bluuebunny/crossref_metadata_2025_split huggingface dataset:
A coarse-grained model of disordered RNA for simulations of biomolecular condensates
Authors: Yasuda Ikki , von Bülow Sören , Tesei Giulio , Yamamoto Eiji , Yasuoka Kenji , Lindorff-Larsen Kresten 
Published: November 2024

AbstractProtein-RNA condensates are involved in a range of cellular activities. Coarse-grained molecular models of intrinsically disordered proteins have been developed to shed light on and predict single-chain properties and phase separation. An RNA model compatible with such models for disordered proteins would enable the study of complex biomolecular mixtures involving RNA. Here, we present a sequence-independent coarse-grained, two-bead-per-nucleotide model of disordered, flexible RNA based on a hydropathy scale. We parameterize the model, which we term CALVADOS-RNA, using a combination of bottom-up and top-down approaches to reproduce local RNA geometry and intramolecular interactions based on atomistic simulations and in vitro experiments. The model semi-quantitatively captures several aspects of RNA-RNA and RNA-protein interactions. We examined RNA-RNA interactions by comparing calculated and experimental virial coefficients, and non-specific RNA-protein interaction by studying reentrant phase behavior of protein-RNA mixtures. We demonstrate the utility of the model by simulating the formation of mixed condensates consisting of the disordered region of MED1 and RNA chains, and the selective partitioning of disordered regions from transcription factors into these, and compare the results to experiments. Despite the simplicity of our model we show that it captures several key aspects of protein-RNA interactions and may therefore be used as a baseline model to study several aspects of the biophysics and biology of protein-RNA condensates.
Preparing for Disease X requires CLARITY – Lessons learned from COVID-19 – A systematic Review
Authors: Boivin Michael , Bourbeau Jean , Sedeno Maria , Horvat Emily , Li Pei-Zhi , Noueihed Baraa , Connelly Kim A. , Jain Akshay B. , Lin Peter , Mazer Bruce D. , Saposnik Gustavo , Strain William D. 
Published: November 2024

AbstractObjectivesThe COVID-19 pandemic has highlighted the critical need for comprehensive preparedness strategies for future pandemics, particularly those caused by unknown pathogens, or Disease X.Study DesignOur systematic review examined current literature on COVID-19 risk factors, identifying significant gaps and inconsistencies in data reporting.MethodsA systematic literature search was conducted including all English language published retrospective and prospective observational studies which documented clinical outcomes of COVID-19 in adult patients, on Ovid MEDLINE(R) and Epub databases (December 2019 to March 2023).ResultsThe search yielded 440 articles of which 29 were included in the systematic review. We identified major risk factors for severe outcomes. However, inconsistencies in reporting comorbidities, age, disease control levels, medication use, vaccination status, and variant type, limited our analysis. In many publications, this information was not included. Additionally, variations in public attitudes, knowledge, and behaviours regarding COVID-19 vaccines further complicated resource distribution. We propose the CLARITY model to address these gaps by standardizing risk factor reporting, encompassing detailed comorbidity profiles, disease control metrics, age analyses, medication and vaccination data, and variant-specific information.ConclusionsImplementing the CLARITY model could improve preparedness and response strategies for Disease X, enabling healthcare professionals and systems to allocate resources more effectively and mitigate the impact of future pandemics. This review underscores the necessity for a coordinated global effort to enhance pandemic preparedness through improved data reporting and risk stratification.FundingThis study received financial support from Moderna Biopharma Canada Corporation.Trial RegistrationPROSPERO Identifier CRD42023449647
Structural insights into the force-transducing mechanism of a motor-stator complex important for bacterial outer membrane lipid homeostasis
Authors: Yeow Jiang , Chia Chee Geng , Lim Nadege Zi-Lin , Chng Shu-Sin 
Published: November 2024

AbstractGram-negative bacteria assemble an asymmetric outer membrane (OM) that functions as an effective barrier against antibiotics. Building a stable and functional OM requires assembly and maintenance of balanced levels of proteins, lipopolysaccharides, and phospholipids into the bilayer. InEscherichia coli, the trans-envelope Tol-Pal complex has recently been established to play a primary role in maintaining OM lipid homeostasis. It is believed that the motor-stator complex TolQR exploits the proton motive force in the inner membrane to induce conformational changes in the TolA effector, ultimately generating a force across the cell envelope to activate processes at the OM. Molecular details of how such force transduction occurs via the TolQRA complex is unknown. Here, we solve structures of theE. coliTolQRA complex using single particle cryo-EM, capturing the transmembrane (TM) regions of the purified complex in two distinct states at ∼3.6 Å and ∼4.2 Å nominal resolutions. We define how the TolA N-terminal TM helix interacts with an asymmetric TolQ5R2sub-complex in two different positions, revealing how the two TolQRA states are related by rotation of the TolQ pentamer. By considering structural prediction of the periplasmic domains of the complex, we propose a working model for how proton passage through the complex induces rotary movement that can be coupled to TolA for force transduction across the cell envelope.
Variable inhibition of different Legionella species by antagonistic bacteria
Authors: Cavallaro Alessio , Probst Silke , Duft Tobias , Rieder Max , El Fateh Oliver Abo , Stricker Josch , Gabrielli Marco , Robinson Serina , Hammes Frederik 
Published: November 2024

AbstractThe genus Legionella includes opportunistic pathogens inhabiting engineered aquatic ecosystems, where managing their presence and abundance is crucial for public health. In these environments, Legionella interact positively or negatively with multiple members of the microbial communities. Here, we identified bacteria and compounds with Legionella-antagonistic properties. We isolated 212 bacterial colonies from various water sources in Switzerland and screened them for their ability to inhibit one reference strain of L. pneumophila. Ten selected antagonistic isolates were subsequently tested with spot-on-lawn-assays for inhibition towards seven environmental and two clinical isolates of Legionella, representing different species and strains. The antagonists produced highly variable inhibition patterns, highlighting distinct differences in susceptibility among Legionella species, and even strains. Only three isolates, all identified as Pseudomonas lurida, inhibited all Legionella species. Furthermore, we analysed the genomes of the antagonistic bacteria, and identified genes for several probable inhibitory compounds. We specifically found the gene cluster for the biosurfactant viscosin to be uniquely encoded by three Pseudomonas lurida isolates. This compound was subsequently detected in the supernatant of co-cultures inoculated with the antagonists and Legionella. This study provides new insights on the ability of aquatic microorganisms to compete with Legionella in controlled laboratory settings. It also highlights the diversity across and within Legionella species in their resistance to external antagonistic stress, and confirms the anti-Legionella activity of selected biosurfactants. These results can contribute to the understanding of how different species inhabit separate niches in the environment, and expand the discussion around alternative Legionella mitigation strategies.
Resting-state alpha reactivity is reduced in Parkinson’s disease and associated with gait variability
Authors: Lirani-Silva Ellen , Silva Layla C. S. , Orcioli-Silva Diego , Beretta Victor S. , França Lucas G. S. , Coelho Daniel B. , Vitorio Rodrigo 
Published: November 2024

ABSTRACTBackgroundThe extent to which the cholinergic system contributes to gait impairments in Parkinson’s disease (PD) remains unclear. Electroencephalography (EEG) alpha reactivity, which refers to change in alpha power over occipital electrodes upon opening the eyes, has been suggested as a marker of cholinergic function. We compared alpha reactivity between people with PD and healthy individuals and explored its potential association with gait measures.MethodsEyes-closed and eyes-open resting-state EEG data were recorded from 20 people with idiopathic PD and 19 healthy individuals with a 64-channel EEG system. Alpha reactivity was calculated as the relative change in alpha power (8-13 Hz) over occipital electrodes from eyes-closed to eyes-open. Gait spatiotemporal measures were obtained with an electronic walkway.ResultsAlpha reactivity was reduced in people with PD compared to healthy individuals (U = 105, p = 0.017); the rank-biserial correlation of 0.447 indicated a moderate effect size. When controlling for global cognition (Mini Mental State Examination), the group difference in alpha reactivity was no longer significant. Alpha reactivity associated with measures of gait variability only (rho = −0.437 to −0.532).ConclusionsReduced alpha reactivity in PD is driven by levels of global cognition and suggests impaired cholinergic function in PD. Reduced alpha reactivity was associated with greater gait variability, indicating a role of the cholinergic system in the mechanisms underlying gait variability. Therefore, the cholinergic system may represent a target for treatments aiming to reduce gait variability and alpha reactivity should be further explored as an endpoint for clinical trials.
Multi-stream predictions in human auditory cortex during natural music listening
Authors: Robert Paul , Van Cang Mathieu Pham , Mercier Manuel , Trébuchon Agnès , Bartolomei Fabrice , Arnal Luc H. , Morillon Benjamin , Doelling Keith 
Published: November 2024

AbstractReal-world perception involves the prediction and integration of multiple dynamic objects and features in parallel, yet most research focuses on single-stream sequences. We present PolyRNN, a recurrent neural network designed to model predictions across multiple, simultaneous information streams, using polyphonic music as a case study. We recorded neurophysiological activity non invasively (MEG) and within the human cortex (intracranial EEG) while participants listened to real piano music. Musical expectations are encoded in P2- and P3-like components in auditory regions. Compared to a state-of-the-art generative music model, we demonstrate that parallelization better reflects the brain’s processing of simultaneous sequences compared to serialization. Overall, our approach enables the study of predictive processing in ecologically valid polyphonic music and provides a general framework for modeling predictions in simultaneous streams.
Mechanistic Insight into pH-Driven Phase Transition of Lipid Nanoparticles
Authors: Trollmann Marius F.W. , Böckmann Rainer A. 
Published: November 2024

AbstractLipid nanoparticles (LNPs) are essential delivery vehicles in mRNA-based vaccines, with their functionality largely governed by aminolipids. At low pH, protonated aminolipids facilitate efficient mRNA encapsulation, while their deprotonation at physiological pH drives LNP remodeling into a stable spherical structure, potentially aiding mRNA release during endosomal re-protonation and concomitant restructuring at low pH.Our study uncovers the pH-dependent phase transition of theComirnatylipid formulation at the molecular scale, highlighting the intricate interplay between lipid reorganization and aminolipid protonation. We observe a substantial shift in the aminolipid pKa, from 7-8 at the LNP surface to below 4 within the hydrophobic LNP core, resulting in an overall apparent pKaof the lipid nanoparticle of 6.3. The pH-dependent protonation significantly affects the aminolipid’s localization, with protonated aminolipids enriched in vicinity of the mRNA and at the LNP surface at neutral pH. The lipid monolayer covering LNPs at neutral pH comprises cholesterol (60–65%), helper phospholipids (20–25%), PEGylated lipids (5%), and a mix of protonated and deprotonated aminolipids (5–10%). These findings provide mechanistic insights into aminolipids behavior in LNPs, offering a foundation for optimizing LNP design to enhance stability, tunable pH responses, and therapeutic efficacy.
Immunofocusing on the conserved fusion peptide of HIV envelope glycoprotein in rhesus macaques
Authors: Pratap Payal P. , Cottrell Christopher A. , Quinn James , Carnathan Diane G. , Bader Daniel L.V. , Tran Andy S. , Enemuo Chiamaka A. , Ngo Julia T. , Richey Sara T. , Gao Hongmei , Shen Xiaoying , Greene Kelli M. , Hurtado Jonathan , Michaels Katarzyna Kaczmarek , Ben-Akiva Elana , Allen Joel D. , Ozorowski Gabriel , Crispin Max , Briney Bryan , Montefiori David , Silvestri Guido , Irvine Darrell J. , Crotty Shane , Ward Andrew B. 
Published: November 2024

Abstract/SummaryDuring infection, the fusion peptide (FP) of HIV envelope glycoprotein (Env) serves a central role in viral fusion with the host cell. As such, the FP is highly conserved and therefore an attractive epitope for vaccine design. Here, we describe a vaccination study in non-human primates (NHPs) where glycan deletions were made on soluble HIV Env to increase FP epitope exposure. When delivered via implantable osmotic pumps, this immunogen primed immune responses against the FP, which were then boosted with heterologous trimers resulting in a focused immune response targeting the conserved FP epitope. Although autologous immunizations did not elicit high affinity FP-targeting antibodies, the conserved FP epitope on a heterologous trimer further matured the lower affinity, FP-targeting B cells. This study suggests using epitope conservation strategies on distinct Env trimer immunogens can focus humoral responses on desired neutralizing epitopes and suppress immune-distracting antibody responses against non-neutralizing epitopes.
Hippocampal CA2 neurons disproportionately express AAV-delivered genetic cargo
Authors: Alexander Georgia M. , He Bo , Leikvoll Austin , Jones Stephanie , Wine Rob , Kara Prakash , Martin Negin , Dudek Serena M. 
Published: November 2024

ABSTRACTHippocampal area CA2 is unique in many ways, largely based on the complement of genes expressed there. We and others have observed that CA2 neurons exhibit a uniquely robust tropism for adeno-associated viruses (AAVs) of multiple serotypes and variants. In this study, we aimed to systematically investigate the propensity for AAV tropism toward CA2 across a wide range of AAV serotypes and variants, injected either intrahippocampally or systemically, including AAV1, 2, 5, 6, 8, 9, DJ, PHP.B, PHP.eB, and CAP-B10. We found that most serotypes and variants produced disproportionally high expression of AAV-delivered genetic material in hippocampal area CA2, although two serotypes (AAV6 and DJ) did not. In an effort to understand the mechanism(s) behind this observation, we considered perineuronal nets (PNNs) that ensheathe CA2 pyramidal cells and, among other functions, buffer diffusion of ions and molecules. We hypothesized that PNNs might attract AAV particles and maintain them in close proximity to CA2 neurons, thereby increasing exposure to AAV particles. However, genetic deletion of PNNs from CA2 had no effect on AAV transduction. Next, we next considered the AAV binding factors and receptors known to contribute to AAV transduction. We found that the AAV receptor (AAVR), which is critical to transduction, is abundantly expressed in CA2, and knockout of AAVR nearly abolished expression of AAV-delivered material by all serotypes tested. Additionally, we found CA2 enrichment of several cell-surface glycan receptors that AAV particles attach to before interacting with AAVR, including heparan sulfate proteoglycans, N-linked sialic acid and N-linked galactose. Indeed, CA2 showed the highest expression of AAVR and the investigated glycan receptors within the hippocampus. We conclude that CA2 neurons are endowed with multiple factors that make it highly susceptible to AAV transduction, particularly to the systemically available PHP variants, including CAP-B10. Given the curved structure of hippocampus and the relatively small size of CA2, systemic delivery of engineered PHP or CAP variants could all but eliminate the need for intrahippocampal AAV injections, particularly when injecting recombinase-dependent AAVs into animals that express recombinases in CA2.
Deciphering Ca2+Permeation and Valence Selectivity in CaV1: Molecular Dynamics Simulations Reveal the Three-Ion Knock-on Mechanism
Authors: Xue Lingfeng , Yan Nieng , Song Chen 
Published: November 2024

AbstractVoltage-gated calcium (CaV) channels are pivotal in cellular signaling due to their selective calcium ion permeation upon membrane depolarization. While previous studies have established the highly selective permeability of CaVchannels, the detailed molecular mechanism remains elusive. Here we use extensive atomistic molecular dynamics simulations to elucidate the mechanisms governing ion permeation and valence selectivity in CaV1 channels. Employing the electronic continuum correction method, we simulated a calcium conductance of approximately 9–11 pS, aligning closely with experimental measurement. Our simulations uncovered a three-ion knock-on mechanism critical for efficient calcium ion permeation, necessitating the binding of at least two calcium ions within the selectivity filter (SF) and the subsequent entry of a third ion.In silicomutation simulations further validated the importance of multi-ion coordination in the SF for efficient ion permeation, identifying two critical residues, D706 and E1101, that are essential for the binding of two calcium ions in the SF. Moreover, we explored the competitive permeation of calcium and sodium ions, and obtained a valence selectivity favoring calcium over sodium at a ratio of approximately 35:1 under the bi-cation condition. This selectivity arises from the strong electrostatic interactions of calcium ions in the confined SF and the three-ion knock-on mechanism. Our findings provide novel insights into the molecular underpinnings of CaVchannel function, with implications for understanding calcium-dependent cellular processes.
Mapping of the country-wide prevalence of non-malarial febrile illnesses in areas with varying malaria transmission intensities in Mainland Tanzania
Authors: Mandai Salehe S. , Kisambale Angelina J. , Petro Daniel A. , Bakari Catherine , Chacha Gervas A. , Budodo Rule , Madebe Rashid A. , Pereus Dativa , Challe Daniel P. , Moshi Ramadhani , Mbwambo Ruth B. , Kanyankole Grace K. , Aaron Sijenunu , Mbwambo Daniel , Kajange Stella , Lazaro Samwel , Kapologwe Ntuli , Mandara Celine I. , Seth Misago D. , Ishengoma Deus S. 
Published: November 2024

AbstractRecent reports revealed a declining malaria burden, but non-malaria febrile illnesses (NMFIs) have either remained unchanged or increased. This study assessed the country-wide prevalence of NMFIs and their patterns across various malaria transmission settings in Mainland Tanzania. A cross-sectional study recruited patients aged ≥ 6 months from 86 health facilities in all 26 regions of Tanzania. All patients were tested for malaria using rapid diagnostic tests (RDTs) and the prevalence of NMFIs was determined for all patients with negative results. Logistic regression was used to determine factors associated with NMFIs. Of the 18,568 patients tested, 8,273 (44.6%) had NMFIs due to negative RDT results. Higher prevalence of NMFIs occurred in females (45.8%) than males (42.8%), adults (aged ≥ 15 years, with 50.6%) compared to under-fives (42.6%) and school children (aged 5 -< 15 years, 34.3%), and in very low (71.5%) compared to high transmission areas (33.9%). NMFIs were significantly more likely in females than in males (aOR = 1.14, 95% CI = 1.07–1.22), in very low transmission areas (aOR = 4.85, 95% CI = 4.42–5.33), adults (aOR = 1.60, 95% CI = 1.46–1.75) and under-fives (aOR = 1.60, 95% CI = 1.47–1.76). The findings show high prevalence of NMFIs overall, and higher prevalence and odds of NMFIs in females, under-fives and individuals from low and very low transmission areas. These groups should be targeted with appropriate point-of-care tests and treatment strategies.
Genomic Analysis ofLegionella pneumophilain the Drinking Water System of a Large Building over 25 Years
Authors: Seth-Smith Helena MB , Egli Adrian , Gautsch Sylvia , Bornstein Michael M. , Kulik Eva M. 
Published: November 2024

AbstractLegionella pneumophila,the causative agent of Legionnaires’ disease, is often found in the plumbing systems of buildings from where it can be transmitted to humans via inhalation or aspiration of contaminated water drops. Annual routine water sampling from the potable water system of an occupational healthcare building in Basel over 25 years was performed in accordance with national guidelines. Overall, 309 water samples were collected at 38 time points over the period of 25 years.L. pneumophilawas recovered from 120 water samples (38.8%) from 26 time points. No clinical infections were recorded during this period. Initial decontamination measures were successful for approximately 12 years, after which an increase in the total number ofLegionellacolony forming units as well as ofL. pneumophila-positive sites was noticed, in 2008. Whole genome sequencing (WGS) analysis of n=123 isolates from n=113 samples showed allL. pneumophilato be sequence type (ST)-45 (Sequence based typing scheme). The isolates are closely related, with only 408 single nucleotide polymorphisms (SNPs) among all isolates after the bioinformatic removal of recombination events. Over the 25 years, a single lineage deriving from a recent common ancestor colonized the water system of this building. The phylogeny of isolate genomes can be interpreted as inferring good water circulation, possible recolonization from a common source after cleaning, with genome evolution and insertion / loss of large elements evident. Regular monitoring of waterlines in healthcare settings helps to identify concentrations ofLegionellaspp. and WGS is recommended for detailed investigation.Data SummaryAll data is submitted to the ENA under project PRJEB79004 under accession numbers ERR13662450-ERR13662572.Impact StatementThis is the most detailed, long-term study ofL. pneumophilain the water system of a single building recorded to date. TheL. pneumophilaisolates found in the building over the sampling period of 25 years were all closely related, belonging to ST45. SNP analysis suggested that the common ancestor of the cluster was from around 1938 (range 1911 to 1959), and movement of a large genomic island and plasmid transfer were observed. Despite several decontamination measures, it was impossible to completely eradicateLegionellaspp. from the water system of the historic building. No infections could be attributed to the presence ofL. pneumophilain this building. To mitigate the risk of Legionellosis from such buildings, awareness, regular water testing based on official national guidelines and recommendations, and other control measures, such as the use of sterile water for critical procedures can be recommended.