bluuebunny/crossref_metadata_2025 huggingface dataset:
EU Regulatory Responses to Crises
Authors: Fromage Diane , Héritier Adrienne , Weismann Paul
Published: January 2025

This final contribution provides a summary of the previous chapters on selected policy fields. It looks at their main findings in a horizontal perspective, and eventually draws conclusions on the developments addressed. The summaries relate to the seven areas covered by this book—economic and monetary policy, financial regulation and supervision, health policy, state aid control, energy policy, migration policy, and foreign and security policy—thereby concentrating on their respective essential outcomes. On this basis, a horizontal perspective will be taken, arranging the various developments with regard to different (assumed) features of rule-making in reaction to crises, such as the broad interpretation of competence clauses, the increased use of soft law, or the establishment or reinforcement of European agencies. Eventually, more general conclusions will be drawn on the crisis-induced development of EU rule-making in the EU.
Legislative choices
Authors: Steinbach Armin
Published: January 2025

EU law-makers choose between regulations and directives as main tools for rule-setting in the EU, which connects to the law and economics literature distinguishing between ‘standards’ and ‘rules’. A cost-benefit analysis determines the optimal degree of specificity of laws and the capability of rules and standards to deal with uncertainty. In turn, the EU principle of ‘mutual recognition’ reduces the cost of regulation across states, because states aim to deliver public policy functions of regulation at the minimum available cost. The underlying notion of rules competition is one that accepts certain legislative diversity and as such differs from harmonization as a legislative technique. ‘Mutual recognition’ reinforces this kind of interjurisdictional competition, while harmonization of rules undermines competition. By default, mutual recognition is preferred over harmonization because it allows for a wider range of public policies, hence allowing a better match with diverse preferences, and, from a dynamic efficiency perspective, it serves as a continuous learning process to make sure that laws adapt to changing external circumstances. The advantage of legal harmonization lies in the transaction costs savings.
The European Commission
Authors: Steinbach Armin
Published: January 2025

This chapter addresses the institutional structures and payoff logics that incentivize and constrain the conduct of the European Commission. Agency costs arise from the limited political control of the European Commission by the electorate when exercising its functions. The European public does not serve as an effective accountability mechanism vis-à-vis the Commission, nor can the European Parliament minimize agency costs. Also, Commissioners and Commission bureaucrats perform different functions. While the Commission’s civil service exhibits divergent attitudes towards integration, Commissioners are sent by their Member States’ governments questioning both their independence and Community interest alignment.
Adjudication
Authors: Steinbach Armin
Published: January 2025

This chapter discusses the various roles of adjudication in the EU. It highlights the role of the ECJ in facilitating the disclosure of information held privately by Member States and Union institutions, thereby acting as a repository of information. Adjudication helps to address the problems associated with the potential incompleteness of the European Treaties. Efficient breaches of EU Treaties may sometimes be desirable, requiring a balance between rigidity and flexibility through adjudication in order to arrive at efficient solutions. Finally, the chapter discusses leeway afforded to judicial authorities and the constraints placed upon them.
PCA-based spatial domain identification with state-of-the-art performance
Authors: Schaub Darius P , Yousefi Behnam , Kaiser Nico , Khatri Robin , Puelles Victor G , Krebs Christian F , Panzer Ulf , Bonn Stefan
Published: January 2025

Motivation

The identification of biologically meaningful domains is a central step in the analysis of spatial transcriptomic data.

Results

Following Occam’s razor, we show that a simple PCA-based algorithm for unsupervised spatial domain identification rivals the performance of ten competing state-of-the-art methods across six single-cell spatial transcriptomic datasets. Our reductionist approach, NichePCA, provides researchers with intuitive domain interpretation and excels in execution speed, robustness, and scalability.

Availability and implementation

The code is available at https://github.com/imsb-uke/nichepca.
Neuro-Behçet’s disease: an update of clinical diagnosis, biomarkers, and immunopathogenesis
Authors: Zhan Haoting , Cheng Linlin , Li Yongzhe
Published: January 2025

Neuro-Behçet’s disease (NBD) is a more severe but rare symptom of Behçet’s disease, which is mainly divided into parenchymal NBD (p-NBD) involving brain stem, spinal cord, and cerebral cortex. Non-p-NBD manifests as intracranial aneurysm, cerebral venous thrombosis, peripheral nervous system injuries, and mixed parenchymal and non-parenchymal disease. p-NBD is pathologically characterized by perivasculitis presenting with cerebrospinal fluid (CSF) pleocytosis, elevated total protein, and central nervous system (CNS) infiltration of macrophages and neutrophils, which are subdivided into acute and chronic progressive stages according to relapsing–remitting courses and responses to steroids. The diagnosis of NBD depends heavily on clinical features and magnetic resonance imaging (MRI) findings. The lack of laboratory biomarkers has hindered standard diagnostics. CSF interleukin (IL)-6 is the most investigated dimension of NBD and correlates with NBD activity, therapeutic responses, and prognosis. Further investigations have focused on inflammatory biomarkers that reflect the activation of innate and adaptive immune responses. Higher levels of CSF migration inhibitory factor and immunosuppressive acidic protein indicated the activation of macrophages in the CNS; increased IL-17, IL-10, T-bet/GATA-3, and retinoic acid related orphan receptor (ROR)-γt/Foxp3 ratios, marking the disrupted scale of the Th1/Th2 and Th17/Treg axis; and elevated B-cell activating factor of the TNF family (BAFF) and IgA/IgM intrathecal synthesis, suggesting that B cells play a dominant role in NBD. CNS destruction and degeneration as a consequence of neuroinflammatory cascades were confirmed by elevated CSF levels of NFL, β2MG, and MBP. Autoantibodies, including anti-STIP-1, anti-Mtch1, anti-B-Crystallin, and anti-m-Hsp65, provide substantial evidence for autoimmune essence and underlying microbiological infections in NBD immunopathogenesis. We summarized opinions on the clinical diagnosis, biomarkers, and pathological findings of NBD.
Thigh Injections of Cabotegravir + Rilpivirine in Virally Suppressed Adults With Human Immunodeficiency Virus Type 1: A Substudy of the Phase 3b ATLAS-2M Study
Authors: Ford Susan L , Felizarta Franco , Han Kelong , Wang Kehui , Crauwels Herta , Dari Anna , Masia Mar , Garcia Deltoro Miguel , Degen Olaf , Angel Jonathan B , Hsiao Chiu-Bin , Acuipil Carolina , Kolobova Irina , Harrington Conn , Rimler Kelly , Spreen William , D’Amico Ronald
Published: January 2025

Background

Cabotegravir + rilpivirine (CAB + RPV) administered via intramuscular gluteal injections is the first complete long-acting regimen for maintaining human immunodeficiency virus type 1 (HIV-1) virologic suppression. We present substudy results on short-term repeat intramuscular CAB + RPV long-acting thigh injections in participants with ≥3 years of experience with gluteal administration during the ATLAS–2M study.

Methods

Substudy phases included screening, thigh injection (day 1–week 16), and return to gluteal injection (week 16–week 24). The injection schedule was unchanged from the main study. Outcomes included pharmacokinetics, safety, tolerability, efficacy, and patient-reported outcomes. Pharmacokinetic parameters were determined using noncompartmental analysis and mixed-effects modeling. Population pharmacokinetic simulations were performed.

Results

There were 118 participants. In the arm that received injections every 2 months (Q2M), first CAB thigh injection including area under the concentration–time curve and maximum observed concentration (Cmax) and first RPV thigh injection Cmax and all last RPV thigh injection parameters were statistically higher vs gluteal injections (paired comparison). No significant differences occurred with once-monthly (QM) dosing. No participants had HIV-1 RNA ≥50 copies/mL after thigh injections. Overall, 4%–7% of injection site reactions (ISRs) were grade 3. Five participants withdrew due to an ISR or injection intolerability. Overall, 30% preferred thigh vs gluteal injections. Simulations demonstrated the potential for chronic/continuous QM or ≤2 consecutive Q2M thigh injections.

Conclusions

These data demonstrate the potential use of chronic/continuous QM and rotational/short-term QM or Q2M (≤4 months of continuous dosing), CAB + RPV long-acting intramuscular thigh administration for HIV-1 treatment.
Epicardial adipose tissue from computed tomography: a missing link in premature coronary artery disease?
Authors: Ritvo Paul-Gydeon , Charpentier Etienne , Zeitouni Michel , Rahoual Ghilas , Boussouar Samia , Croisille Cédric , Silvain Johanne , Kerneis Mathieu , Procopi Niki , Rouanet Stéphanie , Kachenoura Nadjia , Montalescot Gilles , Redheuil Alban
Published: January 2025

Aims

Epicardial adipose tissue (EAT) could contribute to the specific atherosclerosis profile observed in premature coronary artery disease (pCAD) characterized by accelerated plaque burden (calcified and non-calcified), high-risk plaque (HRP) features, and ischaemic recurrence. Our aims were to describe EAT volume and density in pCAD compared with asymptomatic individuals matched on cardiovascular risk factors and to study their relationship with coronary plaque severity extension and vulnerability.

Methods and results

Two hundred and eight patients who underwent coronary computed tomography angiography were analysed. It included 104 consecutive individuals with pCAD (acute or stable obstructive CAD before the age of 45 years) and 104 controls, matched 1:1 on age, sex, and cardiovascular risk factors. EAT volume, volume index (EATi), and density were measured with a semi-automated artificial-intelligence based segmentation method and CAD-RADS V2.0 determined according to guidelines. EAT volume and density were compared across groups, and associations with plaque burden and characteristics were investigated. EAT volume and EATi were significantly higher in patients with pCAD compared with matched controls (71.5 mL/m² [45.7;99.8] vs. 58.5 mL/m² [41.3;81.7] P = 0.002), and EAT density was significantly lower in patients with pCAD compared with matched controls (−82 HU [−87; −79] vs. −82 [−85; −78], P = 0.025). EATi was found to be positively correlated with increasing number of plaques, stenosis severity, and HRP features.

Conclusion

Patients with pCAD had EAT expansion with a higher lipid concentration, compared with controls matched for traditional risk factors. Increased EAT volume and low EAT density were imaging biomarkers related to severe and potentially vulnerable CAD features.
Surface soil per- and polyfluoroalkyl substance mixtures dominated by perfluorooctane sulfonate: prioritization for ecotoxicity testing and ecological risk assessment at current and former U.S. Air Force bases
Authors: East Andrew G , Anderson Richard H , Duncan Candice M , Salice Christopher J
Published: January 2025

Per- and polyfluoroalkyl substances (PFAS) detection at military installations where current and historical aqueous film-forming foam (AFFF) use has occurred drive a need for empirical derivation of environmentally relevant PFAS mixtures to facilitate toxicity testing and risk assessment efforts. We applied a formalized prioritization method to a large dataset of PFAS concentrations in surface soil at AFFF-affected sites on active and former U.S. Air Force installations. Our approach revealed several observations about PFAS at these sites. First, perfluorooctane sulfonate (PFOS) occurred most commonly and often at the highest concentration across the PFAS measured. Second, two to three PFAS contributed 86% to 91%, respectively, of the sum PFAS in any given site-specific mixture. Third, after PFOS, the most common and high concentration PFAS among target analytes were perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonamide (PFOSA), and/or perfluorohexanoic acid (PFHxA), in that order. Site-specific PFAS mixtures are approximately 5% to 12% PFHxS, PFOA, PFOSA, and PFHxA behind approximately 82% PFOS. Another observation relevant to future sampling is the high concentration but inconsistent prevalence of the 6:2 and 8:2 fluorotelomer sulfonates (FTSs). An uncertainty that could also be addressed through future sampling is the detection of less abundant or yet unmeasured PFAS that have unknown or poorly characterized toxicological potency. These results support the continued importance of efforts to understand effects and exposure of PFOS but highlight the need to consider other PFAS such as PFHxS and fluorotelomers in exposure and effect estimations to support ecological risk assessments and ecotoxicological testing of PFAS mixtures.
Microbial changing patterns across lateral and vertical horizons in recently formed permafrost after the outburst of Zonag Lake, Tibetan Plateau
Authors: Li Saifei , Liu Yang , Wang Wenqiang , Liu Yongqin , Ji Mukan
Published: January 2025

In polar and alpine regions, global warming and landform changes are draining lakes, transforming them into permafrost with altered microbial communities and element cycling. In this study, we investigated bacterial and archaeal (prokaryotic) community changes in the newly exposed sediment of Zonag Lake (Tibetan Plateau), focusing on prokaryotic diversity, community structure, and genes involved in carbon fixation and nitrogen cycling across lateral (up to 800 m) and vertical (up to 80 cm) horizons. The results showed that prokaryotic richness decreased across the lateral horizons, coinciding with reductions in carbon concentrations. Dramatic changes in community structure were also observed, primarily influenced by the distance from the lake and then by sediment depth, with environmental filtering and dispersal limitations shaping the lateral and vertical distributions, respectively. Based on PICRUSt2 results, the relative abundance of genes related to carbon fixation increased along the lateral horizon, suggesting that microbial carbon fixers are counteracting the carbon loss during permafrost formation. In contrast, the genes related to denitrification also increased, which may lead to nitrogen loss and contribute to global warming by releasing nitric oxide gas. This study highlights the resilience of prokaryotic communities in drained lake basins and their ecological implications under global warming.
Oral amoxicillin treatment disrupts the gut microbiome and metabolome without interfering with luminal redox potential in the intestine of Wistar Han rats
Authors: Bermúdez-Sánchez Sandra , Bahl Martin Iain , Hansen Egon Bech , Licht Tine Rask , Laursen Martin Frederik
Published: January 2025

Oral antibiotic treatment is well known to be one of the main factors affecting gut microbiota composition by altering bacterial diversity. It decreases the abundance of butyrate-producing bacteria such as Lachnospiraceae and Ruminococcaceae, while increasing abundance of Enterobacteriaceae. The recovery time of commensal bacteria post-antibiotic treatment varies among individuals, and often, complete recovery is not achieved. Recently, gut microbiota disruption has been associated with increased gut oxygen levels and higher redox potential in faecal samples. Given that redox balance is crucial for microbial metabolism and gut health, influencing fermentation processes and maintaining anaerobic conditions, we investigated the impact of oral amoxicillin treatment on the redox potential in the caecum. We used 24 Wistar Han male rats and measured caecal redox potential in situ with a probe, before and after 7 days of amoxicillin treatment, as well as after 7 days of recovery. Additionally, we analysed caecal weight, pH, antioxidant capacity, caecal microbiota, metabolome, and colonic tissue expression of relevant genes involved in the redox potential state. Our findings show that oral amoxicillin treatment significantly reduced archaeal load, and decreased the bacterial alpha diversity and affected bacterial composition of the caecal microbiome. The caecal metabolome was also significantly affected, exemplified by reduced amounts of short chain fatty acids during amoxicillin treatment. While the caecal metabolome fully recovered 7 days post amoxicillin treatment, the microbiome did not fully recover within this time frame. However, amoxicillin did not lead to an increase in luminal redox potential in the cecum during or post amoxicillin treatment. Limited differences were observed for colonic expression of genes involved in intestinal barrier function and generation of reactive oxygen species, except for the catalase gene, which was significantly upregulated post-amoxicillin treatment. Our results suggest that while oral amoxicillin disrupts the gut microbiome and metabolome, it does not directly interfere with gut luminal redox state.
Cardiac Biomarkers, Subclinical Brain Vascular Changes, and Cognitive Decline: Post Hoc Analysis of the SPRINT Trial
Authors: Zhang Wenxin , Ascher Simon B , Dolui Sudipto , Nasrallah Ilya M , Lu Yuan , Neitzel Julia , Toledo Estefania , Glodzik Lidia , Shaltout Hossam A , Hughes Timothy M , Berry Jarett D , Ma Yuan
Published: January 2025

Background

The association between subclinical cardiovascular disease (CVD) and cognitive decline in hypertensive adults and the underlying brain pathologies remain unclear. It is also undetermined whether intensifying blood pressure (BP) treatment slows down cognitive decline associated with subclinical CVD.

Methods

We conducted a post hoc analysis of the Systolic Blood Pressure Intervention Trial. Subclinical CVD at baseline was identified by elevated levels of high-sensitivity cardiac troponin T (hs-cTnT≥14 ng/L) and N-terminal pro-B-type natriuretic peptide (NT-proBNP≥125 pg/mL). Global cognitive function and domain-specific measures (memory, processing speed, language, and executive function) were assessed at baseline and follow-up (years 2, 4, and 6) in 2733 participants. White matter lesions, cerebral blood flow, and brain tissue volume were assessed by MRI at baseline and years 4 in a subset of 639 participants.

Results

Both elevated hs-cTnT and NT-proBNP levels at baseline were associated with accelerated cognitive decline across all domains after adjusting for potential confounding factors. The group with elevated levels of both cardiac biomarkers showed the fastest decline, with a larger annual decline rate of 0.033 (95% CI: 0.024-0.041) in the z-score of global cognitive function compared to the group with normal levels. Elevated levels of both biomarkers were also associated with a faster progression in white matter lesions, but not with changes in total brain tissue volume or cerebral blood flow. Intensive BP treatment did not attenuate these associations compared to standard treatment.

Conclusions

Subclinical CVD may contribute to faster white matter lesion progression and accelerated cognitive decline in patients with hypertension, regardless of intensive BP treatment.
Unveiling GRACE-based Estimation Techniques: Insights from Multichannel Singular Spectrum Analysis of Geocenter Motion
Authors: Yu Hongjuan , Zhang Yong , Sun Yu , Sośnica Krzysztof
Published: January 2025

This study aims to provide valuable scientific insights into various estimation techniques of Geocenter Motion (GCM) from the perspective of signal analysis, thereby enhancing GRACE users' understanding and application of GCM. Initially, it utilizes the Satellite Laser Ranging (SLR) technique with the network shift approach to estimate over 30 years of weekly GCM time series from 1994 to 2024. Subsequently, we employ two approaches to estimate three types of monthly GCM time series spanning more than 20 years from 2002 to 2023: combining GRACE data with an Ocean Bottom Pressure model (GRACE-OBP approach), the fingerprint approach (FPA), and the fingerprint approach with satellite altimetry data (FPA-SA, up to 2022). The former is referred to as SLR-based GCM estimates, while the latter, which uses GRACE Earth's gravity field models, is termed GRACE-based GCM estimates. Furthermore, this study pioneers the use of Multichannel Singular Spectrum Analysis (MSSA) for GCM analysis, especially focusing on the latest GRACE-based GCM estimates from the GRACE-OBP and FPA/FPA-SA approaches, marking the first comprehensive analysis of GCM estimated by various techniques. The results show that MSSA can effectively extract common signals from the three components of the GCM time series. The seasonal components extracted from GRACE-based GCM estimates using MSSA are consistent with those from SLR-based GCM estimates, although the former exhibit slightly larger amplitudes of the annual and semi-annual signals. After correcting the Atmosphere-Ocean Dealiasing, the amplitudes of the SLR-based estimates correspondingly decrease, remaining slightly larger but becoming closer to those of the GRACE-based estimates. However, a periodic signal with an approximate 160-day period is detectable in all GRACE-based GCM estimates, but it is absent in SLR-based GCM estimates. Further investigation using MSSA into higher degree spherical harmonic (SH) coefficients of the Earth's gravity field models reveals that these SH coefficients contain a 160-day periodic signal. This finding suggests that the signal detected in GRACE-based GCM estimates originates from systematic errors in these SH coefficients, offering new insights for improving the accuracy of GRACE Earth's gravity field solutions. Additionally, GRACE-based GCM estimates show significant secular non-zero trends, noticeably larger than those in SLR-based GCM estimates, which are not expected to exhibit any trends, especially in the Z component. However, the reliance of GRACE-based GCM estimates on geophysical models (e.g. glacier melting, Glacial Isostatic Adjustment, and hydrological models) limits the accuracy of their trends, underscoring the need for further validation. Overall, this study highlights new challenges regarding the accuracy of GRACE-based GCM estimates and emphasizes the necessity for further validation in mass change research.
Suicide literacy, suicide stigma, and help-seeking attitudes among men in a university setting in Ireland
Authors: O’Donnell Shane , Richardson Noel , McGrath Aisling
Published: January 2025

This study sought to explore the relationship between sociodemographic-, mental health-, knowledge-, attitudinal-, and conformity to masculine norms variables with suicide literacy, suicide stigma, and help-seeking attitudes among men in a university setting (n = 471) in Ireland. Multiple linear regression with backward elimination was used to determine the independent variables associated with suicide literacy, suicide stigma, and help-seeking attitudes. Lower suicide literacy was associated with an ethnic minority background, living in a rural community, postgraduate students compared to undergraduate students, no depression symptoms in the past year, decreasing loneliness, greater suicide stigma, more negative help-seeking attitudes, lower resilience, greater conformity to the masculine norm power over women and lower conformity to the masculine norm emotional control. Greater suicide stigma was associated with a non-ethnic minority background, all departments of study compared to health and sports science, lower suicide literacy, more negative help-seeking attitudes, and greater conformity to the masculine norms of power over women, dominance, and heterosexual self-presentation. More negative help-seeking attitudes were associated with no generalized anxiety disorder symptoms in the past year, depression symptoms in the past year, greater suicide risk, lower suicide literacy, greater suicide stigma, greater resilience, and greater conformity to the masculine norms emotional control, self-reliance, violence, and heterosexual self-presentation. Findings highlight a need for gender-responsive psychoeducational programmes to target suicide literacy, suicide stigma, and/or help-seeking attitudes among men in university settings. They also highlight that such initiatives need to be co-produced alongside ethnic minority and rural-dwelling men to ensure they are culturally sensitive and acceptable.
Predictive Markers of Incident Tuberculosis in Close Contacts in Brazil and India
Authors: Nogueira Betânia M F , Rangel Francys , Andrade Alice M S , Daniel Evangeline Ann , Figueiredo Marina C , Staats Cody , Rolla Valeria C , Kritski Afrânio L , Cordeiro-Santos Marcelo , Gupta Amita , Hanna Luke Elizabeth , Sterling Timothy R , Araújo-Pereira Mariana , Andrade Bruno B
Published: January 2025

There are insufficient predictors of progression to tuberculosis among contacts. A case-control study within RePORT-Brazil matched 20 QuantiFERON-positive progressors and 40 nonprogressors by sex, age, and exposure duration. Twentynine cytokines were measured using a Luminex assay with QuantiFERON-TB Gold Plus supernatants collected at baseline and evaluated using machine learning for tuberculosis prediction. The same markers were evaluated in 8 QuantiFERON-positive progressors and 12 nonprogressors from India. Interleukin 8, interleukin 10, and CCL3 levels predicted incident tuberculosis (area under the receiver operating characteristic curve, 0.75) in 2 years with sensitivity and specificity >80%, in both cohorts. This signature predicted tuberculosis progression in close contacts meeting World Health Organization goals.
Helminth Infection Induces Innate Immune Priming in Plasmacytoid Dendritic Cells
Authors: Cham Lamin B , Whitehead Bradley , Werner Marvin , Jensen Frederikke , Zippor Mads , Mogensen Trine H , Netea Mihai G , Williams Andrew R , Nejsum Peter
Published: January 2025

Heligmosomoides polygyrus coinfection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for 2 weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with Toll-like receptor agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected compared to naive control mice. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections.
Development and validation of computable social phenotypes for health-related social needs
Authors: Gregory Megan E , Kasthurirathne Suranga N , Magoc Tanja , McNamee Cassidy , Harle Christopher A , Vest Joshua R
Published: January 2025

Objective

Measurement of health-related social needs (HRSNs) is complex. We sought to develop and validate computable phenotypes (CPs) using structured electronic health record (EHR) data for food insecurity, housing instability, financial insecurity, transportation barriers, and a composite-type measure of these, using human-defined rule-based and machine learning (ML) classifier approaches.

Materials and Methods

We collected HRSN surveys as the reference standard and obtained EHR data from 1550 patients in 3 health systems from 2 states. We followed a Delphi-like approach to develop the human-defined rule-based CP. For the ML classifier approach, we trained supervised ML (XGBoost) models using 78 features. Using surveys as the reference standard, we calculated sensitivity, specificity, positive predictive values, and area under the curve (AUC). We compared AUCs using the Delong test and other performance measures using McNemar's test, and checked for differential performance.

Results

Most patients (63%) reported at least one HRSN on the reference standard survey. Human-defined rule-based CPs exhibited poor performance (AUCs=.52 to .68). ML classifier CPs performed significantly better, but still poor-to-fair (AUCs = .68 to .75). Significant differences for race/ethnicity were found for ML classifier CPs (higher AUCs for White non-Hispanic patients). Important features included number of encounters and Medicaid insurance.

Discussion

Using a supervised ML classifier approach, HRSN CPs approached thresholds of fair performance, but exhibited differential performance by race/ethnicity.

Conclusion

CPs may help to identify patients who may benefit from additional social needs screening. Future work should explore the use of area-level features via geospatial data and natural language processing to improve model performance.
SSB promotes DnaB helicase passage through DnaA complexes at the replication origin oriC for bidirectional replication
Authors: Akama Yusuke , Yoshida Ryusei , Ozaki Shogo , Kawakami Hironori , Katayama Tsutomu
Published: January 2025

For bidirectional replication in Escherichia coli, higher order complexes are formed at the replication origin oriC by the initiator protein DnaA, which locally unwinds the left edge of oriC to promote the loading of two molecules of DnaB helicases onto the unwound region via dynamic interactions with the helicase-loader DnaC and the oriC-bound DnaA complex. One of the two helicases must translocate rightwards through oriC-bound DnaA complex. Here, we used a synthetic forked oriC DNA, which mimics the unwound state of oriC, to examine DnaB translocation through the oriC-bound DnaA complex. We found that DnaB helicase alone cannot pass through the oriC-bound DnaA complex without the help of single-strand binding protein (SSB). In the presence of SSB, DnaB passed through this complex along with its helicase function, releasing DnaA molecules. In addition, DnaB helicase activity is known to be inhibited by oversupply of DnaC, but this inhibition was relieved by SSB. These results suggest a mechanism that when two DnaB helicases are loaded at oriC, one translocates leftwards to expand the DnaA-unwound region and allows SSB binding to the single-stranded DNA, and such SSB molecules then stimulate translocation of the other helicase rightwards through the oriC-bound DnaA complex.
Spatial histomorphometry reveals that local peripheral nerves modulate but are not required for skeletal adaptation to applied load in mice
Authors: Beeve Alec T , Hassan Mohamed G , Li Anna , Migotsky Nicole , Silva Matthew J , Scheller Erica L
Published: January 2025

Mechanical loading is required for bone health and results in skeletal adaptation to optimize strength. Local nerve axons, particularly within the periosteum, may respond to load-induced biomechanical and biochemical cues. However, their role in the bone anabolic response remains controversial. We hypothesized that spatial alignment of periosteal nerves with sites of load-induced bone formation would clarify this relationship. To achieve this, we developed RadialQuant, a custom tool for spatial histomorphometry. Tibiae of control and neurectomized (sciatic/femoral nerve cut) pan-neuronal Baf53b-tdTomato reporter mice were loaded for 5-days. Bone formation and periosteal nerve axon density were then quantified simultaneously in non-decalcified sections of the mid-diaphysis using RadialQuant. In control animals, anabolic loading induced maximal periosteal bone formation at the site of peak compression, as has been reported previously. By contrast, loading did not significantly change overall periosteal nerve density. Neurectomy depleted ~90% of all periosteal axons, with near-total depletion on load-responsive surfaces. Neurectomy alone also caused de novo bone formation on the lateral aspect of the mid-diaphysis. However, neurectomy did not inhibit load-induced increases in periosteal bone area, mineralizing surface, or bone formation rate. Rather, neurectomy spatially redistributed load-induced bone formation towards the lateral tibial surface with a reduction in periosteal bone formation at the posterolateral apex (-63%) and enhancement at the lateral surface (+1360%). Altogether, this contributed to comparable load-induced changes in cortical bone area fraction. Our results show that local skeletal innervation modulates but is not required for skeletal adaptation to applied load in our model. This supports the continued use of loading and weight-bearing exercise as an effective strategy to increase bone mass, even in patients with peripheral nerve damage or dysfunction.
Does Inequality Affect the Needs of the Poor?
Authors: Bellet Clément S , Colson-Sihra Eve
Published: January 2025

We investigate how inequality affects what is considered most necessary to purchase. Combining detailed consumption surveys in India with an instrumental variable approach, we first provide evidence that inequality is associated with a decrease in calorie consumption for poor households. This effect is driven by upward comparisons and associated with poor households spending more on luxuries, consistent with the relative deprivation theory. We then estimate a structural demand system to isolate the impact of inequality on needs from supply-side effects. We find that inequality increases the need of the poor for “little luxuries” (e.g., dairy products, energy use) at the expense of necessities (e.g., cereals). This shift in the hierarchy of needs accounts for more than two-thirds of the decline in the calorie consumption of the poor over the period.
Chronological changes in etiology, pathological and imaging findings in primary liver cancer from 2001 to 2020
Authors: Tsuzaki Junya , Ueno Akihisa , Masugi Yohei , Tamura Masashi , Yamazaki Seiichiro , Matsuda Kosuke , Kurebayashi Yutaka , Sakai Hiroto , Yokoyama Yoichi , Abe Yuta , Hayashi Koki , Hasegawa Yasushi , Yagi Hiroshi , Kitago Minoru , Jinzaki Masahiro , Sakamoto Michiie
Published: January 2025

Purpose

To achieve a historical perspective, the chronological changes in primary liver cancer over a 20-year period were investigated at a single institution, focusing on shifts in etiology and the impact on imaging and pathological findings using The Liver Imaging Reporting and Data System.

Materials and methods

A retrospective study of surgically resected primary liver cancer in 680 patients from 2001 to 2020 resulted in 434 patients with 482 nodules being analyzed. Dynamic contrast-enhanced computed tomography imaging and the Liver Imaging Reporting and Data System 2018 classification were employed. Two pathologists and two radiologists independently evaluated specimens and images.

Results

This study highlighted a significant decline in cases of viral hepatitis and cirrhosis in primary liver cancer patients but an increase in intrahepatic cholangiocarcinoma and scirrhous hepatocellular carcinoma. Notably, there was a rise in non-viral hepatitis cases, potentially pointing toward an increase in steatohepatitic hepatocellular carcinoma cases in the future. Intrahepatic cholangiocarcinoma, scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma tumors exhibited slightly different distributions in the Liver Imaging Reporting and Data System classification compared with ordinary hepatocellular carcinoma, which may reflect the presence of fibrosis and lipid in tumor parenchyma.

Conclusions

Consistent with past reports, this study demonstrated the emergence of primary liver cancer against a backdrop of non-viral and non-cirrhotic liver. Liver Imaging Reporting and Data System has been consistently useful in diagnosing primary liver cancer; however, among the histological subtypes of hepatocellular carcinoma, an increase is anticipated in scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma, which may present imaging findings different from those of ordinary hepatocellular carcinoma. This development may necessitate a reevaluation of the current approach for diagnosing and treating hepatocellular carcinoma based solely on imaging.
METTL3 modulates colonic epithelium integrity via maintaining the self-renewal and differentiation of Lgr5+ stem cell
Authors: Ding Chenbo , Yang Xinhui , Liu Hua , Roulis Manolis , Chen Huifang , Chen Yunzhu , Xu Hao , Gao Yimeng , Zhong Jie , Li Hua-Bing , Ye Youqiong , Cai Wei , Hu Weiguo , Wang Zhengting
Published: January 2025

The development and homeostasis of intestinal epithelium are mediated by actively proliferating Lgr5+ stem cells, which possess a remarkable self-renewal and differentiation capacity. Recently, our study demonstrated that m6A methylation was essential for the survival of colonic stem cells. Here, we show that METTL3 expression is downregulated in the colon mucosa in ulcerative colitis (UC) patients and strongly associated with the differentiation and maturation of goblet cells during inflammation. In mice, depletion of Mettl3 significantly inhibits the self-renewal and differentiation of Lgr5+ stem cells, especially the differentiation and maturation of goblet cells, resulting in intestinal dysplasia and spontaneous inflammation. Mechanistically, Mettl3 deletion-mediated m6A loss facilitates the expression levels of Grb10 and Ifrd1 via increasing their mRNA stability. We further demonstrate that the levels of GRB10 and IFRD1 are negatively correlated with METTL3 level in UC samples. Collectively, our data indicate that METTL3 enhances the self-renewal and differentiation of Lgr5+ stem cells during intestinal development and inflammation, and thus it may be a potential therapeutic target for UC treatment.
Durable solutions: to what and for whom?
Authors: Maple Nicholas , Hovil Lucy
Published: January 2025

The three durable solutions (resettlement, local integration, and repatriation) are out of reach to most refugees. Even when they are offered, they are often watered down or repackaged, so that their durability has been undermined. This paper examines their contemporary role and framing and proposes an urgent recalibration of our understanding of the solutions based around three interlinked elements. First, to recover the core function of all three durable solutions, namely the (re)gaining of citizenship; in order, second, to shift the conversation away from assumptions about the sedentary nature of durable solutions; which, third, draws out a greater understanding of the potential collaboration and connections between these traditional solutions and ground-level solutions that refugees create for themselves. We argue that not only are each of these elements important in and of themselves, but they also need to be viewed as indivisible.
Design and in vitr
o anticancer assessment of a click chemistry-derived dinuclear copper artificial metallo-nuclease
Authors: Poole Simon , Aning Obed Akwasi , McKee Vickie , Catley Thomas , Nielsen Aaraby Yoheswaran , Thisgaard Helge , Johansson Pegah , Menounou Georgia , Hennessy Joseph , Slator Creina , Gibney Alex , Pyne Alice , McGorman Bríonna , Westerlund Fredrik , Kellett Andrew
Published: January 2025

Copper compounds with artificial metallo-nuclease (AMN) activity are mechanistically unique compared to established metallodrugs. Here, we describe the development of a new dinuclear copper AMN, Cu2-BPL-C6 (BPL-C6 = bis-1,10-phenanthroline-carbon-6), prepared using click chemistry that demonstrates site-specific DNA recognition with low micromolar cleavage activity. The BPL-C6 ligand was designed to force two redox-active copper centres—central for enhancing AMN activity—to bind DNA, via two phenanthroline ligands separated by an aliphatic linker. DNA-binding experiments, involving circular dichroism spectroscopy, agarose gel electrophoresis and fluorescence quenching, revealed a preference for binding with adenine-thymine-rich DNA. The oxidative cleavage mechanism of Cu2-BPL-C6 was then elucidated using in vitro molecular and biophysical assays, including in-liquid atomic force microscopy analysis, revealing potent DNA cleavage mediated via superoxide and hydrogen peroxide oxidative pathways. Single-molecule analysis with peripheral blood mononuclear cells identified upregulated single-strand DNA lesions in Cu2-BPL-C6-treated cells. Using specific base excision repair (BER) enzymes, we showed that Endo IV selectively repairs these lesions indicating that the complex generates apurinic and apyrimidinic adducts. Broad spectrum anticancer evaluation of BPL-C6 was performed by the National Cancer Institute’s 60 human cell line screen (NCI-60) and revealed selectivity for certain melanoma, breast, colon and non-small cell lung cancer cell lines.
Unveiling the unusual i-motif-derived architecture of a DNA aptamer exhibiting high affinity for influenza A virus
Authors: Tsvetkov Vladimir , Mir Bartomeu , Alieva Rugiya , Arutyunyan Alexander , Oleynikov Ilya , Novikov Roman , Boravleva Elizaveta , Kamzeeva Polina , Zatsepin Timofei , Aralov Andrey , González Carlos , Zavyalova Elena
Published: January 2025

Non-canonical nucleic acid structures play significant roles in cellular processes through selective interactions with proteins. While both natural and artificial G-quadruplexes have been extensively studied, the functions of i-motifs remain less understood. This study investigates the artificial aptamer BV42, which binds strongly to influenza A virus hemagglutinin and unexpectedly retains its i-motif structure even at neutral pH. However, BV42 conformational heterogeneity hinders detailed structural analysis. Molecular dynamics simulations and chemical modifications of BV42 helped us to identify a potential binding site, allowing for aptamer redesign to eliminate the conformational diversity while retaining binding affinity. Nuclear magnetic resonance spectroscopy confirmed the i-motif/duplex junction with the three-cytosine loop nearby. This study highlights the unique structural features of the functional i-motif and its role in molecular recognition of the target.
High hydrostatic pressure promotes gene transcription via a cystathionine-β-synthase domain-containing protein in the hyperthermophilic archaeon Pyrococcus yayanosii
Authors: Li Cong , Li Siyuan , Song Qinghao , Da Lin-tai , Xu Jun
Published: January 2025

Cystathionine-β-synthase (CBS) domains are ubiquitously prevalent in all kingdoms of life. Remarkably, in archaea, proteins consisting of solely CBS domains are widespread. However, the biological functions of CBS proteins in archaea are still unknown. Here, we identified a high hydrostatic pressure regulator (HhpR) that comprises four CBS domains serving as a transcriptional activator via specifically binding to the UAS (upstream activating sequence) motif situated within the promoter region of an operon in a hyperthermophilic archaeon Pyrococcus yayanosii under high hydrostatic pressure (HHP). By combining molecular dynamics simulations, in vitro and in vivo assays, we revealed the potential binding interfaces between HhpR and its specific DNA binding site. Particularly, one stem–loop region in HhpR (termed as ‘Arm’) was found to play a critical role in regulating the transcription activity, and the 192 position in the Arm region is an essential site in dictating the conformational changes of HhpR at HHP condition. Our work provides novel insights into the structure–function relationship of CBS-containing proteins that participate in archaeal gene regulation as general transcriptional activators.
Quadruplet codon decoding-based versatile genetic biocontainment system
Authors: Choi Yun-Nam , Kim Donghyeon , Lee Seongbeom , Shin Ye Rim , Lee Jeong Wook
Published: January 2025

Biological resources, such as sequence information, genetic traits, materials and strains, pose risks when inadvertently released or deliberately misused. To address these concerns, we developed Quadruplet COdon DEcoding (QCODE), a versatile genetic biocontainment strategy that introduces a quadruplet codon (Q-codon) causing frameshifts, hindering proper gene expression. Strategically incorporating Q-codons in multiple genes prevents genetic trait escape, unallowed proliferation of microbial strains and unauthorized leakages of genetic materials. This multifaceted strategy, integrating Q-codons for genetic traits, materials and strains, ensures robust biocontainment across various levels. Notably, our system maintains sequence protection, safeguarding genetic sequence information against unauthorized access. The QCODE approach offers a versatile, efficient and compact solution to enhance biosecurity in diverse biological research settings.
tRNA thiolation optimizes appressorium-mediated infection by enhancing codon-specific translation in Magnaporthe oryzae
Authors: Zhang Xinrong , He Rongrong , Li Yinan , Ren Shuchao , Xiang Shikun , Zheng Jing , Qu Zhiguang , Zhou Shu , Zhou Zhipeng , Chen Xiao-Lin
Published: January 2025

Thiolation, a post-transcriptional modification catalyzed by Uba4-Urm1-Ncs2/Ncs6 pathway in three specific transfer RNAs (tRNAs), is conserved from yeast to humans and plays an important role in enhancing codon–anticodon interaction and translation efficiency. Yet, except for affecting effector secretion, its roles in plant pathogenic fungi are not fully understood. Here, we used Magnaporthe oryzae as a model system to illustrate the vital role of s2U34 modification on the appressorium-mediated virulence. The absence of tRNA thiolation leads to diminished translation elongation at AAA/CAA/GAA but not their synonymous codons, resulting in reduced levels of key proteins enriched in these codons, which are critical for appressorium development and function. Importantly, overexpressing these proteins can partially mitigate the defects resulting from NCS2 deletion. Our study sheds light on the s2U34 modification’s role in plant pathogenic fungi, enhancing our understanding of translational control beyond effector secretion.