bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact assessment of vaccine-related negative news and incentive measures on vaccine hesitancy in Hong Kong
Authors: Chen Yifan , Ye Yang , Yuan Hsiang-Yu , Zhang Qingpeng
Published: February 2025

Vaccine hesitancy underscores the critical need to quantify the influence of diverse factors on vaccine uptake. In this study, we develop a social-epidemiological transmission model with an imitation mechanism to characterize the interactions between social and epidemiological dynamics. We introduce a risk score to the payoff function to assess vaccine-related negative news and incentive measures’ impacts on COVID-19 vaccine uptake during the pandemic. By fitting our model with the real data in Hong Kong, we reveal that the vaccine-related negative news drastically impeded vaccination efforts. Scenario analyses suggest that, without incentive measures, the projected fifth wave of COVID-19 in Hong Kong would have infected 98% of the population, resulting in an estimated 51,752 deaths. Both the model simulation and the real data demonstrate that the incentive measures have successfully encouraged vaccine uptake and saved approximately 38,419 lives. However, we found that the willingness to take vaccines quickly declined after the incentive measures were finished, implying limited benefits in mitigating the effect of negative news in the long run. This study also highlights the need for booster doses in the face of the immune escape of the Omicron variants. Our model offers data-driven insights into the interplay between negative news, vaccine hesitancy, and incentive measures, shedding light on the effective preparation for emerging infectious disease outbreaks.
Integrative Multi-omics of Gynecological Tumors Identifies Novel Singular Biomarkers of Disease Progression
Authors: Muthamilsevan Sangeetha , Palaniappan Ashok
Published: February 2025

Gynecological cancers represent a cluster of largely preventable and treatable diseases afflicting women, but with persistent substantial global burden of disease complicated by extant social factors especially in developing countries. Cervical, ovarian and endometrial cancers comprise the major gynecological cancers that might benefit from early-stage diagnosis and personalized treatment strategies. In this work, we performed integrative multi-omics analysis of public-domain omics datasets from The Cancer Genome Atlas consortium and coupled it with custom protocols to identify consensus candidate biomarkers of each of the major gynecological cancers. Such consensus biomarkers were individually evaluated for their ability to classify ‘cancer’ and ‘normal’ samples and those with AUROC > 0.9 were identified as singular biomarkers. Our study yielded the following singular biomarkers: (i) endometrial cancer: MYOZ2, CYP1B1, PPP1R3C, DNASE1L3, ADAMTSL1, LRCH2, RBM20, LOC284276, FAM78B, COL14A1, and PDZRN3; (ii) ovarian cancer: C7 and LONRF2; and (iii) cervical cancer: HAND2, C1QTNF7, JAM3 (with AUROC > 0.99) as well as HSPB7, ACTA2 and DACT7. We demonstrated that factors from multi-omics analysis of endometrial cancer enabled a geometric separation of the ‘cancer’ and ‘normal’ samples. Our results could encourage further research into the multi-omics – based subtypes of these cancers. Our methods could be extended to the analysis of datasets of other cancer types and our studies could pave the way for the development of integrated screening models for the major gynecological cancers.
Time to Medication in School-Age Children with ADHD: Assessing the Effect of Sociodemographic and Clinical Factors
Authors: Kasinathan Sushma , Huffman Lynne C. , Luo Ingrid , Bannett Yair
Published: February 2025

Objective

To assess the timing of attention-deficit/hyperactivity disorder (ADHD) medication prescriptions in relation to the ADHD diagnostic visit in school-aged children seen in developmental-behavioral pediatrics (DBP) clinics and to investigate which sociodemographic and clinical factors affect the timing of medication prescription.

Method

We retrospectively analyzed electronic health records from Stanford’s DBP clinics of children 6-12-years-old seen between 2016 and 2024. ADHD cohort included patients with an ICD-10 ADHD diagnosis and with ≥1 month follow-up. Andersen Health Care Utilization model informed selection of predisposing (age, sex, race/ethnicity), enabling (insurance, clinician type), and need (ADHD subtype, comorbidities) factors. Primary outcome: Time from first ADHD diagnosis to first ADHD medication prescription within 1 year of diagnosis. Cox regression model assessed associations between sociodemographic and clinical factors and study outcome.

Results

Of 823 patients with ADHD, 623 (75.7%) were male; average age at first ADHD diagnosis was 8.2 years (SD=1.5). Of 823 patients, 484 (58.8%) were prescribed medications within 1 year of diagnosis. The average number of days from ADHD diagnosis to first prescription was 51 days (median=4). Longer time to medication prescription was associated with Asian race/ethnicity (predisposing), psychologist clinician (enabling), 1-2 or ≥3 comorbidities (need). Shorter time to prescription was associated with older patient age (predisposing), ADHD combined and hyperactive/impulsive subtypes (need).

Conclusion

Asian race/ethnicity and, unexpectedly, multiple comorbidities, were associated with later ADHD medication prescription by DBPs in school-age children. Further investigation is necessary to understand patient, family, and clinician factors that influence medication initiation in these patient subgroups.
Cancer and Post-therapy Cardiotoxicity Risk in Adolescents, Young Adults, and Adults with Down Syndrome
Authors: Buckman Michelle A. , Vasileva Anastasiia , Jedlicka Charles R. , Kalra Hardik , Vasilyev Mikhail , Dickens David S. , Tomasson Michael H. , Bates Melissa L.
Published: February 2025

The median life expectancy of people with Down syndrome has increased substantially over the past several decades, from 4 years in 1970 to 53 years in 2010. Despite the recent improvement in survival, there is little data about the prevalence of age-related diseases, including age-related malignancies, and the impact of standard cancer treatments on cardiovascular health. We retrospectively reviewed medical records for age- and sex-matched patients ≥15 years old with and without Down syndrome using the TriNetX platform to identify the prevalence of malignancies and explore cardiovascular outcomes after treatment with anthracyclines. We further stratified the populations into adolescent and young adult (AYA, ages 15-39 years old) and adult (≥40 years old) cohorts, given that treatment recommendations can be different. Down syndrome patients in the AYA cohort were more likely to be diagnosed with acute myeloid (OR 8.9, CI 4.99-15.89, p<0.001) and lymphoid (OR 7.33, CI 4.82-11.15, p<0.001) leukemia. The adult cohort with Down syndrome was more likely to be diagnosed with myelodysplastic syndromes (OR 12.25, CI 6.41-23.42, p<0.001), multiple myeloma (OR 1.66, CI 1.06-2.6, p=0.026), and testicular cancer (OR 2.73, CI 1.32-5.65, p=0.005). Overall, Down syndrome patients (≥15 years old) treated with anthracyclines were more likely to be diagnosed with heart failure (OR 2.14, CI 1.07-4.27, p=0.042). Our study demonstrates adolescents and adults with Down syndrome have a higher predisposition to several malignancies and an increased risk of cardiovascular disease after anthracycline treatment and may require specific screening guidelines to address their unique health risks.
Patient-derived organoids to study glycosylation dynamics during gastric disease
Authors: Santos-Ferreira Liliana , Duarte Henrique O. , Moia Eva , Costa Ana F. , Martins Álvaro M. , Faria-Ramos Isabel , Matos Rita , Barros Rita , Silva Marta , Pedrosa Sofia , Batista Diana A. , Gomes Joana , Borén Thomas , Sousa Fabiana , Casanova-Gonçalves Frederica , Barbosa José , Magalhães Ana , Gomes Catarina , Santos-Sousa Hugo , Bartfeld Sina , Carneiro Fátima , Reis Celso A. , Pinto Filipe
Published: February 2025

BACKGROUND AND AIMS

Aberrant cellular glycosylation remains a key event that accompanies and actively sustains gastric neoplastic transformation. Patient-derived organoids (PDOs) have recently emerged as a promisingex vivomodel to study human gastric disorders. Since the PDOs glycosylation landscape remains unknown, this study aims to evaluate PDOs as potentialavatarsofin vivotissue glycosylation profiles in the gastric context.

METHODS

Fresh gastric mucosa samples derived from non-tumoral obese patients (n=11), adjacent tumor mucosa samples (n=29), and tumor tissue samples derived from gastric cancer (GC) patients (n=30) were used to establish a biobank of gastric PDOs (n=56). TheN- andO-glycophenotypes of normal, adjacent, and tumor PDOs and respectivein vivotissues were thoroughly characterized by immunostaining. Additionally, a comparative glycan analysis was performed over time, upon PDO biobanking and xenografting in mice. The binding of twoHelicobacter pylori(H. pylori) isogenic strains with distinct glycan-binding affinities was assessed in parental gastric mucosa tissues and compared with the respective PDOs before and after modulation of their glycan landscape.

RESULTS

Our results show that PDOs mimic different phenotypes of the carcinogenic cascade and recapitulate parental gastric tissues’ glycosylation profile. Tumor PDOs recapitulate the inter- and intra-heterogeneity features observed in GC, which is maintained over time, upon biobanking and xenografting. We demonstrated that the expression of type I and type II Lewis antigens is dynamically controlled by PDOs differentiation status, which results in differential binding toH. pyloristrains displaying distinct glycan-binding adhesins, mirroring the gastric epithelium tissue interactions.

CONCLUSIONS

This study established PDOs as invaluableex vivotools to study the complex glycan dynamics in both gastric physiological and pathological settings.
Spatial mapping of DNA synthesis reveals dynamics and geometry of human replication nanostructures
Authors: Hawgood Micheal , Urién González Bruno , Agostinho Ana , Thiagarajan Praghadhesh , Yang Yiqiu , Zhang Xue , Giglio Giovanni , Quijada Gemma , Fonseca Matilde , Bartek Jiri , Blom Hans , Lemmens Bennie
Published: February 2025

DNA replication is essential to life and ensures the accurate transmission of genetic information, which is significantly disturbed during cancer development and chemotherapy. While DNA replication is tightly controlled in time and space, methods to visualise and quantify replication dynamics within 3D human cells are lacking. Here, we introduce 3D-Spatial Assay for Replication Kinetics (3D-SPARK), an approach enabling nanoscale analysis of DNA synthesis dynamicsin situ. 3D-SPARK integrates optimised nucleotide analogue pulse labelling with super-resolution microscopy to detect, classify, and quantify replication nanostructures in single cells. By combining immunofluorescence techniques with click chemistry-based nascent DNA labelling and transfection of fluorescent nucleotide derivatives, we map multi-colour DNA synthesis events in relation to established replication proteins, local RNA-protein condensates or large subnuclear domains. We demonstrate quantitative changes in size, relative abundance and spatial arrangement of nanoscale DNA synthesis events upon chemotherapeutic treatment, CDC6 oncogene expression and loss of chromatin organiser RIF1. The flexibility, precision and modular design of 3D-SPARK helps bridging the gap between spatial cell biology, genomics, and 2D fibre-based replication studies in health and disease.
Central amygdalar PKCδ neurons mediate fentanyl withdrawal
Authors: Wooldridge Lisa M. , Wu Jacqueline W.K. , Jo Adrienne Y. , Zinn Morgan , Lee Angela M. , Mahmood Malaika , Cohen Savanna A. , Corder Gregory
Published: February 2025

Aversion to opioid withdrawal is a significant barrier to achieving lasting opioid abstinence. The central amygdala (CeA), a key brain region for pain, threat-detection, autonomic engagement, and valence assignment, is active during opioid withdrawal. However, the role of molecularly distinct CeA neural populations in withdrawal remains underexplored. Here, we investigated the activity dynamics, brain-wide connectivity, and functional contribution of Protein Kinase C-delta (PKCδ)-expressing neurons in the CeA lateral capsule (CeLCPKCδ) during fentanyl withdrawal in mice. Mapping activity-dependent gene expression in CeLCPKCδneurons revealed a highly withdrawal-active subregion in the anterior half of the CeA. Fiber photometry calcium imaging showed that opioid-naïve CeLCPKCδneurons respond to salient noxious and startling stimuli. In fentanyl-dependent mice, naloxone-precipitated withdrawal increased spontaneous neural activity and enhanced responses to noxious stimuli. Chronic inhibition of CeLCPKCδneurons throughout fentanyl exposure, via viral overexpression of the potassium channel Kir2.1, attenuated withdrawal signs in fentanyl-dependent mice. Lastly, we identified putative opioid-sensitive inputs to CeLCPKCδneurons using rabies-mediated monosynaptic circuit tracing and color-switching tracers to map mu-opioid receptor-expressing inputs to the CeLC. Collectively, these findings suggest that the hyperactivity of CeLCPKCδneurons underlies the somatic signs of fentanyl withdrawal, offering new insights into the amygdala cell-types and circuits involved in opioid dependence.
Co-expression of Bovine leukemia virus and Bovine foamy virus-derived miRNAs in naturally infected cattle
Authors: Petersen MI , Suarez Archilla G , Perez CV , Gonzalez DD , Trono KG , Mongini C , Jaworski JP , Carignano HA
Published: February 2025

MicroRNAs (miRNAs) derived from viruses play a central role in modulating the expression of both viral and host gene, facilitating immune evasion, viral persistence, and pathogenesis. Among the viruses that encode miRNAs and infect cattle such as Bovine leukemia virus (BLV), Bovine foamy virus (BFV), Bovine herpesvirus type 1 (BoHV-1), and Bovine herpesvirus type 5 (BoHV-5), BLV has gained increasing attention due to the critical role that BLV-miRNAs may play in inducing leukemia and lymphoma in infected animals. BLV is highly prevalent in the Americas and has a negatively affects dairy herds, primarily due to restrictions on the commercialization of dairy products from infected animals and a decrease in milk production.

Mixed infections involving BLV and BFV appear to be common in cattle. Considering the ability of foamy viruses to cross species barriers, preventing their presence within the food chain is essential. In this study, through small RNA sequencing, we identified the co-expression of seven BLV-derived miRNAs (blv-miR-B1-3p,blv-miR-B2-5p,blv-miR-B2-3p,blv-miR-B3-5p,blv-miR-B3-3p,blv-miR-B4-3p,andblv-miR-B5-5p) and three BFV-derived (bfv-miR-BF1-5p,bfv-miR-BF1-3p, andbfv-miR-BF2-5p) in naturally BLV-infected cattle, while no BoHV-1/5 miRNAs were detected. A differential expression analysis revealed seven bovine miRNAs (bta-miR-375,bta-miR-133a,bta-miR-677, bta-miR-1,bta-miR-3613a,bta-miR-9-5p, andbta-miR-95) with altered expression levels (fold change > |1.5| and q-value < 0.05) between cows with a high BLV proviral load (PVL) and uninfected counterparts. A comprehensive functional analysis of protein-protein interaction networks for genes targeted by both viral and host-derived miRNAs highlighted key pathways implicated in tumorigenesis and the regulation of the immune response. Notably,bta-miR-375, previously proposed as an early biomarker for the progression of enzootic bovine leukosis progression, exhibited differential expression in cows with elevated PVL, reinforcing its diagnostic potential. The functional interaction among miRNAs derived from BLV and BFV raises important concerns regarding their potential influence on disease severity and the increased dissemination of BFV. The findings derived from this study offer new perspectives for creating diagnostic and treatment approaches to manage viral persistence and tumor growth in cattle.
Behavioral profiling of hyperbaric oxygen as an intervention for chemotherapy-related functional impairments in male and female mice
Authors: Trinh Oanh T.P. , Ferns Andrew , Zachariah Bethany S. , Sumien Nathalie
Published: February 2025

‘Chemobrain’ or chemotherapy-related cognitive impairment (CRCI) affects up to 75% of cancer patients and survivors following chemotherapy treatments. Chemotherapy typically affects multiple domains including learning, memory, attention, executive function, and mood regulation, persisting for decades after treatment cessation and significantly diminishing cancer survivors’ quality of life. Despite its prevalence and long-term impact, effective interventions for CRCI remain limited. This study investigated the behavioral effects of HBO on mice exposed to chemotherapy drugs methotrexate (MTX) and 5-fluorouracil (5-FU). Adult male and female C57BL/6 mice received intraperitoneal injections of either saline or chemotherapy (Low-dose: MTX 37.5 mg/kg and 5-FU 50 mg/kg; High-dose: MTX 70 mg/kg and 5-FU 100 mg/kg) once a week for three weeks. Concurrently, subsets of mice underwent daily HBO (2.4 ATA, 90 minutes) five days a week for three weeks. Animals’ health was evaluated weekly, and behavioral assessment of cognitive, motor, and affective functions was conducted post-treatment. Our results showed that chemotherapy, especially at high-dose, impaired spatial memory and navigation, avoidance learning, fear discrimination, and anxiety regulation differently between males and females. HBO significantly alleviated chemotherapy-induced avoidance learning impairment in both sexes and improved coordinated running capacity in high-dose treated males. However, chemotherapy-HBO cotreatment increased spatial memory deficit in males and increased anxiety-like behaviors in females. In conclusion, even though HBO had some nuanced effects on the various domains, some reversal of CRCI effects were observed. Therefore, HBO should be further studied and considered as a potential treatment for ‘chemobrain’.
The Myo2 adaptor Ldm1 and its receptor Ldo16 mediate actin-dependent lipid droplet motility
Authors: Zhao Xue-Tong , Vien Diep Duy Trong , Percifull Louis , Fausten Rebecca Martina , Hugenroth Marie , Höhne Pascal , Esch Bianca Marie , Collado Javier , Keller Jenny , Wilmes Stephan , Wälte Mike , Kümmel Daniel , Schuberth Christian , Fernández-Busnadiego Rubén , Fröhlich Florian , Wedlich-Söldner Roland , Bohnert Maria
Published: February 2025

Organelle motility enables strategic cellular reorganizations. In yeast, this process depends on the actin cytoskeleton, type V myosin motor proteins, and organelle-specific myosin adaptor proteins. While the myosin adaptors for most organelles are known, the coupling of myosin to lipid droplets (LDs), the cellular lipid storage organelles, remained enigmatic. Using genome-wide screening, we identified Ldm1 (Lipid Droplet Motility 1/Yer085c) as a myosin adaptor. Ldm1 binds to the globular tail domain of the myosin Myo2 and to the LD surface protein Ldo16 to enable actin-dependent LD motility. Ldo16 has additional roles in LD contact sites to the vacuole and the ER, suggesting a coordination of LD motility and organelle tethering. Ldm1 has a second role in mitochondrial transport and elevated Ldm1 levels rescue defects of the mitochondrial Myo2-adaptors Mmr1/Ypt11. Our work identifies the molecular machinery for LD motility and contributes to a comprehensive understanding of acto-myosin-based cellular reorganization.
Understanding barriers to effective injury care in low-income contexts: a mixed methods analysis of insights from medical trainees and traffic law enforcement first responders in Uganda
Authors: Lule Herman , Oguttu Benson , Mugerwa Micheal , Wilson Michael Lowery , Posti Jussi P.
Published: February 2025

Background

Injury-related mortality exhibits a significant social gradient, particularly in low-middle-income countries (LMICs), with approximately 4.5 million premature deaths annually.

Objective

This study explores prehospital and in-hospital barriers to timely injury care as perceived by frontline healthcare personnel in Uganda.

Methods

We utilized a mixed methods approach, gathering qualitative data from five hundred frontline workers including surgical residents, interns, and law enforcement professionals, alongside quantitative data from 1,003 trauma patients. Barriers were categorized into pre- and in-hospital trauma team-related, patient-related, and systemic healthcare challenges.

Results

From frontline workers, prehospital barriers included delays in emergency medical services activation (21.2%), ambulance arrival (19.3%), and transportation to hospitals (15.2%) whereas in-hospital barriers primarily involved supply shortages (28.3%), delays in identifying life-threatening injuries (27.3%), and insufficient critical care services (26.3%). Among the 1003 audited trauma patients, 41.5% (n=416) faced barriers during treatment. The most common barriers were delays in treatment decisions (n=232, 23.1%) and securing necessary supplies (n=180, 17.9%). Presence of a barrier correlated with higher odds of unfavourable Glasgow Outcome Scale scores compared to those without barriers [OR 1.750, 95% CI (1.497-2.047) vs. OR 0.556, 95% CI (0.436-0.708), p<0.001]. Moreover, the odds of mortality were higher for those whom a barrier was encountered compared to those where there was no barrier [OR 1.901, 95% CI (1.057-3.420) vs. OR 0.588, 95% CI (0.397-0.869), p<0.001].

Conclusions

Our findings highlight the need for multifaceted targeted interventions, integrating frontline healthcare perspectives to improve trauma care delivery in LMICs which face both prehospital and in-hospital disparities to accessing injury care.
Trans-ancestry Genome-Wide Analyses in UK Biobank Yield Novel Risk Loci for Major Depression
Authors: Singh Madhurbain , Chatzinakos Chris , Barr Peter B. , Gentry Amanda Elswick , Bigdeli Tim B. , Webb Bradley T. , Peterson Roseann E.
Published: February 2025

Most genome-wide association studies (GWASs) of depression focus on broad, heterogeneous outcomes, limiting the discovery of genomic risk loci specific to major depressive disorder (MDD). Previous UK Biobank (UKB) studies had limited ability to pinpoint MDD-associated loci due to a smaller sample with strictly defined MDD outcomes and further exclusion of many participants based on ancestry or relatedness, significantly underutilizing this resource’s potential for elucidating the genetic architecture of MDD. Here, we present novel genomic insights into MDD by fully utilizing existing UKB data through (1) a trans-ancestry GWAS pipeline using two complementary approaches controlling for population structure and relatedness and (2) an increased sample with MDD symptom-level data across two mental health assessments. We identified strict MDD outcomes among 211,535 participants, representing a 38% increase in eligible participants from prior studies with only one assessment. Ancestrally inclusive analyses yielded 61 genomic risk loci across depression phenotypes, compared to 47 in the analyses restricted to participants genetically similar to European ancestry. Fourteen of these loci, including five novel, were associated with strict MDD phenotypes, whereas only one locus has been previously reported in UKB. MDD-associated genomic loci and predicted gene expression levels showed little overlap with broad depression, indicating higher specificity. Notably, polygenic scores based on these results were significantly associated with depression diagnoses across ancestry groups in theAll of UsResearch Program, highlighting the shared genetic architecture across populations. While the trans-ancestry analyses, which included non-European participants, increased the number of associated loci, the discovery of non-European ancestry-specific loci was limited, underscoring the need for larger, globally representative studies of MDD. Importantly, beyond these results, our GWAS pipeline will facilitate inclusive analyses of other traits and disorders, helping improve statistical power, representation, and generalizability in genomic studies.
ERM proteins support perinuclear actin rim formation
Authors: Fracchia Andrea , Hadad Yuval , Babele Dagmawit , Gerlitz Gabi
Published: February 2025

The interaction of actin filaments with the nuclear envelope is essential for diverse cellular processes, including cell migration, nuclear positioning, and transcriptional control. The main studied mechanism that links F-actin to the nucleus is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Recently, the formation of a perinuclear actin rim has been identified in various cell types in response to external force or migration signals. This rim depends on the activation of the actin nucleator Inverted formin 2 (INF2) by calcium influx. However, it is not clear how the rim is coupled with the nuclear envelope. Here we show that the nuclear membrane protein Emerin, which has an actin-binding domain, is not required for the perinuclear actin rim formation. Interestingly, we found that the Ezrin-Radixin-Moesin (ERM) proteins, known to link actin filaments to the cell membrane, are also localized to the nuclear envelope in melanoma cells. Overexpression of ERM proteins increased the perinuclear actin rim levels, while knockdown of ERM proteins led to a reduction in the rim levels. Thus, the ERM proteins appear as part of the mechanism that links actin filaments to the nuclear envelope.
Convergence in amino acid outsourcing between animals and predatory bacteria
Authors: Kasalo Niko , Domazet-Lošo Mirjana , Domazet-Lošo Tomislav
Published: February 2025

All animals have outsourced about half of the 20 proteinogenic amino acids (AAs). We recently demonstrated that the loss of biosynthetic pathways for these outsourced AAs is driven by energy-saving selection. Paradoxically, these metabolic simplifications enabled animals to use costly AAs more frequently in their proteomes, allowing them to explore sequence space more freely. Based on these findings, we proposed that environmental AA availability and cellular respiration mode are the two primary factors determining the evolution of AA auxotrophies in animals. Remarkably, our recent analysis showed that bacterial AA auxotrophies are also governed by energy-related selection, thereby roughly converging with animals. However, bacterial AA auxotrophies are highly heterogeneous and scattered across the bacterial phylogeny, making direct ecological and physiological comparisons with the animal AA outsourcing model challenging. To better test the universality of our model, we focused on Bdellovibrionota and Myxococcota—two closely related bacterial phyla that, through aerobic respiration and a predatory lifestyle, best parallel animals. Here, we show that Bdellovibrionota, driven by energy-related selection, outsourced a highly similar set of AAs to those in animals. This sharply contrasts with Myxococcota, which exhibit far fewer AA auxotrophies and rarely show signatures of energy-driven selection. These differences are also reflected in Bdellovibrionota proteomes, which are substantially more expensive than those of Myxococcota. Finally, we found evidence that the expression of costly proteins plays a crucial role in the predatory phase of the Bdellovibrio life cycle. Together, our findings suggest that Bdellovibrionota, through their obligate predatory lifestyle, exhibit the closest analogy to the AA auxotrophy phenotype observed in animals. In contrast, facultative predation, as seen in Myxococcota, appears to substantially limit the evolution of AA auxotrophies. These cross-domain convergences strongly support the general validity of our AA outsourcing model.
Arrayed CRISPR/Cas9 Loss-Of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking
Authors: Ziegler Marvin , Böger Cedric , Alecu Julian E. , Kim Hyo-Min , Saffari Afshin , Davies Alexandra K. , Sahin Mustafa , Ebrahimi-Fakhari Darius
Published: February 2025

Biallelic loss-of-function variants in the adaptor protein complex 4 (AP-4) disrupt trafficking of transmembrane proteins at thetrans-Golgi network, including the autophagy-related protein 9A (ATG9A), leading to childhood-onset hereditary spastic paraplegia (AP-4-HSP). AP-4-HSP is characterized by features of both a neurodevelopmental and degenerative neurological disease. To investigate the molecular mechanisms underlying AP-4-HSP and identify potential therapeutic targets, we conducted an arrayed CRISPR/Cas9 loss-of-function screen of 8,478 genes, targeting the ‘druggable genome’, in a human neuronal model of AP-4 deficiency. Through this phenotypic screen and subsequent experiments, key modulators of ATG9A trafficking were identified, and complementary pathway analyses provided insights into the regulatory landscape of ATG9A transport. Knockdown ofANPEPandNPM1enhanced ATG9A availability outside thetrans-Golgi network, suggesting they regulate ATG9A localization. These findings deepen our understanding of ATG9A trafficking in the context of AP-4 deficiency and offer a framework for the development of targeted interventions for AP-4-HSP.
Long-term development of a motor memory
Authors: Franklin David W. , Nietschmann Pascal , Papadopoulou Thalia , Franklin Sae
Published: February 2025

Human behavior is developed through continuous adaptation to our environment over a range of timescales. Extensive studies have investigated the mechanisms and computations underlying this process of sensorimotor adaptation using several hundred trials. However, most of our motor skills have had countless hours of practice. Here we study a simple motor adaptation task using thousands of training trials over multiple weeks to study the long-term development of a motor memory, and examine changes in adaptation, retention, inter-limb transfer, decay, spontaneous recovery and generalization. Unlike previous studies, participants showed complete compensation to the novel dynamics, along with long-term increases in retention and spontaneous recovery. Moreover, we find narrowing in the angular generalization, suggesting continual tuning of the motor memory to the task. This demonstrates the extensive changes occurring with longer training of motor tasks, highlighting their importance in studies of sensorimotor control, rehabilitation and training.
Diagnostic performance of Alzheimer’s disease blood biomarkers in a Brazilian cohort
Authors: Borelli Wyllians Vendramini , Ferreira Pamela C L , Brum Wagner Scheeren , Ferrari-Souza João Pedro , Carello-Collar Giovanna , Holz Maila , Tizeli Victoria , Strelow Matheus Zschornack , Formoso Carolina , Fagundes Chaves Marcia Lorena , Rocha Andreia , Aguzzoli Cristiano Schaffer , Rohden Francieli , Souza Débora G. , Schumacher Schuh Artur Francisco , Povala Guilherme , Bellaver Bruna , Rosa-Neto Pedro , Castilhos Raphael Machado , Pascoal Tharick A. , Zimmer Eduardo R.
Published: February 2025

Background

Blood-based biomarkers (BBMs) have emerged as promising tools to enhance Alzheimer’s disease (AD) diagnosis. Despite two-thirds of dementia cases occurring in the Global South, research on BBMs has predominantly focused on populations from the Global North. This geographical disparity hinders our understanding of BBM performance in diverse populations. To address this, we evaluated the diagnostic properties of AD BBMs in a real-world memory clinic from Brazil, one of the largest countries in the Global South. We measured blood and cerebrospinal fluid (CSF) biomarkers - amyloid-β (Aβ)40, Aβ42, phosphorylated tau (p-tau) 217, neurofilament light (NfL) chain, and glial fibrillary acidic protein (GFAP) - in 59 individuals. Sample comprised 20 cognitively unimpaired (CU) individuals, 22 with AD dementia, and 17 with vascular dementia (VaD). We compared BBM levels across diagnostic groups and assessed their discriminative ability for AD. Notably, individuals with VaD and AD had lower educational levels (6.8±3.0) compared to CU individuals (61.4±6.6). Among the BBMs tested, plasma p-tau217 demonstrated the best performance, exhibiting high accuracy in differentiating CU from AD (AUC 0.96) and Aβ pathology (AUC 0.98). However, the ability of AD BBMs to distinguish between AD and VaD was lower than expected (AUC from 0.52 to 0.79), particularly when compared to studies from the Global North. Our findings highlight the potential utility of BBMs for AD diagnosis in real-world settings within the Global South. However, they also underscore the need for proper implementation and validation of these biomarkers within these populations to ensure accurate and reliable results.
Performance of an artificial intelligence foundation model for prostate radiotherapy segmentation
Authors: Doucette Matt , Liao Chien-Yi , Lin Mu-Han , Jiang Steve , Nguyen Dan , Yang Daniel X.
Published: February 2025

Importance

Artificial intelligence (AI) foundation models such as Segment Anything Model 2 (SAM 2) offer potential for semi-automated image segmentation with minimal fine-tuning, but their performance in specialized clinical tasks like radiation therapy planning are not well characterized.

Objective

To evaluate the performance of SAM 2 in segmenting pre-operative intact prostate and post-operative prostate fossa targets for prostate radiotherapy planning.

Design, Setting, Participants

Retrospective cohort study deploying and testing a foundation model for AI segmentation for prostate radiotherapy planning. CT simulation images and radiation plans were obtained from a single academic institution for patients undergoing prostate cancer treatment. Data analysis was performed from September 2024 to February 2025.

Exposures

AI segmentation with varying levels of human intervention, ranging from intervals of every 2nd to every 10th ground truth slice provided as input.

Main Outcome and Measures

Segmentation accuracy measured by Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD) for intact and post-operative prostate target delineation.

Results

While SAM 2 outperformed interpolation in DSC and HD for both intact and post-operative prostate cancer patient cases, the AI segmentation accuracy was significantly better in the intact pre-operative patient cases where anatomic boundaries were better defined than post-operative patient cases. This is especially evident when sparse ground truth was provided simulating lower levels of human intervention.

Conclusions and Relevance

AI foundation models show promising application for specialized medical tasks such as prostate cancer radiotherapy segmentation with limited need for fine-tuning or retraining, although their clinical application will require further understanding of task-specific performance.
The neuron-intrinsic membrane skeleton is required for motor neuron integrity throughout lifespan
Authors: Davison Carrie Ann , Garcia Daniela , Feng Chengye , Hao Hongyan , Jorgensen Erik M. , Hammarlund Marc
Published: February 2025

Axons experience physical stress throughout an organism’s lifetime, and disruptions in axonal integrity are hallmarks of both neurodegenerative diseases and traumatic injuries. The spectrin-based membrane periodic skeleton (MPS) is proposed to have a crucial role in maintaining axonal strength, flexibility, and resilience. To investigate the importance of the intrinsic MPS for GABAergic motor neuron integrity inC. elegans, we employed the auxin-inducible degron system to degrade β-spectrin/UNC-70 in a cell-type specific and time-dependent manner. Degradation of β-spectrin from all neurons beginning at larval development resulted in widespread axon breakage and regeneration in VD/DD GABAergic motor neurons in both larval and adult animals. Similarly, targeted degradation of β-spectrin in GABA neurons alone resulted in extensive breakage. Moreover, we found that depleting β-spectrin from the mature nervous system also induced axon breaks. By contrast, epidermal β-spectrin was not required for axon integrity of VD/DD neurons. These findings demonstrate the cell-intrinsic importance of neuronal β-spectrin/UNC-70 for axon integrity both during development and in adulthood.
Quinpirole ameliorates the dysfunction of microglia in human LRRK2-R1441G transgenic mice
Authors: Chen Yuanxin , Cui Shiquan , Wang Huaixin , Zeng Chenbo , Zhang Hui
Published: February 2025

Microglia-mediated neuroinflammation is a key contributor to Parkinson’s disease (PD) pathogenesis. Leucine-rich repeat kinase 2 (LRRK2), the leading genetic contributor to both familial and sporadic PD, has been implicated in driving this connection. However, its precise role remains incompletely understood due to technical challenges. To address this, we utilized a bacterial artificial chromosome (BAC) transgenic mouse model overexpressing human LRRK2-R1441G, which replicates key features of PD. These mice were crossed with Cx3cr1–EGFP mice to enable assessment of microglial dynamics and function using two-photon imaging in awake micein vivoand acute brain slicesex vivo. Furthermore, spatial transcriptomic analysis was performed using GeoMx Digital Spatial Profiler technology to compare transgenic mice with their wild-type counterparts. The R1441G mutation upregulated antigen processing and presentation pathways, increased activated microglia, and enhanced microglial polarization in the dorsal striatum. Mutant microglia exhibited reduced motility and slower responses to focal injury, with processes retracting faster and extending more slowly. Quinpirole, a dopamine D2 receptor (D2R) agonist, successfully reversed microglial deficits. This study provides the first evidence that pathogenic LRRK2 mutations alter microglial motility and responsivenessin vivo, highlighting D2R activation as a promising therapeutic strategy to mitigate neuroinflammation and neurodegeneration in PD.
Characterization and correction of multipole field effect on electron beams from a high-brightness continuous-wave photocathode gun
Authors: Jia Haoyan , Li Tianyi , Liu Juntao , Liu Zhongqi , Zhang Xiang , Li Jingyi , Liu Kexin , Tsai Cheng-Ying , Xu Hang , Huang Senlin
Published: February 2025

Continuous-wave photocathode guns are capable of delivering electron beams with high repetition rates and high average currents. However, they are limited by relatively low accelerating gradients and cathode fields. This limitation leads to a larger beam size at the gun exit due to space-charge forces, making the beam more sensitive to optical aberrations and posing challenges for low-emittance electron beam transmission. This paper focuses on the aberrations induced by multipole fields. We analyze the effects of quadrupole, sextupole, and higher-order fields on beam profile and transverse emittance and propose a beam-based method for the rapid characterization and correction of these multipole fields. Furthermore, we present an experimental study conducted on the DC-SRF-II photocathode gun equipped with dedicated correctors. Both simulation and experimental results demonstrate that our approach effectively mitigates beam aberrations caused by multipole fields, resulting in improved beam symmetry and reduced emittance.

Published by the American Physical Society
2025
New multinucleon knockout model in the NuWro Monte Carlo generator
Authors: Prasad Hemant , Sobczyk Jan T. , Ankowski Artur M. , Bonilla J. Luis , Banerjee Rwik Dharmapal , Graczyk Krzysztof M. , Kowal Beata E.
Published: February 2025

We present the implementation and results of a new model for the n-particle n-hole () contribution in the NuWro event generator, grounded in the theoretical framework established by the Valencia group in 2020. For the component, we introduce a novel nucleon sampling function with tunable parameters to approximate correlations in the momenta of outgoing nucleons. These parameters are calibrated by comparing our results to those of the Valencia model across a range of incoming neutrino energies. In addition, our model incorporates a distinct contribution from the mechanism. We discuss the differences between the new NuWro implementation, the original Valencia model, and the previous NuWro version, focusing on the distribution of outgoing nucleon momenta. Finally, we assess the impact of the hadronic model on experimental analyses involving hadronic observables.

Published by the American Physical Society
2025
Toric gravitational instantons in gauged supergravity
Authors: Benetti Genolini Pietro , Gauntlett Jerome P. , Jiao Yusheng , Lüscher Alice , Sparks James
Published: February 2025

We introduce a general class of toric gravitational instantons in D=4, N=2 gauged supergravity, namely Euclidean supersymmetric solutions with U(1)2 isometry. Such solutions are specified by a “supergravity labeled polytope,” where the labels encode the four-manifold topology, the choice of magnetic fluxes, and certain signs associated with the Killing spinor. Equivariant localization allows us to write down the gravitational free energy for such a solution, assuming it exists, and study its properties. These results open the way for a systematic study of holography in this setting, where the dual large N field theories are defined on the boundary three-manifolds, which are (squashed) lens spaces L(p,q) or generalizations with orbifold singularities.

Published by the American Physical Society
2025
Room-temperature quantum sensing with photoexcited triplet electrons in organic crystals
Authors: Singh Harpreet , D'Souza Noella , Zhong Keyuan , Druga Emanuel , Oshiro Julianne , Blankenship Brian , Montis Riccardo , Reimer Jeffrey A. , Breeze Jonathan D. , Ajoy Ashok
Published: February 2025

Quantum sensors have notably advanced high-sensitivity magnetic field detection. Here, we report quantum sensors constructed from polarized spin-triplet electrons in photoexcited organic chromophores, specifically focusing on pentacene-doped para-terphenyl (≈0.1%). We demonstrate essential quantum sensing properties at room temperature (RT): optically generated electronic polarization and state-dependent fluorescence contrast by leveraging differential pumping and relaxation rates between triplet and ground states. We measure high optically detected magnetic resonance contrast ≈16.8% of the triplet states at RT, along with long coherence times under spin echo and Carr-Purcell-Meiboom-Gill (CPMG) sequences, T2=2.7µs and T2DD=18.4µs, respectively, limited only by the triplet lifetimes. The material offers several advantages for quantum sensing, including the ability to grow large (cm scale) crystals at low cost, absence of paramagnetic impurities, and electronic diamagnetism when not optically illuminated. Utilizing pentacene as a representative of a broader class of spin triplet- polarizable organic molecules, this paper highlights the potential for quantum sensing in chemical systems.

Published by the American Physical Society
2025
Decoherence implies information gain
Authors: Brody Dorje C. , Hughston Lane P.
Published: February 2025

It is shown that if the wave function of a quantum system undergoes an arbitrary random transformation such that the diagonal elements of the density matrix in the decoherence basis associated with a preferred observable remain constant, then (i) the off-diagonal elements of the density matrix become smaller in magnitude, and (ii) the state of the system gains information about the preferred observable from its environment in the sense that the uncertainty of the observable is reduced in the transformed state. These results do not depend on the details of how the system-environment interaction generates the random state transformation, and together imply that decoherence leads, in general, to information gain, not information loss.

Published by the American Physical Society
2025
Prediction of container throughput at Thailand’s major ports with error correction and parameter selection techniques emphasizes optimal smoothing period
Authors: Sujjaviriyasup Thoranin
Published: February 2025

Purpose

A combined approach of additive Holt–Winters, support vector regression, simple moving average and generalized simulated annealing with error correction and optimal parameter selection techniques emphasizing optimal smoothing period in residual adjustment is developed and proposed to predict datasets of container throughput at major ports.

Design/methodology/approach

The additive Holt–Winters model describes level, trend and seasonal patterns to provide smoothing values and residuals. In addition, the fitted additive Holt–Winters predicts a future smoothing value. Afterwards, the residual series is improved by using a simple moving average with the optimal period to provide a more obvious and steady series of the residuals. Subsequently, support vector regression formulates a nonlinear complex function with more obvious and steady residuals based on optimal parameters to describe the remaining pattern and predict a future residual value. The generalized simulated annealing searches for the optimal parameters of the proposed model. Finally, the future smoothing value and the future residual value are aggregated to be the future value.

Findings

The proposed model is applied to forecast two datasets of major ports in Thailand. The empirical results revealed that the proposed model outperforms all other models based on three accuracy measures for the test datasets. In addition, the proposed model is still superior to all other models with three metrics for the overall datasets of test datasets and additional unseen datasets as well. Consequently, the proposed model can be a useful tool for supporting decision-making on port management at major ports in Thailand.

Originality/value

The proposed model emphasizes smoothing residuals adjustment with optimal moving period based on error correction and optimal parameter selection techniques that is developed and proposed to predict datasets of container throughput at major ports in Thailand.
Differentiated behavioural consequences of illegitimate tasks: The role of work motivation and stressor appraisals
Authors: Yang Pengcheng , Jing Linfang
Published: February 2025

Given the stressor essence of illegitimate tasks, we explored their potential bright side and the mechanisms of action that lead to differential behavioural consequences. Based on the Transactional Theory of Stress (TTS) and Self‐Determination Theory (SDT), we hypothesized that illegitimate tasks, as a common stressor in the workplace, could trigger differential appraisal results in employees, leading to distinct behavioural choices. Additionally, different work motivations moderated employees' appraisal results of illegitimate tasks. Through a two‐wave time‐lagged investigation with 317 Chinese employees, we found that when employees were assigned illegitimate tasks, they would either generate challenge appraisal, leading to a positive indirect effect on their voice behaviour, or hindrance appraisal, leading to a positive indirect effect on their silence behaviour. Furthermore, autonomous motivation moderated the relationship between illegitimate tasks and challenge appraisal, while controlled motivation demonstrated a substitution relationship with illegitimate tasks in influencing hindrance appraisal. Theoretical and practical implications are discussed.