bluuebunny/crossref_metadata_2025 huggingface dataset:
First records of invasiveVespa velutina nigrithoraxBuysson, 1905 (Hymenoptera: Vespidae) andMegachile sculpturalisSmith, 1853 (Hymenoptera: Megachilidae) in Slovakia
Authors: Purkart Adrián , Semelbauer Marek , Šima Peter , Lukáš Jozef , Hoffner Simon , Fedor Peter , Senko Dušan
Published: October 2024

Biological invasions are an increasing threat to ecosystems; early identification of invasive species and rigorous monitoring are prerequisites to minimize environmental damage. Currently, two large hymenopterans of Asian origin are spreading across Europe: the yellow-legged hornetVespa velutina nigrithoraxBuysson, 1905 and the giant resin beeMegachile sculpturalisSmith, 1853, populations of which have been gradually being discovered across Europe since 2004 and 2008, respectively. Considering the current distribution of both species in Europe, further spread through Central Europe is expected in recent years. In July 2024, the first record ofM. sculpturaliswas documented in Slovakia, followed by more reports from 11 localities. Less than two months later, the second invasive hymenopteran,V. velutina nigrithorax, was also detected. Utilising multiple methods, their nest was discovered as well. On-site observations showed that the yellow-legged hornets (workers) were active almost two days after colony eradication. The finding of both species was accompanied by an intensive campaign using citizen science.
T Cell Receptor Diversity, Cancer and Sex: Insights from 30,000 TCRβRepertoires
Authors: Zahid H. Jabran , Taniguchi Ruth , Noceda Marco Garcia , Robins Harlan , Greissl Julia
Published: October 2024

Cancer is a widespread disease claiming millions of lives each year, yet the relationship between cancer risk and age-related immune system decline (i.e., immunosenescence), specifically the ability of T cells to detect and eliminate cancerous cells, remains poorly understood. Here we analyze T cell receptor (TCR)βrepertoires from ∼30,000 subjects demonstrating that TCR diversity—a key measure of immunocompetency—systematically declines between the ages of 20 and 80 years. Notably, this decline occurs 11 years later in females compared to males and coincides with their lower incidence of cancer, reinforcing the link between TCR diversity and cancer risk. Thus, we model rising cancer incidence with age as the combined effect of accumulating mutations and the increasing probability that cells harboring these mutations evade immune detection due to loss of TCR diversity. Our analysis suggests that both of these processes significantly contribute to the risk of cancer and that lower cancer incidence in females is due to the delayed onset of immunosenescence. Our results highlight the importance of understanding immunosenescence in carcinogenesis, potentially providing new opportunities for immunotherapies targeting an aging immune system as well as personalized care leveraging TCR diversity as a biomarker.
EFP Analyzer: A fast, accurate, and easy-to-teach program for analyzing Extracellular Field Potentials from iPSC-derived cardiomyocytes
Authors: Patel Nidhi , Shen Alex , Wada Yuko , Blair Marcia , Mitchell Devyn , Vanags Loren , Woo Suah , Ku Matthew , Dauda Kundivy , Morris William , Yang Minjoo , Knollmann Björn C. , Roden Dan M. , Salem Joe-Elie , Glazer Andrew M. , Kroncke Brett M.
Published: October 2024

Rationale

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an emerging model for determining drug effects and modeling disease. Specialized devices can generate Extracellular Field Potential (EFP) measurements from these cells, analogous to the ventricular complex of the electrocardiogram.

Objective

The objective of this study was to develop an easy-to-use, easy-to-teach, reproducible software tool to measure EFPs.

Methods-Results

We present the EFP-Analyzer (EFPA), a semi-automized analyzer for EFP traces, which identifies and averages beats, identifies landmarks, and calculates intervals. We evaluated the tool in an analysis of 358 EFP traces from 22 patient-derived lines. We analyzed spontaneously beating iPSC-CMs, as well as optically paced iPSC-CMs through channelrhodopsin. We developed stringent quality criteria and measured EFP intervals, including Field Potential Duration (FPD). FPD from optically paced iPSC-CMs were shorter than those of spontaneously beating iPSC-CMs (283.7.0±54.2 vs. 293.0±47.5, p: 0.32, respectively). We further analyzed the usability and data replicability of EFPA through an inter-intra observer analysis. Correlation coefficient for inter-reader tangent and threshold measurements for these FPD ranged between r: 0.93-1.00. Bland-Altman plots comparing inter observer results for spontaneously beating and paced iPSC-CMs showed 95% limits of agreement (−13.6 to 19.4ms and −13.2 to 15.3ms, respectively). The EFP-analyzer could accurately detect FPD prolongation due to drug (moxifloxacin) or pathogenic loss of function mutations (CACNA1CN639T). This program is available for download athttps://github.com/kroncke-lab/EFPA. The instructions will be available at the same listed website under the README section of the Github main page.

Conclusions

The EFP-Analyzer tool is a useful tool that enables the efficient use of iPSC-CMs as a model to study drug effects and disease.
hsa-miR-9-5p highly expressed in syncytiotrophoblast-derived extracellular vesicles from early-onset preeclampsia impairs cerebral microvascular endothelial cell pro-angiogenic capacity
Authors: Logenthiran Prassana , Awoyemi Toluwalase , Davis Jones Gabriel , Rahbar Maryam , Akbar Naveed , Cerdeira Ana Sofia , Escudero Carlos , Vatish Manu
Published: October 2024

Background

Cerebrovascular complications are the leading cause of maternal mortality associated with preeclampsia. Extracellular vesicles (EVs) containing microRNAs (miRNAs) and derived from syncytiotrophoblast (STB-EVs) are suspected to play a role in these complications. Previously, we found that STB-EVs from the placentas of women with preeclampsia have a higher content of the angiogenesis regulator hsa-miR-9-5p. We now investigate the effects of hsa-miR-9-5p on the proangiogenic properties of brain endothelial cells and identify potential protein targets involved in these processes.

Methods

Brain endothelial cells (hCMEC/D3) were treated with hsa-miR-9-5p (0, 5 and 10 nM) to assess cell viability and proliferation. Additionally, cell migration and proteomic profile in hCMEC/D3 treated with hsa-miR-9-5p (10 nM) were also analyzed.

Results

Compared to control, hsa-miR-9-5p significantly reduced hCMEC/D3 cell proliferation and migration without affecting cell viability. Proteomic analysis identified several vital proteins potentially mediating these effects, including vascular endothelial growth factor type C (VEGFC), placental growth factor (PLGF or PGF), and platelet-derived growth factor B (PDGFB). Treatment with hsa-miR-9-5p did not impair the capacity of hCMEC/D3 to respond to tumour necrosis factor-α (TNF-α).

Conclusion

hsa-miR-9-5p reduces hCMEC/D3 cell proliferation and migration, and modulates the expression of angiogenic regulators such as VEGFC, PLGF, and PDGFB, without affecting TNF-α mediated activation of hCMEC/D3. This suggests that STB-EVs cargo hsa-miR-9-5p may selectively inhibit the proangiogenic capacity of brain endothelial cells. These findings enhance our understanding of cerebrovascular alterations in preeclampsia and may guide future studies and therapeutic interventions.
“Single-Nuclei Analysis of the Unfolded Protein Response (SNUPR) reveals bortezomib resistance mechanisms in Multiple Myeloma”
Authors: Gigan Julien P. , Garcia-Gonzalez Paulina , Galliot Lou , Reynaud Alexandre , Ghaffar Yoan , Flores-Santibáñez Felipe , Seillier Eve , Lavignolle-Heguy Rosario , Dos Santos Daniela Barros , Fischaux Sharon , Combes Alexis , Narita Miwako , Gatti Evelina , Nal Beatrice , Rocchi Stéphane , Moreaux Jerome , Pierre Philippe , Argüello Rafael J.
Published: October 2024

Abstract

The unfolded protein response (UPR) is a key stress resistance pathway that has become a key potential target for improving the efficacy of cancer chemotherapy. The UPR involves the activation of three ER-resident stress sensors: PERK, IRE-1 and ATF6 with different signalling outcomes leading to cell death or survival. These cell-fate decisions are difficult to predict and are the result of the complex interaction of PERK, IRE-1 and ATF6 downstream events that have differences in their dynamics and their interplay. These characteristics of the UPR are still poorly defined due to lack of methods to monitor their activation simultaneously at single-cell level. We developed SNUPR (Single Nuclei analysis of the Unfolded Protein Response), an accessible technique that allows the profiling of the three UPR branches in nuclear suspensions by flow cytometry, and applied it to study UPR dynamics in a cancer-specific context. By performing transcriptomic analysis, we found that ER-stress sensor specific gene signatures correlate with patient survival in several blood malignancies, and by using SNUPR, we detected high heterogeneity during UPR activationin vitroin different human cancer cell lines, which could not be have been predicted by the level of expression of the sensors. Our SNUPR analyses further indicate that this heterogeneity is explained by variations in the intensity and duration of ER stress-induced protein synthesis inhibition via PERK, acting as upstream regulator of both the IRE-1/XBP1 and ATF6 dependent transcriptional programs. We extend the relevance of these observations by demonstrating that IRE-1/XBP1s pathway plays a critical role in bortezomib resistance of multiple myeloma cells and patients. We present here SNUPR, that can be used to monitor UPR dynamics with single-cell resolution and identified clinical contexts in which targeting a specific UPR branch could be detrimental or help circumventing chemotherapy resistance.

One Sentence Summary

SNUPR method enable single-cell UPR profiling and reveals the role of IRE-1 axis in predicting bortezomib resistance in multiple myeloma.

Highlights

SNUPR allows simultaneous profiling of PERK, IRE-1 and ATF6 activation with single- cell resolution.

Inhibition of protein synthesis via PERK control the activation levels of the IRE-1/XBP1s and ATF6 pathway.

IRE-1 activation and associated transcriptional signatures predict the outcome of patients with multiple myeloma treated with Bortezomib.

IRE-1 activity, but not PERK or ATF6, is essential to acquire bortezomib resistance in multiple myeloma cell lines.

Graphical abstract
Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity
Authors: Kwon Jason J. , Dilly Julien , Liu Shengwu , Kim Eejung , Bian Yuemin , Dharmaiah Srisathiyanarayanan , Tran Timothy H. , Kapner Kevin S. , Ly Seav Huong , Yang Xiaoping , Rabara Dana , Waybright Timothy J. , Giacomelli Andrew O. , Hong Andrew L. , Misek Sean , Wang Belinda , Ravi Arvind , Doench John G. , Beroukhim Rameen , Lemke Christopher T. , Haigis Kevin M. , Esposito Dominic , Root David E. , Nissley Dwight V. , Stephen Andrew G. , McCormick Frank , Simanshu Dhirendra K. , Hahn William C. , Aguirre Andrew J.
Published: October 2024

To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRASG12Dmutant alleles. We defined the spectrum of oncogenic potential for nearly all possibleKRASvariants, identifying several novel transforming alleles and elucidating a model to describe the frequency ofKRASmutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRASG12Dsecond-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.
Epigenetic control of Topoisomerase 1 activity presents a cancer vulnerability
Authors: Lee Tae-Hee , Qiao Colina X , Kuzin Vladislav , Shi Yuepeng , Ramanaranayan Vijayalalitha , Wu Tongyu , Zhou Xianzhen , Corujo David , Buschbeck Marcus , Baranello Laura , Oberdoerffer Philipp
Published: October 2024

DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. By visualizing transcription-induced topological stress in single cells, we find that macroH2A1.1 facilitates PAR-dependent recruitment of the TOP1cc repair effector XRCC1 to protect from ssDNA damage. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.
Angiogenic and Immune Predictors of Neoadjuvant Axitinib Response in Renal Cell Carcinoma with Venous Tumour Thrombus
Authors: Wray Rebecca , Paverd Hania , Machado Ines , Barbieri Johanna , Easita Farhana , Edwards Abigail R , Gallagher Ferdia A , Mendichovszky Iosif A , Mitchell Thomas J , de la Roche Maike , Shields Jaqueline D , Ursprung Stephan , Wallis Lauren , Warren Anne Y , Welsh Sarah J , Crispin-Ortuzar Mireia , Stewart Grant D , Jones James O
Published: October 2024

Venous tumour thrombus (VTT), where the primary tumour invades the renal vein and inferior vena cava, affects 10-15% of renal cell carcinoma (RCC) patients. Curative surgery for VTT is high-risk, but neoadjuvant therapy may improve outcomes. The NAXIVA trial demonstrated a 35% VTT response rate after 8 weeks of neoadjuvant axitinib, a VEGFR-directed therapy. However, understanding non-response is critical for better treatment. We conducted a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders had higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predicted response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features included plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario.

One Sentence Summary

A comprehensive multiparametric assessment of the effect of neoadjuvant axitinib in renal cell carcinoma patients with venous tumour thrombus was performed on tissue and peripheral blood, including an integrative machine learning model, which identified both angiogenic and immune determinants of response to therapy.
Deep generalizable prediction of RNA secondary structure via base pair motif energy
Authors: Zhu Heqin , Tang Fenghe , Quan Quan , Chen Ke , Xiong Peng , Zhou S. Kevin
Published: October 2024

RNA secondary structure plays essential roles in modeling RNA tertiary structure and further exploring the function of non-coding RNAs. Computational methods, especially deep learning methods, have demonstrated great potential and performance for RNA secondary structure prediction. However, the generalizability of deep learning models is a common unsolved issue in the situation of unseen out-of-distribution cases, which hinders the further improvement of accuracy and robustness of deep learning methods. Here we construct a base pair motif library which enumerates the complete space of locally adjacent three-neighbor base pair and records the thermodynamic energy of corresponding base pair motifs through de novo modeling of tertiary structures, and we further develop a deep learning approach for RNA secondary structure prediction, named BPfold, which employs hybrid transformer and convolutional neural network architecture and an elaborately designed base pair attention block to jointly learn representative features and relationship between RNA sequence and the energy map of base pair motif generated from the above motif library. Quantitative and qualitative experiments on sequence-wise datasets and family-wise datasets have demonstrated the great superiority of BPfold compared to other state-of-the-art approaches in both accuracy and generalizability. The significant performance of BPfold will greatly boost the development of deep learning methods for predicting RNA secondary structure and the further discovery of RNA structures and functionalities.
Trait matching without traits: using correspondence analysis to analyze the latent structure of interaction networks
Authors: Nicvert Lisa , Fritz Hervé , Dray Stéphane
Published: October 2024

Species interactions occurring in ecological communities are often represented as networks. The structure of these networks is thought to be linked to species’ interaction niches (or Eltonian niches), which are intimately related to the notion of trait matching, which posits that a species interacts preferentially with partners whose traits are complementary to their own.

Multivariate methods are commonly used to quantify species environmental niches (or Grinnellian niches). More recently, they have also been used to study the interaction niche, but these methods consider only the niche optimum and require trait data.

In this paper, we use the correspondence analysis (CA) framework to study interaction networks and investigate trait matching without requiring traits data, using the notion of latent traits. We use reciprocal scaling, a method related to CA, to estimate niche optima and breadths, defined respectively as the mean and standard deviation of latent traits of interacting partners in CA space. We present the method, test its performance using a simulation model we designed, and analyze a real mutalistic bird-fruits interaction network.

The simulation study shows that the method is able to recover niche breadths and optima for data generated with parameters values typical of ecological networks. The bird-fruit network analysis shows strong relationships between species niche optima and niche breadths: a posteriori correlation with species traits suggest that this latent structure is related to measured traits. In this network, birds and plants of intermediate size tend to have the widest niches and birds with pointed wings (preferentially foraging in the canopy) have smaller niches than birds with rounded wings (preferentially foraging in the understory).

CA and reciprocal scaling are described as fruitful methods to characterize species interaction profiles, provide an ecologically meaningful graphical representation of interaction niches and allow to explore the effect of latent traits on network structure.
Structural Basis for Voltage Gating and Dalfampridine Binding in the Shaker Potassium Channel
Authors: Pinto-Anwandter Bernardo I
Published: October 2024

The generation and propagation of action potentials in neurons depend on the coordinated activation of voltage-dependent sodium and potassium channels. Potassium channels of the Shaker family regulate neuronal excitability through voltage-dependent opening and closing of their ion conduction pore. This family of channels is an important therapeutic target, particularly in multiple sclerosis where the inhibitor dalfampridine (4-aminopyridine) is used to improve nerve conduction. The molecular details of how the voltage sensor domain drives opening of the pore domain has been limited by the lack of closed-state structures, also impairing the search for novel drugs. Using AlphaFold2-based conformational sampling methods we identify a structural model for the closed Shaker potassium channel where movement of the voltage sensor drives the opening trough interactions between the S4-S5 linker and S6 helix. We show experimentally that breakage of a backbone hydrogen bond is a critical part of the activation pathway. Through docking we identify a hydrophobic cavity formed by the pore domain helices that binds dalfampridine in the closed state. Our results demonstrate how voltage sensor movement drives pore opening and provide a structural framework for developing new therapeutic agents targeting the closed state. We anticipate this work will enable structure-based drug design efforts focused on state-dependent modulation of voltage-gated ion channels for the treatment of neurological disorders.
CRISPR knockout of winter-biasedSUT4alters phenology, biomass accrual, and fertility of field-grown hybrid poplar
Authors: Tuma Trevor T. , McInnes Holly A. , Pham Hongduyen , Bewg William P. , Deguchi Michihito , Zhou Ran , Surber Samantha M. , Lipzen Anna , Barry Kerrie W. , Lieb Brent , Weber Wyneken Daniela L. , Harman-Ware Anne E. , Dahlen Joseph , Harding Scott A. , Tsai Chung-Jui
Published: October 2024

Woody perennial trees annually transition between photoautotrophic and heterotrophic states. As carbohydrate accumulation and utilization patterns shift, so does the expression of genes encoding various sucrose-proton symporters (SUTs). The poplar genome contains fiveSUTgene family members involved in intracellular and long-distance sucrose transport. Among these, only the single-copySUT4and theSUT5/SUT6genome duplicates are expressed year-round, withSUT4strongly expressed in winter. Using CRISPR mutagenesis, we investigated the role of winter-expressedSUTsin carbohydrate allocation, biomass accrual, seasonal phenology, and sexual reproduction inPopulus tremula×P. albaunder field conditions. Insut4mutants, fall leaf senescence occurred earlier and spring bud flush was delayed compared to controls, resulting in reduced diameter and overall height growth. These mutants also exhibited altered sugar partitioning and reduced levels of raffinose family oligosaccharides, which are typically associated with cold and desiccation tolerance. Knockouts ofSUT5andSUT6, whether single or double, did not affect seasonal phenology or overall tree growth. All genotypes flowered precociously after two years in the field, butsut4catkins accumulated abnormally high levels of sucrose, galactinol, and raffinose. Transcriptome profiling showed down-regulation of genes associated with proanthocyanidin biosynthesis and vacuolar transport, and up-regulation of genes involved in protein oligomerization, misfolding, and refolding responses. Development ofsut4ovules was compromised, and no seeds were produced insut4catkins following controlled pollination. Our findings suggest that the single-copy tonoplast SUT4 may be more critical than other SUTs for mitigating stress associated with winter fitness and growth transitions during cool seasons.
Transcriptional profiling provides insights on sublethal thermal stress thresholds in juvenile bull trout
Authors: Best C. , Durhack T. C. , Chapelsky A. J. , Aminot M. , Islam S. S. , Heath D. D. , Mochnacz N. J. , Jeffries K. M.
Published: October 2024

Bull trout (Salvelinus confluentus) inhabit mainly cold-water streams in their Western North American range. Multiple anthropogenic stressors, including climate change, have caused population declines and range reduction, leading to classification of bull trout as threatened. Characterizing how fish respond to increasing temperature can identify key thresholds beyond which fish health is impacted, which is useful for developing species recovery strategies.

Juvenile bull trout were acclimated to a range of relevant temperatures (6-21 °C), after which mRNA transcripts involved in responding to thermal stress were measured using high- throughput qPCR, and their upper thermal tolerance (critical thermal maximum,CTmax) was determined. Beyond 18 °C appears to be a critical sublethal threshold for bull trout: capacity to increaseCTmaxthrough acclimation was lost, growth and survival decreased, and transcriptional data suggest widespread activation of cellular stress and growth suppression. Below 18 °C, transcriptional data suggest subtler metabolic adjustments in response to acclimation temperature, preceding changes in whole-animal performance. Altogether, these data provide insight into thermal responses in bull trout, and their capacity to cope with climate-change related warming.
Dose- and time-dependent effects of cobalt protoporphyrin IX on granulocyte mobilization and metabolic markers in mice
Authors: Bednarz Aleksandra , Kozuch Paweł , Kowalski Kacper , Skulimowska Izabella , Kachamakova-Trojanowska Neli , Filipek-Gorzała Jadwiga , Kwiecinska Patrycja , Gawlinska Kinga , Kubiak Andrzej , Bryniarska-Kubiak Natalia , Jozkowicz Alicja , Szade Krzysztof , Szade Agata
Published: October 2024

Recombinant granulocyte colony-stimulating factor (G-CSF) is the most commonly used agent for treating neutropenia and mobilizing hematopoietic stem cells (HSCs) for transplantation. However, some patients do not respond effectively to existing mobilization protocols. To address this, the development of new therapeutic approaches is necessary. One potential strategy is the pharmacological induction of endogenous mobilizing factors, which can be achieved through the administration of cobalt protoporphyrin IX (CoPP). CoPP induces mobilization of HSCs and granulocytes by increasing endogenous G-CSF production, though the optimal dosing and potential side effects remain unclear.

The aim of our study was to optimize the dose and timing of CoPP administration and evaluate its safety in mobilizing cells from the bone marrow to the blood. Our results show that CoPP exerts a dose-dependent mobilizing effect, with the highest G-CSF levels and number of mobilized leukocytes observed in mice treated with 10 mg/kg of CoPP. While there were no severe adverse effects, there were mild fluctuations in markers of liver and kidney function, including a slight reduction in urea nitrogen (BUN) and glucose levels during the five days of administration. Additionally, although most parameters normalized within 30 days after treatment, the decrease in BUN persisted. Mice experienced short-term weight loss following CoPP administration, but they regained their initial weight within two weeks. By day 30, leukocyte counts, hematopoietic stem and progenitor cells (HSPCs) in bone marrow, and G-CSF concentration in the blood had returned to baseline.

This study demonstrates that CoPP mobilizes cells from the bone marrow to the blood in a dose-dependent manner, with mild side effects, including temporary changes in biochemical markers and a sustained reduction in BUN levels.
Rapid ecosystem change after the cod collapse in Newfoundland & Labrador
Authors: Wudrick Alannah , Regular Paul M. , Tam Jamie C. , Bélanger David , Eddy Tyler D.
Published: October 2024

The cod collapse of Newfoundland and Labrador in the early 1990s was predicated by collapses of the key forage fish species in the region, capelin, and the wider groundfish community. After these collapses, rapid changes in ecosystem structure and function have been observed. From the early 2000s to mid 2010s, invertebrates dominated ecosystem biomass and the snow crab fishery became important to the region. During the late 2010s, invertebrates declined as groundfish stocks increased, although not to pre collapse levels. We developed two ecosystem models representing 1) the Grand Banks and 2) the Newfoundland and Labrador Shelf ecosystem structure and function for 2018-2020. We compared these models with existing ecosystem models that represent the combined Grand Banks and Newfoundland and Labrador Shelf ecosystem for the pre collapse (1985-1987) and invertebrate dominated (2013-2015) periods. Variability in primary productivity, species biomass, and catch reveal that the two model regions are distinct in ecosystem structure and function. Primary and secondary production has increased in the most recent period, however capelin biomass – an important factor for cod recovery – has remained low. Harp seals play a strong top-down ecosystem role and may be contributing to impaired cod recovery. Since the decline in capelin abundance, Arctic cod became an important alternative prey on the Newfoundland and Labrador Shelf region compared to reliance on sand lance and squid on the Grand Banks. Capelin has not shown signs of recovery in either region. Overall, the ecosystem structure in 2018-2020 in both regions is closer to the pre-collapse state than it was in 2013-2015, and the rapid change indicates that the system is highly dynamic.
Biocultural vulnerability of traditional crops in the Indian Trans Himalaya
Authors: Jaggi Harman , Anand Akshata , Solari Katherine A. , Echeverri Alejandra , Tobge Rinchen , Tsewang Tanzin , Suryawanshi Kulbhushansingh , Tuljapurkar Shripad
Published: October 2024

Traditional agricultural landscapes in mountain communities are critical for conserving biodiversity, biocultural diversity, and agroecological resources. Despite their significance, traditional farming systems are overlooked in modern agriculture and conservation, leading to genetic erosion and reduced cultivation of local crop landraces. Our research focuses on the fragile ecosystems of northwest Himalaya in India, and examines the ecological and genetic resilience of black pea (lesser known and understudied traditional crop) and barley (Hordeum vulgare) and compares them to the introduced cash crop of green pea (Pisum sativum L.). We conducted field experiments across elevation gradients to assess survival and reproductive traits for the three crops. We performed whole-genome sequencing to investigate the genetic diversity of black pea in relation to otherPisumspecies. Additionally, we analyzed the nutritional profile of black pea in comparison with green pea. Our findings indicate that traditional crops are better adapted to local climatic conditions in terms of their growth performance, and hold considerable genetic diversity and nutritional potential. Our results support the importance of integrating traditional knowledge with modern agroecological research and policy to promote climate-resilient, sustainable food systems. The results also argue for a reevaluation of traditional and often underutilized crops to support small-holding farmers and promote socio-ecological stability in vulnerable mountain regions.
Transposable element small and long RNAs in aging brains and implications in Huntington’s and Parkinson’s disease
Authors: Dayama Gargi , Gupta Shruti , Connizzo Brianne K. , Labadorf Adam T. , Myers Richard H. , Lau Nelson C.
Published: October 2024

Transposable Elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact of brain TE RNA dynamics on these phenomena is not fully understood. Therefore, we quantified TE RNA changes in aging post-mortem human and mouse brains and in the neurodegenerative disorders Huntington’s Disease (HD) and Parkinson’s Disease (PD). We tracked TE small RNAs (smRNAs) expression landscape to assess the relationship to the active processing from TE long RNAs (lnRNAs). Human brain transcriptomes from the BrainSpan Atlas displayed a significant shift of TE smRNA patterns at age 20 years, whereas aging mouse brains lacked any such marked change, despite clear shift in aging-associated mRNA levels. Human frontal cortex displayed pronounced sense TE smRNAs during aging with a negative relationship between the TE smRNAs and lnRNAs indicative of age associated regulatory effects. Our analysis revealed TE smRNAs dysregulation in HD, while PD showed a stronger impact on TE lnRNAs, potentially correlating with the early average age of death for HD relative to PD. Furthermore, TE-silencing factor TRIM28 was down-regulated only in aging human brains, possibly explaining the lack of substantial TE RNA changes in aging mouse brains. Our study suggests brain TE RNAs may serve as novel biomarkers of human brain aging and neurodegenerative disorders.
A DJ123 allele at the heading date quantitative trait locusqHd7.1promotes early heading without yield penalties under natural short-day and low fertility conditions in Madagascar
Authors: Kondo Katsuhiko , Hori Kiyosumi , Rakotondramanana Mbolatantely , Ranaivo Harisoa Nicole , Ueda Yoshiaki , Wissuwa Matthias
Published: October 2024

QTL analysis of heading date (Hd) was performed using a recombinant inbred line population derived from a cross between rice cultivars ʻIR64’ and ʻDJ123’. Phenotypic data was obtained from sites in Japan and Madagascar differing in photoperiod and soil fertility. The Japan site had long-days (LD) and high fertility, while the Madagascar site had short-days (SD) and low fertility conditions. Under LD in Japan, we discovered two Hd QTL on chromosome 7,qHd7.1andqHd7.2, whereas only one of these (qHd7.1) was detected under SD conditions in Madagascar. RILs carrying DJ123 alleles at both QTLs headed 9.5 days earlier in Japan (LD) compared to IR64 alleles, whereas the effect of DJ123 alleles atqHd7.1under SD conditions of Madagascar was 4 days and a combined effect ofqHd7.1andqHd7.2did not exist. In Madagascar, early heading did not carry a yield penalty, whereas it caused reduced grain yield in Japan. These results suggest that RILs harboring the DJ123 allele ofqHd7.1have high yield potential and good adaptation to low fertility conditions in Madagascar and that this can be achieved in a shortened cultivation period, improving resilience to effects of climate change for African rice farmers.
Root Remodeling Mechanisms and Salt Tolerance Trade-Offs: The Roles of HKT1, TMAC2, and TIP2;2 in Arabidopsis
Authors: Alshareef N. O. , Melino V. J. , Saber N. , De Rosa A. , Rey E. , Wang J.Y. , Al Babili S. , Byrt C. , Tester M.A. , Julkowska M. M.
Published: October 2024

Plant responses to salt stress involve complex processes integrating short- and long-term adaptations, including changes in ion transport, systemic signaling, root architecture, and biomass distribution. A key adaptive mechanism involves the regulation of sodium (Na+) and potassium (K+) ion transport via Class 1 HKT1 transporters, which reduce Na+accumulation in shoots, thereby enhancing salinity tolerance but at the expense of lateral root development. In this study, we identified differential roles of TMAC2 in modulating ABA accumulation and lateral root development under salt stress in two distinct Arabidopsis genotypes, Col-0 and C24. Overexpression of TMAC2 in the Col-0 background increased ABA accumulation, resulting in reduced lateral root development, suggesting a positive feedback loop involving HKT1, TMAC2, and ABA signaling. In contrast, TMAC2 overexpression in C24 reduced ABA accumulation in lines overexpressing HKT1, indicating genotype-specific differences in the TMAC2-HKT1 interaction. Additionally, we observed that the co-expression of TMAC2 and HKT1 in Col-0 induced ABI4 and ABI5 transcription factors, which are known to mediate salt sensitivity. These findings reveal a regulatory network where TMAC2 and HKT1 modulate salt stress responses through genotype-dependent feedback mechanisms. Our results highlight the complexity of root remodeling under salt stress and the crucial role of genetic background in shaping these adaptive responses.
Metastable phase-separated droplet generation and long-time DNA enrichment by laser-induced Soret effect
Authors: Kobayashi Mika , Minagawa Yoshihiro , Noji Hiroyuki
Published: October 2024

Spatiotemporally controlled laser-induced phase separation (LIPS) offers unique research avenues and has a potential for biological and biomedical applications. However, LIPS conditions often have drawbacks for practical use, which limit their applications. For instance, LIPS droplets are tentative and diminish after the laser is terminated. Here, we developed a novel LIPS method using laser-induced Soret effect with a simple setup to solve these problems. We generate liquid-liquid phase-separated (LLPS) droplets using LIPS in an aqueous two-phase system (ATPS) of dextran (DEX) and polyethylene glycol (PEG). When DEX-rich droplets were generated in the DEX/PEG mix on the phase boundary, the droplets showed unprecedently high longevity; the DEX droplets were retained over 48 h. This counterintuitive behavior suggests that the droplet is in an unknown metastable state. By exploiting the capability of DEX-rich droplets to enrich nucleic acid polymers, we achieved stable DNA enrichment in LIPS DEX droplets with a high enrichment factor of 1400 ± 400. Further, we patterned DNA-carrying DEX-rich droplets into a designed structure to demonstrate the stability and spatiotemporal controllability of DEX-rich droplet formation. This is the first report for LIPS droplet generation in a DEX/PEG system with flexible conditions for the usage of LIPS droplets, opening new avenues for biological and medical applications of LIPS.
TheMedicago truncatulaLYR4 intracellular domain serves as a scaffold in immunity signaling independent of its phosphorylation activity
Authors: Simonsen Bine , Rübsam Henriette , Kolte Marie Vogel , Larsen Maria Meisner , Krönauer Christina , Gysel Kira , Laursen Mette , Feng Feng , Kaya Gülendam , Oldroyd Giles E. D. , Stougaard Jens , Fort Sébastien , Radutoiu Simona , Andersen Kasper Røjkjær
Published: October 2024

Plants perceive and respond to chitin derived from fungal cell walls through lysine motif (LysM) receptor kinases. In the model legumeMedicago truncatula, CERK1 and LYR4 represent the LysM receptor pair important for chitin-triggered immunity signaling. Here, we show that both the active kinase receptor CERK1 and the pseudokinase receptor LYR4 contribute to immunity signaling, leading to the production of reactive oxygen species (ROS). We determine the crystal structure of the LYR4 core intracellular domain with a bound nucleotide analog in the active site. Biochemical characterization shows that LYR4 binds ATP and has both autophosphorylation as well as transphosphorylation activity towards CERK1. However,in plantaexperiments demonstrate that the phosphorylation ability is not necessary for the function of LYR4 in chitin-triggered ROS production, but that the presence of its intracellular domain is indispensable. Together, we show that in chitin-triggered immunity the intracellular domain of LYR4 serves as a signaling scaffold independent of its catalytic activity.
Regulating ferredoxin electron transfer using nanobody and antigen interactions
Authors: Truong Albert , Silberg Jonathan J.
Published: October 2024

Fission and fusion can be used to generate new regulatory functions in proteins. This approach has been used to create ferredoxins (Fd) whose cellular electron transfer is dependent upon small molecule binding. To investigate whether Fd fragments can be used to monitor macromolecular binding reactions, we investigated the effects of fusing fragments ofMastigocladus laminosusFd to nanobodies and their protein antigens. When Fd fragments arising from fission were fused to green fluorescent protein (GFP) and three different anti-GFP nanobodies, split proteins were identified that supported Fd-mediated electron transfer from Fd-NADP reductase (FNR) to sulfite reductase (SIR) inEscherichia coli. However, the order of nanobody and antigen fusion to the Fd fragments affected cellular electron transfer. Insertion of these anti-GFP nanobodies within Fd had differing effects on electron transfer. One domain-insertion variant was unable to support cellular electron transfer unless it was coexpressed with GFP, while others supported electron transfer in the absence of GFP. These findings show how Fds can be engineered so that their electron transfer is regulated by macromolecules, and they reveal the importance of exploring different nanobody homologs and fusion strategies when engineering biomolecular switches.
AI-readiness for Biomedical Data: Bridge2AI Recommendations
Authors: Clark Timothy , Caufield Harry , Parker Jillian A. , Al Manir Sadnan , Amorim Edilberto , Eddy James , Gim Nayoon , Gow Brian , Goar Wesley , Haendel Melissa , Hansen Jan N. , Harris Nomi , Hermjakob Henning , Joachimiak Marcin , Jordan Gianna , Lee In-Hee , K. McWeeney Shannon , Nebeker Camille , Nikolov Milen , Shaffer Jamie , Sheffield Nathan , Sheynkman Gloria , Stevenson James , Chen Jake Y. , Mungall Chris , Wagner Alex , Kong Sek Won , Ghosh Satrajit S. , Patel Bhavesh , Williams Andrew , Munoz-Torres Monica C.
Published: October 2024

Biomedical research and clinical practice are in the midst of a transition toward significantly increased use of artificial intelligence (AI) and machine learning (ML) methods. These advances promise to enable qualitatively deeper insight into complex challenges formerly beyond the reach of analytic methods and human intuition while placing increased demands on ethical and explainable artificial intelligence (XAI), given the opaque nature of many deep learning methods.

The U.S. National Institutes of Health (NIH) has initiated a significant research and development program, Bridge2AI, aimed at producing new “flagship” datasets designed to support AI/ML analysis of complex biomedical challenges, elucidate best practices, develop tools and standards in AI/ML data science, and disseminate these datasets, tools, and methods broadly to the biomedical community.

An essential set of concepts to be developed and disseminated in this program along with the data and tools produced are criteria for AI-readiness of data, including critical considerations for XAI and ethical, legal, and social implications (ELSI) of AI technologies. NIH Bridge to Artificial Intelligence (Bridge2AI) Standards Working Group members prepared this article to present methods for assessing the AI-readiness of biomedical data and the data standards perspectives and criteria we have developed throughout this program. While the field is rapidly evolving, these criteria are foundational for scientific rigor and the ethical design and application of biomedical AI methods.
A methodological framework for deriving the German food-based dietary guidelines 2024: food groups, nutrient goals, and objective functions
Authors: Schäfer Anne Carolin , Boeing Heiner , Gazan Rozenn , Conrad Johanna , Gedrich Kurt , Breidenassel Christina , Hauner Hans , Kroke Anja , Linseisen Jakob , Lorkowski Stefan , Nöthlings Ute , Richter Margrit , Schwingshackl Lukas , Vieux Florent , Watzl Bernhard
Published: October 2024

Background

For a growing number of food-based dietary guidelines (FBDGs), diet optimization is the tool of choice to account for the complex demands of healthy and sustainable diets. However, decisions about such optimization models’ parameters are rarely reported nor systematically studied.

Objectives

The objectives were to develop a framework for (i) the formulation of decision variables based on a hierarchical food classification system; (ii) the mathematical form of the objective function; and (iii) approaches to incorporate nutrient goals.

Methods

To answer objective (i), food groups from FoodEx2 levels 3-7 were applied as decision variables in a model using acceptability constraints (5thand 95thpercentile for food intakes of German adults (n=10,419)) and minimizing the deviation from the average observed dietary intakes. Building upon, to answer objectives (ii) and (iii), twelve models were run using decision variables from FoodEx2 level 3 (n=255), applying either a linear or squared and a relative or absolute way to deviate from observed dietary intakes, and three different lists of nutrient goals (allNUT-DRV, incorporating all nutrient goals; modNUT-DRV excluding nutrients with limited data quality; modNUT-AR using average requirements where applicable instead of recommended intakes).

Results

FoodEx2 food groups proved suitable as diet optimization decision variables. Regarding deviation, the largest differences were between the four different objective function types, e.g. in the linear-relative modNUT-DRV model, 46 food groups of the observed diet were changed to reach the model’s goal, in linear-absolute 78 food groups, squared-relative 167, and squared-absolute 248. The nutrient goals were fulfilled in all models, but the number of binding nutrient constraints was highest in the linear-relative models (e.g. allNUT-DRV: 11 vs. 7 in linear-absolute).

Conclusion

Considering the various possibilities to operationalize dietary aspects in an optimization model, this study offers valuable contributions to a framework for developing FBDGs via diet optimization.