bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of impurity seeding on shattered pellet injection mitigations on the Joint European Torus
Authors: Sheikh U. , Jachmich S. , Kong M. , Bodner G. , Eidietis N. , Ficker O. , Lehnen M. , Reux C. , Stein-Lubrano B. , Svoboda J. , Contributors JET ,   the EUROfusion Tokamak Exploitation Team
Published: February 2025

Plasma disruptions present a significant challenge to the viability of fusion energy production in tokamak reactors. Among disruption mitigation techniques, shattered pellet injection (SPI) has emerged as a promising approach. The results presented in this paper show novel findings of the impact of nitrogen and neon seeding on the disruption mitigation sequence following SPI on the Joint European Torus (JET). This study exposes an order of magnitude reduction in pre-thermal quench duration for highly seeded plasmas and pure deuterium SPI, a result with significant implications for staggered SPI schemes currently under development. Conversely, no reduction in disruption thermal load mitigation efficacy was observed for single neon and hydrogen mixed SPI across a range of seeding levels, indicating the robustness of this approach. A novel pathway for thermal load mitigation and enhanced runaway electron avoidance with pure deuterium SPI into strongly seeded plasmas is also presented.
New gravitational wave discoveries enabled by machine learning
Authors: Koloniari Alexandra E , Koursoumpa Evdokia C , Nousi Paraskevi , Lampropoulos Paraskevas , Passalis Nikolaos , Tefas Anastasios , Stergioulas Nikolaos
Published: February 2025

The detection of gravitational waves (GWs) has revolutionized our understanding of the Universe, offering unprecedented insights into its dynamics. A major goal of GW data analysis is to speed up the detection and parameter estimation process using machine learning (ML) techniques, in light of an anticipated surge in detected events that would render traditional methods impractical. Here, we present new GW candidate events, the first to be identified in data from a network of interferometric detectors through ML. We discuss several new enhancements of our ResNet-based deep learning code, AresGW, that increased its sensitivity, including a new hierarchical classification of triggers, based on different noise and frequency filters. The enhancements resulted in a significant reduction in the false alarm rate, allowing AresGW to surpass traditional pipelines in the number of detected events in its effective training range (single source masses between 7 and 50 solar masses and source chirp masses between 10 and 40 solar masses), when the new detections are included. We calculate the astrophysical significance of events detected with AresGW using a logarithmic ranking statistic and injections into O3 data. Furthermore, we present spectrograms, parameter estimation, and reconstruction in the time domain for our new candidate events and discuss the distribution of their properties. In addition, the AresGW code exhibited very good performance when tested across various two-detector setups and on observational data from the O1 and O2 observing periods. Our findings underscore the remarkable potential of AresGW as a fast and sensitive detection algorithm for GW astronomy, paving the way for a larger number of future discoveries.
Bone quality assessment around dental implants in cone-beam computed tomography images: effect of scan mode and metal artefact reduction tool
Authors: Bohner Lauren , Parize Hian , Cordeiro João Victor Cunha , Laureano Natalia Koerich , Kleinheinz Johannes , Caldas Ricardo Armini , Dagassan-Berndt Dorothea
Published: February 2025

Objectives

The purpose of this study was to evaluate how artefacts caused by titanium and zirconia dental implants affect the bone quality assessment in CBCT images. The effect of scan mode and the use of metal artefact reduction algorithm (MAR) on artefacts suppression were taken in consideration.

Methods

Titanium and zirconia dental implants were installed in porcine bone samples and scanned with two CBCT devices with adjustments on scan mode and with the use of MAR. Control group consisted of bone sample without implant and scanned with full rotation scan mode without MAR. Artefacts extension was measured by deviation of gray values and bone quality around implants was measured by bone histomorphometry measurements (trabecular volume fraction, bone specific surface, trabecular thickness, and trabecular separation). Mean difference among groups was assessed by within ANOVA with Bonferroni correction. Correlation between bone quality measurements acquired in experimental and control groups were assessed by Spearman correlation test (α = 0.05).

Results

No statistical difference was found for artefacts extension in images acquired by half and full-rotation mode (p = 0.82). The application of MAR reduced artefacts caused by titanium and zirconia dental implants, showing no statistically significant difference to the control group (Titanium: p = 0.20; Zirconia: p = 0.31). However, bone quality measurements did not correlate to the control group (p < 0.05).

Conclusions

Bone quality assessment was affected by the presence of artefacts caused by dental implants. Scan mode did not affect the appearance of artefacts and did not affect the bone qualitative measurements. MAR was able to decrease artefacts, however, it did not improve the accuracy of bone quality measurements.
Hearing loss predictive model in fibrodysplasia ossificans progressiva from a national referral center: developing an hearing loss predictive model
Authors: Cacco Tommaso , Papa Riccardo , Carmisciano Luca , Bruzzo Carola , Semino Lucia , Tonelli Alberto , Matucci-Cerinic Caterina , Di Rocco Maja , Bocciardi Renata , Gattorno Marco , D’Agostino Roberto
Published: February 2025

Fibrodysplasia ossificans progressiva (FOP) is the most dramatic form of progressive heterotopic ossification of soft tissues. Hearing impairment in FOP patient is a common feature, reported by about 50% of affected patients. However, wide case series considering audiologic features are lacking. We report the audiologic history of a group of FOP patients in order to define the hearing loss characteristics, genotype association and possible rehabilitative options. We report audiometric history of 16 FOP patients referred to our Institute from 2014 onwards without ear malformations or other known reason for audiologic impairment.

Major involvement of high frequencies in our FOP cohort suggests that the position of the high-frequency receptors within the cochlea, near the oval window, makes them more exposed to damage than the low-frequency receptors located deeper in the cochlea. Furthermore, the reported gender difference may be secondary to a hormonal effect, as known in patients with otosclerosis. Finally, regarding the genotype, we noted that only the non-classic patient carrying the ACVR1 c.619C > G; p.Q207E mutation, presented a mixed hypoacusia with a sensorineural component prevailing on acute frequencies, currently not deserving hearing aids. This evidence suggests a possible novel genotype association to be confirmed in larger cohort.

The present analysis shows that a longer disease history is associated with a statistically significant worse hearing loss, mainly involving the high frequencies. The advent of new therapeutic options highlights the relevance of having comparative follow-up data in order to evaluate the effectiveness of these new therapies against all the various clinical manifestations of FOP.
Investigation of sex determination in African cichlids reveals lack of fixed sex chromosomes in wild populations
Authors: Smith Sophie Helen , Kukowka Sandra , Böhne Astrid
Published: February 2025

Sex chromosomes are theorised to stop recombining and become fixed, yet many taxa show ambiguous genomic signals of sex consistent with either continuous recombination or sex chromosome turnover. Elucidating the basis of sex chromosome conservation or alternatively, turnover, requires comparative studies among natural populations with shared evolutionary histories. The African Great Lake radiations of cichlid fishes display an outstanding propensity to rapidly evolve novel sex-linked regions, yet older cichlid lineages external to these radiations seem to show conservation of a few sex chromosomes. Here, we studied sex-determining regions of species uniquely representing two older lineages within Lake Tanganyika; Oreochromis tanganicae (Oreochromini) and Tylochromis polylepis (Tylochromini). Using a combined SNP- and kmer-based approach, we confirm a ZW system on linkage group (LG) 3 in O. tanganicae, but not the previously proposed sex-determining gene. However, in T. polylepis, no clear region of sex-association could be identified, although kmer-based analyses point towards LG12 as a candidate sex chromosome. Additionally, we investigated four other species from older, non-East African radiation lineages and confirm LG3 to be frequently associated with sex, but also find stronger signals of sex association on different chromosomes not previously discovered. Combined, these results suggest that homomorphic sex chromosomes are a feature of African cichlids at large. LG3 frequently harbours regions of sex-linkage, but is often polygenic with more strongly sex-linked regions on other chromosomes, possibly denoting its ancestral function as sex-determining across African cichlids, that leaves traces as novel sex-determining regions emerge. Our investigation captures this in a phylogenetic context, from emergence, to fixation, or turnover to a new sex chromosome.
Ethics for the labor and delivery unit
Authors: Mann David G. , Sutton Caitlin D.
Published: February 2025

Purpose of review

The labor and delivery unit poses unique challenges for the clinician faced with an ethical dilemma. Ethics training for physicians is heterogeneous and may not include specifics that are relevant to the obstetric anesthesiologist such as the implications of caring for a maternal–fetal dyad.

Recent findings

Rapid changes to the reproductive healthcare landscape have impacted healthcare professionals in recent years, who are at risk for moral distress when faced with ethical dilemmas in clinical care.

Principlism is the most commonly applied ethical theory in clinical medicine. The four principles are autonomy, beneficence, nonmaleficence, and justice. These principles are prima facie in that no one is defined as being consistently more important than another; it is the clinical situation that determines how to prioritize the principles. This framework allows the obstetric anesthesiologist to assess and manage each of these principles to provide ethically appropriate care for their patient. The aim of this article is to provide the obstetric anesthesiologist with an understanding of the foundational ethical principles that impact the ability to fulfill their fiduciary duty to advocate for patients by offering, and with informed consent, providing indicated and appropriate interventions.
Lumateperone for the Treatment of Major Depressive Disorder With Mixed Features or Bipolar Depression With Mixed Features
Authors: Durgam Suresh , Kozauer Susan G. , Earley Willie R. , Chen Changzheng , Huo Jason , Lakkis Hassan , Stahl Stephen , McIntyre Roger S.
Published: February 2025

Background

This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.

Procedures

Patients (18–75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)–defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters.

Results

Lumateperone met the primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], −5.7; 95% confidence interval [CI], −7.60,−3.84; effect size [ES], −0.64; P < 0.0001), MDD (LSMD, −5.9; 95% CI, −8.61,−3.29; ES, −0.67; P < 0.0001), and bipolar depression (LSMD, −5.7; 95% CI, −8.29,−3.05; ES, −0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (≥5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk.

Conclusions

Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.
Approach to Diagnosis and Management of Clitorodynia
Authors: Krapf Jill , Pope Rachel
Published: February 2025

Clitorodynia, pain involving the clitoris, is considered a localized form of vulvodynia. This review aims to provide the general obstetrician–gynecologist a general framework for diagnostic evaluation of clitorodynia. This is simplified by dividing chronic clitoral pain into structural causes and neuropathic causes. Knowledge of clitoral anatomy, including the corona of the glans clitoris, symptomatology, and evaluation based on the concept of regions is necessary in evaluating chronic clitoral pain. Structural causes are clitoral adhesions or phimosis with debris or keratin pearls, which may be managed with in-office lysis of clitoral adhesions. Neuropathic causes include pudendal neuralgia and meningeal and spinal pathology determined with neurophysiologic testing, imaging studies, and diagnostic nerve blocks. Treatment includes behavioral measures, pelvic floor physical therapy, serial nerve blocks, and targeted nerve release procedures. Obstetrician–gynecologists are well-positioned to identify and provide first-line approaches to diagnosis and treatment of clitorodynia.
Flavored Tobacco Restriction Policy Support in New York and the United States, 2022
Authors: Bunch Stephanie Craven , Coats Ellen M. , Brown Elizabeth M. , Nonnemaker James M. , Lee Jennifer , Fajobi OlaOluwa
Published: February 2025

Context:

Use of flavored commercial tobacco products, including menthol cigarettes, flavored vaping products, and flavored cigars, remains a serious public health concern with implications for health equity. Flavored tobacco use is more prevalent among some populations of adults, including among Black adults; young adults; and adults who identify as lesbian, gay, bisexual, transgender, or questioning or queer.

Objective:

This paper explores the prevalence of support for flavored tobacco sales restrictions among a representative sample of adults in New York (NY) and the United States (U.S.).

Design:

We analyzed cross-sectional data from the New York Adult Tobacco Survey and United States Adult Tobacco Survey collected in 2022 to estimate prevalence of support for policies that ban the sale of menthol cigarettes and flavored tobacco products other than menthol cigarettes.

Results:

In 2022, support for banning the sale of menthol cigarettes and/or flavored tobacco was lower among adults who use tobacco, including flavored and/or menthol tobacco; non-Hispanic White adults; males; and those living outside of urban areas. In the same year, 47.1% of NY adults and 37.3% of adults nationally supported both policies banning the sale of menthol cigarettes and the sale of flavored tobacco products other than cigarettes. Support for one policy but not the other was uncommon in NY and nationally. Support for policies that ban the sale of menthol cigarettes was higher in NY than in the U.S. in 2022 among those who use tobacco (32.0% in NY vs 19.3% in the U.S.) and those who use flavored tobacco products (25.8% in NY vs 16.3% in the U.S.).

Conclusions:

Understanding population support for flavored tobacco restrictions provides opportunities for tobacco control programs to tailor education, communications, and surveillance planning at the local, state, and federal levels.
Assessment of the benefits of bone modifying agents in the management of advanced breast, prostate, and lung cancers
Authors: Leigh Jennifer , Lee Shing Fung , Fawaz Ali , Jia Jason , Theriau Christopher F. , Rodrigues Jessica , Brown Janet , Ng Terry L.
Published: February 2025

Purpose of review

Skeletal metastases occur in approximately 80% of advanced breast, 70% of advanced prostate, and 30% of lung cancers, and place patients at increased risk of skeletal related events (SRE). Bone modifying agents (BMAs) have been shown to prevent or delay SRE development. Our objective was to summarize the role of these agents in the management of these three cancers.

Recent findings

Total 52 studies met our inclusion criteria. These highlighted the benefit of BMAs in reducing SREs in metastatic breast and castrate resistant prostate cancer (mCRPC), with less clear impact on reducing SRE in lung cancer, or on improving progression-free and overall survival due to significant heterogeneity in trial design and outcomes. Benefits in SRE reduction occurred with bisphosphonates and denosumab, however when compared, denosumab was superior. Denosumab however is not more cost effective, and multiple trials support potential de-escalation to either 12 weekly dosing or other reduced duration.

There is a large body of evidence to support the role of BMAs in reducing SREs in metastatic breast and mCRPC. Impact on survival outcomes is heterogeneous, and future large database trials would be helpful in identifying which subgroups of patients truly have survival benefit from BMAs.
Membrane partition and structural reorganization induced by anti-psychotics with distinct clinical profiles
Authors: Gorse Ana , Yordanova Vesela , Bodosa Jessica , Mathelié-Guinlet Marion , Walrant Astrid , Taib-Mamaar Nada , Grélard Axelle , François-Martin Claire , Baccouch Rim , Rascol Estelle , Salgado Gil-mar F. , Moreno Maria João , Bastos Margarida , Klauda Jeffery B. , Staneva Galya , Nuss Philippe , Alves Isabel D.
Published: February 2025

Antipsychotics (APs) are used in the treatment of severe mental disorders. Their mechanism of action involves interaction with multiple brain targets, notably the dopamine D2 receptors (D2R), where they compete with dopamine. Due to their lipophilic nature, APs also partition and accumulate in lipid membranes, particularly around the D2R and in synaptic vesicles. When intercalated into brain membranes, APs slowly accumulate and act as a reservoir, allowing their rapid release on demand to modulate neurotransmitter signaling. They also modify the physicochemical and mechanical properties of the lipid bilayer. These modifications can subsequently affect the conformational changes of embedded membrane proteins like the D2R. The present study investigated two major APs with different pharmacological and clinical profiles: chlorpromazine, which exerts its clinical activity mainly through a strong antagonistic action at the D2R, and clozapine, the weakest D2R antagonist of all APs. Surprisingly, although D2R antagonism is usually associated with AP potency, clozapine has repeatedly demonstrated clinical superior efficacy to all APs and is therefore recommended for treatment-resistant schizophrenia. The current work aims to extend the classical AP receptor mediated paradigmatic mode of action to their potential and unique membrane remodeling properties by thoroughly comparing their partitioning and impact on the physicochemical properties of the lipid membrane. Lipid model membranes mimicking synaptic vesicles have been investigated using a combination of several biophysical methods. The study aims to determine how the partitioning of the two APs modifies membrane order, phase transition, thickness, elasticity, phase separation, membrane integrity and charge. Differences have been demonstrated between these two compounds, which may further differ both over time as they accumulate as well as depending on their pre- or post-synaptic location.
Impact of changes in buffer ionic concentration and mutations on a GH1 β-Glucosidase homodimer
Authors: Chagas Rafael S. , Marana Sandro R.
Published: February 2025

Oligomerization is a key feature of protein function, with approximately 30% of proteins exhibiting this trait. The homodimeric form of proteins, such as the GH1 β-Glucosidase fromSpodoptera frugiperda(Sfβgly), plays a significant role in enzyme activity. In this study, we investigate the homodimerization of Sfβgly, which forms a cyclic C2 dimer with a well-defined interface. Using size exclusion chromatography and SEC-MALS, we characterized the homodimerization behavior of Sfβgly at equilibrium conditions in different ionic concentrations of phosphate buffer. The dissociation constants (KD) increase with decreasing ionic concentration, suggesting that the hydrophobic effect is central to homodimer formation. Site-directed mutagenesis of key residues at the dimer interface further elucidated the contributions of specific amino acid residues to dimer stability. Mutations affecting both, apolar and hydrogen bond-forming residues, significantly increased theKD. However, mutations of hydrogen bond-forming residues caused a smallerKDchange than apolar residue mutations, suggesting that while the latter is the driving factor in the dimerization, the former may play a crucial role in guiding the monomers relative orientation. These findings enhance our understanding of protein oligomerization in GH1 β-Glucosidases and its implications for protein design and function.
Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth
Authors: Vieira Renan FL , Sanchez Sawyer R , Arumugam Menusha , Mower Peyton D , Curtin Meghan C , Gallop Molly R , Wright Jillian , Bowles Alexis , Ducker Gregory S , Hilgendorf Keren I , Chaix Amandine
Published: February 2025

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology. While obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 orthotopic model of obesity-accelerated BC growth in immune-competent mice, we investigated the direct role of systemic lipids in tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in obese individuals.
Effectiveness of Carotid Sinus Massage in Modified Trendelenburg Position for Rapid and Lasting Relief of Acute Headache Episodes: A Pilot Study
Authors: Anaya Pablo , Suarez-Roca Heberto
Published: February 2025

Introduction

Headaches significantly impair quality of life, and primary headaches are among the most common neurological complaints. Stimulating carotid baroreceptors via carotid sinus massage (CSM) combined with modified Trendelenburg positioning may modulate autonomic activity and alleviate acute headache symptoms. Thus, this study evaluated the effectiveness and safety of this combined approach (CSM+T).

Methods

Seventeen patients (14 females; ages 16–64) with tension-type headaches (6), chronic migraines (10), or mixed-headaches (1) and various comorbidities received up to three 15-second CSM+T applications at one-minute intervals. Pain was assessed using a 10-point visual analog scale (VAS), while heart rate (HR), blood pressure (BP), and oxygen saturation (SpO2) were recorded before and after the intervention. A 24-hour follow-up evaluated headache recurrence and adverse effects.

Results

Sixteen patients experienced significant pain reduction (median decrease: 9 VAS points; p < 0.0001) without complications. Pain relief persisted 24 hours without the need for additional medication or adverse effects. HR, BP, and SpO2decreased following CSM+T. A negative correlation was observed between HR reduction and pain relief. Among responders, migraine patients had a smaller mean HR decrease than tension-type headache patients, yet both groups achieved similar median pain relief. These results suggest that a more pronounced cardiovagal response does not necessarily confer greater analgesia, implying additional central or multifactorial mechanisms.

Conclusion

CSM+T appears to be a safe and effective non-pharmacological intervention for rapid headache relief in a heterogeneous patient population. Larger, controlled trials are warranted to confirm these findings and refine clinical protocols.
Prompts to Table: Specification and Iterative Refinement for Clinical Information Extraction with Large Language Models
Authors: Hein David , Christie Alana , Holcomb Michael , Xie Bingqing , Jain AJ , Vento Joseph , Rakheja Neil , Hamza Shakur Ameer , Christley Scott , Cowell Lindsay G. , Brugarolas James , Jamieson Andrew , Kapur Payal
Published: February 2025

Background

Extracting structured data from free-text medical records is laborious and error-prone. Traditional rule-based and early neural network methods often struggle with domain complexity and require extensive tuning. Large language models (LLMs) offer a promising solution but must be tailored to nuanced clinical knowledge and complex, multipart entities.

Methods

We developed a flexible, end-to-end LLM pipeline to extract diagnoses, per-specimen anatomical-sites, procedures, histology, and detailed immunohistochemistry results from pathology reports. A human-in-the-loop process to create validated reference annotations for a development set of 152 kidney tumor reports guided iterative pipeline refinement. To drive nuanced assessment of performance we developed a comprehensive error ontology— categorizing by clinical significance (major vs. minor), source (LLM, manual annotation, or insufficient instructions), and contextual origin. The finalized pipeline was applied to 3,520 internal reports (of which 2,297 had pre-existing templated data available for cross referencing) and evaluated for adaptability using 53 publicly available breast cancer pathology reports.

Results

After six iterations, major LLM errors on the development set decreased to 0.99% (14/1413 entities). We identified 11 key contexts from which complications arose-including medical history integration, entity linking, and specification granularity-which provided valuable insight in understanding our research goals. Using the available templated data as a cross reference, we achieved a macro-averaged F1 score of 0.99 for identifying six kidney tumor subtypes and 0.97 for detecting metastasis. When adapted to the breast dataset, three iterations were required to align with domain-specific instructions, attaining 89% agreement with curated data.

Conclusion

This work illustrates that LLM-based extraction pipelines can achieve near expert-level accuracy with carefully constructed instructions and specific aims. Beyond raw performance metrics, the iterative process itself—balancing specificity and clinical relevance—proved essential. This approach offers a transferable blueprint for applying emerging LLM capabilities to other complex clinical information extraction tasks.
Phosphoproteomics Uncovers Tumor Heterogeneity and Therapeutic Opportunities in Early-Stage Hepatocellular Carcinoma
Authors: Ren Liangliang , Jiang Jiahan , Lin Weiran , Qi Lihui , Li Chaoying , Jiang Ying
Published: February 2025

Hepatocellular carcinoma (HCC) is the third deadliest cancer in the world, however, the mechanisms of genesis, development and recurrence of HCC are not fully clarified yet. Previous studies on phosphoproteome in large-scale of HCC merely investigated the specific regulation on protein phosphorylation levels and identified subgroups consistent with proteomic subgroups. Here, we systematically interrogated the phosphoproteome of early-stage HCC and uncovered the dysregulated signaling pathways and kinases. Unlike previous studies on mRNA and protein levels, we observed a significant decline in phosphorylation regulation of EGFR-mediated canonical ERK/MAPK signaling alongside elevation of atypical MAPK signaling. Classification based on the heterogeneity of the phosphoproteome in tumor identified three phosphoproteomic subtypes, each characterized by distinct phosphorylation signatures, clinical characteristics, cellular signaling pathways and kinase activities. Further validation revealed hyperphosphorylation of SRSF3, one signature in the most malignant subtype, promote proliferation and metastasis of HCC cells. The mechanism of which was further demonstrated to be coordinated by activation of SRPK1/CLKs and potential suppression of PP1 phosphatase via phosphorylation of PPP1R7. Furthermore, inhibitors targeting SRPK1 or CLKs effectively suppressed hyperphosphorylation of SRSF3 mediated migration and invasion in HCC. Our study uncover the dysregulated phosphorylation signatures, offer new insights into the tumor heterogeneity, and identify phosphorylation regulating mechanism and corresponding key kinases with therapeutic value in early-stage HCC, which also spotlight the importance of protein phosphorylation in cancer progression.
Crystal Structure and Catalytic Mechanism of Drimenol Synthase, a Bifunctional Terpene Cyclase-Phosphatase
Authors: Osika Kristin R. , Gaynes Matthew N. , Christianson David W.
Published: February 2025

Drimenol synthase fromAquimarina spongiae(AsDMS) is a highly unusual bifunctional sesquiterpene synthase that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol, which are the first of a terpene cyclase-phosphatase. The AsDMS structure exhibits a two-domain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase (HAD)-like phosphatase domain, with two distinct active sites located on opposite sides of the protein. Mechanistic studies show that dephosphorylation of the drimenyl diphosphate intermediate proceeds through stepwise hydrolysis, such that two equivalents of inorganic phosphate rather than inorganic pyrophosphate are co-products of the reaction sequence. When the AsDMS reaction is performed in H₂18O,18O is not incorporated into drimenol, indicating that the hydroxyl oxygen of drimenol originates from the prenyl oxygen of FPP rather than bulk water. These results correct a mechanistic proposal previously advanced by another group. Surprisingly, AsDMS exhibits unprecedented substrate promiscuity, catalyzing the conversion of substrate mimic farnesyl-S-thiolodiphosphate into cyclic and linear sesquiterpene products. Structural and mechanistic insights gained from AsDMS expand the functional diversity of terpene biosynthetic enzymes and provide a foundation for engineering “designer cyclases” capable of generating new terpenoid products.
Using Artificial Intelligence to Personalize Caring Contact Messages for Recently Discharged Patients: Protocol for a Mixed-Methods Feasibility Study
Authors: Steinberg Rosalie , Amini Jasmine , Wiliszewski Abigail , Chan Prudence Po Ming , Khan Zardar , Martel Anne L. , Starritt Kaleigh , Sinyor Mark , Schaffer Ayal
Published: February 2025

Suicide risk is substantially elevated following discharge from a psychiatric hospitalization. Caring Contact (CC) messages are brief messages of hope, support and information sent post-discharge that can improve mental health outcomes, including suicidal ideation and behaviours. Patients who received CCs in previous studies indicated a desire for increased personalization. To support personalization in an efficient and scalable manner, we will pilot the training of a Large Language Model (LLM) that constructs tailored CCs using information extracted from patients’ electronic health records (EHRs) created during the index psychiatric hospitalization. This is a three-phase, mixed-methods study. In phase 1, psychiatric inpatient clinical staff members will be recruited to generate personalized CC messages from representative, de-identified samples of EHRs. This will be considered the control CCs. Clinical staff focus groups will then identify key components of a successful CC message. In phase 2, the control CCs and focus group feedback will be used to train an LLM on a large number of EHRs to produce personalized CC messages. The LLM will be given the same EHRs used in phase 1 to produce CC messages. In phase 3, we will recruit 30 patients with lived experiences (PWLE) of psychiatric hospitalization to evaluate and compare the control CCs with the LLM-generated messages to determine the acceptability of AI-generated CC messages. We hypothesize that LLM-generated CC messages will achieve acceptability ratings at least as positive as the control CC messages. Since CC messages are modifiable and can be altered to suit the needs of various clinical settings, the findings of this study can potentially be broadly generalizable.
Totipotency and high plasticity in an embryo with a stereotyped, invariant cleavage program
Authors: Rock Amber Q. , Srivastava Mansi
Published: February 2025

Animal embryos begin as totipotent zygotes, which undergo cell divisions and produce progeny with restricted fate potentials over time. However, the timing of when totipotency is lost and the processes through which embryonic cells acquire fates vary across species. Embryos with invariant cleavage programs,e.g.of nematodes and spiralians, tend to show early restriction of blastomere potency and limited robustness to perturbation, particularly after asymmetric cleavages have occurred. In contrast, embryos with variant cleavage programs,e.g.of vertebrates, tend to specify fates later in development and correspondingly show higher plasticity at early stages. Here, we investigate the embryos of the acoelHofstenia miamia, which represents an understudied phylum (Xenacoelomorpha) that is distantly related to well-studied developmental systems. Given the invariant ‘duet’ cleavage program observed inH. miamiaembryos, we found unexpected robustness in this species. Isolated 4-cell stage macromeres, the products of an asymmetric, fate specifying cleavage, were totipotent, forming whole organisms upon isolation. Notably, these isolated macromeres produced pharyngeal and neuronal tissues, which they do not produce during normal development. This assay is highly reproducible and can be done at high throughput inH. miamia, making this species an ideal system to investigate the causes of totipotency after specification. Photoconversion-based lineage tracing revealed that rescued cell types are not merely replaced by neoblasts, the adult pluripotent stem cells inH. miamia, suggesting that the macromere’s totipotency is the result of changes in the fate potentials of early embryonic cells. Remarkably, all blastomeres at the 8-cell stage were capable of reprogramming their fates in embryo reconstitution assays. By assembling different subsets of 8-cell stage blastomeres, none of which are totipotent on their own, we determined that a minimal unit of two blastomeres, one macromere that produces gut and neoblasts and one micromere that is specified to produce muscle and epidermis, was sufficient to develop into a hatchling worm. Future studies of this system could identify the precise mechanisms that can enable tremendous plasticity, including post-zygotic totipotency, in an embryo with well-defined cellular lineages.
A Novel Mouse Model of Parkinson’s Disease for Investigating Progressive Pathology and Neuroprotection
Authors: Subramanya Santhosh Kumar , Shekhar Shreshth , Kumar Devu B , Senthil Sathyapriya , Allimuthu Dharmaraja , Luk Kelvin C , Thakur Poonam
Published: February 2025

Developing animal models that successfully recapitulate the features of progressive Parkinson’s disease (PD) is crucial for understanding disease progression mechanisms and creating effective therapeutic interventions. In this study, we created a mouse model of PD by overexpressing α-synuclein through a combined injection of AAV6-α-synuclein and preformed fibrils (PFFs) into the medial and lateral substantia nigra (SN). We also demonstrated that chronic administration of the c-Abl inhibitor PD180970 provides neuroprotection in this model.

Mice injected with the AAV6-α-synuclein and PFF combination showed a progressive loss of dopaminergic (DA) neurons in the SN and their projections in the striatum over 24 weeks. This neuronal loss coincided with a time-dependent accumulation of phosphorylated α-synuclein (p-syn) in the SN. The p-syn aggregates spread to synaptically connected DARPP-32-positive neurons in the striatum and further extended to the cortex. We also observed a contralateral spread of p-syn aggregates. Additionally, α-synuclein overexpression led to a significant increase in activated microglia and astrocytes at all timepoints, with the strongest activation occurring early and gradually diminishing over time.

Daily administration of PD180970 significantly reduced the loss of DA neurons caused by α-synuclein injection and decreased the accumulation of p-syn in the SN. PD180970 treatment also reduced the neuroinflammation significantly.

Overall, the combined injection of AAV6-α-synuclein and preformed fibrils into the mouse brain establishes a robust PD model, enabling detailed mechanistic studies of the disease. We further demonstrate the model’s utility for chronic neuroprotection studies using the potential drug PD180970, highlighting its broad applicability.

Significance Statement

This study establishes a robust mouse model of Parkinson’s disease (PD) by combining AAV6-mediated α-synuclein overexpression and preformed fibrils (PFFs) to replicate key features of PD, such as progressive dopaminergic neuron loss, phosphorylated α-synuclein accumulation, and neuroinflammation. The model captures the spread of pathological aggregates to synaptically connected brain regions, closely mimicking the human disease. By testing the c-Abl inhibitor PD180970, we demonstrate its neuroprotective effects, including reduced neuronal loss, decreased α-synuclein accumulation, and neuroinflammation highlighting its therapeutic potential. This model offers a valuable platform for investigating PD mechanisms and evaluating novel interventions, bridging the gap between preclinical and clinical applications.
An empirical approach for ESG strategies: policy guidelines for entrepreneurs
Authors: Kim Iksuk , Mollah Muhammad , Lee Freddy , Ardon Jessica
Published: February 2025

Purpose

This study aims to investigate the strategic priorities of environmental, social and governance (ESG) factors in the contexts of the United States, Korea and Bangladesh. Specifically, it examines how entrepreneurs can integrate these priorities into business operations to drive long-term success, including sustainable revenue growth and enhanced brand perception.

Design/methodology/approach

Using a ranked-order approach, this study analyzed a sample of 512 responses from the United States (n = 107), Korea (n = 292) and Bangladesh (n = 113) to prioritize ESG factors for each country. We also conducted a one-way ANOVA to measure how individuals ranked ESG by level of importance in three countries.

Findings

The findings of this study reveal that ESG should be tailored to specific business contexts within each country rather than treated as a universal global standard. More specifically, in the United States, entrepreneurs place significant emphasis on all three ESG dimensions – environmental, social and governance. In contrast, entrepreneurs in Korea prioritize governance factors over social and environmental considerations. Meanwhile, in Bangladesh, the focus is primarily on environmental factors.

Originality/value

This study serves as an eye-opener for entrepreneurs in the United States, Korea and Bangladesh, highlighting where they should focus their efforts when considering ESG factors. It is also the first comparative analysis of ESG priorities across developed and developing countries.
A Multi‐Center Real‐World Study of Clinicopathologic Characteristics and Efficacy of the Malignant Mesothelioma in Chinese Population
Authors: Sun Chenrui , Yang Xue , Chen Lan , Bie Zhixin , Kang Runting , Ai Bin , Ma Junling , Zheng Zitong , Liu Haolan , Liu Juanjuan , Zhong Jia , Yu Jiangyong
Published: February 2025

Objective

Malignant mesothelioma (MM) is a rare malignant tumor. To explore the clinicopathological characteristics and efficacy of Chinese population with MM in the real‐world.

Methods

Two hundred and forty‐eight patients diagnosed with MM between September 2007 and August 2024 from three large medical centers (Beijing Hospital, Peking University Cancer Hospital, and Chinese Academy of Medical Sciences Cancer Hospital) were retrospectively analyzed. Kaplan–Meier and Cox regression were performed. Breast cancer gene 1‐associated protein 1 (BAP1) status was evaluated.

Results

Chinese population with MM had a lower diagnostic age, higher proportion of youth and female, more advanced stage and lower expression of characteristic markers. The median progression‐free survival (mPFS) and median overall survival (mOS) were 8.90 and 25.60 months for the first‐line treatment, and 3.28 and 19.50 months for the second‐line. The first‐line immunotherapy provided a relatively higher objective response rate (33.3% vs. 20.5%, p = 0.402) and a trend to prolong mPFS (12.10 vs. 9.20 months, p = 0.345) and mOS (NA vs. 23.90, p = 0.185) compared with chemotherapy. Bevacizumab combined with chemotherapy relatively prolonged mPFS (10.47 vs. 7.93 months, p = 0.074) and mOS (31.30 vs. 23.20 months, p = 0.673) than chemotherapy alone. Carboplatin relatively improved mPFS than cisplatin (10.87 vs. 8.87 months, p = 0.185). Age and histologic type were predictors for PFS, and gender, histologic subtype, and CK5/6 were prognosis factors for OS. Briefly, 17.78% patients existed BAP1 deletions and correlated with OS benefit.

Conclusion

Chinese population with MM present unique clinicopathologic characteristics and could benefit from the first‐line immunotherapy and bevacizumab combined with chemotherapy. Gender, histologic subtype, and CK5/6 are prognosis factors for OS. BAP1 deletions correlate with OS benefit.
Negative Effect of Gst‐35 on the Health Span of Caenorhabditis elegans Through Lysosomal Dysfunction via the Pmk‐1 and Skr Genes
Authors: Gao Yehui , Zhang Xinyun , Wei Congmin , Lin Hongru , Wu Mengchen , Ma Botian , Jiang Jinyun , Li Shan , Wang Hongbing
Published: February 2025

As global life expectancy increases, the focus has shifted from merely extending lifespan to promoting healthy aging. GSTA1, GSTA2, and GSTA3 (GSTA1‐3), members of the alpha class of glutathione S‐transferases, are involved in diverse biological processes, including metabolism and immune regulation, highlighting their potential influence on human health span and lifespan. In this study, we employed Caenorhabditis elegans as a model organism to investigate the role of gst‐35, an ortholog of mammalian GSTA1‐3, in healthy aging. Our results demonstrated that gst‐35 overexpression has detrimental effects on multiple physiological functions in nematodes. Specifically, gst‐35 overexpression significantly reduced lifespan, impaired development and growth, and substantially diminished reproductive capacity, physical fitness, and stress resistance. In contrast, gst‐35 knockout partially enhanced physical fitness and stress resistance. Comprehensive RNA‐sequencing transcriptome analysis revealed that gst‐35 overexpression disrupted metabolic homeostasis and induced lysosomal dysfunction. These effects were mediated through the activation of the pmk‐1 signaling pathway and suppression of skr genes, which collectively impaired healthy aging processes. These findings illuminate the complex role of gst‐35 in aging and provide valuable insights into the molecular mechanisms underlying healthy aging, offering potential targets for interventions aimed at promoting health span.
Gallbladder cholangiocyte organoids
Authors: Dutta Ankita , Chowdhury Nandita , Chandra Shinjini , Guha Payel , Saha Vaskar , GuhaSarkar Dwijit
Published: February 2025

Organoids are miniature three‐dimensional (3D) organ‐like structures developed from primary cells that closely mimic the key histological, functional, and molecular characteristics of their parent organs. These structures self‐organize through cell‐cell and cell‐matrix interaction in culture. In the last decade, organoids and allied 3D culture technologies have catalyzed studies involving developmental biology, disease biology, high‐throughput drug screening, personalized medicine, biomarker discovery, tissue engineering, and regenerative medicine. Many organoid systems have been generated from the gastrointestinal system, for example, intestine, stomach, liver, pancreas, or colon. Gallbladder cancer (GBC) is the most common and highly aggressive form of biliary tract cancer. GBC is rare in the west but has a high incidence in South America and India. Prolonged chronic inflammation is implicated in the pathogenesis of GBC but the driving molecular pathways leading to neoplasia are not well understood. Gallbladder cholangiocyte organoids (GCO) will facilitate the understanding of the evolution of the disease and novel therapeutic strategies. In this review, we have discussed alternative methodologies and culture conditions developed to generate GCO models, applications that these models have been subjected to and the current limitations for the use of GCOs in addressing the challenges in GBC research.