bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians
Authors: Timmer Antje , Neuser Johanna , de Sordi Dominik , Schmidt-Lauber Martin , Allgayer Hubert , Reichel Christoph , Klebl Frank , Obermeier Florian , Schnoy Elisabeth , Jessen Petra , Morgenstern Julia , Helwig Ulf , Maaser Christian , Leifeld Ludger , Schmidt Sebastian , Meinhardt Christian , Böcker Ulrich , Arlt Alexander , Bästlein Elke , Bokemeyer Arne , Preiß Jan C , Otto-Sobotka Fabian , Kaltz Birgit , Sander Cornelia , Kruis Wolfgang 
Published: June 2024

Abstract

Background
The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA).

Methods
In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold &gt;22 points.

Results
The primary analysis included 89 pairs (46 Crohn’s disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC.

Conclusions
The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.
Paternal Inflammatory Bowel Disease and the Risk of Pregnancy Loss
Authors: Friedman Sonia , Thorarinsson Caroline Thingholm , Wod Mette , Fedder Jens , Nørgård Bente Mertz 
Published: June 2024

Abstract

Background
Only about 30% of conceptions end in live births, yet there are little data on paternal causes of pregnancy loss. Men with inflammatory bowel disease may have multiple disease-related issues that may affect fertility. We aimed to examine pregnancy outcomes in women undergoing assisted reproduction whose male partners had Crohn’s disease or ulcerative colitis.

Methods
This nationwide study included all embryo transfers registered in the Danish Assisted Reproduction Registry from January 2, 2006, to September 3, 2019. The exposed cohort included embryo transfers from couples in which the male partners had Crohn’s disease or ulcerative colitis. The unexposed cohort included embryo transfers in which male partners did not have inflammatory bowel disease.

Results
For fathers with ulcerative colitis, the adjusted odds ratio for a positive biochemical pregnancy (positive human chorionic gonadotropin) was 1.14 (95% confidence interval [CI], 0.92-1.42), for a clinical pregnancy (positive vaginal ultrasonography at 7-8 weeks) was 0.91 (95% CI, 0.59-1.40), and for a live birth was 0.99 (95% CI, 0.71-1.60). For fathers with Crohn’s disease, the adjusted odds ratio for a biochemical pregnancy was 0.83 (95% CI, 0.63-1.09), for a clinical pregnancy was 0.58 (95% CI, 0.34-0.97), and for a live birth was 0.88 (95% CI, 0.51-1.55).

Conclusions
These findings may indicate that partners of men with Crohn’s disease may have an increased risk of early pregnancy loss. Future studies should confirm these results and examine the impact of paternal medications, paternal disease activity, and other factors associated with chronic inflammatory bowel disease.
Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis
Authors: Naito Takeo , Osaka Ryuya , Kakuta Yoichi , Kawai Yosuke , Khor Seik-Soon , Umeno Junji , Tokunaga Katsushi ,   NCBN Controls WGS Consortium, Ishibashi-Ueda Hantsue , Tomita Tsutomu , Noguchi Michio , Takahashi Ayako , Goto Yu-ichi , Yoshida Sumiko , Hattori Kotaro , Matsumura Ryo , Iida Aritoshi , Maruoka Yutaka , Gatanaga Hiroyuki , Sugiyama Masaya , Suzuki Satoshi , Miyo Kengo , Matsubara Yoichi , Umezawa Akihiro , Hata Kenichiro , Kaname Tadashi , Ozaki Kouichi , Tokuda Haruhiko , Watanabe Hiroshi , Niida Shumpei , Noiri Eisei , Kitajima Koji , Omae Yosuke , Miyahara Reiko , Shimanuki Hideyuki , Kawai Yosuke , Tokunaga Katsushi , Nagai Hiroshi , Shimoyama Yusuke , Moroi Rintaro , Shiga Hisashi , Nagasaki Masao , Kinouchi Yoshitaka , Masamune Atsushi 
Published: June 2024

Abstract

Background
It is crucial to pinpoint the metabolites that cause Crohn’s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC.

Methods
As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance–weighted method, while stability of the findings was evaluated through sensitivity analyses.

Results
After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10−3; and OR, 0.64; P = 1.90 × 10−2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10−4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10−2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10−2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10−2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites.

Conclusions
In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.
Anisotropies in the spatial distribution and kinematics of dwarf galaxies in the Local Group and beyond
Authors: Santos-Santos Isabel M E , Navarro Julio F , McConnachie Alan 
Published: June 2024

ABSTRACT
The mass distribution in the Local Group (LG), dominated by the Andromeda (M31) and Milky Way (MW) pair, is highly anisotropic. We use the APOSTLE simulations to examine how this anisotropy manifests on the spatial distribution and kinematics of dwarf galaxies out to a distance of $d_{\rm MW}\sim 3$ Mpc from the MW. The simulations indicate a preference for dwarfs to be located near the axis defined by the MW-M31 direction, even for dwarfs in the LG periphery (LGP; i.e. at distances $1.25\ \lt\ d_{\rm MW}/$Mpc $\lt\ 3$). The ‘Hubble flow’ in the periphery is also affected; at fixed $d_{\rm MW}$ the mean recession speed, $\langle V_{\rm rad} \rangle$, varies with angular distance to M31, peaking in the anti-M31 direction and reaching a minimum behind M31. The M31-MW mass decelerates the local expansion; the LG ‘turnaround radius’ (i.e. where $\langle V_{\rm rad} \rangle =0$) in APOSTLE is at $r \sim 1.25$ Mpc from the LG barycentre and the pure Hubble flow (where $\langle V_{\rm rad} \rangle \sim H_0*d$) is reached beyond $r\sim 3$ Mpc. The predicted flow is very cold, with a barycentric dispersion of $\lt 40$ km s−1. Comparing these predictions with observations yields mixed results. There is little evidence for a preferred alignment of dwarfs along the MW-M31 direction, but some evidence for an angular anisotropy in $\langle V_{\rm rad} \rangle$. Although the ‘coldness’ of the Hubble flow is consistent with the simulations, it is less decelerated: relative to the MW all galaxies beyond $d_{\rm MW} \sim 1.25$ Mpc seem to be already on a pure Hubble flow. We argue that these oddities may result at least partly from incompleteness and inhomogeneous sky coverage in our current inventory of nearby dwarfs.
Molecular profile of driver genes in lung adenocarcinomas of Brazilian patients who have never smoked: implications for targeted therapies
Authors: Cavagna Rodrigo de Oliveira , Escremim de Paula Flávia , Berardinelli Gustavo Noriz , Bonatelli Murilo , Santana Iara , Albino da Silva Eduardo Caetano , Teixeira Gustavo Ramos , Zaniolo Beatriz Garbe , Mourão Dias Josiane , Ferreira da Silva Flávio Augusto , Baston Silva Carlos Eduardo , Guimarães Marcela Gondim Borges , Barone Camila Pinto , Jacinto Alexandre Arthur , Noleto da Nóbrega Oliveira Rachid Eduardo , Miziara José Elias , De Marchi Pedro , Molina-Vila Miguel A , Leal Letícia Ferro , Reis Rui Manuel 
Published: June 2024

Abstract

Introduction
Lung cancer in never-smoker (LCINS) patients accounts for 20% of lung cancer cases, and its biology remains poorly understood, particularly in genetically admixed populations. We elucidated the molecular profile of driver genes in Brazilian LCINS.

Methods
The mutational and gene fusion status of 119 lung adenocarcinomas from self-reported never-smoker patients, was assessed using targeted sequencing (NGS), nCounter, and immunohistochemistry. A panel of 46 ancestry-informative markers determined patients’ genetic ancestry.

Results
The most frequently mutated gene was EGFR (49.6%), followed by TP53 (39.5%), ALK (12.6%), ERBB2 (7.6%), KRAS (5.9%), PIK3CA (1.7%), and less than 1% alterations in RET, NTRK1, MET∆ex14, PDGFRA, and BRAF. Except for TP53 and PIK3CA, all other alterations were mutually exclusive. Genetic ancestry analysis revealed a predominance of European (71.1%), and a higher African ancestry was associated with TP53 mutations.

Conclusion
Brazilian LCINS exhibited a similar molecular profile to other populations, except the increased ALK and TP53 alterations. Importantly, 73% of these patients have actionable alterations that are suitable for targeted treatments.
Effects of reservoir mechanical properties on induced seismicity during subsurface hydrogen storage
Authors: Burtonshaw J. E. J. , Paluszny A. , Mohammadpour A. , Zimmerman R. W. 
Published: June 2024

The intermittent storage of hydrogen in subsurface porous media such as depleted gas fields could be pivotal to a successful energy transition. Numerical simulations investigate the intermittent storage of hydrogen in a porous, depleted subsurface reservoir. Various parametric studies are performed to assess the effect of mechanical properties of the reservoir (i.e. Young’s modulus, Poisson’s ratio, Biot coefficient and permeability) on the induced fault slip of a single through-going fault that transverses the entire reservoir. Simulations are run using a three-dimensional, finite element, fully coupled hydromechanical code with explicit representations of layers and faults. The effect of the domain mesh refinement and fault mesh refinement on the fault slip versus operation time solution is investigated. The fault is observed to slip in two distinct events, one during the second injection period and one in the third injection period. The fault is not observed to slip during the storage or withdrawal periods. It is found that in order to minimize seismic risk, a reservoir rock with high Young’s modulus (>40 GPa), high Poisson’s ratio (>0.30) and high Biot coefficient (>0.65) would be preferable for hydrogen storage. Reservoir rocks of low Young’s modulus (10–30 GPa), intermediate Poisson’s ratio (0.00–0.30) and low-to-intermediate Biot coefficient (0.25–0.65), at high injection rates, were found to have higher potential of inducing large seismic events.
This article is part of the theme issue ‘Induced seismicity in coupled subsurface systems’.
Modelling of mixed-mechanism stimulation for the enhancement of geothermal reservoirs
Authors: Dang-Trung Hau , Keilegavlen Eirik , Berre Inga 
Published: June 2024

Hydraulic stimulation is a critical process for increasing the permeability of fractured geothermal reservoirs. This technique relies on coupled hydromechanical processes induced through pressurized fluid injection into the rock formation. The injection of fluids causes poromechanical stress changes that can lead to fracture slip and shear dilation, as well as tensile fracture opening and propagation, so-called mixed-mechanism stimulation. The effective permeability of the rock is particularly enhanced when new fractures connect with pre-existing fractures. While hydraulic stimulation can significantly improve the productivity of fractured geothermal reservoirs, the process is also related to induced seismicity. Hence, understanding the coupled physics is central, for both reservoir engineering and seismic risk mitigation. This article presents a modelling approach for simulating the deformation, propagation and coalescence of fractures in porous media under the influence of anisotropic stress and fluid injection. It uses a coupled hydromechanical model for poroelastic, fractured media. Fractures are governed by contact mechanics and a fracture propagation model. For numerical solutions, we employ a two-level approach, combining a finite volume method for poroelasticity with a finite element method for fracture propagation. The study investigates the impact of injection rate, matrix permeability and stress anisotropy on stimulation outcomes.
This article is part of the theme issue ‘Induced seismicity in coupled subsurface systems’.
Exploring the role of EMT in Ovarian Cancer Progression: Insights from a multiscale mathematical model
Authors: Oliver Samuel , Williams Michael , Jolly Mohit Kumar , Gonzalez Deyarina , Powathil Gibin 
Published: June 2024

AbstractEpithelial-to-mesenchymal transition (EMT) plays a key role in the progression of cancer tumours and can make treatment significantly less successful for patients. EMT occurs when a cell gains a different phenotype and possesses different behaviours to those previously exhibited. This may result in enhanced drug resistance, higher cell plasticity, and increased metastatic abilities. It has therefore has become essential to encapsulate this change and study tumour progression and its response to treatments. Here, we use a 3D agent-based multiscale modelling framework based on Physicell to investigate the role of EMT over time in two cell lines, OVCAR-3 and SKOV-3. The impact of conditions in the microenvironment are incorporated into the model by modifying cellular behaviours dependant on variables such as substrate concentrations and proximity to neighbouring cells. OVCAR-3 and SKOV-3 cell lines possess highly contrasting tumour layouts, allowing a vast array of different tumour dynamics and morphologies to be tested and studied. The model encapsulates the biological observations and trends seen in tumour growth and development, thus can help to obtain further insights into OVCAR-3 and SKOV-3 cell line dynamics. Sensitivity analysis was performed to investigate the impact of parameter sensitivity on model outcome. Sensitivity analysis showed that parameters used in generating the rate of EMT and cycle rates within the cells are relatively more sensitive than other parameters used.
Predictions of bimanual self-touch determine the temporal tuning of somatosensory perception
Authors: Cemeljic Noa , Job Xavier , Kilteni Konstantina 
Published: June 2024

AbstractWe effortlessly distinguish between touching ourselves with our hands and being touched by other people or objects. Motor control theories posit that this distinction is made possible by the brain predicting the somatosensory consequences of our voluntary movements based on an ‘efference copy’, and attenuating our responses to the predicted self-touch. However, it remains unclear how these predictions impact somatosensory perception at times other than during self- touch: for example, as our hand reaches to touch our body or moves away from it. Here participants discriminated forces applied on their left index finger by a motor. The forces were applied during the reaching movement of their right hand towards the left hand, including the time the reaching ended by simulating self-touch between the hands, or after the reaching movement. We observed that the forces on the left hand felt progressively weaker during the reaching phase, reached their minimum perceived intensity at the time of self-touch, and quickly recovered after the end of the reaching. All effects were replicated with a new cohort of participants that further demonstrated that this gradual attenuation of the perceived magnitude of touch vanished during similar right hand reaching movements that did not produce expectations for self-touch between the two hands. Together, our results indicate a temporal tuning of somatosensory perception during movements to self-touch and underscore the role of sensorimotor context in forming predictions that attenuate the intensity of self- generated touch.
KATMAP: Inferring splicing factor activity and regulatory targets from knockdown data
Authors: McGurk Michael P. , McWatters David C. , Burge Christopher B. 
Published: June 2024

AbstractTypical RNAseq experiments uncover hundreds of splicing changes, reflecting underlying changes in splicing factor (SF) activity. Understanding transcriptomic variation in terms of SF activity requires elucidating the rules by which each SF impacts splicing. Here we present an interpretable regression model, KATMAP, which models splicing changes transcriptome-wide in terms of changes in SF binding and resulting altered regulation. The regulatory principles KATMAP learns generalize to predict the SF’s regulation at individual exons, with potential for design of splice-switching antisense oligonucleotides and inference of the displaced factor. We also discover cooperative splicing regulation by QKI and RFBOX proteins. KATMAP interprets RNAseq data by uncovering the factors responsible for transcriptomic changes, distinguishing direct SF targets from indirect effect, and infers relevant SFs from clinical RNAseq data.
AggressiveKRASmutations direct TGF-β response towards partial EMT in patient-derived colorectal cancer tumoroids
Authors: Mair Theresia , König Philip , Mijović Milena , Tran Loan , Saldaña Pedro Morata , Malla Carlos Uziel Pérez , Draganić Kristina , Pfneissl Janette , Tiefenbacher Andreas , Kabiljo Julijan , Atanasova Velina S. , Kalla Jessica , Wozelka-Oltjan Lisa , Müllauer Leonhard , Bergmann Michael , Sheibani-Tezerji Raheleh , Egger Gerda 
Published: June 2024

AbstractTransforming growth factor beta (TGF-β) exhibits complex and context-dependent cellular responses. While it mostly induces tumor-suppressive effects in early stages of tumorigenesis, its tumor promoting properties are evident in advanced disease. This TGF-β duality is still not fully understood, and whether TGF-β supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient-derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell-specific responses to TGF-β. Using medium conditions allowing for the differentiation of PDTs, we observed TGF-β induced tumor-suppressive effects in early-stage tumoroids. PDTs with TGF-β pathway mutations or PDTs derived from metastatic tumors were insensitive to the treatment. Notably, one tumoroid line harboring an atypicalKRASQ22Kmutation underwent partial epithelial-to-mesenchymal transition (EMT), associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell intrinsic responses to TGF-β are critical in determining its tumor-suppressive or -promoting effects.
Single-cell transcriptome and T cell receptor profiling of the tuberculin skin test
Authors: Turner Carolin T. , Rosenheim Joshua , Thakker Clare , Chandran Aneesh , Wilson Holly , Venturini Cristina , Pollara Gabriele , Chain Benjamin M. , Tomlinson Gillian S. , Noursadeghi Mahdad 
Published: June 2024

AbstractThe tuberculin skin test (TST) is a cutaneous delayed hypersensitivity reaction to antigen fromMycobacterium tuberculosis(Mtb). We provide the first single cell sequencing characterisation of the human TST reaction, based on skin suction blisters induced at the site of the TST on day 2 in 31 individuals. Integrated single cell RNA and TCR sequencing showed the immune response to be dominated by T cells, with smaller populations of NK cells and myeloid cells. T cells comprised CD4, CD8, gamma/delta and NK T cells, with 50% of all T cells identified as cytotoxic and 14% as regulatory. Interferon gamma gene expression was strongest in CD8 T cells, and distinct CD4 T helper lineages could not unambiguously be identified at this time point. Amongst myeloid cells, 63% displayed antimicrobial gene expression and 28% were functionally polarised towards antigen presentation with higher levels of HLA class 2 expression. We derived and validated transcriptional signatures for cell types and cellular functions relevant to the immune landscape of the TST. These data help to improve our understanding of the immune response to Mtb and enable further exploration of bulk transcriptomic data through context-specific cellular deconvolution.
Glia-mediated gut-brain cytokine signaling couples sleep to intestinal inflammation
Authors: Malita Alina , Kubrak Olga , Chen Xiaokang , Koyama Takashi , Connolly Elizabeth C. , Ahrentløv Nadja , Andersen Ditte S. , Texada Michael J. , Halberg Kenneth V. , Rewitz Kim 
Published: June 2024

AbstractSickness-induced sleep is a behavior conserved across species that promotes recovery from illness, yet the underlying mechanisms are poorly understood. Here, we show that interleukin-6-like cytokine signaling from theDrosophilagut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress – triggered by immune and inflammatory responses in the intestine – induces sleep. The cytokines Unpaired 2 and -3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK-STAT signaling in glial cells, including those of the blood-brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK-STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributes to our understanding of how sleep disturbances arise from gastrointestinal disturbances.