bluuebunny/crossref_metadata_2025 huggingface dataset:
Training Compute-Optimal Protein Language Models
Authors: Cheng Xingyi , Chen Bo , Li Pan , Gong Jing , Tang Jie , Song Le
Published: June 2024

We explore optimally training protein language models, an area of significant interest in biological research where guidance on best practices is limited. Most models are trained with extensive compute resources until performance gains plateau, focusing primarily on increasing model sizes rather than optimizing the efficient compute frontier that balances performance and compute budgets. Our investigation is grounded in a massive dataset consisting of 939 million protein sequences. We trained over 300 models ranging from 3.5 million to 10.7 billion parameters on 5 to 200 billion unique tokens, to investigate the relations between model sizes, training token numbers, and objectives. First, we observed the effect of diminishing returns for the Causal Language Model (CLM) and that of overfitting for the Masked Language Model (MLM) when repeating the commonly used Uniref database. To address this, we included metagenomic protein sequences in the training set to increase the diversity and avoid the plateau or overfitting effects. Second, we obtained the scaling laws of CLM and MLM on Transformer, tailored to the specific characteristics of protein sequence data. Third, we observe a transfer scaling phenomenon from CLM to MLM, further demonstrating the effectiveness of transfer through scaling behaviors based on estimated Effectively Transferred Tokens. Finally, to validate our scaling laws, we compare the large-scale versions of ESM-2 and PROGEN2 on downstream tasks, encompassing evaluations of protein generation as well as structure- and function-related tasks, all within less or equivalent pre-training compute budgets.
Multi-omics data and model integration reveal the main mechanisms associated with respiro-fermentative metabolism and ethanol stress responses in Kluyveromyces marxianus
Authors: Ferreira Mauricio , Silveira Wendel
Published: June 2024

Kluyveromyces marxianus is a yeast capable of fermenting sugars into ethanol and growing at high temperatures (37 degrees C). However, it is less tolerant to ethanol than Saccharomyces cerevisiae, which limits its application in second-generation ethanol production. Since the mechanisms of ethanol stress response are still poorly described, especially compared to S. cerevisiae, we used an integrative multi-omics approach, combining transcriptomics, co-expression networks, gene regulation, and genome-scale metabolic modelling to gain insights about these mechanisms. Through metabolic modelling, we predicted the occurrence of a respiro-fermentative metabolism and its onset as the dilution rate increased. From gene co-expression networks, we detected that the protein quality control system is a main mechanism involved in the ethanol stress response. Further, we identified key regulators in the ethanol stress response, such as HAP3, MET4, and SNF2, and assessed how disturbances in their gene expression affect cellular metabolism. We also found that amino acid metabolism, membrane lipid metabolism, and ergosterol exhibit increased metabolic flux under the explored conditions. These findings provide useful cues to develop and implement genetic and metabolic engineering strategies to enhance ethanol tolerance.
The role of eye movements in the process of silicone oil emulsification after vitreoretinal surgery
Authors: Nepita Irene , Brusati Camilla , Liggieri Libero , Ravera Francesca , Ferrara Mariantonia , Stocchino Alessandro , Romano Mario R. , Santini Eva , Repetto Rodolfo
Published: June 2024

Background

Emulsification of silicone oil (SO) is a feared and common complication of SO tamponade as potentially associated with significant risks to ocular health, including elevated intraocular pressure (IOP), glaucoma, corneal and retinal changes. The aim of this study was to investigate the role and interplay of major factors on the formation of SO emulsion, such as eye rotations and albumin, a blood serum protein known to affect interfacial properties.

Methods

Experiments were conducted in a realistic model of the vitreous chamber, filled with SO and an aqueous solution containing different concentrations of albumin. The model was subjected to harmonic and saccadic rotations, at body temperature.

Results

No emulsions were detected in the absence of endogenous proteins in the aqueous solution. The presence of albumin significantly influenced emulsion formation, acting as a surfactant. Mechanical energy from eye movements was also found to contribute to emulsification, with higher mechanical energy provided to the system leading to smaller droplet sizes. The emulsions formed were stable over extended times.

Conclusions

This study highlights the complex interplay of factors influencing SO emulsification in the vitreous chamber. A better understanding of the mechanisms underlying SO emulsification is crucial for developing strategies to mitigate SO emulsion and the related complications.
Impairment of brain function in a mouse model of Alzheimer’s disease during the pre-depositing phase: the role of α7 nicotinic acetylcholine receptors
Authors: Lykhmus Olena , Tzeng Wen-Yu , Koval Lyudmyla , Uspenska Kateryna , Zirdum Elizabeta , Kalashnyk Olena , Garaschuk Olga , Skok Maryna
Published: June 2024

Alzheimer’s disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1β and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of α7 nAChR-bound Aβ1-42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with α7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble Aβ1-42but consistently upregulated the α7 nAChR expression, decreased the level of α7- Aβ1-42complexes and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and α7-coupled Aβ1-42within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying α7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.
Endurance rivalry in capelin: insights from semen quality and regeneration
Authors: Wagle Ranjan , Hanley Connor P. , Purchase Craig F.
Published: June 2024

Male-biased adult sexual size dimorphism is often the result of intra-sex sexual selection driven by male-male competition. Capelin (Mallotus villosus) exhibit male-biased sexual size dimorphism but lack contests/fighting, and female mate choice, if present, is unrelated to male size. Consequently, it is hypothesized that adult sexual size dimorphism in capelin is due to a mating system that favours larger males with greater energy reserves, allowing them to compete for prolonged access to mating opportunities through endurance rivalry. To enable this, males need a continual supply of semen through the spawning season. However, they have unusually small testes and are predicted to deplete stored semen rapidly, and their unique sperm physiology (i.e. the only known external fertilizing vertebrate to release pre-activated semen) may constrain the ability to regenerate it. We found that the majority of capelin sampled on beaches in 2023 had adequate semen, but towards the end of the spawning season some fish had none. Capelin held in laboratory tanks could regenerate semen within two days, maintaining their ability to seize continual mating opportunities. These results support the endurance rivalry hypothesis.
AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia
Authors: Sikirzhytskaya Aliaksandra , Tyagin Ilya , Sutton S. Scott , Wyatt Michael D. , Safro Ilya , Shtutman Michael
Published: June 2024

Neurodegenerative pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

Author Summary

This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.
Drivers ofIxodes ricinuspopulation dynamics in Northeast France: a Bayesian modelling approach
Authors: Kim Younjung , Jaulhac Benoît , Vesga Juan F , Zilliox Laurence , Boulanger Nathalie , Edmunds W John , Métras Raphaëlle
Published: June 2024

Ixodes ricinusis the primary vector for Lyme disease and tick-borne encephalitis across Europe. To better understand the environmental and ecological drivers of its population dynamics, we collected monthly tick density data over ten years (2013–2022) in four sites in Northeast France, whereI. ricinushas established, and developed and fitted a mathematical model using a Bayesian approach. Our model estimated oviposition, hatching, and moulting rates across a range of temperature or saturation deficit, as well as questing and vertebrate host contact rates. Furthermore, we showed the importance of diapause in reproducing the observed seasonal population dynamics. Finally, model projections indicated a significant decrease inI. ricinusabundance over the next 20 years under several climate change scenarios. This study elucidatesI. ricinuspopulation dynamics in Northeast France, provides foundations for developing models ofI. ricinus-borne pathogen transmission, and is adaptable to otherIxodidaepopulations of public health significance.
Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer
Authors: Rodman Esther P.B. , Emch Michael J. , Hou Xiaonan , Bajaj Archit , Pearson Nicole A. , John August J. , Ortiz Yamillie , Bass Adam D. , Singh Saloni , Baldassarre Gustavo , Kaufmann Scott H. , Weroha S. John , Hawse John R.
Published: June 2024

Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.

Statement of significance

Lestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.
Lag3 and PD-1 pathways regulate NFAT-dependent TCR signalling programmes during early CD4+T cell activation
Authors: Sheriff Lozan , Copland Alastair , Lecky David A.J. , Done Reygn , George Lorna S , Jennings Emma K. , Rouvray Sophie , Elliot Thomas A.E. , Jinks Elizabeth S. , Pallan Lalit , Bending David
Published: June 2024

Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early CD4+T cell activation remains unclear. Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4+T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA-sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOShiT follicular helper (Tfh) cell differentiation. NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent geneNr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor (TCR) signals during CD4+T cell re-activation. Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and NFAT-dependent transcriptional activity during early CD4+T cell re-activation.

Highlights

PD-1 and Lag3 pathways exhibit layered control of early CD4+T cell activation

Their co-blockade enhances NFAT-dependent TCR transcriptional programmes

Inhibition of NFAT signalling reverses the functional effects of PD-1 and Lag3 co-blockade

Mechanistically, PD-1 and Lag3 function to additively regulate TCR signal duration during re-activation of CD4+T cells
SpotSweeper: spatially-aware quality control for spatial transcriptomics
Authors: Totty Michael , Hicks Stephanie C. , Guo Boyi
Published: June 2024

Quality control (QC) is a crucial step to ensure the reliability and accuracy of the data obtained from RNA sequencing experiments, including spatially-resolved transcriptomics (SRT). Existing QC approaches for SRT that have been adopted from single-nucleus RNA sequencing (snRNA-seq) methods are confounded by spatial biology and are inappropriate for SRT data. In addition, no methods currently exist for identifying histological tissue artifacts unique to SRT. Here, we introduce SpotSweeper, spatially-aware QC methods for identifying local outliers and regional artifacts in SRT. SpotSweeper evaluates the quality of individual spots relative to their local neighborhood, thus minimizing bias due to biological heterogeneity, and uses multiscale methods to detect regional artifacts. Using SpotSweeper on publicly available data, we identified a consistent set of Visium barcodes/spots as systematically low quality and demonstrate that SpotSweeper accurately identifies two distinct types of regional artifacts, resulting in improved downstream clustering and marker gene detection for spatial domains.
Does force depression resulting from shortening against series elasticity contribute to the activation dependence of optimum length?
Authors: Mayfield Dean L , Holt Natalie C
Published: June 2024

The optimum length for force generation (L0) increases as activation is reduced, challenging classic theories of muscle contraction. Although the activation dependence ofL0is seemingly consistent with length-dependent Ca2+sensitivity, this mechanism can’t explain the apparent force dependence ofL0, or the effect of series compliance on activation-related shifts inL0. We have tested a theory proposing that the activation dependence ofL0relates to force depression resulting from shortening against series elasticity. This theory predicts that significant series compliance would cause tetanicL0to be shorter than the length corresponding to optimal filament overlap, thereby increasing the activation dependence ofL0. We tested this prediction by determiningL0and maximum tetanic force (P0) with (L0_spring,P0_spring) and without added compliance in bullfrog semitendinosus muscles. The activation dependence ofL0was characterised with the addition of twitch and doublet contractions. Springs attached to muscles gave added fixed-end compliances of 11-39%, and this added compliance induced force depression for tetanic fixed-end contractions (P0_spring/P0< 1). We found strong, negative correlations between spring compliance and bothP0_spring(r2= 0.89-91) andL0_spring(r2= 0.60-63;P< 0.001), while the activation dependence ofL0was positively correlated to added compliance (r2= 0.45,P= 0.011). However, since the compliance-mediated reduction inL0was modest relative to the activation-related shift reported for the bullfrog plantaris muscle, additional factors must be considered. Our demonstration of force depression under novel conditions adds support to the involvement of a stress-induced inhibition of cross-bridge binding.
A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane
Authors: Massidda Miles W. , Ashirov David , Demkov Andrei , Sices Aidan , Baker Aaron B.
Published: June 2024

Mechanical forces applied to cells are known to regulate a wide variety of biological processes. Recent studies have supported that mechanical forces can cause nuclear deformation, leading to significant alterations in the gene expression and chromatin landscape of the cell. While the stresses and strains applied to cells is it is often known or controlled experimentally on a macroscopic length scale, it is often unclear what the actual forces and displacements are at the microscopic level of the cell. In this work, we created a model of cell deformation during application of mechanical stretch to cultured cells growth on a flexible membrane. This configuration is commonly used is in experimental studies as a means to apply controlled mechanical strains to adherent cultured cells. The parameters used in the study were used for application of strain to a mesenchymal stem cell stretched on a membrane. computational model was created to simulate the stresses and strains within the cell under a variety of stain amplitudes, waveforms and frequencies of mechanical loading with the range of commonly used experimental systems. The results demonstrate the connection between mechanical loading parameters applied through the flexible membrane and the resulting stresses and strains within the cell and nucleus. Using a viscoelastic model of chromatin, we connected the results provide to a rough model of resulting deformation within chromatin from the forces applied to the nucleus. Overall, the model is useful in providing insight between experimentally applied mechanical forces and the actual forces within the cell to better interpret the results of experimental studies.

Statement of Significance

In this work, we created a computational model of the mechanical stretching of cell on a flexible membrane under cyclic mechanical loading. This model provides insight into the forces and displacements inside of cell that result from that application of stretch. As many experiments use this set up, our work is relevant to interpreting many studies that use mechanical stretch to stimulate mechanotransduction.
Pancreatic cancer cells exchange ribosomes through tunnelling nanotubes
Authors: Martínková Stanislava , Jansová Denisa , Vorel Jana , Lamačová Lucie Josefa , Daniel Petr , Hudec Michael , Boďo Mário , Hajer Jan , Susor Andrej , Trnka Jan
Published: June 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the deadliest types of cancer. Tunnelling nanotubes (TNTs) are thin, membranous, intercellular communication structuresobserved in normal and cancer cells, where they mediate the exchange of intracellular material and promote cell fitness, cancer spread and treatment resistance.

Results

PDAC cells increase the formation of TNTs upon exposure to gemcitabine. In the PANC-1 cell line and in tumour explants from patients, we observe polyadenylated mRNA, 5.8S rRNA, ribosomal proteins and assembled 80S ribosomes within the TNTs. Using HaloTag-labelled small ribosomal subunit component RPS9 we demonstrate the transport of ribosomes via TNTs into acceptor cells.

Conclusions

PDAC cells can exchange components of the translational machinery, including mRNA, which may contribute to the resistance to therapy, highlighting the potential of targeting TNT dynamics as a therapeutic approach for PDAC.

Main points

pancreatic tumor cells from patient biopsies form tunnelling nanotubes in 2D culture

formation of tunnelling nanotubes is promoted by gemcitabine

polyadenylated mRNAs, ribosomal components and assembled ribosomes are present in tunnelling nanotubes

ribosomes or their components are transferred via nanotubes to acceptor cells
Malnutrition disrupts adaptive immunity during visceral leishmaniasis by enhancing IL-10 production
Authors: Sacramento Laís Amorim , Lombana Claudia , Scott Phillip
Published: June 2024

Protein-energy malnutrition (PEM) is a risk factor for developing visceral leishmaniasis (VL). However, the impact on adaptive immunity during infection is unknown. To study the effect of malnutrition on chronic VL, we used a polynutrient-deficient diet (deficient protein, energy, zinc, and iron), which mimics moderate human malnutrition, followed byLeishmania infantuminfection. The polynutrient-deficient diet leads to growth stunting and reduced mass of visceral organs. Malnourished-infected mice harbored more parasites in the spleen and liver, had a reduced number of T lymphocytes, reduced production of IFN-γ by T cells, and exhibited enhanced IL-10 production. To test whether IL-10 blockade would lessen disease in the malnourished mice, we treated infected mice with monoclonal antibody α-IL-10R. α-IL-10R treatment reduced the parasite number of malnourished mice, restored the number of T cells producing IFN-γ, and enhanced hepatic granuloma formation. Our results indicate that malnutrition increases VL susceptibility due to a defective IFN-γ-mediated immunity attributable to increased IL-10 production.

Author Summary

Malnutrition contributes to the development of VL. Despite the advances regarding this association, how malnutrition affects the adaptive immune mechanisms in VL is still unclear. We found that malnutrition disrupts the ability to control parasite replication in the spleen and liver in VL due to defective IFN-γ-mediated immunity, reduced hepatic granuloma formation, and enhanced IL-10 production. Blocking IL-10R signaling restored the protective mechanisms to control parasite replication in the malnourished mice without interfering with the undernutrition state. Thus, we demonstrate that malnutrition disrupts the adaptive immunity against VL due to an aberrant IL-10 production. Understanding the association between malnutrition and VL will provide insights into therapeutic approaches.
Defining cellular determinants of resistance to PD-1 pathway blockade in non-small-cell lung cancer
Authors: Liu Baolin , Feng Kaichao , Yu Kezhuo , Gao Ranran , Hu Xueda , Qin Boyu , Wang Jinliang , Xue Zhiqiang , Han Weidong , Zhang Zemin
Published: June 2024

Despite sustained clinical responses to immune-checkpoint blockade (ICB) therapies in non-small-cell lung cancer (NSCLC), the majority of patients derive no clinical benefits, and the cellular and molecular underpinnings of such resistance remain incompletely understood. To identify cell types that may influence immunotherapy responses, we first integrated newly generated and previously published single-cell RNA sequencing data from 110 treatment-naïve patients with NSCLC. Among tumor-resident cell types, we identifiedMMP1+cancer-associated fibroblasts (CAFs), which were inversely correlated with the level of tumor-reactive T cells—a key determinant of response to ICB. Further single-cell analysis for newly collected 21 tumor samples from NSCLC patients treated with anti-PD-1/PD-L1 agents revealed thatMMP1+fibroblasts were indeed enriched in treatment-refractory patients, and this observation was also validated in an independent dataset of bulk RNA sequencing from 344 NSCLC patients treated with PD-L1 agents. Examination of the spatial architecture showed thatMMP1+fibroblasts were located at the tumor-stroma boundary, forming a single-cell layer that encircled the cancer cell aggregates, and we hence definedMMP1+fibroblasts as tumor-stroma boundary (tsb)CAFs. Such tsbCAFs likely promote resistance to ICB by functioning as a physical barrier that prevents tumor-reactive T cells from recognizing and killing cancer cells. Our study provides a new framework to identify cellular underpinnings of resistance to ICB and suggests new strategies to overcome ICB resistance.

Highlights

◊ Identification and characterization ofMMP1+fibroblasts in lung cancer.

◊ Single-cell meta-analysis reveals cell populations impeding the accumulation of tumor-reactive T cells.

◊MMP1+fibroblasts correlate with the low infiltration of tumor-reactive T cells and the resistance to anti-PD-1/PD-L1 treatment.

◊MMP1+fibroblasts appear to form a space barrier between malignant and T cells.
Accounting for salmon body size declines in fishery management can reduce conservation risks
Authors: Ohlberger Jan , Schindler Daniel E. , Staton Benjamin A.
Published: June 2024

Changes in population demographic structure can have tangible but unknown effects on management effectiveness. Fishery management of Pacific salmon is often informed by estimates of the number of spawners expected to produce maximum sustainable yield (SMSY), which implicitly assumes that reproductive output per spawner does not change over time. However, many salmon populations have experienced long-term trends in age, sex, and length-at-age compositions that have resulted in smaller body sizes of mature fish. We present an empirically-based simulation approach for evaluating management implications of declining reproductive output that results from shifting demographics. We simulated populations with or without demographic trends, selective or unselective harvests, and harvest policies based on assessment methods that did or did not account for demographic trends when estimating SMSY. A management strategy evaluation showed that expected mean harvests and run sizes were reduced when populations exhibited negative demographic trends. Reduced abundances and increased conservation risks could be partially mitigated by using a stock-recruit analysis based on egg mass instead of spawner abundance, or by using a precautionary management strategy where target escapements were higher than the estimated SMSY, especially in fisheries that selectively removed large fish. Accounting for demographic trends in stock-recruit analyses resulted in up to 25% higher run sizes and up to 20% lower conservation risks compared to traditional methods when trends toward smaller, younger, and male-biased runs were present in the population. Conservation of population demographic structure may be critical for sustaining productive fish populations and their benefits to ecosystems and people.
Strong signatures of selection on genes underlying core reinforcement mechanisms in speciating desert tortoises
Authors: Baty Sarah M , Araya-Donoso Raul , Paulsen Avery , Williams Avery , DeNardo Dale F , Kusumi Kenro , Dolby Greer
Published: June 2024

Genomic reinforcement and differential ecological adaptation are thought to be fundamental mechanisms of speciation. In this study we investigate the genomic basis of adaptation and reinforcement between two desert tortoise species of North America that occupy desert habitats with differing seasonal rainfall patterns and have considerable behavioral and reproductive differences yet maintain a narrow hybrid zone. We generated a chromosome-scale reference genome for Gopherus morafkai and performed analysis of synteny, genes under positive selection, and environmental niche modeling. Results show extensive positive selection (422 genes) including related to eye development and function that may relate to environmental differences, as well as prezygotic isolation mechanisms such as sperm-egg recognition, and postzygotic reinforcement mechanisms such as the spindle assembly checkpoint, and sister chromatid pairing. Together, results offer strong genetic support for the role of these classic processes in shaping reproductive isolation and lineage divergence of speciating tortoises.
Landscape and meteorological variables associated withAedes aegyptiandAedes albopictusmosquito infestation in two southeastern USA coastal cities
Authors: Costa-da-Silva Andre Luis , Dye-Braumuller Kyndall C , Wagner-Coello Helen Urpi , Li Huixuan , Johnson-Carson Danielle , Gunter Sarah M , Nolan Melissa S , DeGennaro Matthew
Published: June 2024

Aedestransmitted arboviral human cases are increasing worldwide and spreading to new areas of the United States of America (USA). These diseases continue to re-emerge likely due to changes in vector ecology, urbanization, human migration, and larger range of climatic suitability. Recent shifts in landscape and weather variables are predicted to impact the habitat patterns of urban mosquitoes such asAedes aegyptiandAedes albopictus. Miami (FL) is in the tropical zone and an established hotspot for arboviruses, while Charleston (SC) is in the humid subtropical zone and newly vulnerable. Although these coastal cities have distinct climates, both have hot summers. To understand mosquito infestation in both cities and potentiate our surveillance effort, we performed egg collections in the warmest season. We applied remote sensing with land-use cover and weather variation to identify mosquito infestation patterns. Our study found predominant occurrence ofAe. aegyptiand, to a lesser extent,Ae. albopictusin both cities. We detected statistically significant positive and negative associations between entomological indicators and most weather variables in combined data from both cities. For all entomological indices, weekly wind speed and relative humidity were significantly positively associated, while precipitation and maximum temperature were significantly negatively associated.Aedesegg abundance was significantly positively associated with open land in Charleston but was negatively associated with vegetation cover in combined data. There is a clear need for further observational studies to determine the impact of climate change onAe. aegyptiandAe. albopictusinfestation in the Southeastern region of the USA.
Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury
Authors: Hamilton Adam M. , Blackmer-Raynolds Lisa , Li Yaqing , Kelly Sean , Kebede Nardos , Williams Anna , Chang Jianjun , Garraway Sandra M. , Srinivasan Shanthi , Sampson Timothy R.
Published: June 2024

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.
CXIP4 depletion causes early lethality and pre-mRNA missplicing in Arabidopsis
Authors: Aceituno-Valenzuela Uri Israel , Fontcuberta-Cervera Sara , Micol-Ponce Rosa , Sarmiento-Mañús Raquel , Ruiz-Bayón Alejandro , Ponce María Rosa
Published: June 2024

Zinc knuckle (ZCCHC) motif-containing proteins are present in unicellular and multicellular eukaryotes and most ZCCHC proteins with known functions participate in the metabolism of various classes of RNA, such as mRNAs, ribosomal RNAs, and microRNAs. The Arabidopsis (Arabidopsis thaliana) genome encodes 69 ZCCHC-containing proteins, but the functions of most remain unclear. One of these proteins is CAX-INTERACTING PROTEIN 4 (CXIP4), which has been classified as a PTHR31437 family member, along with human SREK1-interacting protein 1 (SREK1IP1), which is thought to function in pre-mRNA splicing and RNA methylation. Metazoan SREK1IP1-like and plant CXIP4-like proteins only share a ZCCHC motif, and their functions remain almost entirely unknown. We studied two loss-of-function alleles of ArabidopsisCXIP4, the first mutations in PTHR31437 family genes described to date:cxip4-1is likely null and shows early lethality, andcxip4-2is hypomorphic and viable, with pleiotropic morphological defects. Thecxip4-2mutant exhibited deregulation of defense genes and upregulation of transcription factor encoding genes, some of which might explain its developmental defects. This mutant also exhibited increased intron retention events, and the specific functions of misspliced genes, such as those involved in “gene silencing by DNA methylation” and “mRNA polyadenylation factor” suggest that CXIP4 has additional functions. The CXIP4 protein localizes to the nucleus in a pattern resembling nuclear speckles, which are rich in splicing factors. Therefore,CXIP4is required for plant survival and proper development, and mRNA maturation.
RNA-TorsionBERT: leveraging language models for RNA 3D torsion angles prediction
Authors: Bernard Clément , Postic Guillaume , Ghannay Sahar , Tahi Fariza
Published: June 2024

Predicting the 3D structure of RNA is an ongoing challenge that has yet to be completely addressed despite continuous advancements. RNA 3D structures rely on distances between residues and base interactions but also backbone torsional angles. Knowing the torsional angles for each residue could help reconstruct its global folding, which is what we tackle in this work. This paper presents a novel approach for directly predicting RNA torsional angles from raw sequence data. Our method draws inspiration from the successful application of language models in various domains and adapts them to RNA. We have developed a language-based model, RNA-TorsionBERT, incorporating better sequential interactions for predicting RNA torsional and pseudo-torsional angles from the sequence only. Through extensive benchmarking, we demonstrate that our method improves the prediction of torsional angles compared to state-of-the-art methods. In addition, by using our predictive model, we have inferred a torsion angle-dependent scoring function, called RNA-Torsion-A, that replaces the true reference angles by our model prediction. We show that it accurately evaluates the quality of near-native predicted structures, in terms of RNA backbone torsion and pseudo-torsion angle values. Our work demonstrates promising results, suggesting the potential utility of language models in advancing RNA 3D structure prediction.

The source code is freely available on the EvryRNA platform:https://evryrna.ibisc.univ-evry.fr/evryrna/RNA-TorsionBERT.
An atomistic model of myosin interacting heads motif dynamics and their modification by 2’-deoxy-ADP
Authors: Childers Matthew Carter , Geeves Michael A. , Regnier Michael
Published: June 2024

The contraction of striated muscle is driven by cycling myosin motor proteins embedded within the thick filaments of sarcomeres. In addition to cross-bridge cycling with actin, these myosin proteins can enter an inactive, sequestered state in which the globular S1 heads rest along the thick filament surface and are unable to perform motor activities. Structurally, this state is called the interacting heads motif (IHM) and is a critical conformational state of myosin that regulates muscle contractility and energy expenditure. Structural perturbation of the sequestered state via missense mutations can pathologically disrupt the mechanical performance of muscle tissue. Thus, the IHM state has become a target for therapeutic intervention. An ATP analogue called 2’-deoxy-ATP (dATP) is a potent myosin activator which destabilizes the IHM. Here we use molecular dynamics simulations to study the molecular mechanisms by which dATP modifies the structure and dynamics of myosin in a sequestered state. Simulations with IHM containing ADP.Pi in both nucleotide binding pockets revealed residual dynamics in an otherwise ‘inactive’ and ‘sequestered’ state of a motor protein. Replacement of ADP.Pi by dADP.Pi triggered a series of structural changes that modify the protein-protein interface that stabilizes the sequestered state, and changes to this interface were accompanied by allosteric changes in remote regions of the protein complex. A comparative analysis of these dynamics predicted new structural sites that may affect IHM stability.
Nanoporous Platinum Microelectrode Arrays for Neuroscience Applications
Authors: Winter-Hjelm Nicolai , Isdal Leik , Köllensperger Peter A. , Sandvig Axel , Sandvig Ioanna , Sikorski Pawel
Published: June 2024

Microelectrode arrays are invaluable tools for investigating the electrophysiological behaviour of neuronal networks with high spatiotemporal precision. In recent years, it has become increasingly common to functionalize such electrodes with highly porous platinum to increase their effective surface area, and hence their signal-to-noise ratio. Although such functionalization significantly improves the electrochemical performance of the electrodes, the impact of various electrode morphologies on biocompatibility and electrophysiological performance in cell cultures remains poorly understood. In this study, we introduce reproducible protocols for depositing highly porous platinum with varying morphologies on microelectrodes designed for neural cell cultures. We also evaluate the impact of morphology and electrode size on the signal-to-noise ratio in recordings from rat cortical neurons cultured on these electrodes. Our results indicate that electrodes with a uniform layer of highly nanoporous platinum offer the best trade-off between biocompatibility, electrochemical, and electrophysiological performance. While more microporous electrodes exhibited lower impedance, nanoporous electrodes detected higher extracellular signal amplitudes from neurons, suggesting reduced distance between perisomatic neuronal areas and the electrodes. Additionally, these nanoporous electrodes showed fewer thickness variations at their edges compared to the more porous electrodes. Such edges can be mechanically broken off during cell culturing and contribute to long-term cytotoxic effects, which is highly undesirable. We hope this work will contribute to better standardization in creating and utilizing nanoporous platinum microelectrodes for neuroscience applications. Improving the accessibility and reproducibility of this technology is crucial for enhancing the quality of electrophysiological data and advancing our understanding of neuronal network function and dysfunction.
TheCapicuaC1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein
Authors: Luck Cuyler , Jacobs Kyle A. , Okimoto Ross A.
Published: June 2024

Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation ofCICtarget genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.

Significance Statement

Fusion oncogenes are neomorphic entities comprised of fractional coding sequences from two partner genes that have been inappropriately rearranged. The functional domains contributed by the partner genes shape the function of the resulting fusion. We use CIC::DUX4, a transcription factor fusion that drives an ultra-rare soft tissue sarcoma, to explore how preferential retention of a partner gene domain may influence the activity of the overall fusion. Our results indicate that the capicua C1 domain is retained in most CIC::DUX4 transcripts and is required for full activity of the CIC::DUX4 oncoprotein. We demonstrate that knowledge of where breakpoints occur and the resulting impact this has on the retention of functional domains can teach us about fusion behavior.
Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension
Authors: Berger Justin H. , Shi Yuji , Matsuura Timothy R. , Batmanov Kirill , Chen Xian , Tam Kelly , Marshall Mackenzie , Kue Richard , Patel Jiten , Taing Renee , Callaway Russell , Griffin Joanna , Kovacs Attila , Shanthappa Dinesh Hirenallur , Miller Russell , Zhang Bei B. , Roth Flach Rachel J. , Kelly Daniel P.
Published: June 2024

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel “2-hit” model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouseRenin1d. Control mice, HFD only, Renin only and HFD-Renin (aka “HFpEF”) littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e’, IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.

NEW & NOTEWORTHY

Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.