bluuebunny/crossref_metadata_2025 huggingface dataset:
Joint modelling of astrophysical systematics for cosmology with LSST cosmic shear
Authors: Šarčević Nikolina , Leonard C Danielle , Rau Markus M ,   the LSST Dark Energy Science Collaboration
Published: January 2025

We present a novel framework for jointly modelling the weak lensing source galaxy redshift distribution and the intrinsic alignment (IA) of galaxies through a shared luminosity function (LF). In the context of a Rubin Observatory’s Legacy Survey of Space and Time (LSST) Year 1 and Year 10 cosmic shear analysis, we show that our novel approach produces cosmological parameter constraints which are comparable to standard methods, while offering more physical insight into IA and selection effects. We clarify the relationship between individual parameters of a Schechter LF and the redshift distribution of a magnitude-limited sample, showing the consequences of marginalizing over these parameters when modelling IAs in standard cosmic shear analyses. We explore the impact of the shape of the LF on the cosmic shear data vector, and we outline the potential of this method to naturally model selection functions in redshift distribution estimation. Although this work focuses on LSST cosmic shear, the proposed joint modelling framework is broadly applicable to weak lensing surveys.
Extreme metallicity dwarf galaxies in IllustrisTNG
Authors: Carleton Timothy , Monkiewicz Jacqueline
Published: January 2025

The use of extremely metal-deficient dwarf galaxies (XMDs) as nearby analogues for high-redshift protogalaxies is generating renewed interest due to recent JWST observations studying these protogalaxies. However, the existence of a population of unenriched galaxies at $z\sim 0$ raises fundamental questions about how galaxies with such pristine gas reservoirs could be formed. To address these questions, we study XMDs in the IllustrisTNG simulation. We find that XMDs at $z=0$ are not relics of the first galaxies, but dwarf galaxies that experience a dramatic $\sim 0.3$ dex drop in their gas-phase metallicity in the past few Gyr. We investigate possible causes of this drop in metallicity including high gas fractions, outflow efficiency or inflow/outflow rates, unique environments, pristine inflow metallicity, and inflow–SFR interactions. Of these, we find that inflow–outflow interactions, parametrized by the cumulative regional SFR experienced by inflows, has the strongest correlation with dwarf galaxy metallicity and XMD formation. In other words, inefficient gas enrichment during the short time between its accretion from the CGM and the initiation of star formation is the most important cause of XMD formation in the simulation. We identify differences in star formation history between XMDs and non-XMDs (with XMDs having significantly decreased star formation rates on $1\!-\!5$ Gyr time-scales) and differences in galaxy size (with XMDs having a more extended young stellar population) as the primary observable differences between the two populations. These results highlight the importance of inflow enrichment efficiency as a possible driver of dwarf galaxy metallicities.
Directional miscentring dependence in weak lensing mass bias
Authors: Sommer Martin W , Schrabback Tim , Grandis Sebastian
Published: January 2025

Galaxy cluster masses estimated from parametric modelling of weak lensing shear observations are known to be biased by inaccuracies in observationally determined centres. It has recently been shown that such systematic effects can be non-isotropic when centres are derived from X-ray or Compton-Y (Sunyaev–Zeldovich effect) observations, which is often the case in practice. This fact challenges current methods of accurately correcting for weak lensing mass biases using simulations paired with isotropic empirical miscentring distributions, in particular as the effect on determined masses is currently a dominant source of systematic uncertainty. We use hydrodynamical cosmological simulations taken from the Magneticum Pathfinder simulations to show that the non-isotropic component of the mass bias can be reduced to within one per cent of the mass when considering the centre of mass, rather than the bottom of the gravitational potential, as the reference centre of a galaxy cluster.
A long-term decline in downward surface solar radiation
Authors: Song Fengfei , Mao Yudi , Liu Shichu , Wu Lixin , Dong Lu , Su Hui , Wang Yawen , Chtirkova Boriana , Wu Peili , Wild Martin
Published: January 2025

Downward surface solar radiation (DSSR) is critical for the Earth system. It is well-known that DSSR over land has fluctuated on decadal timescales in the past. By utilizing a combination of station observations and the latest CMIP6 simulations, here we show that DSSR had a global consistent decline during 1959–2014, with comparable contributions from greenhouse gases (GHGs) and anthropogenic aerosols. The role of GHGs is even more important in the satellite period. The contribution from GHGs comes through rising temperature, which reduces the DSSR by increasing water vapor but is partly offset by reduced cloud. Future changes of DSSR are heavily dependent on climate change scenarios, which can be predicted well by global mean surface temperature (GMST) and aerosol concentrations. The sharp aerosol reduction and weak temperature rise in the SSP245/SSP126 scenarios will limit or stop the long-term decline of DSSR thus leading to a brighter future.
Foundation models in bioinformatics
Authors: Guo Fei , Guan Renchu , Li Yaohang , Liu Qi , Wang Xiaowo , Yang Can , Wang Jianxin
Published: January 2025

With the adoption of Foundation Models (FMs), Artificial Intelligence (AI) has become increasingly significant in bioinformatics and has successfully addressed many historical challenges, such as pre-training frameworks, model evaluation, and interpretability. FMs demonstrate notable proficiency in managing large-scale, unlabeled datasets, because experimental procedures are costly and labor-intensive. In various downstream tasks, FMs have consistently achieved noteworthy results, demonstrating high levels of accuracy in representing biological entities. A new era in computational biology has been ushered in by the application of FMs, focusing on both general and specific biological issues. In this review, we introduce recent advancements in bioinformatics FMs that employed in a variety of downstream tasks, including genomics, transcriptomics, proteomics, drug discovery, and single cell analysis. Our aim is to assist scientists in selecting appropriate FMs in bioinformatics, according to four model types: language FMs, vision FMs, graph FMs, and multimodal FMs. In addition to understanding molecular landscapes, AI technology can establish the theoretical and practical foundation for continued innovation in molecular biology.
Association between sleep duration and depression in adolescents and young adults: a system review of observational studies and a genetic research of Mendelian randomization analysis
Authors: Zheng Qiu-qiang , Yang Wei-Wei , He Shan-Shu , Li Yi-Ran
Published: January 2025

Objectives

This study aimed to explore the causal association between sleep duration and depression in adolescents and young adults.

Methods

We conducted a systematic review and Mendelian randomization (MR) to research the causal relationship between short sleep duration and adolescent depression risk from an observational and genetic perspective. In the systematic review, we searched observational studies from the PubMed, Embase, and Cochrane Library databases. In the MR analysis part, we screened Single Nucleotide Polymorphism (SNP) significantly relative to short sleep and conforming MR concept to investigate the genetic causality.

Results

All research evidence shows that adolescents who sleep <6 h have the highest rates of depression. According to the MR result, short sleep duration significantly affected the depression risk (odds ratio, 1.034; 95% confidence interval, 1.012–1.058, P = .003). Sleep duration of 7–8 h has the lowest depression incidence. Insufficient sleep (≤6 h) and excessive sleep (≥8 h) also elevates adolescent depression risk. Genetic evidence shows that short sleep duration (<6 h) has significant causal effects on depression risk.

Conclusions

Sleep duration was causally associated with depression in adolescents and young adults. Sleep duration of <6 h or >8 h daily increases the depression risk in adolescents and young adults.
Lattice Fermions with Solvable Wide Range Interactions
Authors: Sasaki Ryu
Published: January 2025

Exactly solvable (spinless) lattice fermions with wide range interactions are constructed explicitly based on exactly solvable stationary and reversible Markov chains  $\mathcal {K}^R$ reported a few years earlier by Odake and myself. The reversibility of $\mathcal {K}^R$ with the stationary distribution $\pi$ leads to a positive classical Hamiltonian $\mathcal {H}^R$. The exact solvability of $\mathcal {H}^R$ warrants that of a spinless lattice fermion $c_x$, $c_x^\dagger$, $\mathcal {H}^R_f=\sum _{x,y\in \mathcal {X}}c_x^\dagger \mathcal {H}^R(x,y) c_y$ based on the principle advocated recently by myself. The reversible Markov chains $\mathcal {K}^R$ are constructed by convolutions of the orthogonality measures of the discrete orthogonal polynomials of the Askey scheme. Several explicit examples of the fermion systems with wide range interactions are presented.
Racial prisms: experimental evidence on families’ race-based evaluations of school safety
Authors: Hailey Chantal A
Published: January 2025

Racial segregation is an enduring social reality in the United States. Since safety is central to residential and educational decisions, one explanation is, when choosing neighborhoods and schools, individuals use racial composition to signal safety. However, few studies have focused on race-based perceptions of school safety. To examine racialized school safety beliefs, I leverage an original survey experiment with 995 White, Asian, Latine, and Black eighth-grade parents and students. Respondents examined school profiles with randomly varied racial compositions, school and neighborhood safety ratings, metal detector presence, and graduation rates. Among Whites, Asians, and Latines, school racial composition shapes their beliefs about school safety, even when schools have identical safety ratings and security measures. White and Asian respondents believed that Black and Latine schools were less safe than White schools; Latine respondents believed that Black schools were less safe than all other schools; and school racial composition did not influence Black respondents’ beliefs about school safety. Non-Black respondents, with stronger anti-Black and anti-Latine personal racial biases and more knowledge of cultural stereotypes of Black violence, were more likely to express race-based beliefs about school safety. Non-Black respondents’ anti-Black perceptions of school safety contributed to their avoidance of Black schools. These findings suggest that anti-Blackness undergirds the public imagination of physical spaces and has implications for understanding contemporary segregation, discrimination, and racial inequality.
Conditional inequality and cooptive inclusion: property managers’ labor and the reproduction of inequalities in the market for rental housing
Authors: Korver-Glenn Elizabeth
Published: January 2025

Occupational inequality, including occupational segregation and associated inequities in working conditions, is a key linchpin of structural racial, gender, and class inequalities among American workers. Building on this scholarship, I center workers who are intermediaries and develop the concept of conditional inequality, which signifies the mediating process by which intermediaries’ experiences of and reactions to structural inequities in work conditions affect the experiences and outcomes of other individuals within their purview. Specifically, I examine how marginalized intermediaries within a segregated profession—residential property management—experience their work conditions, how they react to these conditions, and how their strategies to minimize the burdens of these conditions affect others with whom they interact. Using 80 in-depth interviews and extensive ethnographic data gathered among multifamily managers and leasing consultants (almost all women of color) and renters (predominantly people of color), I demonstrate how managers experience little autonomy and acute, renter-oriented burdens in their work conditions. Managers adopted three strategies to minimize the harms of these conditions and, in so doing, generated financial and health consequences among renters. Finally, I explain cooptive inclusion—the process of White, male-dominated industries relying on marginalized people to enact policies that harm other marginalized people—and its implications for the perpetuation of intersectional capitalism.
Vacuum erectile devices for erectile dysfunction: recommendations from the 5th international consultation on sexual medicine
Authors: Wang Run , Martins Francisco E , Ralph David , Hatzichristodoulou Georgios , Osmonov Daniar , Parker Justin , Park Sung Hun (Sean) , Moncada Ignacio , Bettocchi Carlo , Munarriz Ricardo , Köhler Tobias
Published: January 2025

Introduction

Vacuum erectile device (VED) is 1 of the main approved therapies for erectile dysfunction (ED). The introduction of phosphodiesterase type 5 inhibitor (PDE5i) for ED significantly changed the roles of VED in contemporary sexual medicine.

Objective

To provide updated clinical evidence to inform health care providers on best practices with VED.

Methods

A consensus panel was held with leading sexual medicine experts during the 5th International Consultation on Sexual Medicine (ICSM). Relevant peer-reviewed literature was reviewed with focus on research from the last 10 years, but not limited to the last 10 years. The expert panel generated consensus statements based on the quality of evidence and criteria of Grading of Recommendations Assessment, Development and Evaluation.

Results

As a primary or combination therapy for ED, VED has been shown to be successful in all populations studied, including difficult to treat cohorts, such as diabetes mellitus, spinal cord injury, and post-radical prostatectomy (RP), but long-term attrition rates are high. Available evidence has shown that VED can preserve or restore penile size for patients after RP, after incision and grafting surgery for Peyronie’s disease, before and after penile prosthesis, and after other post pelvic surgeries. However, it has not demonstrated a more rapid recovery of spontaneous erectile function after RP. VED does not increase penile length for subjective short penis. Studies with female specific VED for female sexual dysfunction are very limited.

Conclusions

Since the prior 4th ICSM, more evidence is available to support the new roles of VED in contemporary sexual medicine. Research into the penile pathophysiologic changes with VED therapy and clinical outcomes for various conditions are ongoing. We encourage sexual medicine clinicians to follow the 5th ICSM recommendations, but providers should also use their own judgement and adopt shared decision making with their patients/partners when considering VED for a specific disorder.
A phylogenetic approach to delimitate species in a probabilistic way
Authors: Hua Xia , Moritz Craig
Published: January 2025

Different species concepts and their associated criteria have been used to delimit species boundaries, such as the absence of gene flow for the biological species concept and the presence of morphological distinction for the morphological species concept. The need for different delimitation criteria largely reflects the fact that species are generated under various speciation mechanisms. A key question is how to make species delimitation consistent in a species group, especially when we want to delimit the species boundaries over many newly discovered evolutionary lineages and add these new lineages into a comparative analysis. Instead of forcing a single definition of ‘species’, we can acknowledge different delimitation criteria by modelling how fast lineages in a species group evolve to meet these criteria along a phylogenetic tree. This study presents such a new model and a new delimitation approach that calculates the probability of each possible species identity of a lineage. We use simulations to show that our likelihood function gives accurate estimates of parameters in the model and our approach have high power to correctly identify species identities. We apply the approach to lineages in two real species groups that already have genomic and morphological evidence for their species identities. Our approach gives consistent inference of species identities with these existing pieces of evidence. We also demonstrate how to use our model to test a popular hypothesis about speciation process across all lineages in a species group and discuss further extension of the model to study speciation.
Pass the Expanding Access To (EAT) Local Foods Act to promote farm viability and nutrition security
Authors: Figueroa Roger , Perry Elizabeth , Frederick Gwyneth , Alvarado Mildred , Adams Elizabeth , Bean Melanie K
Published: January 2025

The Society of Behavioral Medicine (SBM) supports passing the Expanding Access To Local Foods Act—a bill to promote economic opportunities for farmers and ranchers to strengthen local food supply chains, and to increase access to nutritious foods among households experiencing food insecurity and chronic disease risk.
lncRNA PART1 improves sevoflurane-induced impairments in learning and cognitive function by regulating miR-16-5p expression and reducing neuroinflammation
Authors: Lin Yu Chan , Yu Wan Ning , Yang Wei Wei , Wang Nan , Zhang Qian Yun , Guan Yu Fei , Wang Si Li , Ma Rui Chen
Published: January 2025

Sevoflurane is a commonly utilized inhalational anesthetic in surgical settings. Nevertheless, sevoflurane has been demonstrated to possess neurotoxic properties. The objective was to examine the neuroprotective function of long non-coding RNA prostate androgen-regulated transcript 1 (PART1) in sevoflurane-induced neurotoxicity and to elucidate its potential mechanism. The level of PART1 was quantified by RT-qPCR. The proliferation and apoptosis of HT22 cells were evaluated through CCK-8 assay and flow cytometry, respectively. To assess the protein level of IL-6, IL-1β, and TNF-α, ELISA was conducted. The levels of malondialdehyde, nitrite, and reduced glutathione along with the activity of superoxide dismutase were determined to evaluate oxidative stress. Verification of the targeting relationship between miR-16-5p and PART1 was performed using the dual-luciferase reporter assay. The Morris water maze test was used to assess the impact of PART1 on sevoflurane-induced learning and cognitive function in rats. PART1 levels were decreased in sevoflurane-treated HT22 cells and rats. PART1 suppressed sevoflurane-induced apoptosis and attenuated its inhibitory effect on cell proliferation. PART1 mitigated sevoflurane-induced inflammatory response and oxidative stress in HT22 cells through the regulation of miR-16-5p. PART1 suppressed oxidative damage and inflammatory response leading to improvement of learning and cognitive function in rats subjected to sevoflurane exposure. PART1 has the potential to regulate the sevoflurane-induced inflammatory response and oxidative stress via miR-16-5p, which in turn improves learning and cognitive function. Consequently, PART1 may be a promising therapeutic target for sevoflurane-induced neurotoxicity.
Clinical efficacy and safety evaluation of traditional Chinese medicine for nourishing yin and Replenishing qi in combination with PD-1/PD-L1 inhibitors in the treatment of NSCLC patients: a meta-analysis
Authors: Pan Lijun , Wang Xueyan , Long Fengxi , Tang Amei
Published: January 2025

To examine the therapeutic effectiveness and safety of traditional Chinese medicine in conjunction with PD-1/PD-L1 inhibitors for nourishing yin and replenishing qi in patients with non-small cell lung cancer. A systematic search was conducted across seven electronic databases, namely PubMed, Cochrane Library, Excerpt Medica Database, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and Wan-fang Database, to identify eligible studies from 2,000 to 2,023. This study includes a total of 14 randomized controlled clinical trials, with 514 patients in the TCM combo therapy group and 506 patients in the control group. The meta-analysis demonstrated the efficacy of combining TCM in oral and injectable forms with PD-1/PD-L1 inhibitors, with or without chemotherapy, in enhancing objective response rate, disease control rate, and quality of life in patients with NSCLC. Additionally, this combination therapy improved the proportion of CD3 + T cells and CD4 + T cells, as well as the ratio of CD4+/CD8 + T lymphocytes. The group receiving combined treatment with TCM successfully decreased the expression of the tumor marker CYFRA21-1. The group receiving combination therapy with TCM decreased the probability of experiencing adverse effects such as nausea, leukopenia, thrombocytopenia, and exhaustion in patients. Additionally, this treatment did not place additional strain on the liver and kidney functions. The integration of TCM techniques that nourishing yin and replenishing qi with PD-1/PD-L1 inhibitors greatly enhances the clinical effectiveness and safety of treating NSCLC. Additionally, the combination of Chinese and Western drugs improves the efficacy of neoadjuvant chemotherapy in NSCLC patients.
Suppression of METTL3 expression attenuated matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the extracellular matrix in pelvic organ prolapse
Authors: Wang Xiuqi , Guo Tao , Li Xiaogang , Tian Zhao , Fu Linru , Sun Zhijing
Published: January 2025

Background:

Fibrosis of the connective tissue in the vaginal wall predominates in pelvic organ prolapse (POP), which is characterized by excessive fibroblast-to-myofibroblast differentiation and abnormal deposition of the extracellular matrix (ECM). Our study aimed to investigate the effect of ECM stiffness on vaginal fibroblasts and to explore the role of methyltransferase 3 (METTL3) in the development of POP.

Methods:

Polyacrylamide hydrogels were applied to create an ECM microenvironment with variable stiffness to evaluate the effects of ECM stiffness on the proliferation, differentiation, and expression of ECM components in vaginal fibroblasts. METTL3 small interfering RNA and an overexpression vector were transfected into vaginal fibroblasts to evaluate the effects of METTL3 silencing and overexpression on matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the ECM. Both procedures were detected by 5-ethynyl-2′-deoxyuridine (EdU) staining, Western blotting (WB), quantitative real-time polymerase chain reaction (RT–qPCR), and immunofluorescence (IF).

Results:

Vaginal fibroblasts from POP patients exhibited increased proliferation ability, increased expression of α-smooth muscle actin (α-SMA), decreased expression of collagen I/III, and significantly decreased expression of tissue inhibitors of matrix metalloproteinases (TIMPs) in the stiff matrix (P <0.05). Compared with those from non-POP patients, vaginal wall tissues from POP patients demonstrated a significant increase in METTL3 content (P <0.05). However, silencing METTL3 expression in vaginal fibroblasts with high ECM stiffness resulted in decreased proliferation ability, decreased α-SMA expression, an increased ratio of collagen I/III, and increased TIMP1 and TIMP2 expression. Conversely, METTL3 overexpression significantly promoted the process of increased proliferation ability, increased α-SMA expression, decreased ratio of collagen I/III and decreased TIMP1 and TIMP2 expression in the soft matrix (P <0.05).

Conclusions:

Elevated ECM stiffness can promote excessive proliferation, differentiation, and abnormal ECM modulation, and the expression of METTL3 plays an important role in alleviating or aggravating matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal ECM modulation.
Steatosis in the Amygdala and Frontal Cortex: Potential Magnetic Resonance Imaging Biomarkers for Alzheimer’s Disease
Authors: de Oliveira Andrade Luís Jesuino , de Oliveira Gabriela Correia Matos , Nunes Carneiro Andrade João Cláudio , de Figueiredo Adriana Malta , Smith Gabriel , de Oliveira Luís Matos
Published: January 2025

Introduction

Alzheimer’s Disease (AD) is characterized by progressive neurodegeneration, with significant alterations in brain biochemistry. While previous studies have investigated various aspects of AD, the specific lipid changes in key brain regions remain inadequately defined.

Objective

To quantitatively evaluate lipid levels within the amygdala and frontal cortex regions of interest using Magnetic Resonance Spectroscopy (MRS) in a cohort of magnetic resonance imaging (MRI) scans of individuals with confirmed AD compared to healthy controls.

Methods

Thirty MRI examinations from individuals with confirmed AD were compared to 30 normal controls. MRS data were acquired using a 1.5T scanner, focusing on lipid peaks within specific frequency ranges. A voxel-based MRS technique was employed to assess lipid concentrations, focusing on spectral data in defined frequency ranges associated with lipid presence. Lipid concentrations were quantified, and statistical comparisons were performed between groups using the t-test.

Results

MRS analysis revealed distinct lipid peaks in both the amygdala and frontal cortex of AD patients, with frequencies indicating elevated lipid concentrations compared to controls. In the amygdala, increased lipid concentrations were observed in the 2.5-3.5 ppm range, suggesting alterations in lipid composition. The similar findings were observed in the frontal cortex, with AD patients showing significantly elevated lipid peaks within the 3.0-4.5 ppm range.

Conclusion

Our results underscore the potential of MRS to identify lipid alterations in AD, suggesting that lipid profiles in the amygdala and frontal cortex could serve as biomarkers for disease progression and provide understanding into neurodegenerative mechanisms.
Optimizing stimulation parameters for anterior thalamic nuclei deep brain stimulation in epilepsy: A randomized cross-over trial
Authors: Alcala-Zermeno Juan Luis , Osman Gamaleldin , Mandrekar Jayawant N. , Starnes Keith , Gregg Nicholas M. , Worrell Gregory , Lundstrom Brian N.
Published: January 2025

Objective

The effects of brain stimulation for diseases like epilepsy are delayed, making stimulation optimization difficult. The parameters for anterior thalamic nuclei (ANT) deep brain stimulation (DBS) for focal drug-resistant epilepsy (DRE) management are often restricted to those used in the SANTE landmark trial. There is little evidence regarding effective alternatives, and low frequency stimulation is typically neglected. We prospectively compare a widely differing stimulation parameter set to typical settings.

Methods

This randomized, modified cross-over, open trial compares the efficacy and safety of an alternative set of parameters using continuous low frequency stimulation with longer pulse-width (cLFS), (7 Hz, 200 msec, continuous) compared to SANTE’s intermittent high frequency stimulation with a short pulse width (iHFS), (145 Hz, 90 msec, cycling 1 min on/5 min off). After 3 months on a randomly assigned first set, patients are switched to the other settings, unless seizure free. Patients are re-evaluated after 3 more months at which point they can either remain on the same settings or switch back.

Results

Sixteen patients with a median baseline seizure frequency of 13.8 sz/month (IQR 2.7-22.8) were included in the analysis. At last-follow up, ANT-DBS significantly reduced median seizure frequency (45%, IQR 3 - 80%; p = .04). Both iHFS (33%, IQR 0 - 65; p = .02) and cLFS (72%, IQR 30 - 79; p = .001) significantly reduced median seizure frequency. cLFS showed improved median seizure frequency reduction compared to iHFS (p = .03) and was not associated with any moderate or severe adverse effects.

Significance

Results support cLFS for ANT-DBS as a safe and effective alternative to typical iHFS parameters. Broadly, stimulation with widely differing parameters sets may be as effective or even more effective than typical stimulation parameters.
Denoising Strategies of Functional Connectivity MRI Data in Lesional and Non-Lesional Brain Diseases
Authors: Wunderlich Stephan , Alici Cagatay , Motevalli Saeed , Stoecklein Veit , von Baumgarten Louisa , Schöberl Florian , Subklewe Marion , Schulz Enrico , Stoecklein Sophia
Published: January 2025

Purpose

Functional connectivity magnetic resonance imaging (fcMRI) is a widely utilized tool for analyzing functional connectivity (FC) in both healthy and diseased brains. However, patients with brain disorders are particularly susceptible to head movement during scanning, which can introduce substantial noise and compromise data quality. Therefore, identifying optimal denoising strategies is essential to ensure reliable and accurate downstream data analysis for both lesional and non-lesional brain conditions.

Approach

In this study, we analyzed data from four cohorts: healthy subjects, patients with brain lesions (glioma, meningioma) and patients with a non-lesional encephalopathic condition. Our goal was to evaluate various denoising strategies using standard quality control (QC) metrics to identify the most effective approach for minimizing noise while preserving the integrity of the blood oxygen level-dependent (BOLD) signal, tailored to each disease type.

Results

The effectiveness of denoising strategies varied based on the data quality and whether the data was derived from lesional or non-lesional diseases. At comparable levels of head motion, combinations involving independent component analysis-based automatic removal of motion artifacts (ICA-AROMA) denoising strategies were most effective for data from an encephalopathic non-lesional condition, while combinations including anatomical component correction (CC) provided the best results for data from lesional conditions.

Conclusion

Here, we present the first comparison of denoising pipelines for patients with lesional and non-lesional brain diseases. A key finding was that, at comparable levels of head motion, the optimal denoising strategy varies depending on the nature of the brain disease.
Plasma proteins are integral to gene-regulatory networks acting within and across blood cells, the arterial wall and major metabolic organs
Authors: Bankier Sean , Talukdar Husain , Khan Mariyam , Mocci Giuseppe , Sukhavasi Katyayani , Hao Ke , Ma Angela , Ruusalepp Arno , Schadt Eric E , Kovacic Jason C. , Michoel Tom , Björkegren Johan LM
Published: January 2025

The plasma proteome is the future for diagnostic markers for common diseases, like cardiometabolic disorders (CMDs) and coronary artery disease (CAD). The reliability of these markers requires identifying their source-organ(s). We profiled 974 plasma proteins in 532 CAD-patients of the STARNET study with arterial wall, major metabolic organ, and blood transcriptomic data. 144 plasma cis-pQTLs colocalized with tissue eQTLs including eight CMD/CAD GWAS genes. 262 plasma proteins correlated with their corresponding tissue “seed” genes whereof 101 in the liver. 851 plasma proteins were strongly associated with the activity of gene-regulatory networks (GRNs), particularly cross-tissue GRNs. The Adipose-Liver Plasma LeptIN-regulating GRN78 with the top key driverUCHL1in fat stood out. Beyond genetics, explaining up to 20% of plasma protein variation, and a limited number of mostly hepatic seed genes, plasma proteins are integral to GRNs acting within and across blood cells, the arterial wall and major metabolic organs.
Uncertainty and Inconsistency of COVID-19 Non-Pharmaceutical Intervention Effects with Multiple Competitive Statistical Models
Authors: Müller Bernhard , Padberg Inken , Lorke Michael , Brinks Ralph , Cripps Sally , Gomes M. Gabriela M. , Haake Daniel , Ioannidis John P. A.
Published: January 2025

Quantifying the effect of non-pharmaceutical interventions (NPIs) is essential for formulating lessons from the COVID-19 pandemic. To enable a more reliable and rigorous evaluation of NPIs based on time series data, we reanalyse the data for the original official evaluation of NPIs in Germany using an ensemble of 9 competitive statistical methods for estimating the effects of NPIs and other determinants of disease spread on the effective reproduction number ℛ(t) and the associated error bars. A proper error analysis for time series data leads to significantly wider confidence intervals than the official evaluation. In addition to vaccination and seasonality, only few NPIs – such as restrictions in public spaces – can be confidently associated with variations in ℛ(t), but even then effect sizes have large uncertainties. Furthermore, due to multicollinearity in NPI activation patterns, it is difficult to distinguish potential effects of NPIs in public spaces from other interventions that came into force early, such as physical distancing. In future, NPIs should be more carefully designed and accompanied by plans for data collections to allow for a timely evaluation of benefits and harms as a basis for an effective and proportionate response.
Machine learning prediction algorithms for 2- , 5- and 10-year risk of Alzheimer’s, Parkinson’s and dementia at age 65: a study using medical records from France and the UK General Practitioners
Authors: Nedelec Thomas , Zaidi Karim , Montaud Charlotte , Guinebretiere Octave , Sipilä Pyry , Wei Dang , Yang Fen , Freydenzon Anna , Belloir Antoine , Fournier Nemo , Hamieh Nadine , Lekens Beranger , Slaouti Yanis , McRae Allan , Couvy-Duchesne Baptiste , Hswen Yulin , Fang Fang , Kivimäki Mika , Ansart Manon , Durrleman Stanley
Published: January 2025

Structured abstract

Background

Leveraging machine learning on electronic health records offers a promising method for early identification of individuals at risk for dementia and neurodegenerative diseases. Current risk algorithms heavily rely on age, highlighting the need for alternative models with strong predictive power, especially at age 65, a crucial time for early screening and prevention.

Methods

This prospective study analyzed electronic health records (EHR) from 76,427 adults (age 65, 52.1% women) using the THIN database. A general risk algorithm for Alzheimer’s disease, Parkinson’s disease, and dementia was developed using machine learning to select predictors from diagnoses, and medications.

Results

Medications (e.g., laxatives, urological drugs, antidepressants), along with sex, BMI, and comorbidities, were key predictors. The algorithm achieved a 38.4% detection rate at a 5% false-positive rate for 2-year dementia prediction.

Conclusion

The validated prediction algorithms, easy to implement in primary care, identify high-risk 65-year-olds using medication records. Further refinement and broader validation are needed.
Quantification of HER2-low and ultra-low expression in breast cancer specimens by quantitative IHC and artificial intelligence
Authors: Aidt Frederik , Arbel Elad , Remer Itay , Ben-David Oded , Ben-Dor Amir , Rabkin Daniela , Hoff Kirsten , Salomon Karin , Aviel-Ronen Sarit , Nielsen Gitte , Mollerup Jens , Jacobsen Lars , Tsalenko Anya
Published: January 2025

Recent advancements in antibody drug conjugate therapies have significantly broadened treatment options for a substantial subgroup of breast cancer patients. However, sensitive, accurate and quantitative evaluation of HER2 expression based on current immunohistochemistry (IHC) assays remain challenging, especially in low and ultra-low HER2 expression ranges.

We developed a novel methodology for quantifying HER2 protein expression, targeting breast cancer cases in the HER2 IHC 0 and 1+ categories. We measured HER2 expression using quantitative IHC (qIHC) that enables precise and tunable HER2 detection across different expression levels as demonstrated in formalin-fixed paraffin-embedded cell lines. Additionally, we developed an AI-based interpretation of HercepTest™ mAb pharmDx (Dako Omnis) (HercepTest™ mAb) using qIHC measurements as the ground truth. Both methodologies allowed spatial resolution and visualization of low and ultra-low levels of HER2 expression across entire tissue sections to demonstrate and enable quantification of heterogeneity of HER2 expression.

Serial sections of 82 formalin-fixed paraffin-embedded tissue blocks of invasive breast carcinoma with HER2 IHC scores 0 or 1+ were stained with H&E, HercepTest™ (mAb), qIHC and p63, then scanned and digitally aligned. Tumor areas were manually selected and reviewed by expert pathologists. HER2 expression was quantitatively evaluated based on the qIHC assay in each 128×128µm2area within tumor regions. We observed statistically significant differences in HER2 expression between IHC 0, 0<IHC<1+, and IHC 1+ groups, and high level of spatial heterogeneity of the HER2 expression levels within the same tissue, up to five-fold in some cases. We demonstrated high slide-level tumor region agreement of estimates of HER2 expression between the AI-based interpretation of HercepTest™ mAb and the qIHC ground truth with a Pearson correlation of 0.94, and R2of 0.87.

The developed methodologies can be used to stratify HER2 low-expression patient groups, potentially improving the interpretation of IHC assays and maximizing therapeutic benefits. This method can be implemented in histology labs without requiring a specialized workflow.
Spontaneous spatial sorting by cell shape in growing colonies of rod-like bacteria
Authors: Ratman Mateusz , Gonzalez Nuñez Jimmy , Beller Daniel A.
Published: January 2025

Mechanical interactions among cells in a growing microbial colony can significantly influence the colony’s spatial genetic structure and, thus, evolutionary outcomes such as the fates of rare mutations. Here, we computationally investigate how this spatial genetic structure changes as a result of heritable phenotypic variations in cell shape. By modeling rod-like bacterial cells as lengthening and dividing circo-rectangles in a 2D Brownian dynamics framework, we simulate the growth of a colony containing two populations with different aspect ratios. Compared to monodisperse colonies, such bidisperse colonies exhibit diminished intermixing between sub-populations when the less elongated cells are too short to nematically order, instead forming large clusters. We find that the cells with longer aspect ratio gradually segregate to the colony periphery. We present evidence that this demixing is related to nematic order in the bulk and to active nematic mixing dynamics near the periphery. These findings are qualitatively robust across different growth rate protocols and initial conditions. Because the periphery is often an advantageous position when nutrients are limited, our results suggest a possible evolutionary selective pressure of mechanical origin that favors large cell aspect ratio.
Attenuated adenosine mediated immune-dampening increases natural killer cell activity in early age-related macular degeneration
Authors: Nair Archana Padmanabhan , Ghosh Sayan , Babu Vishnu Suresh , Praveen Machiraju , Xin Ying , Sahu Ganesh Ram , Vaidya Tanuja Arun , Debnath Jayasree , Raja Karthik , Krishna Gadde Santhosh Gopi , Thirumalesh M B , Shetty Naren , Saxena Aishwarya , Shetty Rohit , Hose Stacey , Deshpande Vrushali , Chakrabarty Koushik , Handa James T. , Jiang Qian J. , Sethu Swaminathan , Sinha Debasish , Ghosh Arkasubhra
Published: January 2025

Non-exudative age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) dysfunction and has been linked to altered intraocular immunity. Our investigation focuses on immune cell subsets and inflammation-associated factors in the eyes with early and intermediate AMD. We observed elevated levels of activated natural killer (NK) cells and interferon-γ, concurrent with reduced myeloid-derived suppressor cells (MDSCs) and adenosine in AMD eyes. Aqueous humor from AMD patients had diminished ability to dampen NK cell activation, an effect rescued by adenosine supplementation. TheCryba1cKO mouse model recapitulated these immune alterations, and single-cell RNA-sequencing identified NK cell-related genes and NK cell-RPE interactions. Co-culture of activated NK cells with RPE cells induced barrier dysfunction and Gasdermin-E driven pyroptosis providing a functional link relevant to AMD. These findings suggest a double-hit model where elevated immune activation and loss of immune dampening mechanisms drive AMD progression. Resetting the intraocular immune balance may be a promising therapeutic strategy for managing early and intermediate AMD.Graphical abstract

Illustra tion of pro posed mechanism underlying NK cell-RPE interaction in early AMD pathogenesis. Dysregulated NK cell communicate s with stressed RPE in early AMD immunopathology. Aberrant AMD aqueous humor and retina shows increased NK cells and NK effector molecules like IFNγ with reduced MDSC and adenosine in human subjects, don or eye and animal model. Activated NK cells interaction with RPE causes dysfunction and pyroptotic cell death via Gasdermin-E pathway in AMD.. Created withBioRender.com
Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium
Authors: Pellon-Cardenas O , Rout P , Hassan S , Fokas E , Ping He , Patel I , Patel J , Plotsker O , Wu A , Kumar R , Akther M , Logerfo A , Wu S , Wagner DE , Boffelli D , Walton KD , Manieri E , Tong K , Spence JR , Bessman NJ , Shivdasani RA , Verzi MP
Published: January 2025

Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis1and provide a niche that supports adjacent epithelial stem cells. Here we report thatPdgfra-expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoidsex vivo. Genetic reduction ofCdx2in the β-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissuein vivo. These results demonstrate that Pdgfra+fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.
Warming disrupts plant-fungal endophyte symbiosis more strongly in leaves than roots
Authors: Edwards Joseph D. , Kazenel Melanie R. , Luo Yiqi , Lynn Joshua S. , McCulley Rebecca L. , Souza Lara , Young Carolyn , Rudgers Jennifer A. , Kivlin Stephanie N.
Published: January 2025

Disruptions to species interactions from global change will negatively impact plant primary production, with broader consequences for species’ abundances, distribution, and community composition. Fungal endophytes that live inside plant leaves and roots could potentially mitigate plant heat stress from global warming. Conversely, disruptions of these symbioses could exacerbate the negative impacts of warming. To better understand the consistency and strength of warming-induced changes to fungal endophytes, we examined fungal leaf and root endophytes in three grassland warming experiments in the US ranging from 2 to 25 years and spanning 2000 km, 12 °C of mean annual temperature, and 600 mm of precipitation. We found that experimental warming disrupted symbiosis between plants and fungal endophytes. Colonization of plant tissues by septate fungi decreased in response to warming by 90% in plant leaves and 35% in roots. Warming also reduced fungal diversity and changed community composition in plant leaves but not roots. The strength, but not direction, of warming effects on fungal endophytes varied by up to 75% among warming experiments. Finally, warming decoupled fungal endophytes from host metabolism. Overall, warming-driven disruption of fungal endophyte community structure and function suggests that this symbiosis may not be a reliable mechanism to promote plant resilience and ameliorate stress responses under global change.
TRAIL-mediated PMN-MDSC depletion prevents CD4+T cell loss in HIV-infected humanized mice
Authors: Abeynaike Shawn , Frank Kayla , Gandarilla Angel , Paust Silke
Published: January 2025

Myeloid-derived suppressor cells (MDSCs) are critical regulators of HIV immunity, but the mechanisms behind their expansion and value as a therapeutic target remain unclear. We investigated MDSC function in HIV using a humanized mouse model. Acute HIV-1 infection triggered the systemic expansion of polymorphonuclear MDSCs (PMN-MDSCs), with their frequency correlating positively with plasma viral load. Notably, PMN-MDSC expansion increased further when natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) were depleted, suggesting these immune cells restrain MDSC proliferation. We identified Tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-induced apoptosis as a regulatory mechanism, as MDSCs expressed high levels of TRAIL receptor 2 (R2), while NK cells and CTLs upregulated TRAIL expression during HIV infection. Treating HIV-1-infected mice with a TRAIL-R2 agonist significantly reduced MDSC levels to those of uninfected mice and significantly improved NK cell and CTL immune function. Crucially, in viremic humanized mice, the treatment prevented CD4+ T cell loss, a hallmark of HIV-1 pathogenesis and acquired immune deficiency syndrome (AIDS) progression. These findings reveal the therapeutic potential of targeting MDSC apoptosis to mitigate CD4+ T cell depletion and enhance HIV-specific immunity, offering a new clinical target to prevent AIDS and insights into MDSC– NK/CTL cross-regulation during HIV-1 infection.
Deep learning-driven morphology analysis enables label-free classification of therapeutic agentnaive versus resistant cancer cells
Authors: Ramathal Cyril , Saini Kiran , Lian Zhouyang , Corona Christian , Pham Tiffine , Carelli Ryan , Boutet Stephane C. , Ray Manisha , Sethuraman Sunantha , Prindle Vivian , Lattmann Evelyn , Molvetti Maria-Grazia , Dzung Andreas , Levesque Mitchell P. , Barnes Matt , Jovic Andreja
Published: January 2025

Therapeutic drug treatments of solid tumors are often undermined by various resistance mechanisms. Identification of drug-resistance phenotypes at the single cell level is challenging because conventional molecular methods are cell-destructive, labor-intensive, and cost-prohibitive. To overcome these challenges, we developed an orthogonal approach to drug-resistance phenotyping, through the use of deep-learning-driven morphology analysis of single, high resolution cell images.

Specifically, we trained deep learning-based drug resistance classifiers using cell images from 5 different cell lines that were rendered resistant to 5 different therapeutic agents, using a foundation model framework. With high accuracy, the classifier correctly predicted naive or resistance phenotypes across all cancer types and across all the therapeutic agent types (chemotherapeutic, targeted) tested. These results showed that morphology can capture complex phenotype information in the context of drug treatment. To demonstrate the potential clinical utility of the drug resistance classifier, it was applied to a dissociated tumor biopsy and the resulting phenotype predictions were in close concordance with scRNASeq analysis of the biopsy.

Our study highlights the potential of deep-learning-driven morphology analysis to provide complex phenotype information, and ultimately shape oncology drug treatment strategies at the patient-level in a clinical context.