bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Value Analysis in Pressure Injury Prevention
Authors: Constable Stephanie , Spitzer Mandy
Published: January 2025

PURPOSE:

Global pressure injury (PI) statistics reveal that hospital-acquired pressure injuries (HAPIs) remain a substantial burden, with over 1 in 10 hospitalized adults being affected. The purpose of this analysis is to describe how consistent collection, analysis, and use of data allow hospitals to validate their clinical and economic outcomes and to adjust PI prevention strategies.

PARTICIPANTS AND SETTING:

HAPI incidence data for acute care patients at a 280-bed regional community hospital in the Mid-Atlantic region of the United States (West Virginia) were collected from January 2012 to July 2023.

APPROACH:

Multilayered silicone foam dressings from 3 manufacturers were used during data collection and outcomes evaluated. The average annual HAPI incidence was calculated retrospectively to allow comparison of outcomes during the time periods that various soft silicone multilayered foam manufacturers were used.

OUTCOMES:

When using dressing 1, the hospital experienced an average of 10.40 HAPI per year. When using dressing 2, the hospital experienced an average of 5.56 HAPI per year, and when using dressing 3, the average was 26.29 HAPI per year. Additionally, an estimated sum of US $451 229.91 was saved when using dressing 2 compared to dressing 3, and US $105 352.28 was saved during the use of dressing 2 as compared to dressing 1.

IMPLICATIONS FOR PRACTICE:

Monitoring data over time can validate product selection decisions to ensure they are advantageous to both costs and the delivery of quality care.
Risk Factors for Incontinence-Associated Dermatitis in Adults
Authors: Jiang Tianxiang , Zhang Xiuzhi , Wu Jinju , Gao Lei , Tung Tao-Hsin
Published: January 2025

PURPOSE:

A meta-analysis was conducted to comprehensively identify risk factors of incontinence-associated dermatitis (IAD) in adults and provide evidence-based support for healthcare professionals to formulate IAD preventive interventions and bundled interventions.

METHODS:

Systematic review and meta-analysis of pooled findings.

SEARCH STRATEGY:

Two researchers independently searched databases PubMed, EBSCO, Cochrane Library, Embase, Medline, Web of Science and Scopus and 4 Chinese databases (CNKI, Wanfang Data, VIP and CBM) for relevant studies published from their inception to March 15, 2023. Two researchers independently extracted relevant data and literature characteristics and evaluated the quality of the included studies.

FINDINGS:

Twenty-seven studies that collectively enrolled 4046 participants were included in our systematic review. Five were written in English, 1 was written in Spanish, and the other 21 were written in Chinese. The odds ratios (ORs) and 95% confidence intervals (CIs) of the risk factors for IAD were determined. Fecal incontinence, an etiologic factor (OR = 5.79; 95% CI = [1.88-17.87]), stool characteristics (OR = 5.28; 95% CI = [2.51-11.07]), and daily frequency of bowel movements (OR = 5.76; 95% CI = [4.48-7.42]) were associated with an increased likelihood of IAD. The following risk factors: fever (OR = 4.23; 95% CI = [1.89-9.46]), age (OR = 1.04; 95% CI = [1.01-1.09]), hypoproteinemia (OR = 3.30; 95% CI = [1.90-5.72]), impaired consciousness (OR = 2.43; 95% CI = [1.66-3.54]), days of antibiotic use (OR = 4.13; 95% CI = [3.11-5.49]), diabetes mellitus (OR = 2.90; 95% CI = [1.73-4.86]), and a higher overall Perineal Assessment Tool (PAT) score (OR = 2.56; 95% CI = [1.23-5.30]) emerged as independent risk factors for IAD in adult patients. In contrast, a higher serum albumin level (OR = 0.88; 95% CI = [0.84-0.93]), a higher Braden Scale for Predicting Pressure Score Risk (Braden Scale) score (OR = 0.66; 95% CI = [0.56-0.77]), and a higher Braden Scale mobility subscale score (OR = 0.86; 95% CI = [0.74-1.00]) were protective factors that reduced the likelihood of IAD.

IMPLICATIONS:

Identification of risk factors for IAD may be used to identify patients at risk and in need of preventive interventions. Identification of modifiable risk factors may be used to design novel preventive interventions.
Short prescribed exercises can quantify upper limb functioning in neurodegenerative disease
Authors: Straczkiewicz Marcin , Burke Katherine M. , Calcagno Narghes , Premasiri Alan , Carney Kendall T. , Vieira Fernando G. , Onnela Jukka-Pekka , Berry James D.
Published: January 2025

Digital health technologies (DHTs) can quantify movements in daily routines but rely heavily on participant adherence over prolonged wear times. Here we analyze accelerometry data from wrist-worn devices during short episodes of prescribed exercises (PEs) performed by 329 individuals living with amyotrophic lateral sclerosis (ALS) in a longitudinal study. We developed an automated and interpretable signal processing method to estimate upper limb movement counts, duration, intensity, and similarity of repetitions during PEs. Upper limb swing duration increased while intensity and similarity of movement decreased over time, indicating longer but less vigorous and less consistent upper limb movements over time. Intensity emerged as the most robust predictor of changes in upper limb function. The results suggest that PEs can effectively quantify upper limb function comparable to certain free-living measurements, providing greater flexibility in the clinical application of DHTs.
Characterizing dog communities adjacents to key shorebird sites in Chile
Authors: Contreras Gabriela , Peredo Ronny , Sandvig Erik M. , Rodríguez Betsabé , Gallardo Benjamín , Norambuena Heraldo V. , Medrano Fernando
Published: January 2025

Free-ranging domestic dogs can cause numerous negative impacts on public health, tourism, and the environment. Some of these impacts on wildlife are compounded and facilitated by human communities, for example through the provision of food, health care, and shelter, which altogether increase the dog’s life expectancy. Shorebirds are one of the groups adversely affected by dogs through nest predation, behavioral changes, and persecution during foraging and roosting periods. In Chile, dogs are a ubicutous threat in wetlands. In this study, we characterized the dog populations at the mouth of the Lluta River (Chacalluta area) and the Coihuín wetland (Coihuín-Chamiza area), both of international importance for shorebirds. We estimated the total abundance of dogs, their seasonal survival, and demographic and behavioral traits by photographic capture-recapture methods in eight surveys of 6.6 km2for Chacalluta and 2.0 km2for Coihuín-Chamiza. We estimated a population size of 167 individuals in Chacalluta and 505 individuals in Coihuín-Chamiza, a relatively low survival rate in both sites, a healthy body status in more than 80% of the dogs, small group sizes (1-2 individuals), and movements of 1,000 to 3,000 meters between locations. We report patterns associated with human ownership, indicating irresponsible pet ownership. This information will be the basis for developing public policies and evaluating strategies to lessen their impact on shorebirds, such as demographic control of the animal population, reduction of abandonment, and promotion of responsible pet ownership practices.
Genomic Analysis of Date Palm Fruit Size Traits and Identification of Candidate Genes through GWAS
Authors: Younuskunju Shameem , Mohamoud Yasmin A. , Mathew Lisa Sara , Mayer Klaus F. X. , Suhre Karsten , Malek Joel A.
Published: January 2025

The commercial value of economically significant fruits, including date palm fruit (dates), is influenced by various factors, such as biochemical composition and morphological features like size, shape, and visual appearance, which are key determinants of their quality and market value. Dates are typically consumed at the dry stage (Tamar), during which they exhibit a wide range of physical characteristics, such as color, length, weight, and skin appearance. Understanding the genetic basis of these traits is crucial for improving crop quality and breeding new cultivars. In this study, we integrated a genome dataset from highly diverse date cultivars with phenotypes of dry fruit such as length, width, area, and weight, identifying multiple significant genetic loci (SNPs) associated with these traits. We also identified candidate genes located near the associated SNPs that are involved in biological processes such as cell differentiation, proliferation, growth, and the regulation of signalling pathways for growth regulators like auxin and abscisic acid, as observed in other plants. Gene expression analysis reveals that many of these genes are highly expressed in the early stage of fruit development when the fruit attains its maximum size and weight. These findings will enhance our understanding of genetic determinants of fruit size particularly at the commercially important Tamar stage.
Single Cell Transcriptome Signatures of Sarcoidosis in Lung Immune Cell Populations
Authors: Moore Camille , Liao Shu-Yi , Wood Cheyret , Sarkar Arunangshu , Cardwell Jonathan , MacPhail Kristyn , Mroz Margaret M. , Riley Christina , Mould Kara , Restrepo Clara , Li Li , Maier Lisa A. , Yang Ivana V.
Published: January 2025

Rationale

To identify cell specific molecular changes associated with sarcoidosis risk and progression, we aimed to characterize the cellular composition, gene expression patterns, and cell-cell interactions in BAL cells from patients with sarcoidosis (both progressive and non-progressive) and healthy controls.

Methods

Single cell RNA-seq data were collected on 12 sarcoidosis and 4 control participants. We combined scRNA-seq data from these participants with our previously collected data on 4 sarcoidosis and 10 control participants for a final sample size of 16 sarcoidosis cases (8 progressive and 8 non-progressive) and 14 controls. Following initial preprocessing in CellRanger, data were quality controlled, combined, and clustered in Seurat. We tested differences in cell proportions by disease group using F-tests on cell proportions and differences in gene expression using pseudobulk analysis. Cell to cell communication and pathway analysis were performed using CellChat.

Results

We identified five macrophage populations: resident, high metallothionein (MT) resident, recruited, profibrotic recruited, and proliferating macrophages. Each subpopulation displayed unique gene expression profiles, with notable differential expression of genes and pathways linked to sarcoidosis in resident macrophages, recruited macrophages, and proliferating macrophages. We also observed changes in gene expression associated with disease progression in resident and recruited macrophages. In non-macrophages cells, we observed a significant reduction in the number of B cells in sarcoidosis patients compared to controls. Among T cell populations, we identified specific transcriptional alterations at gene and pathway level. Additionally, we observed distinct differences in cell-to-cell interactions of macrophages and T cells between sarcoidosis patients and healthy controls.

Conclusions

These findings underscore the complexity of immune cell involvement in sarcoidosis and highlight potential cellular and molecular targets for further investigation.
Nanoscale Dynamics of Enhancer-Promoter Interactions during Exit from Pluripotency
Authors: Stumberger Gabriela , Hörl David , Steinek Clemens , Leonhardt Heinrich , Harz Hartmann
Published: January 2025

While there is compelling genetic evidence for the role of enhancers in regulating promoter activity even over large genomic distances, it is unclear to what extent physical proximity with the respective promoters is involved. Here we combine DNA fluorescence in situ hybridization (FISH) with confocal and stimulated emission depletion (STED) super resolution microscopy to investigate enhancer-promoter (E-P) distances at selected loci (Dppa3, Nanog, Dnmt3a, Sox2, Prdm14) that contain multiple enhancers and undergo transcriptional changes at the transition from naive to primed pluripotency in mouse embryonic stem cells. Automated distance measurements in thousands of cells revealed that both pairwise and multiway E-P conformations undergo only small (Δ median distance = ∼22 nm) changes, despite large, up to 1500-fold changes in transcription, arguing against lasting changes in genome architecture at these loci. As transcription often occurs in transient bursts in a small fraction of cells, we performed RNA FISH to identify actively transcribed alleles. We found that in actively transcribed Dppa3 alleles (<10%) the median E-P distances are significantly shorter (Δ median distance = ∼90 nm) than in non-transcribed ones. These data are consistent with a transient spatial interaction of enhancers and promoter during the initiation of transcription.

GRAPHICAL ABSTRACT
PERK orchestrates MERCS formation and mitochondrial remodelling promoting physiological adaptations during adaptive UPR signalling
Authors: Casas-Martinez Jose C. , Xia Qin , Li Penglin , Borja-Gonzalez Maria , Miranda-Vizuete Antonio , McDermott Emma , Dockery Peter , Quinlan Leo R. , Goljanek-Whysall Katarzyna , Samali Afshin , McDonagh Brian
Published: January 2025

The transfer of information and metabolites between mitochondria and the ER is mediated by mitochondria-ER contact sites (MERCS), facilitating adaptations following changes in cellular homeostasis. MERCS are dynamic structures, essential for maintaining cellular homeostasis through modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Acute ER stress in myoblasts promoted myogenesis that required the PERK arm of the UPRERfor increased MERCS assembly, mitochondrial turnover and function. Similarly, induction of acute UPRERduring early development inC. elegansresulted in increased lifespan and healthspan. Adaptive UPRERsignalling in myoblasts andC. elegans, increased MERCS assembly and activated autophagy, ultimately promoting mitochondrial remodelling. Adaptations were dependent on the developmental stage, as treatment of myotubes or adultC. elegansresulted in a maladaptive response. The results identify that PERK is required for increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.

Graphical Abstract
Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane
Authors: Wong Sara , Bertram Katherine R. , Raghuram Nidhi , Knight Thomas , Hughes Adam L.
Published: January 2025

Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.

Significance Statement

Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.

Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.

These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.
A Recessiveoca2Mutation Underlies Albinism inXiphophorusfish
Authors: Xing Yanting , Boswell William , Parker Jessica , Du Kang , Schartl Manfred , Lu Yuan
Published: January 2025

Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by impaired melanin production, leading to reduced pigmentation in the skin, hair, and eyes.Xiphophorus, a genus of small freshwater fish, has been a pivotal model organism in pigmentation disorder research, providing key findings in the genetic pathways governing physiological and pathological pigment cell biology. Leveraging the well-established research framework provided byXiphophorus, we have identified a spontaneously occurring albinism phenotype in swordtail fishXiphophorus hellerii. Genetic mapping of albino fish showed that albinism is associated with a recessive mutation in theoca2gene. This discovery provides a novel opportunity to explore functions ofoca2gene in pigment cell differentiation, pigment synthesis, melanosome assembly and transportation function and amelanotic melanoma development.
Volatile-suppressed peptide signaling enhances volatile responses in plant-plant interactions
Authors: Wang Lei , Hoefer Sara , Jimenez-Sandoval Pedro , Yu Hao , Spiegelhalder Roxane , Waterman Jamie , Hurni Luke , Hu Lingfei , Liu Lei , Jackson David , Raissig Michael , Erb Matthias
Published: January 2025

Plant volatiles shape plant-plant interactions by acting as defense regulators and response factors. While plant volatile biosynthesis is well understood, how their emission is regulated remains largely elusive. Here, we show that small peptide signaling regulates induced volatile release in maize. Following herbivore attack, green leaf volatiles such as (Z)-3-hexenyl acetate (HAC) are released and induce terpene and indole emissions from neighboring plants. This process is accompanied by reduced expression of the ZmCLE1E9 gene and the ZmBAM1A, ZmBAM1B and ZmBAM3C receptor genes in HAC-exposed plants. Exogenous ZmCLE1E9 peptide inhibits HAC-triggered volatile release by limiting stomatal aperture. This inhibition disappears in theZmbam1a/Zmbam1b/Zmbam3ctriple mutant. Molecular docking supports ZmCLE1E9 and ZmBAMs as ligand-receptor pairs. Furthermore,Zmcle1e9andZmbamstriple mutants show increased volatile emissions upon HAC exposure. In summary, we show that upon HAC perception, maize plants enhance their capacity to release terpenes and indole via the suppression of CLE1E9 signaling. This behavior allows maize plants to rapidly deploy volatile cues in response to stress volatiles and thus shape the infochemical dynamics of multitrophic environments.
Rare variants and founder effect in an understudied Quebec population
Authors: Gagnon Mylène , Moreau Claudia , Ricard Jasmin , Boisvert Marie-Claude , Bureau Alexandre , Maziade Michel , Girard Simon L.
Published: January 2025

Founder events influenced the genetic diversity within the Quebec province, increasing the frequency of certain rare pathogenic variants in regional populations. Some regions such as Beauce remain understudied despite evidence of a regional founder effect. Leveraging extensive genealogical data, we found a specific regional structure emerging in Beauce following the initial settlement, with a gradual increase of the inbreeding and kinship coefficients and a low ancestors’ diversity. Profiting from the genetic distinctiveness of the region, we identified 28 rare pathogenic variants with higher carrier rates in Beauce than in urban regions due to its regional founder effect. This provides the first in-depth study of Beauce’s genetic and genealogical landscape, revealing a distinct structure and suggesting that other overlooked regions, in Quebec and elsewhere, could benefit from fine-scale population structure study to improve the understanding and management of rare diseases.
VR-based Gamma Sensory Stimulation: A feasibility study
Authors: Reis C. , Azizollahi H. , Headley G. , Navarro S. , Hanslmayr S. , Clouter A. , Zanto T , Certain R.
Published: January 2025

Alzheimer’s disease (AD) presents a critical global health challenge, with current therapies offering limited efficacy and safety in halting disease progression. Gamma sensory stimulation (GSS) has emerged as a promising non-invasive neuromodulation technique that enhances gamma neural synchrony, potentially counteracting AD pathology by reducing neuroinflammation, promoting glymphatic clearance, and improving synaptic plasticity. However, existing GSS delivery methods rely on simplistic sensory stimuli that lack user engagement, creating adherence barriers and limiting the full therapeutic potential of GSS.

This pilot study assessed the feasibility, safety, and efficacy of delivering GSS via virtual reality (VR), combining EEG recordings to monitor neural activity and a digital questionnaire to evaluate safety and tolerability. Sixteen cognitively healthy older adults participated in three experiments designed to assess modulation of gamma activity in response to 40Hz stimuli. EEG recordings confirmed that unimodal auditory and visual stimuli reliably induced gamma oscillations in their respective cortical regions, while multimodal stimulation enhanced both gamma power and inter-trial phase coherence, demonstrating robust modulation of gamma activity. Notably, significant gamma activity modulation was also achieved when diversified multimedia content was modulated at 40Hz and integrated into a cognitive task, highlighting the flexibility and effectiveness of this approach.

The findings of this study validate VR as a scalable tool for delivering engaging and cognitively relevant GSS, paving the way for personalized therapies that maximize adherence and therapeutic outcomes. By integrating interactive elements, VR-based GSS may uniquely target memory-related neural networks, offering a novel approach to mitigate neurotoxicity and cognitive decline in AD.
Symbiont-specific uptake is mediated by integrins in cnidarian larvae
Authors: Jones Victor A. S. , Dorr Melanie , Siemers Isabelle , Rupp Sebastian , Surm Joachim M. , Maegele Ira , Gornik Sebastian G , Ferguson Meghan , Guse Annika
Published: January 2025

The symbiotic relationship between dinoflagellate algae and their cnidarian hosts is fundamental to the health of coral reefs. The selection of appropriate symbionts is paramount for the host to gain valuable nutrients and could be tailored to increase stress tolerance against anthropogenic induced changes in ocean environments, such as coral bleaching in response to ocean warming. Previous research suggests glycan-lectin interactions play a role in symbiont uptake; however, blockage of such interactions does not fully inhibit symbiosis establishment, suggesting other receptors are at play. Potential candidates include RGD peptide binding integrins, which are known to mediate phagocytosis of microbes in other systems. Here, we used a combination of cnidarian model systems and human cell lines to determine if integrins facilitate symbiont recognition and uptake. Integrins are highly expressed in the endodermal tissue of the host, where symbiosis takes place, and upon uptake into endodermal cells, symbionts altered the expression of integrins and downstream signaling molecules. Blockage of integrin binding sites with RGD competitor peptides reduced symbiont uptake, but had no effect on the general uptake of non-symbiotic algae, or uptake in a non-symbiotic cnidarian. In addition, inert beads coated with integrin RGD peptide ligands were phagocytosed more readily than beads coated with scrambled peptide. Finally, overexpression of RGD-binding integrins in human cells increased symbiont uptake and mutation of the active binding site abolished uptake. Our findings reveal RGD-binding integrins as key players in symbiosis establishment and shed light on the evolutionary functions of integrins as phagocytic receptors.
CD271 sorting for improved liver cell isolation: Semiautomated and simultaneous preparation of parenchymal and non-parenchymal cells from mouse and human livers
Authors: Dropmann Anne , Dewidar Bedair , Gould Kerry , Baccetto Raquel L. , Meyer Christoph , Caccamo Tiziana , Erdoesi Pia , Ayvaz Samil , Scheffschick Andrea , Damm Georg , Seehofer Daniel , Feiner Laura Kim , Kruse Bianca , Rubie Claudia , Glanemann Matthias , Orth Vanessa , Birgin Emrullah , Rahbari Nuh , Ebert Matthias P , Dooley Steven , Hammad Seddik
Published: January 2025

Background: A detailed understanding of the dynamic fate changes of hepatocytes, hepatic stellate cells (HSC), Kupffer cells (KC), and liver sinusoidal endothelial cells (LSEC) is critical for studying liver (patho)physiology during disease progression. Current isolation methods often focus on single cell types, limiting utility in comprehensive research. Aim: To develop a novel, semi-automated protocol for the simultaneous isolation of hepatocytes and non-parenchymal cells (NPCs), including HSC, KC, and LSEC, from mouse and human, with high yield, purity, and viability from healthy and diseased livers. Method: The protocol employs a two-step EGTA and collagenase II perfusion for tissue digestion. Hepatocytes were isolated by low-speed centrifugation and a Percoll gradient. Subsequently, magnetic-activated cell separation, using CD271 as a selective surface marker for HSC, CD11b for KC and CD146 for LSEC) was performed. Validation was achieved with immunofluorescence staining, flow cytometry, RT-PCR, and UV fluorescence, whereby yield, purity, and viability were assessed. Results: With our method, yield of hepatocytes, HSC, KC, and LSEC, is 33.4±5.5×10⁶, 5.2±6.3×10⁴, 12.4±4.8×10⁵ and 18.2±8.9×10⁵ cells per healthy mouse liver, respectively, with cell viabilities exceeding 89%, and purity surpassing 90%. CD271 was validated as an effective marker for purifying HSC in healthy and diseased human (n=4-6) and mouse livers. Compared to microfluidic and organ-on-a-chip approaches, with our protocol, we achieve higher yield and purity values while enabling the simultaneous isolation of multiple cell types from a single sample. Conclusion: Our semi-automated protocol offers a scalable, reliable, and versatile solution for isolating main liver cell types with high yield, purity, and viability from both healthy and diseased tissues, advancing liver research and facilitating downstream investigations
Proteome changes associated with effect of high-dose single-fractionation radiation on lung adenocarcinoma cell lines
Authors: Leis Elina , Modhukur Vijayachitra , Lust Helen , Vardja Markus , Saarma Merilin , Ilves Ivar , Jaal Jana , Lavogina Darja
Published: January 2025

Lung cancer is a leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) representing 85% of cases. Advances in treatment modalities, including the emergence of antibody-drug conjugates and stereotactic radiation therapy, have improved outcomes. However, the possible synergistic effects of these therapies remain underexplored at the molecular level. This study investigated high-dose radiation-induced proteomic changes in lung adenocarcinoma cell line HCC-44 grown adherently and cell line A549, grown as adherent cells and 3D spheroids. Our hypothesis was that proteins upregulated by 10 Gy irradiation serve as resistance drivers in cancerous cells and can thus represent potential therapeutic targets.

The label-free mass spectrometry revealed distinct proteomic responses to 10 Gy irradiation, varying by cell line and culturing conditions. Differentially expressed proteins elevated in the irradiated samples included ephrin type-A receptor 2 (EPHA2) in adherent cells and insulin-like growth factor 2 receptor (IGF2R), tetraspanin 3 (TSPAN3) as well as cathepsin D (CTSD) in spheroids. The validation of these targets was carried outviaWestern blot, immunofluorescence, viability assay and spheroid formation assay. The functional assays demonstrated that irradiation sensitized A549 cells to EPHA2 and CTSD inhibitors. These findings underscore the potential of integrating radiation and targeted therapies in NSCLC treatment, and highlight EPHA2 as a promising candidate for future therapeutic strategies.
iPSC-derived hepatocytes accurately recapitulate population diversity in alpha-1-antitrypsin deficiency and offer a novelin vitromodel for large-scale drug efficacy screening studies
Authors: Gil Carlos , Papastavrou Vanesa , Gatti Gemma , Chung Samuel , Kiloh George , Cheung Ka , Łukasiak Magdalena , Robinson Chloe , Panman Lia , Kasioulis Ioannis , Nikolaou Nikolaos
Published: January 2025

Background

Alpha-1 antitrypsin deficiency (A1ATD) is a hereditary recessive disorder caused by mutations in theSERPINA1gene. It is a clinically under-recognised disease characterised by low circulating A1AT levels and intracellular accumulation of misfolded A1AT in hepatocytes. Deposition of excessive abnormal A1AT in the liver leads to liver failure, yet no specific treatments are available due to the lack of physiologically relevant disease modelling platforms.

Methods

We have hypothesised that human induced pluripotent stem cell (iPSC)-derived hepatocytes can provide an efficient platform to study A1ATD. Using CRISPR/Cas9, we have generated wild-type and A1ATD iPSC-derived hepatocytes (Opti-HEP) from healthy and A1ATD donors and developed a bioassay that mimics the accumulation of misfolded A1AT in the liver. Responses to the reference drug carbamazepine (CBZ), known to reduce intracellular misfolded A1AT levels, and RNA-based therapeutics were subsequently investigated.

Results

All lines successfully differentiated into hepatocytes as measured by comparable key hepatic and disease markers to those seen in primary human hepatocytes. The diseased lines displayed increased intracellular accumulation of misfolded A1AT compared to isogenic controls. Diseased cell lines showed significant decreases in intracellular accumulation of polymeric A1AT following transfection with RNA-based therapeutics, but a differential response upon treatment with CBZ.

Conclusion

We have developed a specific and robustin vitromodel of A1ATD that recapitulates disease pathophysiology and responds to small molecule-based treatments and advanced therapeutic strategies. These data demonstrate the suitability of this model for large-scale efficacy screening studies for the treatment of A1ATD and help pave the way towards the development of novel therapies.
Regulation of hematopoietic stem cell (HSC) proliferation by Epithelial Growth Factor Like-7 (EGFL7)
Authors: Kulkarni Rohan , Goda Chinmayee , Rudich Alexander , Karunasiri Malith , Urs Amog P , Bustos Yaphet , Balcioglu Ozlen , Li Wenjun , Chidester Sadie , Rodgers Kyleigh A , Garfinkle Elizabeth AR , Patel Ami , Miller Katherine E , Popovich Phillip G , Elf Shannon , Garzon Ramiro , Dorrance Adrienne M
Published: January 2025

Understanding the pathways regulating normal and malignant hematopoietic stem cell (HSC) biology is important for improving outcomes for patients with hematologic disorders. Epithelial Growth Factor Like-7 (EGFL7)is ∼30 kDa secreted protein that is highly expressed in adult HSCs. UsingEgfl7genetic knock-out (Egfl7KO) mice and recombinant EGFL7 (rEGFL7) protein, we examined the role of Egfl7 in regulating normal hematopoiesis. We found thatEgfl7KO mice had decreases in overall BM cellularity resulting in significant reduction in the number of hematopoietic stem and progenitor cells (HSPCs), which was due to dysregulation of normal cell-cycle progression along with a corresponding increase in quiescence. rEGFL7 treatment rescued our observed hematopoietic defects ofEgfl7KO mice and enhanced HSC expansion after genotoxic stress such as 5-FU and irradiation. Furthermore, treatment of WT mice with recombinant EGFL7 (rEGFL7) protein expands functional HSCs evidenced by an increase in transplantation potential. Overall, our data demonstrates a role for EGFL7 in HSC expansion and survival and represents a potential strategy for improving transplant engraftment or recovering bone marrow function after stress.
The RNA-binding protein RSRC2 promotes mitotic fidelity by interacting with the lncRNAC1QTNF1-AS1
Authors: Georgieva Kaliya , Coomer Alice O , Babaei Parnia , Guiducci Giulia , Dodel Martin , Maniati Eleni , Thind Anisha , Krishnamurthy Sneha , Nawrocka Anna , Wallis Sam , Shkumatava Alena , Wang Jun , Mardakheh Faraz K , Stojic Lovorka
Published: January 2025

Mitotic fidelity depends on proper chromosome alignment at the spindle equator, a process known as chromosome congression, driven by well-established protein networks. Whereas RNA-binding proteins and noncoding RNAs have been implicated in cell division, their interplay during this process remains unknown. Here, we discover that RSRC2, an arginine/serine-rich RNA-binding protein, plays an essential role in cell division by interacting with the long non-coding RNAC1QTNF1-AS1. The loss of either RSRC2 orC1QTNF1-AS1results in defects in chromosome congression and mitotic progression. We show that RSRC2 interacts with distinct sets of proteins involved in splicing and centrosome biogenesis, contributing to the fidelity of cell division through two different mechanisms: one linked to the splicing of mitotic regulators and the other by localising to mitotic centrosomes for which the interaction with theC1QTNF1-AS1RNA is required. Our study uncovers RSRC2 as a new regulator of cell division and illustrates how RNA-protein complexes promote error-free mitosis.
Jk DNA GAGA MOTIFS ARE REQUIRED FOR LOCAL NUCLEOSOME REMODELING AND Vk-Jk RECOMBINATION
Authors: Veselits Margaret , McLean Kaitlin , Wright Nathaniel E , Okoreeh Michael , Maienschein-Cline Mark , Mandal Malay , Clark Marcus
Published: January 2025

Immunoreceptor gene recombination requires complementary 12 bp and 23 bp recombination signal sequences (RSSs). In addition, the RSSs that assemble the RAG proteins, recombination centers, must be accessible yet flanked by a 5’ nucleosome decorated with H3K4me3. InDrosophila, DNA GAGA motifs play an important role in nucleosome positioning. Herein, we report that 5’ to each functional Jk RSS is a DNA GAGA motif conserved across mammalian species. In mice, the GAGA motif 5’ to Jk1 regulated local RSS accessibility and 5’ nucleosome placement. Furthermore, it was required for Vk-Jk1 recombination. Murine Jk3 is nonfunctional, having mutations in both RSS and GAGA motifs. Restoring both GAGA and RSS motifs rescued Vk-Jk3 recombination. In contrast, restoring the RSS alone did not. Genome-wide, strong cryptic 23 RSSs were preferentially bound to nucleosomes. Furthermore, evolutionary selection against cRSS only occurred in the A Compartment of B lymphocytes, not embryonic stem cells. These data indicate that in developing B cells, nucleosome positioning both enables and restricts recombination to Jk. Furthermore, our data suggest an expanded definition of recombination center-associated RSSs to include a 5’ GAGA sequence that dictates the local epigenetic state required for gene recombination.

Recombination center assembly requires a specific epigenetic topology at recombination signal sequences. Herein, we report that conserved GAGA motifs 5’ to each Jk segment are required for establishing this epigenetic topology and subsequent local gene recombination.
Heat-responsive dynamic shifts in alternative splicing of the coralAcropora cervicornis
Authors: Stankiewicz Kathryn H. , Valenzuela Jacob J. , Turkarslan Serdar , Wu Wei-Ju , Gomez-Campo Kelly , Locatelli Nicolas S. , Conn Trinity L. , Radice Veronica Z. , Parker Katherine E. , Alderdice Rachel , Bay Line K. , Voolstra Christian R. , Barshis Daniel J. , Baums Iliana B. , Baliga Nitin S.
Published: January 2025

Climate change has caused drastic declines in corals. As sessile organisms, response to shifting environmental conditions may include changes in gene expression, epigenetic modifications, or the microbiome, but as of yet, a common mechanism of stress response, alternative splicing (AS), has been underexplored in corals. Using short-term acute thermal stress assays, we investigated patterns of AS in the scleractinian coralAcropora cervicornisduring response to and a subsequent overnight recovery phase from low (33℃), medium (35℃), and high (37℃) levels of heat stress. We find that 40% of the genomic gene set is subject to AS. Our findings demonstrate conserved and dynamic shifts in splicing profiles during the heat treatment and subsequent recovery phase. AS increased in response to heat stress and was primarily dominated by intron retention in specific classes of transcripts, including those related to splicing regulation itself. While AS returned to baseline levels post-exposure to low heat, AS persisted even after reprieve from higher levels of heat stress. Partial overlap of AS transcripts with differentially expressed genes suggests that AS may represent a distinct and previously underappreciated regulatory mechanism for thermal stress response in corals.
Method for costing a health system using a Health Systems Model
Authors: Mohan Sakshi , Mangal Tara D. , Manthalu Gerald , Mfutso-Bengo Joseph , Molaro Margherita , Nkhoma Dominic , She Bingling , Tafesse Wiktoria , Twea Pakwanja Desiree , Walker Simon , Chalkley Martin , Colbourn Tim , Hallett Timothy B. , Phillips Andrew , Revill Paul
Published: January 2025

Objectives

Modelling approaches that consider system-wide delivery platforms rather than single diseases are increasingly recognized as crucial for the economic evaluation of policy and investment choices and can be instrumental in forward-looking policy formulation. This paper develops a costing approach tailored to one such model, the Thanzi La Onse (TLO) model of Malawi’s healthcare system, to estimate healthcare delivery costs under varying health system assumptions.

Methods

We developed a mixed-method costing approach to estimate the total cost of healthcare delivery in Malawi using the TLO model, from a healthcare provider perspective. Through an iterative adjustment of key costing parameters, we attempted to align our model-based estimates with real-world expenditure and budget data. Costs were estimated over an 8-year period (2023–2030) under alternative scenarios of health system capacity, including supply chain performance and the size of the health workforce.

Results

A detailed comparison of our cost estimates against expenditure and budget data demonstrates the reliability of our costing method and assumptions, for the conditions and resources captured by the model. Under current health system capacity, the total cost of healthcare delivery in Malawi between 2023 and 2030 was estimated at $1.53 billion [95% confidence interval, $1.51b -$1.54b], which translates to an average annual cost of $309.83 million [$306.17m -$313.56m]. The estimation of costs under alternative scenarios demonstrates the importance of capturing feedback effects to correctly forecast healthcare costs.

Conclusion

Mixed-method costing used within health system models, such as TLO, is a feasible and robust method for estimating healthcare delivery costs. This approach can provide valuable insights for health sector planning and resource allocation.
Anti-racism in postgraduate medical curricula
Authors: Sharma Chetna , Nacer Hadjer , Koay Aaron , McKee Martin , Devakumar Delan
Published: January 2025

Racism is a public health threat and is firmly ingrained in the healthcare system. The reasons for this are complex as racism is rooted in historical, political, economic and social structures of society. To improve the health of their patients and the public, doctors must be able to recognise, name and act on the impact of racism. This study aims to understand action taken by postgraduate medical organisations in the UK in the aftermath of the global public reckoning of structural racism and its longstanding impacts on societal health in 2020. We analysed the public statements made by postgraduate medical organisations and then how this relates to the learning outcomes that doctors in training need to complete. We found that while many institutions (n=14) issued public commitments to anti-racism, reviewing the content of all GMC-approved postgraduate curricula (n=102) shows that the majority of UK doctors are receiving minimal or no education or training in anti-racism. As such, we call institutions involved in postgraduate medical education to include anti-racism competencies in medical curricula to support doctors to develop the skills, behaviours and knowledge to name and address the role of racism in health inequalities.
Recent Advances in the Diagnosis of Autoimmune Inner Ear Disease: A Scoping Review
Authors: Liu Jialin , Wang Changyu , Liu Siru
Published: January 2025

Autoimmune inner ear disease (AIED) is a rare cause of sensorineural hearing loss, typically characterized by progressive bilateral hearing loss and vestibular symptoms. Diagnosing AIED is challenging due to the lack of specific biomarkers and its overlapping clinical features with other causes of hearing loss. This scoping review examines the recent advancements in the diagnostic approaches for AIED from 2020 to 2024, focusing on studies indexed in SCI, MEDLINE, and INSPEC. The review highlights progress in laboratory tests, imaging techniques, and genetic assessments, and discusses the implications of these advances in improving early diagnosis and treatment outcomes.
A scoping review protocol examining the application of large language models in healthcare education and public health learning spaces
Authors: Ndukwe Henry , Otukpa Emmanuel
Published: January 2025

Objective

Through this scoping review, we aim to explore and synthesize existing knowledge and evidence on the learning approaches for incorporating LLMs into healthcare education and public health learning spaces. Specifically, we will attempt to investigate methods for auditing prompts for accuracy; tailoring prompts to improve task-specific accuracy and utility; and exploring how end-user feedback is used to refine and optimize LLM prompts over time. This review will provide a comprehensive understanding of how LLMs are being tailored and improved in these fields, contributing to the development of evidence-based strategies for their implementation. It will also identify areas for future research and innovation.

Introduction

The increasing integration of large language models (LLMs) into healthcare and public health practice and research highlights their potential to revolutionize service delivery, decision-making, and patient care. Despite these advancements, understanding how LLMs can be effectively tailored, audited, and refined for healthcare-specific tasks remains a critical area of inquiry. Key issues include, the accuracy of generated information, and their relevance to the medical and public health fields.

Inclusion criteria

Inclusion criteria will focus on studies addressing LLM applications in healthcare and public health, prompt engineering techniques, prompt auditing methods, and processes geared towards integrating user feedback. Articles that do not focus on healthcare or public health contexts and lack relevance to LLM learning approaches will be excluded.

Methods

The review is guided by the JBI methodology for scoping reviews complemented by updates from Levac et al. Databases including PubMed, Scopus, IEEE Xplore, and Web of Science will be searched for peer-reviewed articles, conference proceedings, and grey literature published in English and French from 2015 to 2025. Data extraction will include information on study characteristics, LLM models, prompt engineering strategies, auditing methodologies, and user feedback mechanisms. We will synthesize to identify trends, gaps, and best practices in leveraging LLMs to generate baseline data for auditing prompts that optimize AI learning and education needs in the healthcare and public health sector.
Distinct Mechanisms of Recognition of Phosphorylated RNAPII C-Terminal Domain by BRCT Repeats of the BRCA1–BARD1 Complex: Insights from Structural and Functional Analyses
Authors: Klapstova V. , Sedova K. , Houser J. , Sebesta M.
Published: January 2025

Transcription competes with other DNA-dependent processes, such as DNA repair, for access to its substrate, DNA. However, the principles governing the interplay between these processes remain poorly understood. Evidence suggests that the BRCA1-BARD1 complex, a key player in the DNA damage response, may act as a mediator of this crosstalk. In this study, we investigated the molecular mechanism underpinning the interaction between RNA polymerase II (RNAPII) and the BRCA1-BARD1 complex, as well as its functional implications. Our findings reveal that the BRCT repeat of BRCA1 binds the Ser5-phosphorylated CTD of RNAPII, utilising a mechanism previously established for other BRCT ligands. Furthermore, we demonstrate that this interaction is critical for the organisation of RNAPII into condensates with liquid-like properties. Analysis of disease-associated variants within the BRCT repeats further supports the biological relevance of this condensation. Collectively, our results suggest that the BRCA1-BARD1 complex may coordinate transcription and DNA repair by facilitating the organisation of RNAPII into transcription factories.
Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans
Authors: Mallick Avijit , Du YunGuang , Ramalho Theresa , Li Rui , Ali Levi , Kim Sookyung , Zhu Lihua Julie , Haynes Cole
Published: January 2025

The mitochondrial unfolded protein response (UPRmt) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans. Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1-deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1-deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1. We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1. Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1, in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans, S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5-knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.