts using neurite orientation dispersion and density imaging. Results indicated that high brain iron concentration was associated with low neurite density (ND) within the task-relevant WM network. Further, regional associations were observed such that brain iron in cortical regions was linked with lower ND in neighboring but not distant WM tracts. Our results provide novel evidence suggesting that age-related increases in brain iron concentration are associated with the disruption of WM tracts supporting cognitive function in normal aging.
Anatomical considerations and clinical interpretation of the 12-lead ECG in the prone position: a prospective multicentre study
Authors: Romero Jorge , Garcia Mario , Diaz Juan Carlos , Gabr Mohamed , Rodriguez-Taveras Joan , Braunstein Eric D , Purkayastha Sutopa , Gamero Maria T , Alviz Isabella , Marín Jorge , Aristizábal Julián , Reynbakh Olga , Peralta Adelqui O , Duque Mauricio , Dave Kartikeya P , Rodriguez Daniel , Nino Cesar , Briceno David , Velasco Alejandro , Ferrick Kevin , Slipczuk Leandro , Natale Andrea , Di Biase Luigi
Published: October 2022

Aims

The aim of this study is to provide guidance for the clinical interpretation of electrocardiograms (ECGs) in prone position and to establish the electroanatomic explanations for the possible differences to supine position ECGs that may be observed. Additionally, to determine if prone back ECG can be used as an alternative to standard ECG in patients who may benefit from prone position.

Methods and results

The ECG in supine (standard ECG), prone back (precordial leads placed on the patient’s back), and prone anterior position (precordial leads placed in the standard position with the subjects in prone position) were prospectively examined on 85 subjects. Comparisons of ECG parameters between these positions were performed. Computed tomography (CT) scans were performed in both positions to determine possible electroanatomic aetiologies for prone-associated ECG changes. There were significant differences in QRS amplitude in Leads V1–V5 between supine and prone positions. Q waves were more frequently observed in prone back position vs. supine position (V1: 74.1 vs. 10.6%, P < 0.0001; V2: 23.5 vs. 0%, P < 0.0001, respectively). Flat and inverted T waves were more common in prone back leads (V1: 98 vs. 66%, P < 0.0001; V2: 96 vs. 8%, P < 0.0001; V3: 45 vs. 7%, P < 0.0001). The 3D-CT reconstructions measurements corroborated the significant inverse correlation between QRS amplitude and the distance from the centre of the heart to the estimated lead positions.

Conclusion

In prone back position ECG, low QRS amplitude should not be misinterpreted as low voltage conditions, neither should Q waves and abnormal T waves are considered anteroseptal myocardial infarction. These changes can be explained by an increased impedance (due to interposing lung tissue) and by the increased distance between the electrodes to the centre of the heart.
Regional Neuroanatomic Effects on Brain Age Inferred Using Magnetic Resonance Imaging and Ridge Regression
Authors: Massett Roy J , Maher Alexander S , Imms Phoebe E , Amgalan Anar , Chaudhari Nikhil N , Chowdhury Nahian F , Irimia Andrei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2022

The biological age of the brain differs from its chronological age (CA) and can be used as biomarker of neural/cognitive disease processes and as predictor of mortality. Brain age (BA) is often estimated from magnetic resonance images (MRIs) using machine learning (ML) that rarely indicates how regional brain features contribute to BA. Leveraging an aggregate training sample of 3 418 healthy controls (HCs), we describe a ridge regression model that quantifies each region’s contribution to BA. After model testing on an independent sample of 651 HCs, we compute the coefficient of partial determination R¯p2 for each regional brain volume to quantify its contribution to BA. Model performance is also evaluated using the correlation r between chronological and biological ages, the mean absolute error (MAE ) and mean squared error (MSE) of BA estimates. On training data, r=0.92, MSE=70.94 years, MAE=6.57 years, and R¯2=0.81; on test data, r=0.90, MSE=81.96 years, MAE=7.00 years, and R¯2=0.79. The regions whose volumes contribute most to BA are the nucleus accumbens (R¯p2=7.27%), inferior temporal gyrus (R¯p2=4.03%), thalamus (R¯p2=3.61%), brainstem (R¯p2=3.29%), posterior lateral sulcus (R¯p2=3.22%), caudate nucleus (R¯p2=3.05%), orbital gyrus (R¯p2=2.96%), and precentral gyrus (R¯p2=2.80%). Our ridge regression, although outperformed by the most sophisticated ML approaches, identifies the importance and relative contribution of each brain structure to overall BA. Aside from its interpretability and quasi-mechanistic insights, our model can be used to validate future ML approaches for BA estimation.
Constructing Discrimination Rights: Comparisons Among Staff in Long-Term Care Health Facilities
Authors: Perone Angela K
Published: October 2022

Background and Objectives

Despite increased attention to racial and gender justice in the workplace in recent years, discrimination complaints remain vastly underreported. Building on legal consciousness theory―which explains how individuals invoke (or do not invoke) legal principles to define everyday experiences―this study examines how long-term care facility staff understand experiences of discrimination by residents and why staff fails to report discrimination.

Research Design and Methods

This qualitative comparative study uses in-depth semistructured ethnographic interviews to compare experiences among facility staff (n = 80) at three levels (floor staff, mid-management, and upper-management). The qualitative content analysis incorporated both inductive and deductive coding approaches.

Results

Findings reveal extensive unreported instances of discrimination from residents. Staff at all levels rarely invoked discrimination concepts to describe interactions between residents and staff. Floor staff framed residents’ discriminatory behavior as a condition of employment or attributed resident behavior to their health or cognitive status. Mid-management framed experiences around staff safety. Upper-management acknowledged staff rights without invoking discrimination rhetoric.

Discussion and Implications

By avoiding naming experiences as discrimination and blaming residents, most floor staff never reached the claiming process that would result in a report or complaint of discrimination. Managers’ framings also shaped how front-line staff and managers named, blamed, and claimed experiences of discrimination and help explain why staff may be hesitant to report discrimination by residents. These findings suggest the need for new and targeted policy and practice approaches that address the nuances accompanying how staff understands workplace experiences as discrimination.
Regional epithelial cell diversity in the small intestine of pigs
Authors: Wiarda Jayne E , Becker Sage R , Sivasankaran Sathesh K , Loving Crystal L
Published: October 2022

Understanding regional distribution and specialization of small intestinal epithelial cells is crucial for developing methods to control appetite, stress, and nutrient uptake in swine. To establish a better understanding of specific epithelial cells found across different regions of the small intestine in pigs, we utilized single-cell RNA sequencing (scRNA-seq) to recover and analyze epithelial cells from duodenum, jejunum, and ileum. Cells identified included crypt cells, enterocytes, BEST4 enterocytes, goblet cells, and enteroendocrine (EE) cells. EE cells were divided into two subsets based on the level of expression of the EE lineage commitment gene, NEUROD1. NEUROD1hi EE cells had minimal expression of hormone-encoding genes and were dissimilar to EE cells in humans and mice, indicating a subset of EE cells unique to pigs. Recently discovered BEST4 enterocytes were detected in both crypts and villi throughout the small intestine via in situ staining, unlike in humans, where BEST4 enterocytes are found only in small intestinal villi. Proximal-to-distal gradients of expression were noted for hormone-encoding genes in EE cells and nutrient transport genes in enterocytes via scRNA-seq, demonstrating regional specialization. Regional gene expression in EE cells and enterocytes was validated via quantitative PCR (qPCR) analysis of RNA isolated from epithelial cells of different small intestinal locations. Though many genes had similar patterns of regional expression when assessed by qPCR of total epithelial cells, some regional expression was only detected via scRNA-seq, highlighting advantages of scRNA-seq to deconvolute cell type-specific regional gene expression when compared to analysis of bulk samples. Overall, results provide new information on regional localization and transcriptional profiles of epithelial cells in the pig small intestine.
WISDOM Project – XII. Clump properties and turbulence regulated by clump–clump collisions in the dwarf galaxy NGC 404
Authors: Liu Lijie , Bureau Martin , Li Guang-Xing , Davis Timothy A , Nguyen Dieu D , Liang Fu-Heng , Choi Woorak , Smith Mark R , Iguchi Satoru
Published: October 2022

We present a study of molecular structures (clumps and clouds) in the dwarf galaxy NGC 404 using high-resolution (≈0.86 × 0.51 pc2) Atacama Large Millimeter/sub-millimeter Array 12CO(2-1) observations. We find two distinct regions in NGC 404: a gravitationally stable central region (Toomre parameter Q = 3–30) and a gravitationally unstable molecular ring (Q ≲ 1). The molecular structures in the central region have a steeper size–linewidth relation and larger virial parameters than those in the molecular ring, suggesting gas is more turbulent in the former. In the molecular ring, clumps exhibit a shallower mass–size relation and larger virial parameters than clouds, implying density structures and dynamics are regulated by different physical mechanisms at different spatial scales. We construct an analytical model of clump–clump collisions to explain the results in the molecular ring. We propose that clump–clump collisions are driven by gravitational instabilities coupled with galactic shear, which lead to a population of clumps whose accumulation lengths (i.e. average separations) are approximately equal to their tidal radii. Our model-predicted clump masses and sizes (and mass–size relation) and turbulence energy injection rates (and size–linewidth relation) match the observations in the molecular ring very well, suggesting clump–clump collisions are the main mechanism regulating clump properties and gas turbulence in that region. As expected, our collision model does not apply to the central region, where turbulence is likely driven by clump migration.
mocca: dynamics and evolution of single and binary stars of multiple stellar populations in tidally filling and underfilling globular star clusters
Authors: Hypki Arkadiusz , Giersz Mirek , Hong Jongsuk , Leveque Agostino , Askar Abbas , Belloni Diogo , Otulakowska-Hypka Magdalena
Published: October 2022

We present an upgraded version of the mocca code for the study of dynamical evolution of globular clusters (GCs) and its first application to the study of evolution of multiple stellar populations. We explore initial conditions spanning different structural parameters for the first (FG) and second generation of stars (SG) and we analyse their effect on the binary dynamics and survival. Here, we focus on the number ratio of FG and SG binaries, their spatial variation, and the way their abundances are affected by various cluster initial properties. We find that present-day SG stars are more abundant in clusters that were initially tidally filling. Conversely, FG stars stay more abundant in clusters that were initially tidally underfilling. We find that the ratio between binary fractions is not affected by the way we calculate these fractions [e.g. only main-sequence binaries (MS) or observational binaries, i.e. MS stars >0.4 M⊙ mass ratios >0.5]. This implies that the MS stars themselves are a very good proxy for probing entire populations of FG and SG. We also discuss how it relates to the observations of Milky Way GCs. We show that mocca models are able to reproduce the observed range of SG fractions for Milky Way GCs for which we know these fractions. We show how the SG fractions depend on the initial conditions and provide some constraints for the initial conditions to have more numerous FG or SG stars at the Hubble time.
Searching for young runaways across the sky
Authors: Kounkel Marina , Mcbride Aidan , Stassun Keivan G , Leigh Nathan
Published: October 2022

We present a catalogue of 3354 candidate young stars within 500 pc that appear to have been ejected from their parent associations with relative speeds of >5 km s−1. These candidates have been homogeneously selected through performing a 2D spherical traceback of previously identified pre-main-sequence candidates to various star-forming regions, ensuring that the traceback age as well as the estimated age of a star is consistent with the age of the population, and excluding contaminants from the nearby moving groups that follow the dominant velocity currents in the field. Among the identified candidates we identify a number of pairs that appear to have interacted in the process of the ejection; these pairs have similar traceback time, and their trajectory appears to be diametrically opposite from each other, or they have formed a wide binary in the process. As the selection of these candidates is performed solely in 2D, spectral follow-up is necessary for their eventual confirmation. Unfortunately, recently released Gaia DR3 radial velocities appear to be unsuitable for characterizing the kinematics of low-mass stars with ages <100 Myr, as the accretion, activity, and a variety of other spectral features that make them distinct from the more evolved stars do not appear to have been accurately accounted for in the data, resulting in significant artificially inflated scatter in their RV distribution.
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019
Authors: Ostrom Quinn T , Price Mackenzie , Neff Corey , Cioffi Gino , Waite Kristin A , Kruchko Carol , Barnholtz-Sloan Jill S
Published: October 2022

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention and the National Cancer Institute, is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors available and supersedes all previous reports in terms of completeness and accuracy. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 24.71 per 100,000 population (malignant AAAIR=7.02 and non-malignant AAAIR=17.69). This overall rate was higher in females compared to males (27.62 versus 21.60 per 100,000) and non-Hispanic persons compared to Hispanic persons (25.09 versus 22.95 per 100,000). The most commonly occurring malignant brain and other CNS histopathology was glioblastoma (14.2% of all tumors and 50.1% of all malignant tumors), and the most common non-malignant histopathology was meningioma (39.7% of all tumors and 55.4% of all non-malignant tumors). Glioblastoma was more common in males, and meningiomas were more common in females. In children and adolescents (ages 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.20 per 100,000 population. An estimated 93,470 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US population in 2022 (26,670 malignant and 66,806 non-malignant). There were 84,264 deaths attributed to malignant brain and other CNS tumors between 2015 and 2019. This represents an average annual mortality rate of 4.41 per 100,000 population and an average of 16,853 deaths per year. The five-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 35.7%, while for non-malignant brain and other CNS tumors the five-year relative survival rate was 91.8%.
Immediate Switching to Reduced Nicotine Cigarettes in a U.S.-Based Sample: The Impact on Cannabis Use and Related Variables at 20 Weeks
Authors: Meier Ellen , Rubin Nathan , Dermody Sarah S , Tessier Katelyn M , Hecht Stephen S , Murphy Sharon , Jensen Joni , Donny Eric C , al’Absi Mustafa , Drobes David , Koopmeiners Joe , Denlinger-Apte Rachel , Tidey Jennifer W , Vandrey Ryan , Thorne Cole , Hatsukami Dorothy
Published: October 2022

Introduction

The FDA proposed rule-making to reduce nicotine in cigarettes to minimally addictive levels. Research suggests decreasing nicotine levels (i.e. very low nicotine content cigarettes [VLNCs]) produced greater quit attempts, reduced smoking, and reduced exposure to harmful constituents among smokers. The impact of long-term VLNC use among people who co-use cigarettes and cannabis on non-tobacco-specific toxicant and carcinogen exposure has not been investigated.

Aims and Methods

This study presents secondary analyses of a controlled clinical trial examining switching to VLNC (versus a normal nicotine cigarettes control group [NNCs]) between people who co-use cigarettes and cannabis (n = 174) versus smoked cigarettes (n = 555). Linear mixed-effects models compared changes in smoking behavior, and tobacco-specific (i.e. total nicotine equivalents [TNE], 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK; total NNAL]) and non-tobacco-specific (i.e. carbon monoxide (CO), 2-cyanoethylmercapturic acid [CEMA], phenanthrene tetraol [PheT]) toxicant and carcinogen exposure at week 20 (with random intercept for participants). Cannabis use was measured among co-use groups.

Results

CO was significantly lower only among the cigarette-only group assigned VLNCs (interaction: p = .015). Although both VLNC groups demonstrated decreased CEMA, greater decreases emerged among the cigarette-only group (interaction: p = .016). No significant interactions emerged for TNE, cigarettes per day (CPD), NNAL, and PheT (ps > .05); both VLNC groups decreased in TNE, CPD, and NNAL. Only the cigarette-only group assigned VLNCs demonstrated decreased PheT (p < .001). The VLNC co-use group showed increased cannabis use over time (p = .012; 0.5 more days per week by week 20).

Conclusions

Those who co-use cannabis and cigarettes may still be at risk for greater exposure to non-tobacco-specific toxicants and carcinogens compared to those who only smoke cigarettes.

Implications

The present study is the longest longitudinal, prospective comparison study of smoking behavior and exposure to harmful constituents among those who co-use cigarettes and cannabis versus cigarette-only after immediately switching to very low nicotine content cigarettes (VLNC). Those who co-use experienced similar reductions in CPD and tobacco-specific exposure, compared to those who only use cigarettes. However, co-use groups experienced smaller reductions in non-tobacco-specific toxicants and carcinogens compared to the cigarette-only group, potentially because of combustible cannabis use. Additionally, those who co-use and switched to VLNC may be susceptible to slight increases in cannabis use (approximately two more days per year).
Culinary Tourism
Authors: Long Lucy M.
Published: October 2022

Culinary tourism, also known as food tourism and gastronomic tourism, is simultaneously a scholarly field of inquiry, a niche within the tourism industry, and a human impulse to “eat out of curiosity” and try new food experiences. Two key themes emerge in the current scholarship around food and travel: developing critical frameworks for a cohesive discipline and connecting both the practice and study of culinary tourism to sustainability in the broadest sense of the word to ensure that these projects benefit us all. This chapter offers an overview of these developments, contextualizing them within larger historical events and trends. It demonstrates that culinary tourism emerged out of paradigm shifts in how we think of food and of tourism, and that these shifts then have allowed for food to become the subject of touristic imaginations. It suggests that culinary tourism has also played a significant role in encouraging those shifts and that it now offers both a field of scholarship and an activity that is of growing interest and recognition. It also observes that the historical dimensions of culinary tourism have generally been overlooked but such attention offers a productive area of cross-disciplinary engagement.
The SLC26A9 inhibitor S9‐A13 provides no evidence for a role of SLC26A9 in airway chloride secretion but suggests a contribution to regulation of ASL pH and gastric proton secretion
Authors: Jo Sungwoo , Centeio Raquel , Park Jinhong , Ousingsawat Jiraporn , Jeon Dong‐kyu , Talbi Khaoula , Schreiber Rainer , Ryu Kunhi , Kahlenberg Kristin , Somoza Veronika , Delpiano Livia , Gray Michael A. , Amaral Margarida D. , Railean Violeta , Beekman Jeffrey M. , Rodenburg Lisa W. , Namkung Wan , Kunzelmann Karl
Published: October 2022

The solute carrier 26 family member A9 (SLC26A9) is an epithelial anion transporter that is assumed to contribute to airway chloride secretion and surface hydration. Whether SLC26A9 or CFTR is responsible for airway Cl− transport under basal conditions is still unclear, due to the lack of a specific inhibitor for SLC26A9. In the present study, we report a novel potent and specific inhibitor for SLC26A9, identified by screening of a drug‐like molecule library and subsequent chemical modifications. The most potent compound S9‐A13 inhibited SLC26A9 with an IC50 of 90.9 ± 13.4 nM. S9‐A13 did not inhibit other members of the SLC26 family and had no effects on Cl− channels such as CFTR, TMEM16A, or VRAC. S9‐A13 inhibited SLC26A9 Cl− currents in cells that lack expression of CFTR. It also inhibited proton secretion by HGT‐1 human gastric cells. In contrast, S9‐A13 had minimal effects on ion transport in human airway epithelia and mouse trachea, despite clear expression of SLC26A9 in the apical membrane of ciliated cells. In both tissues, basal and stimulated Cl− secretion was due to CFTR, while acidification of airway surface liquid by S9‐A13 suggests a role of SLC26A9 for airway bicarbonate secretion.
Galangin inhibited ferroptosis through activation of the PI3K/AKT pathway in vitro and in vivo
Authors: Chen Ke , Xue Ran , Geng Yaping , Zhang Shenshen
Published: October 2022

Ferroptosis is an iron‐dependent form of nonapoptotic cell death characterized by the accumulation of lipid peroxides in cells. In recent years, extensive attention has been dedicated to exploring safe and effective natural ferroptosis regulators which can provide novel treatment strategies for ferroptosis‐related diseases. This study identified galangin, a natural flavonoid, as an effective inhibitor of ferroptosis, which could increase cell viability in RSL3‐inhibited HT1080 cells, decrease levels of lipid ROS and MDA, improve PTGS2 mRNA expression, and enhance the expression of glutathione peroxidase 4 (GPX4). Ferroptosis is widely present in ischemia‐reperfusion (IR) injury. This study found that galangin significantly ameliorated the pathological damage of liver tissue in mice with IR, reduced levels of serum ALT, AST, and MDA, and increased the expression of GPX4. The results of RNA‐seq exhibited ferroptosis was significant and the PI3K/AKT pathway deserved to explore the inhibition effects of galangin on ferroptosis. Indeed, galangin treatment significantly rescued RSL3‐inhibited phosphorylation levels of PI3K, AKT, and CREB proteins, and the ferroptosis inhibitory effects of galangin were counteracted by PI3K inhibitor LY294002. These findings indicated that galangin may exert its anti‐ferroptosis effects via activating the PI3K/AKT/CREB signaling pathway and it will hopefully serve as a promising effective measure to attenuate IR injury by inhibiting ferroptosis.
Development of fluorescent peptide G protein‐coupled receptor activation biosensors for NanoBRET characterization of intracellular allosteric modulators
Authors: Farmer James P. , Mistry Shailesh N. , Laughton Charles A. , Holliday Nicholas D.
Published: October 2022

G protein‐coupled receptors (GPCRs) are widely therapeutically targeted, and recent advances in allosteric modulator development at these receptors offer further potential for exploitation. Intracellular allosteric modulators (IAM) represent a class of ligands that bind to the receptor–effector interface (e.g., G protein) and inhibit agonist responses noncompetitively. This potentially offers greater selectivity between receptor subtypes compared to classical orthosteric ligands. However, while examples of IAM ligands are well described, a more general methodology for assessing compound interactions at the IAM site is lacking. Here, fluorescent labeled peptides based on the Gα peptide C terminus are developed as novel binding and activation biosensors for the GPCR‐IAM site. In TR‐FRET binding studies, unlabeled peptides derived from the Gαs subunit were first characterized for their ability to positively modulate agonist affinity at the β2‐adrenoceptor. On this basis, a tetramethylrhodamine (TMR) labeled tracer was synthesized based on the 19 amino acid Gαs peptide (TMR‐Gαs19cha18, where cha = cyclohexylalanine). Using NanoBRET technology to detect binding, TMR‐Gαs19cha18 was recruited to Gs coupled β2‐adrenoceptor and EP2 receptors in an agonist‐dependent manner, but not the Gi‐coupled CXCR2 receptor. Moreover, NanoBRET competition binding assays using TMR‐Gαs19cha18 enabled direct assessment of the affinity of unlabeled ligands for β2‐adrenoceptor IAM site. Thus, the NanoBRET platform using fluorescent‐labeled G protein peptide mimetics offers novel potential for medium‐throughput screens to identify IAMs, applicable across GPCRs coupled to a G protein class. Using the same platform, Gs peptide biosensors also represent useful tools to probe orthosteric agonist efficacy and the dynamics of receptor activation.
PLIS: A metabolomic response monitor to a lifestyle intervention study in older adults
Authors: Bogaards Fatih A. , Gehrmann Thies , Beekman Marian , van den Akker Erik Ben , van de Rest Ondine , Hangelbroek Roland W. J. , Noordam Raymond , Mooijaart Simon P. , de Groot Lisette C. P. G. M. , Reinders Marcel J. T. , Slagboom P. Eline
Published: October 2022

The response to lifestyle intervention studies is often heterogeneous, especially in older adults. Subtle responses that may represent a health gain for individuals are not always detected by classical health variables, stressing the need for novel biomarkers that detect intermediate changes in metabolic, inflammatory, and immunity‐related health. Here, our aim was to develop and validate a molecular multivariate biomarker maximally sensitive to the individual effect of a lifestyle intervention; the Personalized Lifestyle Intervention Status (PLIS). We used 1H‐NMR fasting blood metabolite measurements from before and after the 13‐week combined physical and nutritional Growing Old TOgether (GOTO) lifestyle intervention study in combination with a fivefold cross‐validation and a bootstrapping method to train a separate PLIS score for men and women. The PLIS scores consisted of 14 and four metabolites for females and males, respectively. Performance of the PLIS score in tracking health gain was illustrated by association of the sex‐specific PLIS scores with several classical metabolic health markers, such as BMI, trunk fat%, fasting HDL cholesterol, and fasting insulin, the primary outcome of the GOTO study. We also showed that the baseline PLIS score indicated which participants respond positively to the intervention. Finally, we explored PLIS in an independent physical activity lifestyle intervention study, showing similar, albeit remarkably weaker, associations of PLIS with classical metabolic health markers. To conclude, we found that the sex‐specific PLIS score was able to track the individual short‐term metabolic health gain of the GOTO lifestyle intervention study. The methodology used to train the PLIS score potentially provides a useful instrument to track personal responses and predict the participant's health benefit in lifestyle interventions similar to the GOTO study.
Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms
Authors: Filiberto Amanda C. , Ladd Zachary , Leroy Victoria , Su Gang , Elder Craig T. , Pruitt Eric Y. , Hensley Sara E. , Lu Guanyi , Hartman Joseph B. , Zarrinpar Ali , Sharma Ashish K. , Upchurch Gilbert R.
Published: October 2022

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω‐3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase‐treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase‐treated FPR2−/− mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell α‐actin expression compared to elastase‐treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2−/− mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non‐aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1‐mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis.
Screening for Social Risk Factors in the ICU During the Pandemic
Authors: Ge Derek , Weber Alec M. , Vatson Jayanth , Andrews Tracy , Levytska Natalia , Shu Carol , Hussain Sabiha
Published: October 2022

IMPORTANCE:

Due to limitations in data collected through electronic health records, the social risk factors (SRFs) that predate severe illness and restrict access to critical care services are poorly understood.

OBJECTIVES:

This study explored the feasibility and utility of directly eliciting SRFs in the ICU by implementing a screening program.

DESIGN, SETTING, AND PARTICIPANTS:

Five hundred sixty-six critically ill patients at the medical ICU of Robert Wood Johnson University Hospital from July 1, 2019, to September 31, 2021, were interviewed for SRFs using an adapted version of the American Academy of Family Physicians’ Social Needs Screening Tool.

MAIN OUTCOMES AND MEASURES:

For each SRFs, we compared basic demographic factors, proxies of socioeconomic status, and severity score between those with and without the SRFs through chi-square tests and Wilcoxon rank-sum tests. Furthermore, we determined the prevalence of SRFs overall, before, and during the COVID-19 pandemic.

RESULTS:

Of critically ill patients, 39.58% reported at least one SRF. Age, zip-code matched median household income, and insurance type differed depending on the SRFs. Notably, patients with SRFs were admitted with a lower average severity score, indicating reduced risk in mortality. Since March 2020, the prevalence of SRFs in the ICU overall fell from 54.47% to 35.44%. Conversely, the proportion of patients unable to afford healthcare increased statistically significantly from 7.32% to 18.06%.

CONCLUSIONS AND RELEVANCE:

Screening for SRFs in the ICU detected the presence of disproportionally low-risk patients whose access to critical care services became restricted throughout the pandemic.
Rare Case of Paraneoplastic Pemphigus Associated With Prostatic Cancer
Authors: Hui Hai-zhen , Guo Hong-xing , Wang Ying-jun , Shi Bing-jun
Published: October 2022

The combination of paraneoplastic pemphigus and prostate cancer is extremely unusual and has not been reported yet. Paraneoplastic pemphigus is caused by tumor-induced autoantibodies, which cause damage to the skin and mucosa. The essential treatment is active tumor control. Our patient received a robot-assisted radical prostatectomy and glucocorticoid therapy to improve his condition and relieve his skin lesions.
Two Cases of Insulin-Derived Amyloidosis With Acanthosis Nigricans-Like Changes
Authors: Godse Rama , Rauck Corinne , Woods Rachel , Steele Katherine T. , Elenitsas Rosalie
Published: October 2022

Insulin-derived amyloidosis (AIns) is a rare iatrogenic subtype of cutaneous amyloidosis occurring at frequent insulin injection sites. Here, we describe 2 cases of AIns accompanied by acanthosis nigricans (AN)-like changes, a rare finding which has been reported fewer than 5 times in the literature. We also report the first case of an AIns nodule being misdiagnosed as a keloid. Both of our patients presented with asymptomatic, hyperkeratotic, pigmented plaques at frequent insulin injection sites, and histopathologic examination showed (1) nodular aggregates of amyloid demonstrating apple-green birefringence with Congo red staining and (2) AN-like features, such as epidermal papillomatosis, hyperkeratosis, and hyperpigmentation. Accurate diagnosis of AIns is crucial, because repeated insulin injection into a nodule can impair glycemic control. However, misdiagnosis is common, as observed with our second patient, whose AIns nodule was misdiagnosed by an outside provider as a keloid, perhaps because of the presence of AN-like features. Our case report adds to the limited but growing body of literature on AIns and significantly increases the number of reported cases of AIns with AN-like features, an even rarer phenomenon.
Glaucoma in Patients With Endothelial Keratoplasty
Authors: Saini Chhavi , Davies Emma C. , Chodosh James , Shen Lucy Q.
Published: October 2022

Endothelial keratoplasty (EK), including Descemet stripping endothelial keratoplasty and Descemet membrane endothelial keratoplasty, is now the most performed corneal transplant procedure in the United States. Intraocular pressure (IOP) elevation and glaucoma are common complications and can cause irreversible vision loss and corneal graft failure. This review will cover the incidence, risk factors, and management of glaucoma and IOP elevation after EK. Higher preoperative IOP, preoperative glaucoma, and certain indications for EK, such as bullous keratopathy, are associated with increased risk of glaucoma and glaucoma progression in patients undergoing EK. In addition, we summarize the studies assessing graft outcomes in EK patients with glaucoma or glaucoma surgery. Finally, we provide future directions to improve clinical care in EK patients with glaucoma.
Training of Non-expert Users Using Remotely Delivered, Point-of-Care Tele-Ultrasound
Authors: Grubic Nicholas , Belliveau Daniel J. , Herr Julia E. , Nihal Salwa , Wong Sheung Wing Sherwin , Lam Jeffrey , Gauthier Stephen , Montague Steven J. , Durbin Joshua , Mulvagh Sharon L. , Johri Amer M.
Published: October 2022

Many physicians, particularly those practicing in remote regions, lack training opportunities to develop point-of-care ultrasound (POCUS) skills. This pretest-posttest study quantified the skill improvement of learners after participating in a virtual training program that used real-time, remotely delivered point-of-care tele-ultrasound (tele-POCUS) for teaching and learner feedback provision. Ten physicians practicing in an urban tertiary (Kingston, Ontario, Canada, n = 6) or remote care center (Moose Factory, Ontario, Canada, n = 4) completed a 3-week educational program that consisted of e-learning module review, independent image acquisition practice, and expert-guided tele-POCUS consultations. Pretraining and posttraining assessments were performed to evaluate skill enhancement in image acquisition, image quality, and image interpretation for cardiac and lung/pleura POCUS using a 5-point Likert scale. A total of 76 tele-POCUS consultations were performed during the study period. Significant improvements in image quality were noted following remotely delivered mentorship and guidance (all P < 0.01). In cardiac POCUS, pretraining and posttraining comparisons noted significant improvements in image acquisition (means, 2.69–4.33; P < 0.02), quality (means, 2.40–4.03; P < 0.01), and interpretation (means, 2.50–4.40; P < 0.02). In lung/pleura POCUS, significant improvements in image acquisition (means, 3.00–4.43; P < 0.01), quality (means, 3.23–4.37; P < 0.01), and interpretation (means, 3.00–4.40; P < 0.01) were demonstrated. Introductory ultrasound can be taught to novice users using a virtual, live-streamed training format with tele-POCUS while demonstrating significant enhancement in imaging skills.
Group augmentation on trial: helpers in small groups enhance antipredator defence of eggs
Authors: García-Ruiz Irene , Taborsky Michael
Published: October 2022

Mechanisms selecting for the evolution of cooperative breeding are hotly debated. While kin selection theory has been the central paradigm to explain the seemingly altruistic behaviour of non-reproducing helpers, it is increasingly recognized that direct fitness benefits may be highly relevant. The group augmentation hypothesis proposes that alloparental care may evolve to enhance group size when larger groups yield increased survival and/or reproductive success. However, there is a lack of empirical tests. Here we use the cooperatively breeding cichlid fish
Neolamprologus pulcher
, in which group size predicts survival and group stability, to test this hypothesis experimentally by prompting two cooperative tasks: defence against an egg predator and digging out sand from the breeding shelter. We controlled for alternative mechanisms such as kin selection, load lightening and coercion. As predicted by the group augmentation hypothesis, helpers increased defence against an egg predator in small compared with large groups. This difference was only evident in large helpers owing to size-specific task specialization. Furthermore, helpers showed more digging effort in the breeding chamber compared with alternative personal shelters, indicating that digging is an altruistic service to the dominant breeders.
The “ForensOMICS” approach to forensic post-mortem interval estimation: combining metabolomics, lipidomics and proteomics for the analysis of human bone
Authors: Bonicelli Andrea , Mickleburgh Hayley L. , Chighine Alberto , Locci Emanuela , Wescott Daniel J. , Procopio Noemi
Published: October 2022

The combined use of multiple omics methods to answer complex system biology questions is growing in biological and medical sciences, as the importance of studying interrelated biological processes in their entirety is increasingly recognized. We applied a combination of metabolomics, lipidomics and proteomics to human bone to investigate the potential of this multi-omics approach to estimate the time elapsed since death (i.e., the post-mortem interval, PMI). This “ForensOMICS” approach has the potential to improve accuracy and precision of PMI estimation of skeletonized human remains, thereby helping forensic investigators to establish the timeline of events surrounding death. Anterior midshaft tibial bone was collected from four female body donors in a fresh stage of decomposition before placement of the bodies to decompose outdoors at the human taphonomy facility managed by the Forensic Anthropological Center at Texas State (FACTS). Bone samples were again collected at selected PMIs (219, 790, 834 and 872 days). Liquid chromatography mass spectrometry (LC-MS) was used to obtain untargeted metabolomic, lipidomic and proteomic profiles from the pre- and post-placement bone samples. Multivariate analysis was used to investigate the three omics blocks by means of Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies (DIABLO), to identify the reduced number of markers that could effectively describe post-mortem changes and classify the individuals based on their PMI. The resulting model showed that pre-placement bone metabolome, lipidome and proteome profiles were clearly distinguishable from post-placement profiles. Metabolites associated with the pre-placement samples, suggested an extinction of the energetic metabolism and a switch towards another source of fuelling (e.g., structural proteins). We were able to identify certain biomolecules from the three groups that show excellent potential for estimation of the PMI, predominantly the biomolecules from the metabolomics block. Our findings suggest that, by targeting a combination of compounds with different post-mortem stability, in future studies we could be able to estimate both short PMIs, by using metabolites and lipids, and longer PMIs, by including more stable proteins.
Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina
Authors: Soucy Jonathan R , Todd Levi , Kriukov Emil , Phay Monichan , Reh Thomas A , Baranov Petr
Published: October 2022

Ongoing cell replacement studies and clinical trials have demonstrated the need to control donor and newborn cell behavior within their target tissue. Here we present a methodology to guide stem cell-derived and endogenously regenerated neurons by engineering the microenvironment. Being an “approachable part of the brain,” the eye provides a unique opportunity to study donor neuron fate, migration, and integration within the central nervous system. Glaucoma and other optic neuropathies lead to the permanent loss of retinal ganglion cells (RGCs) – the neurons in the retina that transfer all visual information from the eye to the brain. Cell transplantation and transdifferentiation strategies have been proposed to restore RGCs, and one of the significant barriers to successful RGC integration into the existing retinal circuitry is cell migration towards their natural position in the retina. Here we describe a framework for identifying, selecting, and applying chemokines to direct cell migration in vivo within the retina. We have performed an in silico analysis of the single-cell transcriptome of the developing human retina and identified six receptor-ligand candidates to guide stem cell-derived or newborn neurons. The lead candidates were then tested in functional in vitro assays for their ability to guide stem cell-derived RGCs. For the in vivo studies, donor and newborn neurons were differentiated in human and mouse retinal organoids or endogenously reprogrammed with proneuronal transcription factors, respectively. An exogenous stromal cell-derived factor-1 (SDF1) gradient led to a 2.7-fold increase in donor RGC migration into the ganglion cell layer and a 3.3-fold increase in the displacement of newborn RGCs out of the inner nuclear layer. Furthermore, by altering the migratory profile of donor RGCs toward multipolar migration, overall migration was improved in mature retinal tissues. Together, these results highlight the ability and importance of engineering the tissue microenvironment and the individual cells for research and clinical applications in gene and cell therapies.

Graphical Abstract

In brief, the “in silico – in vitro – in vivo” funnel holds significant potential for identifying targets to control cellular processes in research and clinical applications. In this report, Soucy et al. describes a framework for identifying, selecting, and applying chemokines to direct retinal ganglion cell migration in vivo within the adult mouse retina.