bluuebunny/crossref_metadata_2025 huggingface dataset:
Interrelationships between tuberculosis and chronic obstructive pulmonary disease
Authors: Zavala Michael J. , Becker Greta L. , Blount Robert J.
Published: January 2023

Purpose of review

Our objective was to review the current literature regarding socioeconomic, environmental, clinical, and immunologic factors common to chronic obstructive pulmonary disease (COPD) and tuberculosis (TB).

Recent findings

Recent studies suggest that TB patients might be at increased risk for developing COPD. Conversely, additional prospective cohort studies have determined that COPD patients are at increased risk for active TB: a risk that appears to be partially mediated through inhaled corticosteroid use. Tobacco smoking, poverty, air pollution, and malnutrition are associated with COPD and TB. Vitamin D has been shown to prevent COPD exacerbations, but its use for preventing TB infection remains unclear. Surfactant deficiency, elevated matrix metalloproteinases, and toll-like receptor 4 polymorphisms play key roles in the pathogenesis of both diseases.

Recent studies have elucidated interrelationships between COPD and TB. Future research is needed to optimize clinical and public health approaches that could mitigate risk factors contributing to both diseases.
Acinar Cystic Transformation of the Pancreas
Authors: Luchini Claudio , Mattiolo Paola , Basturk Olca , Mafficini Andrea , Ozcan Kerem , Lawlor Rita T. , Hong Seung-Mo , Brosens Lodewijk A. , Marchegiani Giovanni , Pea Antonio , Manfrin Erminia , Sciacca Giuseppe , Zampieri Federica , Polati Rita , De Robertis Riccardo , Milella Michele , D’Onofrio Mirko , Malleo Giuseppe , Salvia Roberto , Adsay Volkan , Scarpa Aldo
Published: January 2023

Acinar cystic transformation (ACT) of the pancreas, previously called acinar cell cystadenoma, is a poorly understood and rare entity among pancreatic cystic lesions. This study aims to clarify its real nature. This research cohort included 25 patients with pancreatic ACT, representing the largest series in the literature. We describe their clinicopathological features and molecular profile using next-generation sequencing. ACT arose more often in women (F/M≃2:1), in the body-tail region, with a mean size of ~4 cm. At the latest follow-up, all patients were alive and disease free. Histologically, a typical acinar epithelium lined all cysts, intermingled with ductal-like epithelium in 11/25 (44%) cases. All the cases lacked any evidence of malignancy. Three ACT showed peculiar features: 1 showed an extensive and diffuse microcystic pattern, and the other 2 harbored foci of low-grade pancreatic intraepithelial neoplasia (PanIN) in the ductal-like epithelium. Next-generation sequencing revealed the presence of 2 pathogenic/likely pathogenic mutations in 2 different cases, 1 with ductal-like epithelium and 1 with PanIN, and affecting KRAS (c.34G>C, p.G12R) and SMO (c.1685G>A, p.R562Q) genes, respectively. The other case with PanIN was not available for sequencing. Overall, our findings support that ACT is a benign entity, potentially arising from heterogeneous conditions/background, including: (1) acinar microcysts, (2) malformations, (3) obstructive/inflammatory setting, (4) genetic predisposition, (5) possible neoplastic origin. Although all indications are that ACT is benign, the potential occurrence of driver mutations suggests discussing a potential role of long-term surveillance for these patients.
Protective Effect of Calpain Inhibition During Cold Ischemia on Ischemia–reperfusion Injury After Lung Transplantation
Authors: Matsui Yuuki , Kanou Takashi , Matsui Takahiro , Fukui Eriko , Kimura Toru , Ose Naoko , Funaki Soichiro , Shintani Yasushi
Published: January 2023

Background.

Necroptosis, one of the types of regulated necrosis, causes ischemia–reperfusion (IR) lung injury. N-acetyl-leucyl-leucyl-norleucinal (ALLN), a calpain inhibitor, is known to attenuate necroptosis and apoptosis, and the purpose of this study was to evaluate the protective effect of ALLN during cold ischemia against IR injury in a rat lung transplant model.

Methods.

Male Lewis rats (250–350 g) were divided into 3 groups: sham group (n = 4), nontransplantation; control group (n = 8), transplantation with IR lung injury; and ALLN group (n = 8), transplantation with IR lung injury/ALLN. Rats in the sham group underwent a simple thoracotomy, and the remaining 2 groups of rats underwent an orthotopic left lung transplant. Cold ischemic time was 15 h. After 2 h of reperfusion, physiological function, inflammatory cytokine expression, pathway activation, and the degrees of necroptosis and apoptosis were evaluated.

Results.

Lung gas exchange (PaO2/FiO2) was significantly better, and pulmonary edema was significantly improved in the ALLN group compared with the control group (P = 0.0009, P = 0.0014). Plasma expression of interleukin-1β was significantly lower in the ALLN group than in the control group (P = 0.0313). The proportion of necroptotic and apoptotic cells was significantly lower in the ALLN group than in the control group (P = 0.0009), whereas the proportion of apoptotic cells remained unchanged (P = 0.372); therefore, the calpain inhibitor was thought to suppress necroptosis.

Conclusions.

The administration of ALLN during cold ischemia appears to improve IR lung injury in a lung transplant animal model via the inhibition of necroptosis.
Evaluating the Role of Circulating MicroRNAs in Predicting Long-Term Survival Outcomes in Breast Cancer: A Prospective, Multicenter Clinical Trial
Authors: Davey Matthew G , McGuire Andrew , Casey Maire Caitlin , Waldron Ronan M , Paganga Maxwell , Holian Emma , Newell John , Heneghan Helen M , McDermott Ailbhe M , Keane Maccon M , Lowery Aoife J , Miller Nicola , Kerin Michael J
Published: January 2023

BACKGROUND:

While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis.

STUDY DESIGN:

This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3.

RESULTS:

A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival.

CONCLUSIONs:

ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.
Distress, Depression, and the Effect of ZIP Code in Pancreaticobiliary Cancer Patients and Their Significant Others
Authors: Yeo Theresa P , Cannaday Shawnna , Thompson Richard E , Fogg Ryan , Nevler Avinoam , Lavu Harish , Yeo Charles J
Published: January 2023

BACKGROUND:

Distress screening of cancer patients is mandated by the American College of Surgeons Commission on Cancer. Clinical implementation remains limited, particularly in surgical oncology settings in individuals with pancreaticobiliary cancers.

STUDY DESIGN:

This study evaluated differences in mean distress scores based on the National Comprehensive Cancer Network Distress Thermometer & Problem List for patients with pancreaticobiliary cancers, benign pancreatic conditions, and for their significant others (SOs). The distress screening was conducted at the first office visit and postoperatively in a subset of those who had surgery. Distress Thermometer (DT) scores were dichotomized at ≤5 vs >5 and at ≥7 and correlated with Problem List items. The US ZIP Code database was used to correlate income range, percent poverty, and unemployment in the patient’s self-identified ZIP code. Regression models were fitted to identify independent predictors of distress.

RESULTS:

A total of 547 patients and 184 SOs were evaluated. Thirty percent of patients had DT scores >5, with pancreatic adenocarcinoma patients reporting the highest levels of distress. SOs of pancreatic adenocarcinoma patients reported even greater distress than the patients themselves. As the number of pre-existing medical problems increased; so did DT scores. Distress correlated with physical and emotional problems and worry about insurance coverage and transportation. Higher income level predicted higher DT scores, although poverty predicted lower DT scores. Depression was present in 12% of the patients. Distress improved in those undergoing surgery.

CONCLUSIONS:

Distress and depression in pancreaticobiliary cancer patients and SOs are prevalent. The findings of this study have multiple actionable implications and require diagnosis, treatment, and referral to supportive care resources.
Impact of Rapid Weight Loss after Bariatric Surgery in Systemic Inflammatory Response and Pulmonary Hemodynamics in Severely Obese Subjects with Pulmonary Hypertension
Authors: Valera Roberto J , Fonnegra Cristina Botero , Cogollo Vicente J , Sarmiento-Cobos Mauricio , Rivera Carlos , Lo Menzo Emanuele , Szomstein Samuel , Rosenthal Raul J
Published: January 2023

BACKGROUND:

Pulmonary hypertension (PH) can be associated with obesity. The excessive production of proinflammatory mediators by dysfunctional adipocytes may enhance remodeling of the pulmonary vasculature and worsen pulmonary hemodynamics. This study aimed to describe the changes in pulmonary arterial pressures and systemic inflammation in patients with obesity with PH after bariatric surgery (BaS).

STUDY DESIGN:

In this retrospective cohort study, we compared patients with PH who underwent BaS from 2008 to 2018 at our institution (group 1) to a group of severely obese patients with PH (group 2). Echocardiographic right ventricular systolic pressure (RVSP) was used as an indirect measurement of pulmonary arterial pressures. Red blood cell distribution width (RDW) was used as a marker of systemic inflammation.

RESULTS:

A total of 40 patients were included, 20 per group. In group 1, the RVSP decreased from 44.69 ± 7.12 mmHg to 38.73 ± 12.81 mmHg (p = 0.041), and the RDW decreased from 15.22 ± 1.53 to 14.41 ± 1.31 (p = 0.020). In group 2, the RVSP decreased from 60.14 ± 18.08 to 59.15 ± 19.10 (0.828), and the RDW increased from 15.37 ± 1.99 to 15.38 ± 1.26 (0.983). For both groups, we found a positive correlation between RVSP and RDW changes, although the correlation was not statistically significant.

CONCLUSIONs:

Previous studies suggest BaS could be a safe and effective procedure to achieve weight loss in obese patients with PH, with an additional modest improvement in pulmonary hemodynamics. The results of this study reinforce this observation and suggest that such improvement could be related to a decrease in systemic inflammation. Further prospective studies with bigger samples are needed to better understand these findings.
Iron homeostasis in Bacillus subtilis relies on three differentially expressed efflux systems
Authors: Steingard Caroline H. , Pinochet-Barros Azul , Wendel Brian M. , Helmann John D.
Published: January 2023

In Bacillus subtilis, iron homeostasis is maintained by the ferric uptake regulator (Fur) and manganese homeostasis relies on the manganese transport regulator (MntR). Both Fur and MntR function as bi-functional metalloregulators that repress import and activate metal ion efflux systems. The ferrous iron efflux ATPase, PfeT, is derepressed by hydrogen peroxide (H2O2) as sensed by PerR and induced by iron as sensed by Fur. Mutants lacking PfeT are sensitive to iron intoxication. Here, we show that mntR mutants are also iron-sensitive, largely due to decreased expression of the MntR-activated MneP and MneS cation diffusion facilitator (CDF) proteins previously defined for their role in Mn2+ export. The ability of MneP and MneS to export iron is apparent even when their expression is not induced by Mn2+. Our results demonstrate that PfeT, MneP and MneS each contribute to iron homeostasis, and a triple mutant lacking all three is more iron-sensitive than any single mutant. We further show that sensitivity to H2O2 does not correlate with iron sensitivity. For example, an mntR mutant is H2O2-sensitive due to elevated Mn(II) that increases PerR-mediated repression of peroxide resistance genes, and this repression is antagonized by elevated Fe2+ in an mntR pfeT mutant. Thus, H2O2-sensitivity reflects the relative levels of Mn2+ and Fe2+ as sensed by the PerR regulatory protein. These results underscore the complex interplay between manganese, iron and oxidative stress in

B. subtilis

.
Magnetic Resonance Fingerprinting based Thermometry (MRFT): application to ex vivo imaging near DBS leads
Authors: Qian Enlin , Poojar Pavan , Fung Maggie , Jin Zhezhen , Vaughan Thomas , Shrivastava Devashish , Gultekin David , Fernandes Tiago , Geethanath Sairam
Published: January 2023

The purpose of this study is to demonstrate the first work of T1-based magnetic resonance thermometry using magnetic resonance fingerprinting (dubbed MRFT). We compared temperature estimation of MRFT with proton resonance frequency shift (PRFS) thermometry onex vivobovine muscle. We demonstrated MRFT’s feasibility in predicting temperature onex vivobovine muscles with deep brain stimulation (DBS) lead. B0maps generated from MRFT were compared with gold standard B0maps near the DBS lead.

All experiments were performed on a 3 Tesla whole-body GE Premier system equipped with a 21-channel receive head coil (GE Healthcare, Milwaukee, WI). Four fluoroptic probes were used to measure the temperature at the center of a cold muscle (probe 1), the room temperature water bottle (probe 2), and the center and periphery of the heated muscle (probes 3 and 4). We selected regions of interest (ROIs) around the location of the probes and used simple linear regression to generate the temperature sensitivity calibration equations that convert T1maps and Δs maps to temperature maps. We then repeated the same setup and compared MRFT, PRFS thermometry temperature estimation with gold standard probe measurements. For the MRFT experiment on DBS lead, we taped the probe to the tip of the DBS lead and used a turbo spin echo (TSE) sequence to induce heating near the lead. We selected ROIs around the tip of the lead to compare MRFT temperature estimation with probe measurements. Vendor-supplied B0mapping sequence was acquired to compare with MRFT-generated B0maps.

We found strong linear relationships (R2>0.958) between T1and temperature and Δs and temperatures in our temperature sensitivity calibration experiment. MRFT and PRFS thermometry both accurately predict temperature (RMSE<1.55 °C) compared to probe measurements. MRFT estimated temperature near DBS lead has a similar trend as the probe temperature. Both B0maps show inhomogeneities around the lead.
The Nucleotide Transformer: Building and Evaluating Robust Foundation Models for Human Genomics
Authors: Dalla-Torre Hugo , Gonzalez Liam , Mendoza Revilla Javier , Lopez Carranza Nicolas , Henryk Grywaczewski Adam , Oteri Francesco , Dallago Christian , Trop Evan , De Almeida Bernardo P , Sirelkhatim Hassan , Richard Guillaume , Skwark Marcin , Beguir Karim , Lopez Marie , Pierrot Thomas
Published: January 2023

Closing the gap between measurable genetic information and observable traits is a longstanding challenge in genomics. Yet, the prediction of molecular phenotypes from DNA sequences alone remains limited and inaccurate, often driven by the scarcity of annotated data and the inability to transfer learnings between prediction tasks. Here, we present an extensive study of foundation models pre-trained on DNA sequences, named the Nucleotide Transformer, ranging from 50M up to 2.5B parameters and integrating information from 3,202 diverse human genomes, as well as 850 genomes selected across diverse phyla, including both model and non-model organisms. These transformer models yield transferable, context-specific representations of nucleotide sequences, which allow for accurate molecular phenotype prediction even in low-data settings. We show that the developed models can be fine-tuned at low cost and despite low available data regime to solve a variety of genomics applications. Despite no supervision, the transformer models learned to focus attention on key genomic elements, including those that regulate gene expression, such as enhancers. Lastly, we demonstrate that utilizing model representations can improve the prioritization of functional genetic variants. The training and application of foundational models in genomics explored in this study provide a widely applicable stepping stone to bridge the gap of accurate molecular phenotype prediction from DNA sequence. Code and weights available at: https://github.com/instadeepai/nucleotide-transformer in Jax and https://huggingface.co/InstaDeepAI in Pytorch. Example notebooks to apply these models to any downstream task are available on https://huggingface.co/docs/transformers/notebooks#pytorch-bio.
Integrating physics in deep learning algorithms: A force field as a PyTorch module
Authors: Orlando Gabriele , Serrano Luis , Schymkowitz Joost , Rousseau Frederic
Published: January 2023

Deep learning algorithms applied to structural biology often struggle to converge to meaningful solutions when limited data is available, since they are required to learn complex physical rules from examples. State-of-the-art force-fields, however, cannot interface with deep learning algorithms due to their implementation. We present MadraX, a forcefield implemented as a differentiable PyTorch module, able to interact with deep learning algorithms in an end-to-end fashion. MadraX is available at madrax.readthedocs.io
BnIR: a multi-omics database with various tools for Brassica napus research and breeding
Authors: Yang Zhiquan , Wang Shengbo , Wei Lulu , Huang Yiming , Liu Dongxu , Jia Yupeng , Luo Chengfang , Lin Yuchen , Liang Congyuan , Hu Yue , Dai Cheng , Guo Liang , Zhou Yongming , Qing-Yong Yang
Published: January 2023

In the post-GWAS era, multi-omics techniques have shown great power and potential for candidate gene mining and functional genomics research. However, due to the lack of effective data integration and multi-omics analysis platforms, such techniques have not still been applied widely in rapeseed, an important oil crop worldwide. Here, we constructed a rapeseed multi-omics database (BnIR; http://yanglab.hzau.edu.cn/BnIR), which provides datasets of six omics including genomics, transcriptomics, variomics, epigenetics, phenomics and metabolomics, as well as numerous "variation-gene expression-phenotype" associations by using multiple statistical methods. In addition, a series of multi-omics search and analysis tools are integrated to facilitate the browsing and application of these datasets. BnIR is the most comprehensive multi-omics database for rapeseed so far, and two case studies demonstrated its power to mine candidate genes associated with specific traits and analyze their potential regulatory mechanisms.
Experimentally induced drought and growing season stage modulate community-level functional traits in a temperate grassland
Authors: Fenollosa E. , Fernandes P. , Hector A. , King H. , Lawson C.S. , Jackson J. , Salguero-Gomez R.
Published: January 2023

Extreme precipitation events are expected to become more intense and frequent with climate change. This climatic shift may impact the structure and dynamics of natural communities and the key ecosystem services they provide. Changes in species abundance under these extreme conditions are thought to be driven by functional traits, morpho-physiological characteristics of an organism that impact its fitness. Future environmental conditions may, therefore, favour different functional traits to those in present-day communities.

Here, we measure functional traits on 586 vascular plants in a temperate grassland where precipitation has been experimentally manipulated for six years. We calculated community-weighted means of five functional traits (plant height, leaf dry matter content, leaf thickness, specific leaf area, and leaf phosphorus concentration) and compared community-weighted means between three levels of precipitation: drought (−50%), irrigated (+50%), and control. Additionally, we contrasted treatments at two different timings along the growing season: mid-season and late-season.

We expected altered community-weighted means for traits associated with a conservative use of water that will result from increased summer stress-induced intraspecific variability in the mid-season and from community composition changes in the late-season, after the field is cut, a common management action across most European grasslands.

In the drought treatment, we found significantly lower community-weighted mean plant height and leaf dry matter content. However, we only observed these differences after the mid-season cut. We also observed an increase in leaf phosphorus concentration in the drought treatment before the mid-season cut. A combination of changes in community composition and intraspecific variation contributed to these differences, with community composition being more important after the cut. Species with higher height, leaf dry matter content, and lower leaf thickness showed a more pronounced abundance decline at the drought plots. We observed no changes in functional traits community-weighted means in the irrigated treatment compared to those in control and drought treatments.

Synthesis. Our results suggest how the functional trait composition of grassland communities may shift under climate change-induced drought, stressing the interacting effects with growing season stages.
Fluorescent protein lifetimes report increased local densities and phases of nuclear condensates during embryonic stem cell differentiation
Authors: Joron Khalil , Viegas Juliane Oliveira , Haas-Neill Liam , Bier Sariel , Drori Paz , Dvir Shani , Lim Patrick Siang Lin , Rauscher Sarah , Meshorer Eran , Lerner Eitan
Published: January 2023

Fluorescent proteins (FP) are frequently used for studying proteins inside cells. In advanced fluorescence microscopy, FPs can report on additional intracellular variables. One variable is the local density near FPs, which can be useful in studying densities within cellular bio-condensates. Here, we show that a reduction in fluorescence lifetimes of common monomeric FPs reports increased levels of local densities. We demonstrate the use of this fluorescence-based variable to report the distribution of local densities within heterochromatin protein 1α (HP1α) in mouse embryonic stem cells (ESCs), before and after early differentiation. We find that local densities within HP1α condensates in pluripotent ESCs are heterogeneous and cannot be explained by a single liquid phase. Early differentiation, however, induces a change towards a more homogeneous distribution of local densities, which can be explained as a liquid-like phase. In conclusion, we provide a fluorescence-based method to report increased local densities and apply it to distinguish between homogeneous and heterogeneous local densities within bio-condensates.
An assay to reliably achieve Tar Spot symptoms on corn in a controlled environment
Authors: Breunig Mikaela , Bittner Richard , Dolezal Andrea , Ramcharan Amanda , Bunkers Greg
Published: January 2023

Tar Spot continues to threaten U.S. corn production (Telenko et al., 2022). A reliable assay under controlled conditions is needed to study the epidemiology and management of Tar Spot. Researchers have reported controlled environment infections, but incidence and severity were low and the ability to screen germplasm has not yet been reported. In this paper, we describe a controlled environment assay that reliably achieves Tar Spot symptoms on corn plants allowing differentiation of susceptible and resistant germplasm.
Integration of spatial and single-cell data across modalities with weak linkage
Authors: Chen Shuxiao , Zhu Bokai , Huang Sijia , Hickey John W. , Lin Kevin Z. , Snyder Michael , Greenleaf William J. , Nolan Garry P. , Zhang Nancy R. , Ma Zongming
Published: January 2023

single-cell sequencing methods have enabled the profiling of multiple types of molecular readouts at cellular resolution, and recent developments in spatial barcoding, in situ hybridization, and in situ sequencing allow such molecular readouts to retain their spatial context. Since no technology can provide complete characterization across all layers of biological modalities within the same cell, there is pervasive need for computational cross-modal integration (also called diagonal integration) of single-cell and spatial omics data. For current methods, the feasibility of cross-modal integration relies on the existence of highly correlated, a priori “linked” features. When such linked features are few or uninformative, a scenario that we call “weak linkage”, existing methods fail. We developed MaxFuse, a cross-modal data integration method that, through iterative co-embedding, data smoothing, and cell matching, leverages all information in each modality to obtain high-quality integration. MaxFuse is modality-agnostic and, through comprehensive benchmarks on single-cell and spatial ground-truth multiome datasets, demonstrates high robustness and accuracy in the weak linkage scenario. A prototypical example of weak linkage is the integration of spatial proteomic data with single-cell sequencing data. On two example analyses of this type, we demonstrate how MaxFuse enables the spatial consolidation of proteomic, transcriptomic and epigenomic information at single-cell resolution on the same tissue section.
Scalable gaussian process inference of neural responses to natural images
Authors: Goldin Matías A. , Virgili Samuele , Chalk Matthew
Published: January 2023

1

Predicting the responses of sensory neurons is a long-standing neuroscience goal. However, while there has been much progress in modeling neural responses to simple and/or artificial stimuli, predicting responses to natural stimuli remains an ongoing challenge. One the one hand, deep neural networks perform very well on certain data-sets, but can fail when data is limited. On the other hand, gaussian processes (GPs) perform well on limited data, but are generally poor at predicting responses to high-dimensional stimuli, such as natural images. Here we show how structured priors, e.g. for local and smooth receptive fields, can be used to scale up GPs to high-dimensional stimuli. We show that when we do this, a GP model largely outperforms a deep neural network trained to predict retinal responses to natural images, with largest differences observed when both models are trained on a very small data-set. Further, since GPs compute the uncertainty in their predictions, they are well-suited to closed-loop experiments, where stimuli are chosen actively so as to collect ‘informative’ neural data. We show how this can be done in practice on our retinal data-set, so as to: (i) efficiently learn a model of retinal responses to natural images, using little data, and (ii) rapidly distinguish between competing models (e.g. a linear vs a non-linear model). In the future, our approach could be applied to other low-level sensory areas, beyond the retina.
Bioen-OSMOSE: A bioenergetic marine ecosystem model with physiological response to temperature and oxygen
Authors: Morell Alaia , Shin Yunne-Jai , Barrier Nicolas , Travers-Trolet Morgane , Halouani Ghassen , Ernande Bruno
Published: January 2023

Marine ecosystem models have been used to project the impacts of climate-induced changes in temperature and oxygen on biodiversity mainly through changes in species spatial distributions and primary production. However, fish populations may also respond to climatic pressures via physiological changes, leading to modifications in their life history that could either mitigate or worsen the consequences of climate change.

Building on the individual-based multispecies ecosystem model OSMOSE, Bioen-OSMOSE has been developed to account for high trophic levels’ physiological responses to temperature and oxygen in future climate projections. This paper presents an overview of the Bioen-OSMOSE model, mainly detailing the new developments. These consist in the implementation of a bioenergetic sub-model that mechanistically describes somatic growth, sexual maturation and reproduction as they emerge from the energy fluxes sustained by food intake under the hypotheses of a biphasic growth model and plastic maturation age and size represented by a maturation reaction norm. These fluxes depend on temperature and oxygen concentration, thus allowing plastic physiological responses to climate change.

To illustrate the capabilities of Bioen-OSMOSE to represent realistic ecosystem dynamics, the model is applied to the North Sea ecosystem. The model outputs are confronted with population biomass, catch, maturity ogive, mean size-at-age and diet data of each species of the fish community. A first exploration of current species spatial variability in response to temperature or oxygen is presented in this paper. The model succeeds in reproducing observations, with good performances for all indicators.

This new model development opens the scope for new fields of research such as the exploration of seasonal or spatial variation in life history in response to biotic and abiotic factors at the individual, population and community levels. Understanding such variability is crucial to improve our knowledge on potential climate change impacts on marine ecosystems and to make more reliable projections under climate change scenarios.
Cytoplasmic Aggregation of RPB1 Predicts Failure of Neoadjuvant Chemotherapy
Authors: Nagy-Mikó Bence , Németh-Szatmári Orsolya , Faragó-Mészáros Réka , Csókási Aliz , Bognár Bence , Ördög Nóra , Borsos Barbara N. , Majoros Hajnalka , Ujfaludi Zsuzsanna , Oláh-Németh Orsolya , Nikolényi Aliz , Dobi Ágnes , Kószó Renáta , Sántha Dóra , Lázár György , Simonka Zsolt , Paszt Attila , Ormándi Katalin , Pankotai Tibor , Boros Imre M. , Villányi Zoltán , Vörös András
Published: January 2023

We aimed to investigate the contribution of co-translational protein aggregation to the chemotherapy resistance of tumor cells. Increased co-translational protein aggregation reflects altered translation regulation that may have the potential to buffer transcription under genotoxic stress. As an indicator for such event, we followed cytoplasmic aggregation of RPB1, the aggregation prone largest subunit of RNA polymerase II, in biopsy samples taken from patients with invasive carcinoma of no special type. RPB1 frequently aggregates co-translationally in the absence of proper HSP90 chaperone function or in ribosome mutant cells as revealed formerly in yeast. We found that cytoplasmic foci of RPB1 occur in larger sizes in tumors that showed no regression after therapy. Based on these results, we propose that monitoring the cytoplasmic aggregation of RPB1 may be suitable for determining – from biopsy samples taken before treatment – the effectiveness of neoadjuvant chemotherapy.
Top-down Modulation of Brain Responses in Spelling Error Recognition
Authors: Larionova Ekaterina , Garakh Zhanna , Martynova Olga
Published: January 2023

The task being undertaken can influence orthographic, phonological and semantic processes. In linguistic research, two tasks are most often used: a task requiring a decision in relation to the presented word and a passive reading task which does not require a decision regarding the presented word. The results of studies using these different tasks are not always consistent. This study aimed to explore brain responses associated with the process of recognition of spelling errors, as well as the influence of the task on this process. Event-related potentials (ERPs) were recorded in 40 adults during an orthographic decision task to determine correctly spelled words and words written with errors that did not change the phonology and during the passive reading. During spelling recognition, the early stages up to 100 ms after the stimulus were automatic and did not depend on the requirements of the task. The amplitude of the N1 component (90-160 ms) was greater in the orthographic decision task, but did not depend on the correct spelling of the word. Late word recognition after 350-500 ms was task dependent, but spelling effects were similar across the two tasks: misspelled words evoked an increase in the amplitude of the N400 component related to lexical and semantic processing regardless of the task. In addition, the orthographic decision task modulated spelling effects, this was reflected in an increase in the amplitude of the P2 component (180-260 ms) for correctly spelled words compared with misspelled words. Thus, our results show that spelling recognition involves general lexico-semantic processes independent of the task. Simultaneously, the orthographic decision task modulates the spelling-specific processes necessary to quickly detect conflicts between orthographic and phonological representations of words in memory.

Highlights

The influence of task on the recognition of correct spelling of words was studied

Sublexical stages during spelling recognition are task-independent

The amplitude of the P1, N1 and P600 components is not sensitive to the spelling of words

The orthographic decision task modulates the spelling processes at 180–260 ms

Spelling recognition modulates the N400 component regardless of the task
The evolution of parthenogen fertilization rates in switching environments: from facultative cell-fusion to oogamy
Authors: Liu Xiaoyuan , Pitchford Jon , Constable George W.A.
Published: January 2023

Organisms with external fertilisation exhibit a broad range of reproductive modes, from simple parthenogenesis to sexual reproduction encompassing isogamy, anisogamy, and oogamy, and including environmentally-mediated facultative sex. Here we develop a unifying mathematical model which explains the emergence of these modes via the coevolution of fertilization rate and cell size. Using a minimal assumption that survival is dependent on cell mass, and by carefully accounting for biological and evolutionary time scales, we find two distinct evolutionary outcomes: high fertilization rate (obligate sexuality) is selected when costs to cell fusion are low, while zero fertilization rate (obligate asexuality) is selected for when these costs are high. Surprisingy, in high fertilization rate scenarios evolving populations can transition from isogamy to anisogamy and oogamy via evolutionary branching. Furthermore, in variable environments we show that, without phenotypic plasticity, intermediate fertilization rates and isogamy can be maintained through bet-hedging. Allowing phenotypic plasticity can give rise to facultative sex; sexual reproduction in harsh environmental conditions, and asexuality in more benign conditions. These results parsimoniously explain a large range of empirically observed parthenogen reproduction strategies, and offer an hypothesis for the origin of binary cell fusion, a key step in the evolution of syngamy and sexual reproduction itself.
Tissue-specific chromatin binding patterns ofC. elegansheterochromatin proteins HPL-1 and HPL-2 reveal differential roles in the regulation of gene expression
Authors: de la Cruz Ruiz Patricia , Rodríguez-Palero María Jesús , Askjaer Peter , Artal-Sanz Marta
Published: January 2023

Heterochromatin is characterized by an enrichment of repetitive elements and low gene density and is often maintained in a repressed state across cell division and differentiation. The silencing is mainly regulated by repressive histone marks, such as H3K9 and H3K27 methylated forms and the heterochromatin protein 1 (HP1) family. Here, we analyzed in a tissue-specific manner the binding profile of the two HP1 homologs inCaenorhabditis elegans, HPL-1 and HPL-2, at the L4 developmental stage. We identified the genome-wide binding profile of intestinal and hypodermal HPL-2 and intestinal HPL-1 and compared them to heterochromatin marks and other features. HPL-2 associated preferentially to the distal arms of autosomes and correlated positively with methylated forms of H3K9 and H3K27. HPL-1 was also enriched in regions containing H3K9me3 and H3K27me3 but exhibited a more even distribution between autosome arms and centers. HPL-2 showed a differential tissue-specific enrichment for repetitive elements, conversely with HPL-1 that exhibited a poor association. Finally, we found a significant intersection of genomic regions bound by the BLMP-1/PRDM1 transcription factor and intestinal HPL-1, suggesting a co-repression role during cell differentiation. Our study uncovers both shared and singular properties of conserved HP1 proteins, providing information about genomic binding preferences in relation to their role as heterochromatic markers.
Functional microRNA-Targeting Drug Discovery by Graph-Based Deep Learning
Authors: Arshadi Arash Keshavarzi , Salem Milad , Karner Heather , Garcia Kristle , Arab Abolfazl , Yuan Jiann Shiun , Goodarzi Hani
Published: January 2023

MicroRNAs are recognized as key drivers in many cancers, but targeting them with small molecules remains a challenge. We present RiboStrike, a deep learning framework that identifies small molecules against specific microRNAs. To demonstrate its capabilities, we applied it to microRNA-21 (miR-21), a known driver of breast cancer. To ensure the selected molecules only targeted miR-21 and not other microRNAs, we also performed a counter-screen against DICER, an enzyme involved in microRNA biogenesis. Additionally, we used auxiliary models to evaluate toxicity and select the best candidates. Using datasets from various sources, we screened a pool of nine million molecules and identified eight, three of which showed anti-miR-21 activity in both reporter assays and RNA sequencing experiments. One of these was also tested in mouse models of breast cancer, resulting in a significant reduction of lung metastases. These results demonstrate RiboStrike’s ability to effectively screen for microRNA-targeting compounds in cancer.
The role of intestine in metabolic dysregulation in murine Wilson disease
Authors: Sarode Gaurav V. , Mazi Tagreed A. , Neier Kari , Shibata Noreene M. , Jospin Guillaume , Harder Nathaniel H.O. , Heffern Marie C. , Sharma Ashok K. , More Shyam K. , Dave Maneesh , Schroeder Shannon M. , Wang Li , LaSalle Janine M. , Lutsenko Svetlana , Medici Valentina
Published: January 2023

Background and aims

Major clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, and little is known about other tissues involvement in metabolic changes in WD.In vitrostudies suggested that the loss of intestinal ATP7B could contribute to metabolic dysregulation in WD. We tested this hypothesis by evaluating gut microbiota and lipidome in two mouse models of WD and by characterizing a new mouse model with a targeted deletion ofAtp7bin intestine.

Methods

Cecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and theAtp7bnull global knockout mouse models of WD were profiled and integrated. Intestine-specificAtp7bknockout mice (Atp7bΔIEC) was generated using B6.Cg-Tg(Vil1-cre)997Gum/J mice andAtp7bLox/Loxmice, and characterized using targeted lipidome analysis following a high-fat diet challenge.

Results

Gut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated tri- and diglyceride, phospholipid, and sphingolipid metabolism in WD models. When challenged with a high-fat diet,Atp7bΔIECmice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells.

Conclusion

Coordinated changes of gut microbiome and lipidome analyses underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence phenotypic presentations.
Engineered symbiotic bacteria interferingNosemaredox system inhibit microsporidia parasitism in honeybees
Authors: Lang Haoyu , Wang Hao , Wang Haoqing , Xie Xianbing , Hu Xiaosong , Zhang Xue , Zheng Hao
Published: January 2023

Nosema ceranaeis an emergent microsporidia parasite of the European honey bee (Apis mellifera), which causes serious nosemosis implicated in honeybee colony losses worldwide.N. ceranaeis an obligate intracellular eukaryotic parasite that mainly invades the midgut of honeybees. Recent studies find that bee gut microbiota is potentially involved in protecting against parasitism. Here, using laboratory-generated bees mono-associated with gut members, we find thatSnodgrassella alviinhibited microsporidia proliferation, potentially via the stimulation of host oxidant-mediated immune response. Accordingly,N. ceranaeemploys the thioredoxin and glutathione systems to defend against oxidative stress and maintain a balanced redox equilibrium, which is essential for the infection process. We knocked down the gene expression using nanoparticle-mediated RNA interference, which targets the γ-glutamyl-cysteine synthetase and thioredoxin reductase genes of microsporidia. It significantly reduces the spore load, confirming the importance of the antioxidant mechanism for the intracellular invasion of theN. ceranaeparasite. Finally, we genetically modified the symbioticS. alvito deliver dsRNA corresponding to the genes involved in the redox system of the microsporidia. The engineeredS. alviinduces RNA interference and represses parasite gene expression, thereby inhibits the parasitism by up to 99.8%. Specifically,N. ceranaewas most suppressed by the recombinant strain corresponding to the glutathione synthetase or by a mixture of bacteria expressing variable dsRNA. Our findings extend our previous understanding of the protection of gut symbionts againstN. ceranaeand provide a symbiont-mediated RNAi system for inhibiting microsporidia infection in honeybees.
Region-Based Epigenetic Clock Design Improves RRBS-Based Age Prediction
Authors: Simpson Daniel J. , Zhao Qian , Olova Nelly N. , Dabrowski Jan , Xie Xiaoxiao , Crespo Eric Latorre , Chandra Tamir
Published: January 2023

Recent studies suggest that epigenetic rejuvenation can be achieved using drugs that mimic calorie restriction and techniques such as reprogramming induced rejuvenation. To effectively test rejuvenationin vivo, mouse models are the safest alternative. However, we have found that the recent epigenetic clocks developed for mouse reduced-representation bisulphite sequencing (RRBS) data have significantly poor performance when applied to external datasets. We show that the sites captured and the coverage of key CpGs required for age prediction vary greatly between datasets, which likely contributes to the lack of transferability in RRBS clocks. To mitigate these coverage issues in RRBS-based age prediction, we present two novel design strategies that use average methylation over large regions rather than individual CpGs, whereby regions are defined by sliding windows (e.g. 5 kb), or density-based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs) compared to published individual-CpG-based techniques when applied to external datasets. The RegBCs are also more robust when applied to low coverage data and detect a negative age acceleration in mice undergoing calorie restriction. Our RegBCs offer a proof of principle that age prediction of RRBS datasets can be improved by accounting for multiple CpGs over a region, which negates the lack of read depth currently hindering individual-CpG-based approaches.
Listeria monocytogenesrequires DHNA-dependent intracellular redox homeostasis facilitated by Ndh2 for survival and virulence
Authors: Smith Hans B. , Lee Kijeong , Stevenson David M. , Amador-Noguez Daniel , Sauer John-Demian
Published: January 2023

Listeria monocytogenesis a remarkably well-adapted facultative intracellular pathogen that can thrive in a wide range of ecological niches.L. monocytogenesmaximizes its ability to generate energy from diverse carbon sources using a respiro-fermentative metabolism that can function under both aerobic and anaerobic conditions. Cellular respiration maintains redox homeostasis by regenerating NAD+while also generating a proton motive force (PMF). The end products of the menaquinone (MK) biosynthesis pathway are essential to drive both aerobic and anaerobic cellular respiration. We previously demonstrated that intermediates in the MK biosynthesis pathway, notably 1,4-dihydroxy-2-naphthoate (DHNA), are required for the survival and virulence ofL. monocytogenesindependent of their role in respiration. Furthermore, we found that restoration of NAD+/NADH ratio through expression of water-forming NADH oxidase (NOX) could rescue phenotypes associated with DHNA deficiency. Here we extend these findings to demonstrate that endogenous production or direct supplementation of DHNA restored both the cellular redox homeostasis and metabolic output of fermentation inL. monocytogenes. Further, exogenous supplementation of DHNA rescues thein vitrogrowth andex vivovirulence ofL. monocytogenesDHNA-deficient mutants. Finally, we demonstrate that exogenous DHNA restores redox balance inL. monocytogenesspecifically through the recently annotated NADH dehydrogenase Ndh2, independent of the extracellular electron transport (EET) pathway. These data suggest that the production of DHNA may represent an additional layer of metabolic adaptability byL. monocytogenesto drive energy metabolism in the absence of respiration-favorable conditions.