bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiolipin clustering promotes mitochondrial membrane dynamics
Authors: Zuccaro Kelly E. , Abriata Luciano A. , Meireles Fernando Teixeira Pinto , Moss Frank R. , Frost Adam , Dal Peraro Matteo , Aydin Halil 
Published: May 2024

AbstractCardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.TeaserThis study reveals how CL modulates the activity of OPA1 and how MLCL impacts its ability to govern mitochondrial function.
Turgor pressure affects transverse stiffness and resonant frequencies of buzz-pollinated poricidal anthers
Authors: Alvord Mitchell , McNally Jenna , Casey Cailin , Jankauski Mark 
Published: May 2024

AbstractSeveral agriculturally valuable plants store their pollen in tube-like poricidal anthers, which release pollen through buzz pollination. In this process, bees rapidly vibrate the anther using their indirect flight muscles. The stiffness and resonant frequency of the anther are crucial for effective pollen release, yet the impact of turgor pressure on these properties is not well understood. Here, we perform three-point flexure tests and experimental modal analysis to determine anther transverse stiffness and resonant frequency, respectively. Dynamic nanoindentation is used to identify the anther’s storage modulus as a function of excitation frequency. We subsequently develop mathematical models to estimate how turgor pressure changes after the anther is removed from a flower, thereby emulating zero water availability. We find that 30 minutes post-ablation, anther stiffness decreases 60%. Anther resonant frequency decreases 20% 60 minutes post-ablation. Models indicate turgor pressure in the fresh anther is about 0.2 – 0.3 MPa. Our findings suggest that natural fluctuations in turgor pressure due to environmental factors like temperature and light intensity may require bees to adjust their foraging behaviors. Interestingly, anther storage modulus increased with excitation frequency, underscoring the need for more sophisticated mechanical models that consider viscous fluid transport through plant tissue moving forward.
Massively parallel screening of TIR-derived peptides reveals vast TLR-targeting immunomodulatory peptides
Authors: Lim Yun , Kang Tae Kyeom , Kim Meong Il , Kim Dohyeon , Kim Ji-Yul , Jung Sang Hoon , Park Keunwan , Lee Wook-Bin , Seo Moon-Hyeong 
Published: May 2024

AbstractToll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR-TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration of the vast unsequenced space of the TIR domain family. Here, we developed a comprehensive parallel screening method to uncover novel TIR-binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. We constructed a large peptide library, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIRand MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR-binding peptides. The selected peptides inhibited TLR signaling, demonstrated anti-inflammatory effects in macrophages and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR-targeted therapeutics.
A pilot dose-finding study of Terazosin in humans
Authors: Schultz Jordan L. , Gander Phillip E. , Workman Craig D. , Ponto Laura L. , Cross Stephen , Nance Christopher S. , Groth Christopher L. , Taylor Eric B. , Ernst Sarah E. , Xu Jia , Uc Ergun Y. , Magnotta Vincent A. , Welsh Michael J. , Narayanan Nandakumar S. 
Published: May 2024

ABSTRACTBackgroundParkinson’s disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects.MethodsEighteen healthy men and women (60 – 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels,31Phosphorous magnetic resonance spectroscopy for brain ATP levels,18F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics.ResultsOur results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral18F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response.ConclusionsTZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ’s efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.
The anthropogenic fingerprint on emerging infectious diseases
Authors: Gibb Rory , Ryan Sadie J. , Pigott David , Fernandez Maria del Pilar , Muylaert Renata L. , Albery Gregory F. , Becker Daniel J. , Blackburn Jason K. , Caceres-Escobar Hernan , Celone Michael , Eskew Evan A. , Frank Hannah K. , Han Barbara A. , Hulland Erin N. , Jones Kate E. , Katz Rebecca , Kucharski Adam , Limmathurotsakul Direk , Lippi Catherine A. , Longbottom Joshua , Martinez Juan Fernando , Messina Jane P. , Nsoesie Elaine O. , Redding David W. , Romero-Alvarez Daniel , Schmid Boris V. , Seifert Stephanie N. , Sinchi Anabel , Trisos Christopher H. , Wille Michelle , Carlson Colin J. 
Published: May 2024

AbstractEmerging infectious diseases are increasingly understood as a hallmark of the Anthropocene1–3. Most experts agree that anthropogenic ecosystem change and high-risk contact among people, livestock, and wildlife have contributed to the recent emergence of new zoonotic, vector-borne, and environmentally-transmitted pathogens1,4–6. However, the extent to which these factors also structure landscapes of human infection and outbreak risk is not well understood, beyond certain well-studied disease systems7–9. Here, we consolidate 58,319 unique records of outbreak events for 32 emerging infectious diseases worldwide, and systematically test the influence of 16 hypothesized social and environmental drivers on the geography of outbreak risk, while adjusting for multiple detection, reporting, and research biases. Across diseases, outbreak risks are widely associated with mosaic landscapes where people live alongside forests and fragmented ecosystems, and are commonly exacerbated by long-term decreases in precipitation. The combined effects of these drivers are particularly strong for vector-borne diseases (e.g., Lyme disease and dengue fever), underscoring that policy strategies to manage these emerging risks will need to address land use and climate change10–12. In contrast, we find little evidence that spillovers of directly-transmitted zoonotic diseases (e.g., Ebola virus disease and mpox) are consistently associated with these factors, or with other anthropogenic drivers such as deforestation and agricultural intensification13. Most importantly, we find that observed spatial outbreak intensity is primarily an artefact of the geography of healthcare access, indicating that existing disease surveillance systems remain insufficient for comprehensive monitoring and response: across diseases, outbreak reporting declined by a median of 32% (range 1.2%-96.7%) for each additional hour’s travel time from the nearest health facility. Our findings underscore that disease emergence is a multicausal feature of social-ecological systems, and that no one-size-fits-all global strategy can prevent epidemics and pandemics. Instead, ecosystem-based interventions should follow regional priorities and system-specific evidence, and be paired with investment in One Health surveillance and health system strengthening.
High-throughput competitive binding assay for targeting RNA with small molecules: discovery of new PreQ1riboswitch ligands
Authors: Wintermans Sophie E.L. , Hoffmann Jana S. , Tacoma Mariska D. , Broekhuizen Indy , van Doodewaerd Bjorn R. , Geurink Paul P. , Janssen Antonius P.A. , Artola Marta , Olsthoorn René R.C.L. 
Published: May 2024

AbstractIn the evolving landscape of RNA targeting, there is an indisputable need for new screening methodologies to find small molecules targeting relevant tertiary RNA structures, like viral pseudoknots or bacterial riboswitches. Here, we developed a competitive binding high-throughput screening assay to identify ligands for the bacterial PreQ1-I riboswitch. In this assay, ligands compete with a rationally designed quencherlabeled antisense for binding to the riboswitch. The method is validated for theFusobacterium nucleatum(Fnu),Thermoanaerobacter tengcongensis(Tte),Bacillus subtilis(Bsu) andEnterococcus faecalis(Efa) PreQ1riboswitches, using the natural riboswitch ligand PreQ1 and various analogues. A commercial RNA-focused library consisting of ∼15,000 compounds was then screened against theFnuriboswitch, leading to the identification of 4 hits exhibiting competitive binding activity. These hits were evaluated in in vitro translation assays against several PreQ1riboswitches. The most promising hit4494showed competitive binding activity to theFnu,Tte,BsuandEfariboswitches, and was able to inhibit translation of aTteriboswitch-regulated reporter gene, making it an interesting starting point for the development of new antibiotics. In essence, this HTS assay has the potential to discover highly sought-after RNA targeting small molecules for complex and clinically relevant RNA structures.Graphical abstract
Exploring the ability of the MD+FoldX method to predict SARS-CoV-2 antibody escape mutations using large-scale data
Authors: Chi L. América , Barnes Jonathan E. , Suresh Patel Jagdish , Ytreberg F. Marty 
Published: May 2024

ABSTRACTAntibody escape mutations pose a significant challenge to the effectiveness of vaccines and antibody-based therapies. The ability to predict these escape mutations with computer simulations would allow us to detect threats early and develop effective countermeasures, but a lack of large-scale experimental data has hampered the validation of these calculations. In this study, we evaluate the ability of the MD+FoldX molecular modeling method to predict escape mutations by leveraging a large deep mutational scanning dataset, focusing on the SARS-CoV-2 receptor binding domain. Our results show a positive correlation between predicted and experimental data, indicating that mutations with reduced predicted binding affinity correlate moderately with higher experimental escape fractions. We also demonstrate that better performance can be achieved using affinity cutoffs tailored to distinct antibody-antigen interactions rather than a one-size-fits-all approach. We find that 70% of the systems surpass the 50% precision mark, and demonstrate success in identifying mutations present in significant variants of concern and variants of interest. Despite promising results for some systems, our study highlights the challenges in comparing predicted and experimental values. It also emphasizes the need for new binding affinity methods with improved accuracy that are fast enough to estimate hundreds to thousands of antibody-antigen binding affinities.
Diurnal variations in digestion and luminal flow determine microbial population dynamics along the human large intestine
Authors: Salari Alinaghi , Cremer Jonas 
Published: May 2024

AbstractThe human large intestine harbors a highly dynamic microbial ecosystem in which growing microbes regularly replenish biomass lost via feces. Understanding this population dynamics is biomedically important but remains a significant challenge due to rapid changes in microbial biomass and intestinal fluid flows. Leveraging experimental data on fluid turnover, nutrient supply, and microbial growth, we here derive a biophysical model of population dynamics. We show how the digestion of meals in batches triggers strong fluctuations in fluid movement and bacteria growth along the proximal large intestine. Comparing different model scenarios, we further analyze how the expandable nature of the proximal large intestine, the presence of a pouch-like cecum off major flow paths, and the periodic exit of luminal content via ‘mass movements’ are required in combination to maintain the high microbial population observed in the proximal large intestine. Since the microbial population undergoes several bottlenecks followed by rapid growth each day, the effective population size in the proximal large intestine is small,Ne∼ 107− 1011, promoting the fast evolution of microbes. The diurnal fluctuations in flow also hamper the accumulation of slower-growing bacteria and lead to substantial variations in the uptake of fermentation products by the host. Our findings underscore the highly intertwined population dynamics of the gut microbiota, determined by the physics of fluid flow and growth with strong consequences for the microbiome and the host.Significance statementThe density of microbial biomass within the large intestine is a key determinant of microbiome-host interactions and their impact on the human body. Studies with animal models have suggested highly intertwined population dynamics with strong variations of microbial densities over time and space. To elucidate the physiological drivers of these spatiotemporal dynamics along the human large intestine, we introduce a biophysical modeling framework that considers at its core the diurnal variation of digestion and fluid flow. Our analysis reveals how nutrient supply and the rapid movement of luminal content cause strong fluctuations in microbial biomass turnover throughout the day. The intertwined dynamics provide the host with ample mechanisms to control the microbiota, suppressing, for example, the emergence of slow-growing cross-feeding microbes.
Strong pairwise interactions do not drive interactions in a plant leaf associated microbial community
Authors: Höhn Franziska , Chaudhry Vasvi , Bagci Caner , Mahmoudi Maryam , Klenk Elke , Berg Lara , Stincone Paolo , Hughes Chambers C. , Petras Daniel , Brötz-Oesterhelt Heike , Kemen Eric , Ziemert Nadine 
Published: May 2024

AbstractMicrobial communities that promote plant growth show promise in reducing the impacts of climate change on plant health and productivity. Understanding microbe-microbe interactions in a community context is paramount for designing effective microbial consortia that enhance plant resilience. In this study, we investigated the dynamics of a synthetic microbial community (SynCom) assembled fromArabidopsis thalianaleaves to elucidate factors shaping community composition and stability. We found notable disparities betweenin vitropairwise interactions and those inferred from correlation networksin planta. Our findings suggested that secondary metabolites, particularly antimicrobials, might mediate interactionsin vitro, but fade into the background in the community context. Through co-cultivation experiments, we identified the siderophore pseudobactin as a potent antimicrobial agent against several SynCom members, but its impact on community compositionin plantawas negligible. Notably, dominant SynCom members, such asPseudomonas koreensis, Flavobacterium pectinovorum, andSporobolomyces roseus, exhibited only positive correlations, suggesting synergism based on for example exopolysaccharides and biotransformation might drive community dynamics rather than competition. Two correlations between SynCom members in the co-abundance network corresponded with their pairwisein vitrointeractions, highlighting the potential for further research, and demonstrating the usefulness of correlation networks in identifying key microbe-microbe interactions. Our findings highlight the importance of considering microbiome-wide interaction studies and synthetic communities in understanding and manipulating plant microbiomes.
Autonomous Shaping of the piRNA Sequence Repertoire by Competition between Adjacent Ping-Pong Sites
Authors: Yu Jie , Izumi Natsuko , Tomari Yukihide , Shoji Keisuke 
Published: May 2024

SUMMARYPIWI-interacting RNAs (piRNAs) are crucial for silencing transposable elements (TEs). In many species, piRNAs are generated via a complex process known as the ping-pong pathway, which couples TE cleavage with new piRNA amplification. However, the biological significance of this complexity and its impact on the piRNA sequence repertoire remain unclear. Here, we systematically compared piRNA production patterns in two closely related silkworm cell lines and found significant changes in their piRNA sequence repertoire. Importantly, the changeability of this repertoire showed a strong negative correlation with the efficiency of piRNA biogenesis. This can be explained by competition between adjacent ping-pong sites, as supported by our mathematical modeling. Moreover, this competition can rationalize how piRNAs autonomously avoid deleterious mismatches to target TEs. These findings unveil the intrinsic plasticity and adaptability of the piRNA system to combat diverse TE sequences and highlight the universal power of competition and self-amplification to drive autonomous optimization.
Differential biological effect of low doses of ionizing radiation depending on the radiosensitivity in a cell line model
Authors: Palma-Rojo Elia , Barquinero Joan-Francesc , Pérez-Alija Jaime , González Juan R , Armengol Gemma 
Published: May 2024

ABSTRACTPurposeExposure to low doses (LD) of ionizing radiation (IR), such as the ones employed in computed tomography (CT) examination, can be associated with cancer risk. However, not all individuals respond the same to IR, and cancer development could depend on the individual radiosensitivity. Notably, inter-individual differences in the response to IR have been very well studied for high and medium doses, but not for LD. In the present study, we wanted to evaluate the differences in the response to a CT-scan radiation dose of 20 mGy in two lymphoblastoid cell lines with different radiosensitivity.Materials and MethodsSeveral parameters were studied: gene expression, DNA damage, and its repair (by analyzing gamma-H2AX foci, chromosome breaks, and sister chromatid exchange), as well as cell viability, proliferation, and death.ResultsAfter 20 mGy of IR, the radiosensitive (RS) cell line showed an increase in DNA damage, and higher cell proliferation and apoptosis, whereas the radioresistant (RR) cell line was insensitive to this LD. Interestingly, gene expression analysis showed a higher expression of an antioxidant gene in the RR cell line, which could be used by the cells as a protective mechanism. After a dose of 500 mGy, both cell lines were affected by IR but with significant differences. The RS cells presented an increase in DNA damage and apoptosis, but a decrease in cell proliferation and cell viability, as well as less antioxidant response.ConclusionsA differential biological effect was observed between two cell lines with different radiosensitivity, and these differences are especially interesting after a CT scan dose. If this is confirmed by further studies, one could think that individuals with radiosensitivity-related genetic variants may be more vulnerable to long-term effects of IR, potentially increasing cancer risk after LD exposure.
Pipolins are bimodular platforms that maintain a reservoir of defense systems exchangeable with various bacterial genetic mobile elements
Authors: Mateo-Cáceres Víctor , Redrejo-Rodríguez Modesto 
Published: May 2024

ABSTRACTDefense genes gather in diverse types of genomic islands in bacteria and provide immunity against viruses and other genetic mobile elements. Here, we disclose pipolins, previously found in diverse bacterial phyla and encoding a primer-independent PolB, as a new category of widespread defense islands. The analysis of the occurrence and structure of pipolins revealed that they are commonly integrative elements flanked by direct repeats in Gammaproteobacteria genomes, mainlyEscherichia,VibrioorAeromonas, often taking up known mobile elements integration hotspots. Remarkably, integrase dynamics correlates with alternative integration spots and enables diverse lifestyles, from integrative to mobilizable and plasmid pipolins, such as in members of the generaLimosilactobacillus,PseudosulfitobacterorStaphylococcus.Pipolins harbor a minimal core and a large cargo module enriched for defense factors. In addition, analysis of the weighted gene repertoire relatedness revealed that many of these defense factors are actively exchanged with other mobile elements. These findings indicate pipolins and, potentially other defense islands, act as orthogonal reservoirs of defense genes, potentially transferable to immune autonomous MGEs, suggesting complementary exchange mechanisms for defense genes in bacterial populations.
SARS-CoV-2 3CLPro Dihedral Angles Reveal Allosteric Signaling
Authors: Evans Daniel , Sheraz Samreen , Lau Albert 
Published: May 2024

AbstractIn allosteric proteins, identifying the pathways that signals take from allosteric ligand-binding sites to enzyme active sites or binding pockets and interfaces remains challenging. This avenue of research is motivated by the goals of understanding particular macromolecular systems of interest and creating general methods for their study. An especially important protein that is the subject of many investigations in allostery is the SARS-CoV-2 main protease (Mpro), which is necessary for coronaviral replication. It is both an attractive drug target and, due to intense interest in it for the development of pharmaceutical compounds, a gauge of the state-of-the-art approaches in studying protein inhibition. Here we develop a computational method for characterizing protein allostery and use it to study Mpro. We propose a role of the protein’s C-terminal tail in allosteric modulation and warn of unintuitive traps that can plague studies of the role of protein dihedrals angles in transmitting allosteric signals.