bluuebunny/crossref_metadata_2025 huggingface dataset:
Intense FAP Expression of Ovarian Metastatic Breast Cancer Detected by [68Ga]RTX-1363 PET/CT
Authors: Glantschnig Lisa , Reitsam Nic G. , Kircher Malte , Segmiller Diana , Lapa Constantin , Dierks Alexander
Published: January 2025

PET/CT targeting fibroblast activation protein α (FAP) in cancer-associated fibroblasts shows promise in theranostics. Here, we report the case of a 31-year-old woman with hormone receptor–positive/human epidermal growth factor receptor 2–negative breast cancer who presented with rising CA15-3 for further diagnostic workup. Whereas [18F]FDG PET/CT was unremarkable, novel [68Ga]RTX-1363 PET/CT revealed intense tracer accumulation in thoracoabdominal lymph nodes and both ovaries. Follow-up imaging confirmed tumor progression, and diagnostic laparoscopy verified metastatic disease in the ovaries with high FAP expression in the tumor stroma. This case underscores the superior sensitivity of [68Ga]RTX-1363 PET/CT over [18F]FDG PET/CT, enhancing breast cancer diagnostic and therapeutic strategies.
Evaluation of Lower Lip Hypoesthesia Using Trigeminal Somatosensory Evoked Potential After Sagittal Split Ramus Osteotomy: Retrospective Study
Authors: Gomi Karen , Moroi Akinori , Kohara Riku , Ono Sumire , Yoshizawa Kunio , Ueki Koichiro
Published: January 2025

Objective:

This study evaluated the degree of paresthesia and recovery of the lower lip and chin in patients who underwent sagittal split ramus osteotomy (SSRO) by measuring the preoperative and postoperative trigeminal somatosensory evoked potential (TSEP).

Study Design:

Thirty-seven patients with skeletal class II and III malocclusion who underwent SSRO were included. TSEP was measured at 7 points: preoperatively and 1 week, 1, 3, 6, 12, and 18 months postoperatively. The Semmes-Weinstein monofilament test (SW test) was also performed concurrently.

Results:

Patients were considered to have recovered when the preoperative values were achieved postoperatively. Stimulation and latency N25 showed significant positive correlations with the SW test. Stimulation measured using TSEP was significantly lower than that measured in the SW test at each time point (P<0.001). In contrast, latency N25 measured using TSEP was significantly higher than that measured in the SW test (P<0.001). TSEP measurements indicated earlier remission compared with the SW test (P<0.001).

Conclusion.

The gap between qualitative and quantitative evaluations was indicated. Therefore, TSEP may be a more sensitive alternative for evaluating trigeminal nerve paresthesia after orthognathic surgery. Furthermore, it enables a detailed analysis of the degree of nerve recovery.
Dysregulated Clot Mechanics and Kinetics Impacted by Injury Severity, Predict Mortality After Trauma
Authors: Gosselin Andrew R. , Bargoud Christopher G. , Sawalkar Abhishek , Mathew Shane , Toussaint Ashley , Greenen Matthew , Coyle Susette M. , Macor Marie , Krishnan Anandi , Goswami Julie , Hanna Joseph S. , Tutwiler Valerie
Published: January 2025

Introduction: Coagulopathy following traumatic injury impairs stable blood clot formation and exacerbates mortality from hemorrhage. Understanding how these alterations impact blood clot stability is critical to improving resuscitation. Furthermore, the incorporation of machine learning algorithms to assess clinical markers, coagulation assays and biochemical assays allows us to define the contributions of these factors to mortality. In this study, we aimed to quantify changes in clot formation and mechanics after traumatic injury and their correlation to mortality.

Materials and Methods: Plasma was isolated from injured patients upon arrival to the emergency department prior to blood product administration, or procedural intervention. Coagulation kinetics and mechanics of healthy donors and patient plasma were compared with rheological, turbidity and thrombin generation assays. ELISA’s were performed to determine tissue plasminogen activator (tPA) and D-dimer concentration. Recursive elimination with random forest models were used to assess the predictive strength of clinical and laboratory factors.

Results: Sixty-three patients were included in the study. Median injury severity score (ISS) was 17, median age was 38 years, and mortality was 30%. Trauma patients exhibited reduced clot stiffness, increased fibrinolysis, and reduced thrombin generation compared to healthy donors. Deceased patients exhibited the greatest deviation from healthy levels. Fibrinogen, clot stiffness, D-dimer and tPA all demonstrated significant correlation to ISS. Machine-learning algorithms identified the importance of coagulation kinetics and clot structure on patient outcomes.

Conclusions: Rheological markers of coagulopathy and biochemical factors are associated with injury severity and are highly predictive of mortality after trauma, providing evidence for integrated predictive models and therapeutic strategies.
The Role of Occupational Therapy in Addressing the Mental Health of Dementia Clients’ Caregivers
Authors: Patton Jenna , Sweetman Melissa M
Published: January 2025

Caregiving for a client with dementia brings extensive responsibility as the caregiver manages their loved one’s finances, health, appointments, and daily living. The caregiver can experience a decreased quality of life due to mental health challenges such as stress, strain, depression, and anxiety from the pressures of caregiving. By implementing a caregiver mental health screening with referrals as indicated, an occupational therapist can facilitate more holistic and individualized care for both the client and the caregiver.
Upper Extremity Performance Test for the Older Adult (TEMPA) in Thai Version
Authors: Punyanirun Numpung
Published: January 2025

The objectives of this study were to translate TEMPA into Thai (TEMPA-Thai) and to assess intra-rater reliability in older adults. The original TEMPA was translated into Thai in 2 copies by 2 translators (T1 and T2). The researcher combined both Thai versions into 1 Thai version (T12), which was then translated back into English by 2 native Thai speakers (BT1 and BT2). After that, 3 experts (the physical therapists) analyzed the final synthesis draft (TEMPA-Thai). The researcher then assessed the intra-rater reliability of TEMPA-Thai in 30 older adults. Intra-class correlation coefficients (ICC (3,1)) were used to measure intra-rater reliability. The TEMPA-Thai had excellent reliability (ICC = 0.956-1.00). Furthermore, the standard error of measurement in this study was calculated to be between 0.00 and 3.75. The TEMPA-Thai had a minimal detectable change value between 0.00 and 10.41 seconds. This study was registered at the Thai Clinical Trial Registry (TCTR 20230206004).
Effectiveness of Transcranial Direct Current Stimulation for Migraine Treatment
Authors: Rodríguez-Prieto Daniel , Remohí-Balanza David , Ávila-López Vicente , Muñoz Fernández Alberto C. , Vicente de Frutos Gonzalo , Martín Pérez Sebastián , Martín Pérez Isidro M. , Alonso Pérez José L. , Villafañe Jorge H. , Sosa Reina M Dolores
Published: January 2025

The study aimed to conduct a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of transcranial direct current stimulation (tDCS) in treating migraines. tDCS is a noninvasive technique that modulates neuronal excitability and is considered an innovative non-pharmacological treatment for migraines. The research, conducted from February to June 2022, involved a comprehensive search across various databases, including PubMed, Trip Database, SCOPUS, Cochrane, and PEDro. The risk assessment of randomized controlled trials was performed using the RoB 2.0 tool, and the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. The meta-analysis included 6 studies with a total of 337 migraine participants. The findings revealed significant benefits of tDCS treatment, including a notable reduction in pain intensity (mean differences [MD] = −2.85 [−4.72 to −0.98], P < .001), a decrease in the number of monthly migraine episodes (MD = −7.62 [−11.23 to −4.01], P < .001), and a reduction in the monthly consumption of migraine medication (MD = −9.42 [−13.60 to −5.24], P < .001). In the short term, tDCS seems effective for migraine treatment. Yet, it is crucial to recognize study heterogeneity, moderate methodological quality, and potential biases. Consequently, future research must uphold rigorous methodologies to validate these findings and explore tDCS’s long-term implications in migraine therapy.
Investigation of the Effects of Counseling in Elderly Individuals Attending Vestibular Rehabilitation Program
Authors: Aydogan Zehra , Aksoy Songül
Published: January 2025

Subjects:

The effects of counseling service given together with vestibular rehabilitation in elderly individuals with a history of age-related-imbalance were examined.

Material and Methods:

21 volunteer elderly individuals presbyastasis were included in the study. Sensory Organization Test, Mini-BESTest, Tinetti Balance-Gait Test, daily living activities with in Vestibular Disorders, and quality of life was evaluated.

Results:

Before the vestibular rehabilitation protocol, counseling was given to the elderly individuals for an average of 45 minutes. Vestibular rehabilitation training was applied in Computerized Dynamic Posturography twice a week for 8 weeks. After the training, balance and walking, activities of daily living, and quality of life improved (P < .05).

Conclusions:

According to these results, it was concluded that the inclusion of vestibular rehabilitation, which is provided with counseling service, in the rehabilitation program of elderly individuals may be beneficial in improving balance, activities of daily living and quality of life.
Avoiding the Use of Outpatient Rehabilitation Services Under Long-Term Care Insurance During the COVID-19 Pandemic
Authors: Matsugaki Ryutaro , Saeki Satoru , Matsuda Shinya
Published: January 2025

Introduction:

This study clarifies why patients avoided the use of outpatient rehabilitation services covered by long-term care insurance during the COVID-19 pandemic.

Method:

Self-administered online questionnaires targeted 474 outpatient rehabilitation facilities under long-term care insurance in Fukuoka prefecture, Japan.

Results:

Main avoidance reasons were users avoiding contact with other users, families avoiding contact with users and other users, and users avoiding contact with staff. Users’ physical and cognitive functions, motivation for activities, and assistance levels subsequently deteriorated.

Conclusion:

Methods for providing rehabilitation are needed in future pandemics to ensure patients maintain physical and cognitive functions and live independently.
The Effect of Virtual Intelligence Games Applied to Older Adults on Cognitive Skills
Authors: Sertel Meral , Gündoğan Muhammed , Bostanoğlu Beyzanur , Çolak Müberra
Published: January 2025

Objective: This study aimed to evaluate cognitive status, quality of life, and mood in older adults through intelligence games loaded onto smartphones.

Methods: In this study, 60 older adults aged 65 and over, who voluntarily participated and visited the outpatient clinic of the Department of Physical Therapy and Rehabilitation at Kırıkkale University Faculty of Medicine, were evaluated. The sociodemographic information of the older adults such as age, height, weight, etc., was recorded. The cognitive statuses were assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), the quality of life was evaluated using the Nottingham Health Profile, and the depression statuses were assessed with the Geriatric Depression Scale (GDS). Those older adults meeting the inclusion criteria, with a MMSE score below 24, were included in the study, totaling 50 participants. Subsequently, the individuals were randomly divided into 2 groups: training and control, with each group consisting of 25 older adults. The training group was requested to play intelligence games developed by researchers and installed on their smartphones at least once a day for 8 weeks. Both the training and control groups were assessed using a questionnaire created before and after the training period.

Results: According to the statistical analysis conducted, a significant difference was found between the training and control groups in the MMSE, MoCA, and GDS scores after the training. There was a significant difference found in the total score of sleep, emotional state, and overall quality of life (P < .05), while no significant differences were detected among the other parameters (P > .05).

Conclusion: In conclusion, it was determined that technological advancements and the intelligence games loaded onto their smartphones, which they can access anytime and anywhere, improved the cognitive status of older adults in areas such as memory, attention, calculation, and shape matching and, it was observed that these activities enhanced their mood, sleep, and overall quality of life.
Reusable Intermittent Catheters are Acceptable but Product Innovation is Needed
Authors: Clancy Bridget , Murphy Cathy , Avery Miriam , Macaulay Margaret , May Carl , Fader Mandy
Published: January 2025

PURPOSE:

The purpose of this study was to explore the experiences of intermittent catheter users after using both reusable and single-use catheters, with a particular focus on factors that affected acceptability.

DESIGN:

Qualitative descriptive study following a clinical trial.

PARTICIPANTS AND SETTING:

Thirty-six participants who had used both reusable and single-use catheters in a clinical trial were interviewed between June 2022 and March 2024. All were living at home in England or Wales, UK.

METHODS:

Participants were invited to interview following one-year’s use of a reusable catheter as part of a clinical trial. The reusable catheter was used in combination with their usual single-use catheter. Semi-structured telephone and video interviews were used to enable participants to describe their experiences. Data were analyzed using inductive methods and framework analysis to develop themes and subthemes.

RESULTS:

Data analysis identified 4 themes. Successful use of the reusable catheter depended on capacity, confidence and willingness of the individual to adapt. Most people found reuse easier to do at home but there were significant barriers when going out. The design of the catheter used in the trial and the process of reuse did not suit everyone. While there was a desire to continue reuse, this was conditional on the provision of single-use catheters to enable users to mix and match both types in different situations.

CONCLUSIONS:

This study presents data from participants who were enthusiastic to try reusable catheters, mainly for environmental reasons, as part of a trial. For most there was a desire to mix and match, combining single use and reusable catheters for different situations. Innovation is needed to create a range of reusable catheter designs and cleaning processes that better meet individual needs.
Characterization of extracellular vesicles released from
Prochlorococcus
MED4 at the steady state and under a light–dark cycle
Authors: Peng Ziqing , Liu Yaxin , Ma Haiying , Xiao Shiwei , Au-Yeung Allan , Zhang Liang , Zeng Qinglu , Guo Yusong
Published: January 2025

Bacterial extracellular vesicles (EVs) are vesicles secreted by bacteria into the extracellular environment. Containing DNA, RNA and proteins, EVs are implicated to mediate intercellular communications. The marine cyanobacterium
Prochlorococcus
, the most abundant photosynthetic organism in marine ecosystems, has been shown to generate EVs continuously during cell growth. However, biogenesis and functions of EVs released by
Prochlorococcus
remain largely unclear. Here, we isolated and characterized EVs released by
Prochlorococcus
MED4 culture. We found that the majority of MED4 EVs are elliptical and enriched with specific proteins performing particular cellular functions. The light–dark cycle has been demonstrated to affect the cell cycle of
Prochlorococcus
, with cell division occurring at night time. Interestingly, we found that the net production of MED4 EVs was faster during the night time. Moreover, we revealed that MED4 EVs that are released or absorbed in the night time are enriched with distinct proteins, suggesting the release and absorbance of EVs are influenced by the diel cycle. We found that inhibiting cell division decreased the net production of MED4 EVs during the night time, suggesting that cell division is important for the biogenesis of MED4 EVs. These analyses provide novel insights into biogenesis and functions of EVs released from bacteria.

This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
Circadian gating: concepts, processes, and opportunities
Authors: Paajanen Pirita , Kimmey Jacqueline M. , Dodd Antony N.
Published: January 2025

Circadian clocks provide a biological measure of time that coordinates metabolism, physiology and behaviour with 24 h cycles in the environment. Circadian systems have a variety of characteristic properties, such as entrainment to environmental cues, a self-sustaining rhythm of about 24 h and temperature compensation of the circadian rhythm. In this perspective, we discuss the process of circadian gating, which refers to the restriction of a biological event to particular times of day by the circadian clock. We introduce principles and processes associated with circadian gating in a variety of organisms, including some associated mechanisms. We highlight socioeconomic opportunities presented by the investigation of circadian gating, using selected examples from circadian medicine and agricultural crop production to illustrate its importance.

This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
Circadian metabolic adaptations to infections
Authors: Costantini Claudio , Brancorsini Stefano , Grignani Francesco , Romani Luigina , Bellet Marina Maria
Published: January 2025

Circadian clocks are biological oscillators that evolved to coordinate rhythms in behaviour and physiology around the 24-hour day. In mammalian tissues, circadian rhythms and metabolism are highly intertwined. The clock machinery controls rhythmic levels of circulating hormones and metabolites, as well as rate-limiting enzymes catalysing biosynthesis or degradation of macromolecules in metabolic tissues, such control being exerted both at the transcriptional and post-transcriptional level. During infections, major metabolic adaptation occurs in mammalian hosts, at the level of both the single immune cell and the whole organism. Under these circumstances, the rhythmic metabolic needs of the host intersect with those of two other players: the pathogen and the microbiota. These three components cooperate or compete to meet their own metabolic demands across the 24 hours. Here, we review findings describing the circadian regulation of the host response to infection, the circadian metabolic adaptations occurring during host–microbiota–pathogen interactions and how such regulation can influence the immune response of the host and, ultimately, its own survival.

This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
Endocrine and molecular regulation of seasonal avian immune function
Authors: Sur Sayantan , Tiwari Jyoti , Malik Shalie , Stevenson Tyler
Published: January 2025

Birds have evolved seasonal adaptations in multiple aspects of the innate and adaptive immune systems. Seasonal immunological adaptations are crucial for survival in harsh environmental conditions and in response to increased prevalence of acute and chronic diseases. Similar to other vertebrates, birds exhibit remarkable plasticity in cytokine production, chemotaxis, phagocytosis and inflammation across the year. In this review, we provide a comparative perspective on seasonal rhythms in bird immune function. We describe advances in our understanding of annual changes in immune cells and responses to innate and adaptive immune challenges. Then, the role of glucocorticoids, sex steroids, thyroid hormones (THs) and melatonin to act as immunomodulators is described. We then discuss the impact of a major and emerging disease, the high pathogenicity avian influenza, as one of the most critical seasonal diseases with significant implications for poultry and wild bird populations. The review identifies the need to enhance our knowledge of annual rhythms in immune cells and tissues in birds, at molecular, cellular and hormonal levels across the year. Moreover, there is a significant absence of information on sex-specific seasonal variation in immune function. Understanding seasonal immune system dynamics will aid in addressing the negative impacts of pathogenic diseases, minimize global economic losses and aid conservation efforts.

This article is part of the Theo Murphy meeting issue ‘Circadian rhythms in infection and immunity’.
A novel NLP-based method and algorithm to discover RNA-binding protein (RBP) motifs, contexts, binding preferences, and interactions
Authors: Elhajjajy Shaimae I. , Weng Zhiping
Published: January 2025

RNA-binding proteins (RBPs) are essential modulators in the regulation of mRNA processing. The binding patterns, interactions, and functions of most RBPs are not well-characterized. Previous studies have shown that motif context is an important contributor to RBP binding specificity, but its precise role remains unclear. Despite recent computational advances to predict RBP binding, existing methods are challenging to interpret and largely lack a categorical focus on RBP motif contexts and RBP-RBP interactions. There remains a need for interpretable predictive models to disambiguate the contextual determinants of RBP binding specificityin vivo. Here, we present a novel and comprehensive pipeline to address these knowledge gaps. We devise a Natural Language Processing-based decomposition method to deconstruct sequences into entities consisting of a central targetk-mer and its flanking regions, then use this representation to formulate the RBP binding prediction task as a weakly supervised Multiple Instance Learning problem. To interpret our predictions, we introduce a deterministic motif discovery algorithm designed to handle our data structure, recapitulating the established motifs of numerous RBPs as validation. Importantly, we characterize the binding motifs and binding contexts for 71 RBPs, with many of them being novel. Finally, through feature integration, transitive inference, and a new cross-prediction approach, we propose novel cooperative and competitive RBP-RBP interaction partners and hypothesize their potential regulatory functions. In summary, we present a complete computational strategy for investigating the contextual determinants of specific RBP binding, and we demonstrate the significance of our findings in delineating RBP binding patterns, interactions, and functions.
Discovery of single-stranded DNA in meteorite-derived cultures: evidence of novel genetic elements
Authors: López Ramón y Cajal Carlos
Published: January 2025

This study presents the first evidence of single-stranded DNA (ssDNA) sequences identified through shotgun metagenomic analysis of meteorite-derived cultures. These ssDNA sequences, predominantly isolated from the "no-hits" zone with no significant matches in existing genomic databases, exhibit conserved motifs, distinct secondary structural features, and a unique AT-rich composition. These characteristics suggest potential roles in autoreplication, molecular stabilization, and resilience under extreme conditions, consistent with extremophilic adaptations. Notably, this discovery aligns with observations of a provisionally termed New Biological Structure (NBS) detected in diverse contexts, including meteorites and biogenic materials, though its characterization lies beyond the scope of this study.

The sequences were detected using a rigorous methodology that included stringent contamination controls, advanced metagenomic assembly techniques, and exhaustive taxonomic filtering to ensure robustness and minimize false positives. Their consistent detection across meteorites of varying types and geographic origins further underscores the reliability of the findings. Repeat analyses revealed specific motifs associated with potential regulatory or structural roles, while secondary structure predictions suggested configurations that could support autoreplication and stability under extreme conditions.

This groundbreaking discovery highlights the potential of meteorites to harbor previously uncharacterized genomic elements, offering profound insights into molecular diversity, prebiotic chemistry, and molecular evolution. By situating these findings within the broader context of extremophilic biology and astrobiological exploration, this study establishes a foundation for investigating the structural, functional, and evolutionary implications of these sequences. Future research will also explore their relevance as biosignatures in the search for life under extreme and extraterrestrial conditions.
Bioinformatic analysis reveals the molecular mechanisms of Trefoil factor 3 involved in asthma pathogenesis
Authors: He Fang , Wang Shu , Huang Pengfei , Fan Xiaoyun
Published: January 2025

Objective

Investigate the expression, regulatory network and function of TFF3 in asthma from a multi-omics perspective through bioinformatics and cellular experiments to provide clues for understanding its molecular mechanisms in asthma.

Methods

Downloaded two asthma-related datasets (GSE67472 and GSE147878) from GEO. Conducted differential expression analysis and WGCNA to find common genes related to asthma phenotype and TFF3 expression. Constructed a PPI network to identify key genes interacting with TFF3. Performed GO and pathway enrichment analysis using DAVID. Analyzed the relationship between TFF3 and immune cell infiltration with CIBERSORTx. Used molecular docking to validate interactions. In vitro, induced 16HBE cells with HDM to establish asthma model and detected inflammatory indicators and TFF3 by RT-qPCR and western blotting.

Results

TFF3 expression was significantly increased in asthma patients in both datasets. ROC analysis showed good diagnostic specificity and sensitivity. 57 co-expressed genes related to asthma and TFF3 were screened, with 11 genes directly interacting with TFF3 and upregulated. Functional enrichment analysis indicated involvement in asthma-related processes. Immune infiltration analysis showed increased M2 macrophages and mast cells, decreased M1 macrophages, and positive correlation with TFF3. Molecular docking confirmed stable binding. In vitro experiments showed increased inflammation index and TFF3 expression after HDM intervention.

Conclusion

The study used bioinformatics and cellular experiments to show TFF3’s key roles in asthma pathogenesis in aspects like gene expression, protein interaction, and immune microenvironment. TFF3 may regulate genes like AGR2 and AKT1, affect immune cells, and be involved in processes like cell migration and immune response. It provides clues for exploring molecular mechanisms and may offer new directions for asthma diagnosis and treatment.
Nonlinear continuum description of the E. coli cell wall under high turgor pressure
Authors: Albarran Octavio , Garces Renata , Po Giacomo , Schmidt Christoph F , Eldredge Jeff D
Published: January 2025

The principal stress-bearing component of bacterial cell walls is the tough, covalently linked peptidoglycan network. It is an active material that maintains shape and integrity of bacterial cells in the presence of high turgor pressures while constantly growing. It is not well understood how its extremal material properties derive from its molecular structure. The large stress in the cell wall demands a description going beyond small-strain approximations, an approach that has not been taken in the biomaterials community. We here derive a continuum elastic model of E. coli peptidoglycan (PG) in two steps: We first reduce the complex microscopic structure of the PG layer to the spring elements of a 2D hyperelastic triangular network, and then interpret those results in the context of finite-strain continuum theory. We present a self-contained formalism to study stress-strain relationships for large deformations and arbitrary anisotropies. We obtain the minimal model compatible with the available data on E. coli morphology and mechanics. We show that the strain hardening of PG leads to a stiffness matrix that is linearly proportional to the turgor pressure of the cell.
Glycoprotein 130 Antagonism Counteracts Metabolic and Inflammatory Alterations to Enhance Right Ventricle Function in Pulmonary Artery Banded Pigs
Authors: Mendelson Jenna B. , Sternbach Jacob D. , Moon Ryan A. , Hartweck Lynn M. , Clark Sophia R. , Tollison Walt , Lahti Matthew T. , Carney John P. , Markowski Todd , Higgins LeeAnn , Kazmirczak Felipe , Prins Kurt W.
Published: January 2025

Background

Right ventricular dysfunction (RVD) is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of glycoprotein-130 (GP130) signaling with the small molecule SC144 improves RV function in rodent RVD via anti-inflammatory and metabolic mechanisms. However, SC144’s efficacy and molecular effects in a translational large animal model of RVD are unknown.

Methods

4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144,n=5] or vehicle [PAB-Veh,n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac MRI quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue. Quantitative proteomics examined RV mitochondrial protein regulation.

Results

SC144 significantly improved RV ejection fraction (Control: 60±4%, PAB-Veh: 22±10%, PAB-SC144: 37±6%) despite similar RV afterload. Single-nucleus RNA sequencing demonstrated PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared to control, and many of these changes were blunted by SC144. SC144 combatted the downregulation of cardiomyocyte metabolic genes induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 activation. Correspondingly, SC144 rebalanced RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed SC144 restored fatty acid metabolism. Finally, CellChat analysis revealed SC144 restored pericyte-endothelial cell cross-talk.

Conclusion

GP130 antagonism blunts elevated immune cell abundance, reduces pro-inflammatory gene transcription in macrophages and lymphocytes, rebalances autophagy and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte communication to improve RV function.
Mathematical modelling of the immune response during endometriosis lesion onset
Authors: Miller Claire M. , Germano Domenic P.J. , Chenoweth Alicia M. , Holdsworth-Carson Sarah
Published: January 2025

The immune system is hypothesised to contribute to the onset of endometriosis lesions. However, the precise mechanisms underlying its role are not yet known. This paper introduces a novel compartmental mathematical model that describes the predicted interactions between the innate immune system (specifically macrophages and natural killer cells) and endometrial cells occurring within the peritoneal fluid during the early stages of endometriosis lesion onset. Our model suggests that an increased retrograde influx of endometrial cells into peritoneal fluid correlates with heightened M1-type macrophage activation, but does not lead to an increase in disease. We compare the system’s response to changes in immune cytotoxicity and ability to detect ectopic endometrial cells. The model indicates that a reduction in cytotoxicity is a key driver of disease. These findings align with the increased immune activation observed clinically. Lastly, our model predicts that an individual can transition to a diseased state following a reduction in immune system cytotoxicity and/or reduced ability to detect ectopic cells. Due to hysteresis, a significant improvement is then required to restore an individual to the disease-free state. This work provides a valuable framework to explore hypotheses of endometriosis lesion onset and assist in understanding of the disease.
Standardised TruAI automated quantification of intracellular neuromelanin granules in human brain tissue sections
Authors: Filimontseva Anastasia , Cuadros Thais , Chatterton Zac , Compte Joan , Fu YuHong , Vila Miquel , Halliday Glenda M
Published: January 2025

Aims

To standardise and automate the quantitation of human-unique neuromelanin granules in catecholamine neurons in post-mortem tissue sections from healthy individuals at different ages to understand any changes in these granules with age.

Methods

5-6µm thick fixed and paraffin-embedded transverse midbrain tissue sections were supplied from 47 cases from three brain banks following ethics approvals. Sections were prepared and automated digital images acquired. Standardisation and automation of the quantification of neuromelanin granules was performed using the TruAI feature of the Olympus VS200 desktop platform. Comparisons between stained and unstained sections as well as correlations with age were performed.

Results

The automated platform reliably identified both stained and unstained intracellular and extracellular neuromelanin granules, showing high reproducibility in measurements across laboratories using different tissue processing methods. Extracellular neuromelanin granules were significantly smaller than intracellular neuromelanin granules. Sections processed for hematoxylin and eosin staining impacted on size and colour of both neuromelanin and the neurons containing neuromelanin. Hematoxylin made neuromelanin bluer and the increased tissue processing made the intracellular area occupied by neuromelanin smaller in younger people. There was an increase in neuromelanin optical density and colour change (more brown) with age.

Conclusions

The TruAI automated platform reliably quantifies individual neuromelanin granules in catecholamine neurons. Extracellular neuromelanin is considerably smaller in size than intracellular neuromelanin, and intracellular neuromelanin changes its properties with age. The darkening and colour change of intracellular neuromelanin suggests an increase in eumelanin over time in healthy individuals. These changes can be reliably identified using the automated platform.

Key points

Standardised, reliable TruAI automated quantitation of intracellular neuromelanin granules in human brain sections gives novel insights into their structure and function

extracellular neuromelanin granules, released from dying pigmented neurons, are significantly smaller than intracellular neuromelanin granules

intracellular neuromelanin granules change their properties with healthy ageing becoming darker, consistent with more antioxidant eumelanin
Macrophages orchestrate elimination ofShigellafrom the intestinal epithelial cell niche via TLR-induced IL-12 and IFN-γ
Authors: Eislmayr Kevin D. , Langner Charlotte , Liu Fitty L. , Yuvaraj Sudyut , Babirye Janet Peace , Roncaioli Justin L. , Vickery Jenna M. , Barton Gregory M. , Lesser Cammie F. , Vance Russell E.
Published: January 2025

Bacteria of the genusShigellareplicate in intestinal epithelial cells and cause shigellosis, a severe diarrheal disease that resolves spontaneously in most healthy individuals. During shigellosis, neutrophils are abundantly recruited to the gut, and have long been thought to be central toShigellacontrol and pathogenesis. However, how shigellosis resolves remains poorly understood due to the longstanding lack of a tractable and physiological animal model. Here, using our newly developedNlrc4−/−Casp11−/−mouse model of shigellosis, we unexpectedly find no major role for neutrophils in limitingShigellaor in disease pathogenesis. Instead, we uncover an essential role for macrophages in the host control ofShigella. Macrophages respond toShigellavia TLRs to produce IL-12, which then induces IFN-γ, a cytokine that is essential to controlShigellareplication in intestinal epithelial cells. Collectively, our findings reshape our understanding of the innate immune response toShigella.
Diagnosis of Blood Diseases and Disorders with Topological Deep Learning
Authors: Koung Philmore F. , Fatema Saba , Pakasticali Nagehan , Luu Hung S. , Coskunuzer Baris
Published: January 2025

Blood diseases and disorders, including leukemia and infectious diseases of red blood cells, pose significant diagnostic challenges due to their complex presentations and reliance on time-consuming cytomorphological analysis to detect subtle morphologic features. While microscopic examination remains the gold standard in their diagnosis, its dependence on expert interpretation high-lights the need for advanced methods to enhance the diagnostic workflow. Recently, deep learning (DL) methods have shown promise in medical imaging by automating and improving accuracy. However, these approaches often require large, annotated datasets, which are scarce for rare diseases, and they often face interpretability issues, limiting their integration into clinical practice.

In this study, we present a novel framework that integrates topological features with state-of-the-art DL techniques to enhance the analysis of cytomorphological images for diagnosing blood disorders. By combining global topological information with the localized patterns captured by DL models, our approach improves diagnostic accuracy while ensuring robustness, interpretability, and reproducibility. Experimental results demonstrate that the inclusion of topological features not only enhances model performance but also proves particularly effective in limited data settings. This methodology addresses critical limitations of existing techniques, advancing the classification and diagnosis of blood disorders while improving efficiency and reliability in medical imaging workflows.
Derivation and Validation of a Point-based Forecasting Tool for SARS-CoV-2 Critical Care Occupancy
Authors: Grima Alicia A. , Lee Clara Eunyoung , Tuite Ashleigh R. , Wilson Natalie J. , Simmons Alison , Fisman David N.
Published: January 2025

Background

The requirement for critical care in even a modest fraction of SARS-CoV-2 infected individuals made ICU resources an important societal chokepoint during the recent pandemic. We developed a simple regression-based point score in 2020 based on an objective of forecasting critical care occupancy in the Canadian province of Ontario based on mean age of cases, case numbers, and testing volume. Evolution of the pandemic (variants of concern, vaccination) led us to re-assess and re-calibrate our earlier work, with inclusion of information vaccination which became widespread in 2021.

Methods

We obtained complete provincial SARS-CoV-2 case, testing, and vaccination data for the period from March 2020 to September 2022, with data subdivided into 6 major “waves”, following the approach applied by other Canadian investigators. Our initial model was fit only using the first two “wild type” SARS-CoV-2 waves; an updated model included wave 3 (N501Y+ variants). Our model was validated by comparing model projections to waves not used for model fitting; validation model fits were evaluated with Spearman’s rho; counterfactuals without vaccination were modeled to impute fraction of critical care admissions prevented with vaccination. Costing was based on published economic estimates.

Results

Our initial model (fit to waves 1 and 2) was well calibrated (rho 0.85) but predictive validity was modest (rho 0.46). Predictive validity improved in models fit to the first 3 pandemic waves without vaccination (rho 0.60) or with vaccination (rho 0.68) (P for inclusion of vaccination 0.013 by Likelihood Ratio Test). Prevented fraction of ICU admissions attributable to vaccination was 144% (22017 admissions expected vs. 9020 observed); based on published estimates of ICU admission cost for SARS-CoV-2 the 12977 admissions averted $2.9 (CDN) billion in economic costs, in contrast to the $3 billion total cost of the vaccination program.

Conclusions

Simple time series regression incorporating case and testing characteristics continues to be useful as a tool for forecasting critical care occupancy due to SARS-CoV-2 but early pandemic models need to be updated to capture the preventive effects of widespread vaccination. The economic benefit of vaccination for prevention of critical care resource consumption during the pandemic is substantial, achieving near cost neutrality with the province’s entire vaccination program.
Effect of JYNNEOS vaccination on mpox clinical progression among cisgender male cases with confirmed infection
Authors: Granskog Lauren , Saadeh Kayla , Lorenz Kieran , Quint Joshua , Vance Joshua , Salih Tarek , Lo Timothy , Jacobson Kathleen , Ramos Marisa , Peters Philip , Chapman Eric , Snyder Robert E. , Lewnard Joseph A.
Published: January 2025

Background

The JYNNEOS modified vaccinia virus Ankara vaccine has proven effective in preventing clade IIb mpox disease during the ongoing global outbreak associated with sexual transmission. However, understanding of the effect of vaccination on mpox clinical presentation remains limited.

Methods

We interviewed cisgender males with confirmed mpox (cases) reported to the California Department of Public Health from May 2022 through December 2023. We ascertained cases’ vaccination statuses via the California Immunization Registry. We estimated JYNNEOS vaccine effectiveness against progression (VEP) to disease involving disseminated lesions via the adjusted odds ratio of vaccination, comparing cases who reported lesions disseminated across multiple anatomical regions to cases who reported lesions contained to a single anatomical region. We used the same approach to estimate VEP for prodromal symptoms.

Findings

Analyses included 4,613 cases, among whom 3,045 (66.0%) reported disseminated lesions and 1,956 (42.4%) had HIV infection. Among cases who reported disseminated lesions, 114 (3.7%) received pre-exposure vaccination and 43 (1.4%) received post-exposure vaccination only. In contrast, among cases who reported lesions contained to a single anatomical region, 286 (18.2%) received pre-exposure vaccination and 146 (9.3%) received post-exposure vaccination only. For any pre-exposure vaccination, VEPwas 58.9% (95% confidence interval: 50.4-65.9%), while VEPfor two pre-exposure doses was 61.0% (47.3-71.1%). For post-exposure vaccination, VEPwas 15.9% (3.3-26.8%). Among cases without HIV and cases with HIV, pre-exposure VEPwas 66.4% (56.6-74.0%) and 45.3% (28.0-58.5%), respectively. Pre-exposure vaccination was also associated with reduced odds for illness involving fever, chills, and lymphadenopathy.

Interpretation

Among cisgender males with mpox, pre-exposure vaccination with JYNNEOS is associated with less severe illness. Awareness of an attenuated disease phenotype involving localized lesions without accompanying prodromal symptoms is needed among providers to ensure accurate diagnosis of mpox in previously-vaccinated individuals.
Structural Insights into Immature Dengue Virus-Like Particles Revealed by Cryo-EM and Molecular Dynamics Simulations
Authors: Palur Venkata Raghuvamsi , Chen Guan-Wen , Chao Day-Yu , Wu Ya-Na , Galula Jedhan U. , Wang Chun-Hsiung , Bond Peter J. , Marzinek Jan K. , Wu Shang-Rung
Published: January 2025

The lack of efficacious vaccines against dengue (DENV) infections imposes an enormous burden on global health and the economy. Virus-like particles (VLPs), such as mature DENV VLPs (mDVLPs), have been shown to induce broadly neutralizing antibodies, making them promising next-generation vaccine candidates. However, the limited structural details have restricted efforts to engineer VLPs to attain the desired biophysical and immunological properties. In the current work, we present the cryo-electron microscopy (cryo-EM) structure of immature dengue serotype 2 VLP (imD2VLPs), revealing an architecture composed of a glycoprotein layer with prominent spikes in a T=1 arrangement. These spikes, composed of envelope (E) and precursor membrane (prM) protein heterodimers capped by pr domains, closely resemble immature flavivirus particles. Complementing the static structural details, we performed multiscale molecular dynamics (MD) simulations to elucidate the functional dynamics of imD2VLPs in the context of different lipid envelope compositions. Additionally, MD simulations uncovered the transition pathway between our previously solved mature VLP structure and immature VLP from this work. Here we show that VLP maturation involves a simple sliding-rotating motion without any clashes between E proteins. Our results also indicated that lipid composition plays a critical role in VLP stability, with phospholipid-dominant environments providing greater stability than diacylglycerol-rich vesicles. In addition, we demonstrated enhanced production efficiency of VLPs by generating a stable mammalian cell line using CHO-K1 cells. These findings enabled us not only to predict and manipulate the immunogenic properties of dengue VLPs but also underscored the potential of VLPs as a simplified and manageable model for investigating the structural basis of the dengue virus more effectively.
Selection and transmission of the gut microbiome alone shifts mammalian behavior
Authors: Suzuki Taichi A. , Akbuğa-Schön Tanja , Waters Jillian L. , Jakob Dennis , Vu Dai Long , Ballinger Mallory A. , Di Rienzi Sara C. , Chang Hao , de Araujo Ivan E. , Tyakht Alexander V. , Ley Ruth E.
Published: January 2025

Natural selection acts on phenotypic variation, which is influenced by genetic and environmental factors including the microbiome. Whether microbiome-mediated host phenotypes can be selected and transmitted remains untested in vertebrates. Here, we first identified locomotor activity as a trait transmissible through the gut microbiome in mice. We then performed a selection experiment, where we serially transferred microbiomes from low-activity mice to independently bred germ-free mice. Over four transfer rounds, microbiome transfer significantly reduced locomotor activity. Reduced locomotion was associated with increased Lactobacilli and their metabolite indolelactate. In a test of causality, independent administration to the mouse gut ofLactobacillus johnsoniior indolelactate reduced locomotion. These findings demonstrate that selection and transmission of microbes can modulate host traits independently of selection on the mammalian genome.

One Sentence Summary

Serial transfer of the gut microbiome of low-activity mice to germfree recipients reproducibly transferred activity levels, revealing the microbiome’s potential to impact the host’s response to selection without host genomic changes.