bluuebunny/crossref_metadata_2025 huggingface dataset:
Organic matter, carbon, and nitrogen relationships of regreened forest soils in an industrially impacted landscape
Authors: Levasseur Patrick A. , Aherne Julian , Basiliko Nathan , Watmough Shaun A.
Published: June 2024

Context Soil organic matter (SOM) is largely composed of carbon (C) and nitrogen (N), the proportions of which often change with soil depth. The relationships between SOM, C, and N in forest soils can be greatly altered in degraded landscapes and understanding these relationships is integral for successful forest restoration planning. Aims The current study investigated SOM, C, and N relationships in highly degraded forest soils by depth following regreening (one-time application of soil amendments and afforestation). Additionally, the use of standard C:OM ratios (which are commonly used to estimate soil C) were assessed. Methods The SOM, C, and N were measured at five different depths, at nine sites, ranging in time since regreening treatment applications across one of the world’s largest regreening programmes in the City of Greater Sudbury, Canada. Key results The C:OM and C:N ratios decreased with soil depth while N:OM increased. The C and N were significantly correlated with SOM at all depths (excluding the L horizon). The C:OM ratio was lower than standard values and did not change between 16 and 41 years since the application of 10 Mg ha−1 of dolomitic limestone. Conclusions Despite massive soil degradation, SOM, C, and N relationships over soil depth at the regreening sites are consistent with unimpacted forest soils. Applying commonly used C:OM ratios drastically overestimated soil C pools, especially at lower depths. Implications Even in the most degraded landscapes, restoration can improve soil properties. Standard C:OM ratios should be used with caution.
Slavery, homeownership, and contemporary perinatal outcomes in the southeast: a test of mediation and moderation
Authors: Stanhope Kaitlyn K , Kramer Michael R , McKinnon Izraelle , Carter Sierra , Boulet Sheree L
Published: June 2024

The objective of this study was to estimate the effect of geographic variation in historic slavery on perinatal outcomes (chronic hypertension, hypertensive disorders of pregnancy [HDP], very preterm birth [VPTB], or very low birth weight birth [VLBW]) among Black people living in states where slavery was legal in 1860; and to test mediation by Black homeownership. We linked data on the proportion of enslaved residents from the 1860 Census to natality data on outcomes (2013-2021) using resident county. The percentage of Black residents in a county who owned their home was a potential mediator. We fit log binomial models to estimate risk ratios (RRs) representing total and controlled direct effects (accounting for Black homeownership) of the proportion enslaved on outcomes, accounting for potential confounding, using marginal structural models. Among 2 443 198 included births, 8.8% (213 829) experienced HDP, 4.1% (100 549) chronic hypertension, 3.3% (81 072) VPTB, and 2.6% (62 538) VLBW. There was an increase in chronic hypertension and VPTB risk, but not HDP or VLBW, in counties with a 10% greater proportion of enslaved residents in 1860 (adjusted RR [95% CI], chronic hypertension: 1.06 [1.02-1.1]; VPTB: 1.02 [1.00-1.05]; HDP: 1.00 [0.98-1.02]; and VLBW: 1.01 [1.00-1.03]). There was not evidence of mediation by Black homeownership. We conclude that historic slavery remains relevant for perinatal health.
Risk factors of peritoneal dialysis–related peritonitis in the Japan Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS)
Authors: Ito Yasuhiko , Tu Charlotte , Yamaguchi Makoto , Koide Shigehisa , Ryuzaki Munekazu , Bieber Brian , Pisoni Ronald L , Perl Jeffrey , Minakuchi Jun , Kawanishi Hideki ,   the Japan PDOPPS Study Committee, Kawanishi Hideki , Minakuchi Jun , Tomo Tadashi , Tsuchiya Ken , Nitta Kousaku , Ryuzaki Munekazu , Fukazawa Mizuya , Ito Yasuhiro , Nakamoto Hidetomo , Yamashita Akihiro
Published: June 2024

Background

Peritoneal dialysis (PD)-related peritonitis is a major complication of PD. Wide variations in peritonitis prevention, treatment strategies and consequences are seen between countries. These between-country differences may result from modifiable risk factors and clinical practices.

Methods

A total of 1225 Japanese PD patients were included and prospectively followed in the Peritoneal Dialysis Outcomes and Practice Patterns Study phase 1 (2014–2018) and phase 2 (2018–2022). Associations between PD-related peritonitis and various risk factors were assessed by Cox proportional hazards survival models.

Results

During follow-up (median 1.52 years), 539 peritonitis episodes were experienced by 364 patients. The country crude peritonitis rate was 0.27 episodes/patient-year. In the fully adjusted model, noticeable patient-level factors associated with experiencing any peritonitis included age {hazard ratio [HR] 1.07 per 5-year increase [95% confidence interval (CI) 1.01–1.14]}, serum albumin level [HR 0.63 per 1 g/dl higher (95% CI 0.48–0.82)] and continuous ambulatory peritoneal dialysis (PD) [HR 1.31 versus automated PD (95% CI 1.05–1.63)]. The adoption of antibiotic prophylaxis practice at the time of PD catheter insertion [HR 0.63 (95% CI 0.51–0.78)] or when having complicated dental procedures [HR 0.74 (95% CI 0.57–0.95)] or lower endoscopy [HR 0.69 (95% CI 0.54–0.89)] were associated with lower hazards of any peritonitis, while a routine facility practice of having more frequent regular medical visits was associated with a higher hazard.

Conclusion

Identification of risk factors in Japan may be useful for developing future versions of guidelines and improving clinical practices in Japan. Investigation of country-level risk factors for PD-related peritonitis is useful for developing and implementing local peritonitis prevention and treatment strategies
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

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 >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

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

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

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

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.
Development and Evaluation of Real-Time Quantitative PCR Assays for Detection of Phellinus noxius Causing Brown Root Rot Disease
Authors: Liu Tse-Yen , Chen Chao-Han , Ko Yi-Chun , Wu Zong-Chi , Liao Ting-Zhi , Lee Hsin-Han , Tsai Isheng Jason , Chang Tun-Tschu , Wu Meng-Ling , Tsai Jyh-Nong , Klopfenstein Ned B. , Kim Mee-Sook , Stewart Jane E. , Atibalentja Ndeme , Brooks Fred E. , Cannon Philip G. , Farid A. Mohd , Hattori Tsutomu , Kwan Hoi-Shan , Ching Lam Regent Yau , Ota Yuko , Sahashi Norio , Schlub Robert L. , Shuey Louise S. , Tang Alvin M. C. , Chung Chia-Lin
Published: June 2024

Brown root rot disease (BRRD) is a highly destructive tree disease. Early diagnosis of BRRD has been challenging because the first symptoms and signs are often observed after extensive tissue colonization. Existing molecular detection methods, all based on the internal transcribed spacer (ITS) region, were developed without testing against global Phellinus noxius isolates, other wood-decay fungi, or host plant tissues. This study aimed to develop SYBR Green real-time quantitative PCR (qPCR) assays for P. noxius. The primer pair Pn_ITS_F/Pn_ITS_R targets the ITS, and the primer pair Pn_NLR_F/Pn_NLR_R targets a P. noxius–unique group of homologous genes identified through a comparative genomics analysis. The homologous genes belong to the nucleotide-binding-oligomerization-domain-like receptor (NLR) superfamily. The new primer pairs and a previous primer pair G1F/G1R were optimized for qPCR conditions and tested for specificity using 61 global P. noxius isolates, 5 other Phellinus species, and 22 non-Phellinus wood-decay fungal species. Although all three primer pairs could detect as little as 100 fg (approximately 2.99 copies) of P. noxius genomic DNA, G1F/G1R had the highest specificity and Pn_NLR_F/Pn_NLR_R had the highest efficiency. To avoid false positives, the cutoff quantification cycle values were determined as 34 for G1F/G1R, 29 for Pn_ITS_F/Pn_ITS_R, and 32 for Pn_NLR_F/Pn_NLR_R. We further validated these qPCR assays using Ficus benjamina seedlings artificially inoculated with P. noxius, six tree species naturally infected by P. noxius, rhizosphere soil, and bulk soil. The newly developed qPCR assays provide sensitive detection and quantification of P. noxius, which is useful for long-term monitoring of BRRD status.
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

Epithelial-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

We 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

Typical 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

Transforming 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

The 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

Sickness-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.
Representational drift as the consequence of ongoing memory storage
Authors: Devalle Federico , Zou Licheng , Cecchini Gloria , Roxin Alex
Published: June 2024

Memory systems with biologically constrained synapses have been the topic of intense theoretical study for over thirty years. Perhaps the most fundamental and far-reaching finding from this work is that the storage of new memories implies the partial erasure of already-stored ones. This overwriting leads to a decorrelation of sensory-driven activity patterns over time, even if the input patterns remain similar. Representational drift (RD) should therefore be an expected and inevitable consequence of ongoing memory storage. We tested this hypothesis by fitting a network model to data from long-term chronic calcium imaging experiments in mouse hippocampus. Synaptic turnover in the model inputs, consistent with the ongoing encoding of new activity patterns, accounted for the observed statistics of RD. This mechanism also provides a parsimonious explanation for the diverse effects of experience on drift found in experiment. Our results suggest that RD should be observed wherever neuronal circuits are involved in a process of ongoing learning or memory storage.
Leveraging Crosslinker Diffusion to Template Stiffness Gradients in Alginate Hydrogels
Authors: Ostrowski Zoe , Price Tyler , Zhang Juntao , Foroozandehfar Azarnoosh , Namanda Fred R. , Kaufmann Tim , Judka Natalia , Gardner Tyler , Thatcher Mary , Miller Emmaline , Mesyk Lily , Koep Abigail , Melvin Adam T. , Ren Juan , Schneider Ian C.
Published: June 2024

Mechanobiology drives many important cell biological behaviors such as stem cell differentiation, cancer drug resistance and cell migration up stiffness gradients, a process called durotaxis. The development of 3D hydrogel systems with tunable 2D mechanical gradient patterns affords the ability to study these mechanosensitive cell behaviors to understand cancer invasion or enhance wound healing through directed migration. In this paper, we developed an approach to spatially imprint within alginate hydrogels, gradients in mechanical properties that can be used to probe mechanobiology. Stencils were easily designed and fabricated using a common craft cutter to control the presentation of a calcium crosslinking solution to alginate gels. Different stencil shapes result in different gradients in opacity that can be imprinted into both thick and thin alginate gels of arbitrary 2D shape. The steepness of the opacity gradient as well as the maximum opacity can be controlled based on reproducible crosslinking kinetics regulated through calcium concentration and gradient developing time. Calcium crosslinking results in both opacity changes as well as increases in elastic modulus in the bulk hydrogel. Opacity correlates with elastic modulus, allowing it to be used as a proxy for local elastic modulus. Functionalized alginate gels with collagen and imprinting stiffness gradients within them resulted in cell invasion that was spatially dependent, where stiffer regions facilitated deeper invasion of breast cancer cells. Consequently, this stenciling approach represents a facile way to control stiffness gradients in alginate gels in order to study mechanosensitive cellular behavior.

Graphical Abstract
Deciphering BRCAness Phenotype in Cancer: A Graph Convolutional Neural Network Approach with Layer-wise Relevance Propagation Analysis
Authors: Yang Jingyu , Chereda Hryhorii , Dönitz Jürgen , Bleckmann Annalen , Beißbarth Tim
Published: June 2024

Background

Cancer variability among patients underscores the need for personalized therapy based on genomic understanding. BRCAness, characterized by vulnerabilities similar to BRCA mutations, particularly in homologous recombination repair, shows potential sensitivity to DNA-damaging agents like PARP inhibitors, highlighting it’s clinical significance.

Methods

We employed Graph Convolutional Neural Networks (GCNNs) with Layer-wise Relevance Propagation (LRP) to analyze gene expression data from the TCGA Pan-Cancer dataset. The study compared the efficacy of GCNNs against traditional machine learning models and differential gene expression analysis, focusing on their ability to elucidate complex genomic interactions defining BRCAness.

Results

Differential Gene Expression (DGE) analysis proved limited in capturing the nuances of BRCAness. In contrast, GLRP significantly identified genes related to transcription regulation and cancer processes, emphasizing the phenotype’s complexity. Gene Set Enrichment Analysis (GSEA) highlighted crucial pathways like Nuclear Receptors signaling, Cellular Senescence, and ESR-mediated signaling, underscoring their roles in BRCAness and therapeutic potential.

Conclusion

GLRP outperformed traditional approaches in analyzing BRCAness, providing deep insights into transcriptional and oncogenic processes critical to the BRCAness phenotype. Our findings suggest new directions for developing targeted and personalized cancer treatments, leveraging intricate molecular interactions associated with BRCAness.
Detection of pharmaceutical contamination in amphipods of Lake Baikal by the HPLC-MS method
Authors: Telnova Tamara Yu. , Morgunova Maria M. , Shashkina Sophie S. , Vlasova Anfisa A. , Dmitrieva Maria E. , Shelkovnikova Victoria N. , Malygina Ekaterina V. , Imidoeva Natalia A. , Belyshenko Alexander Yu. , Konovalov Alexander S. , Misharina Evgenia A. , Axenov-Gribanov Denis V.
Published: June 2024

Pollution by active ingredients is one of the most significant and widespread forms of pollution on Earth. Medicines can have a negative impact on ecosystems, and contamination can have unpredictable consequences. An urgent and unexplored task is to study the Lake Baikal ecosystem and its organisms for the presence of trace concentrations of active pharmaceutical ingredients. Our study aimed to conduct a qualitative analysis of active pharmaceutical ingredients, and quantitative analysis of ibuprofen in endemic amphipods of Lake Baikal, using methods of high-performance liquid chromatography and mass spectrometry (HPLC-MS). Acetylsalicylic acid (aspirin), ibuprofen, acetaminophen, azithromycin, dimetridazole, metronidazole, amikacin, spiramycin, and some tetracycline antibiotics were detected in the studied littoral amphipods. We also detected different annual loads of active pharmaceutical ingredients on amphipods. Using the multiple reaction monitoring (MRM) mode mentioned in GOST International Technical Standards, we detected molecules, fragmented as amikacin, chlortetracycline, doxycycline, oxytetracycline, dimetridazole, metronidazole and spiramycin. Thus, we first revealed that invertebrates of Lake Baikal can encounter pharmaceutical contaminants in the environment.
MICAL2 Is a Super Enhancer Associated Gene that Promotes Pancreatic Cancer Growth and Metastasis
Authors: Garg Bharti , Khan Sohini , Babu Deepa Sheikh , Mose Evangeline , Gulay Kevin , Sharma Shweta , Sood Divya , Wenzel Alexander T. , Martsinkovskiy Alexei , Patel Jay , Jaquish Dawn , Lambies Guillem , D’Ippolito Anthony , Austgen Kathryn , Johnston Brian , Orlando David , Jang Gung Ho , Gallinger Steven , Goodfellow Elliot , Brodt Pnina , Commisso Cosimo , Tamayo Pablo , Mesirov Jill P. , Tiriac Herve , Lowy Andrew M.
Published: June 2024

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed thatMICAL2is a super enhancer-associated gene in human PDAC. MICAL2 is a flavin monooxygenase that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin related transcription factors (MRTF-A and MRTF-B). We found that MICAL2 is overexpressed in PDAC and correlates with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, we observed that MICAL2 promotes both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 expression also inhibited macropinocytosis. Throughin vitrophenotypic analyses, we show that MICAL2, MRTF-A and MRTF-B influence PDAC cell proliferation, migration and promote cell cycle progression. Importantly, we demonstrate that MICAL2 is essential forin vivotumor growth and metastasis. Interestingly, we find that MRTF-B, but not MRTF-A, phenocopies MICAL2-driven phenotypesin vivo. This study highlights the multiple ways in which MICAL2 impacts PDAC biology and suggests that its inhibition may impede PDAC progression. Our results provide a foundation for future investigations into the role of MICAL2 in PDAC and its potential as a target for therapeutic intervention.
Impact of Enteric Neuronal Loss on Intestinal Cell Composition
Authors: Kakiailatu Naomi J.M. , Zhang Wei , Kuil Laura E. , Windster Jonathan D. , Bindels Eric , Zink Joke T.M. , Vermeulen Michael , de Graaf Bianca M. , Sahadew Deepavali , van den Bosch Thierry P.P. , Huijgen Demi , Sloots Cornelius E.J. , Wijnen Rene M.H. , Hofstra Robert M.W. , de Pater Emma , Melotte Veerle , Alves Maria M.
Published: June 2024

Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of an enteric nervous system (ENS) in the distal gut. While the ENS is critical for normal gut function, its broader role in maintaining intestinal homeostasis remains underexplored. Using single-cell RNA sequencing, we investigated the impact of ENS loss on gut composition in wildtype and ret mutant (HSCR model) zebrafish. Significant alterations were identified, including increases in immune cells and shifts in epithelial and extracellular matrix (ECM)-producing cell populations. Immune dysregulation was highlighted by impaired TNF-α signaling via NF-κB, while epithelial cell changes pointed to disrupted energy homeostasis with downregulated fatty acid metabolism and cell cycle pathways. Furthermore, the ECM producing cells showed enriched fibrotic markers. Alterations of the intestinal composition were validated in human HSCR tissues, underscoring the clinical relevance of these findings. These changes can underlie the development of secondary complications and be potentially used to improve patient outcomes.
Rbm24 maintains survival of cochlear outer hair cells by repressing Insm1
Authors: Li Chao , Wang Luyue , Li Shuting , Li Jie , Lu Ying , Liu Zhiyong
Published: June 2024

The inactivation of Rbm24, an RNA-binding protein, results in the degeneration of cochlear outer hair cells (OHCs) during the postnatal period. However, the specific molecular mechanisms underlying this OHC death remain elusive. To address this, we conducted a comprehensive analysis comparing the gene profiles of wild-type OHCs to those lacking Rbm24 (Rbm24-/-)at postnatal day 7 (P7). Our results revealed that the overall differentiation program of OHCs is delayed in the absence of Rbm24. Furthermore, the expression of Insm1, a crucial factor for OHC development that is normally switched off by P2, remains prolonged inRbm24-/-OHCs. Interestingly, when Insm1 is overexpressed, it also leads to OHC death. Significantly, the OHC degeneration is much less severe when bothRbm24andInsm1are simultaneously inactivated. These findings shed light on the important role of Rbm24 in repressing Insm1 and its impact on OHC differentiation and survival. Our study provides valuable insights into the complex genetic signaling pathways involved in OHC development.
Comparative study of gamma radiation tolerance between desiccation-sensitive and desiccation-tolerant tardigrades
Authors: Saigo Tokiko , Satoh Katsuya , Kunieda Takekazu
Published: June 2024

Tardigrades are small metazoans renowned for their exceptional tolerance against various harsh environments in a dehydrated state. Some species exhibited an extraordinary tolerance against high-dose irradiation even in a hydrated state. Given that natural sources of high radiation are rare, the selective pressure to obtain such a high radiotolerance during evolution remains elusive. It has been postulated that high radiation tolerances could be derived from adaptation to dehydration, because both dehydration and radiation cause similar damage on biomolecules at least partly, e.g., DNA cleavage and oxidation of various biomolecules, and dehydration is a common environmental stress that terrestrial organisms should adapt to. Although tardigrades are known for high radiotolerance, the radiotolerance records have been reported only for desiccation-tolerant tardigrade species and nothing was known about the radio-tolerance in desiccation-sensitive tardigrade species. Hence, the relationship between desiccation-tolerance and radio-tolerance remained unexplored. To this end, we examined the radiotolerance of the desiccation-sensitive tardigrade,Grevenius myrops(formerly known asIsohypsibius myrops) in comparison to the well-characterized desiccation-tolerant tardigrade,Ramazzottius varieornatus. The median lethal dose (LD50) ofG. myropswas approximately 2,240 Gy. This was much lower than those reported for desiccation tolerant eutardigrades. The effects of irradiation on the lifespan and the ovipositions were more severe inG. myropscompared to those inR. varieornatus. The present study provides the precise records on the radiotolerance of a desiccation-sensitive tardigrade and the current data supported the certain correlation between desiccation tolerance and radiotolerance at least in eutardigrades.
Coding odor modality in piriform cortex efficiently with low-dimensional subspaces: a Shared Covariance Decoding approach
Authors: Selb Delaney M , Barreiro Andrea K , Gautam Shree Hari , Shew Woodrow , Ly Cheng
Published: June 2024

A fundamental question in neuroscience is how sensory signals are decoded from noisy cortical activity. We address this question in the olfactory system, decoding the route by which odorants arrive into the nasal cavity: through the nostrils during inhalation or sniffing (orthonasal), or through the back of the throat during exhalation (retronasal). We recently showed with modeling and novel experiments on anesthetized rats that orthonasal versus retronasal modality information is encoded in the olfactory bulb (OB, a pre-cortical region). However, key questions remain: is modality information transmitted from OB to anterior piriform cortex (aPC)? How can this information be extracted from a much noisier cortical population with overall less firing? With simultaneous spike recordings of populations of neurons in OB and aPC, we show that an unsupervised and biologically plausible algorithm we call Shared Covariance Decoding (SCD) can indeed linearly encode modality in low dimensional subspaces. Specifically, our SCD algorithm improves encoding of ortho/retro in aPC compared to Fisher's linear discriminant analysis (LDA). Consistent with our theoretical analysis, when noise correlations between OB and aPC are low and OB well-encodes modality, modality in aPC tends to be encoded optimally with SCD. We observe that with several algorithms (LDA, SCD, optimal) that the decoding accuracy distributions are invariant when GABA_A (ant-)agonists (bicuculline and muscimol) are applied to OB. Overall, we show modality information can be encoded efficiently in piriform cortex.