bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sound-mediated nucleation and growth of amyloid fibrils
Authors: Kozell Anna , Solomonov Aleksei , Gaidarov Roman , Benyamin Doron , Rosenhek-Goldian Irit , Greenblatt Harry Mark , Levy Yaakov , Amir Ariel , Raviv Uri , Shimanovich Ulyana 
Published: September 2023

AbstractMechanical energy, specifically in the form of ultrasound, can induce pressure variations and temperature fluctuations when applied to an aqueous media. These conditions can both positively and negatively affect protein complexes, consequently altering their stability, folding patterns, and self-assembling behavior. Despite much scientific progress, our current understanding of the effects of ultrasound on the self-assembly of amyloidogenic proteins remains limited. In the present study, we demonstrate that when the amplitude of the delivered ultrasonic energy is sufficiently low, it can induce refolding of specific motifs in protein monomers, which is sufficient for primary nucleation; this has been revealed by MD. These ultrasound-induced structural changes are initiated by pressure perturbations and are accelerated by a temperature factor. Furthermore, the prolonged action of low-amplitude ultrasound enables the elongation of amyloid protein nanofibrils directly from natively folded monomeric lysozyme protein, in a controlled manner, until it reaches a critical length. Using solution X-ray scattering, we determined that nanofibrillar assemblies, formed either under the action of sound or from natively fibrillated lysozyme, share identical structural characteristics. Thus, these results provide insights into the effects of ultrasound on fibrillar protein self-assembly and lay the foundation for the potential use of sound energy in protein chemistry.Significance StatementUnderstanding how and why proteins form amyloid fibrils is crucial for research into various diseases, including neurodegeneration. Ultrasound is routinely used in research settings as a tool for generating amyloid seeds (nucleation sites) from mature fibrils, which accelerate the rate of fibril growth. However, ultrasound can have various effects on aqueous media including temperature, extreme shear, and free radicals. Here we show that when the ultrasound parameters are precisely adjusted, they can be utilized as a tool for amyloid growth directly from the natively folded monomers. Thus, it is possible to induce minor changes in the folding of proteins, which trigger nucleation and accelerate amyloid growth. This knowledge lays the foundation for the potential use of sound in protein chemistry.
The TcdE holin drives toxin secretion and virulence inClostridioides difficile
Authors: DiBenedetto NV , Oberkampf M , Cersosimo L , Yeliseyev V , Bry L , Peltier J , Dupuy B 
Published: September 2023

AbstractClostridioides difficileis the leading cause of healthcare associated infections. The Pathogenicity Locus (PaLoc) toxins TcdA and TcdB promote host disease. These toxins lack canonical N-terminal signal sequences for translocation across the bacterial membrane, suggesting alternate mechanisms of release, which have included targeted secretion and passive release from cell lysis. While the holin TcdE has been implicated in TcdA and TcdB release, its rolein vivoremains unknown. Here, we show profound reductions in toxin secretion intcdEmutants in the highly virulent strains UK1 (epidemic ribotype 027, Clade 3) and VPI10463 (ribotype 087, Clade 1). Notably,tcdEdeletion in either strain rescued highly susceptible gnotobiotic mice from lethal infection by reducing acute extracellular toxin to undetectable levels, limiting mucosal damage, and enabling long-term survival, in spite of continued toxin gene expression intcdEmutants. Our findings confirm TcdE’s critical functionsin vivofor toxin secretion andC. difficilevirulence.
Live-Attenuated CHIKV Vaccine with Rearranged Genome Replicatesin vitroand Induces Immune Response in Mice
Authors: Tretyakova Irina , Joh Joongho , Lukashevich Igor S. , Alejandro Brian , Gearon Mary , Chung Donghoon , Pushko Peter 
Published: September 2023

ABSTRACTChikungunya fever virus (CHIKV) is a mosquito-borne alphavirus that causes wide-spread human infections and epidemics in Asia, Africa and recently, in the Americas. There is no approved vaccine and CHIKV is considered a priority pathogen by CEPI and WHO. Previously, we developed immunization DNA (iDNA) plasmid capable of launching live-attenuated CHIKV vaccinein vivo. Here we report the use of CHIKV iDNA plasmid to prepare a novel, live-attenuated CHIKV vaccine V5040 with rearranged RNA genome for improved safety. In V5040, genomic RNA was rearranged to encode capsid gene downstream from the glycoprotein genes. To secure safety profile, attenuated mutations derived from experimental CHIKV 181/25 vaccine were also engineered into E2 gene of V5040. The DNA copy of rearranged CHIKV genomic RNA with attenuated mutations was cloned into iDNA plasmid pMG5040 downstream from the CMV promoter. After transfection in vitro, pMG5040 launched replication of V5040 virus with rearranged genome and attenuating E2 mutations. Furthermore, V5040 virus was evaluated in experimental murine models for safety and immunogenicity. Vaccination with V5040 virus subcutaneously resulted in elicitation of CHIKV-specific, virus-neutralizing antibodies. The results warrant further evaluation of V5040 virus with rearranged genome as a novel live-attenuated vaccine for CHIKV.
Agents seeking long-term access to the wisdom of the crowd reduce immediate decision-making accuracy
Authors: Mann Richard P. 
Published: September 2023

AbstractLiving in groups offers social animals the significant advantage of accessing collective wisdom and enhanced information processing, enabling more accurate decisions related to foraging, navigation, and habitat selection. Preserving group membership is crucial for sustaining access to collective wisdom, incentivising animals to prioritise group cohesion. However, when individuals encounter divergent information about the quality of various options this can create a conflict between pursuing immediate rewards and the maintenance of group membership to improve access to future payoffs. In this study I show that rational agents who seek to maximise long-term rewards will be more inclined to follow the decisions of their peers than those with short-term horizons. In doing so, they necessarily make less-rewarding decisions in the short-term, which manifests in a lower individual accuracy when choosing the better of two options. Further, I demonstrate that intuitions about collective wisdom can be misleading in groups of agents who prioritise long-term rewards, with disagreement being a better signal for the accuracy of collective choices than consensus. These results demonstrate that observed patterns of sociality should be interpreted in the context of the life history of an individual and its peers, rather than through the lens of an isolated decision.
Epigenetic coordination of transcriptional and translational programs in hypoxia
Authors: Watt Kathleen , Dauber Bianca , Szkop Krzysztof J , Lee Laura , Jovanovic Predrag , Chen Shan , Masvidal Laìa , Tandoc Kristofersson , Palia Ranveer , Topisirovic Ivan , Larsson Ola , Postovit Lynne-Marie 
Published: September 2023

SUMMARYAdaptation to stresses entails coordination of transcriptional and post-transcriptional gene regulation, but the mechanisms remain largely unknown. We interrogated the effects of hypoxia on transcriptomes, epigenomes and translatomes of T47D breast cancer cells and H9 human embryonic stem cells. This revealed hypoxia-induced alterations in H3K4me3 associating with pervasive changes in transcription start site (TSS) selection, leading to 5’UTR remodeling and a concomitant reshaping of translational landscapes. Importantly, this epigenetically driven reprogramming of translation is distinct from HIF1-dependent transcriptional mechanisms, and TSS switching appears to occur independently of alterations in transcript abundance. While TSS switching is coordinated with the integrated stress response (ISR) and mTOR-guided translational reprogramming, it also acts independently to regulate translation in hypoxia. Moreover, comparable TSS switching was observed following H3K4me3 accumulation in the absence of hypoxia, pinpointing H3K4me3 as underlying TSS selection. These results demonstrate a previously unappreciated mechanism of translational regulation driven by epigenetic reprogramming of the 5’UTRome, which is orchestrated with other hypoxia-triggered adaptive mechanisms.
A Light sheet fluorescence microscopy and machine learning-based approach to investigate drug and biomarker distribution in whole organs and tumors
Authors: Kumar Niyanta , Hrobař Petr , Vagenknecht Martin , Soukup Jindrich , Patterson Nadia , Bloomingdale Peter , Freshwater Tomoko , Bardehle Sophia , Peter Roman , Mangadu Ruban , Pastuskovas Cinthia V. , Chabu Chiswili Y. , Cancilla Mark T. 
Published: September 2023

AbstractTissue clearing and Light sheet fluorescence microscopy (LSFM) provide spatial information at a subcellular resolution in intact organs and tumors which is a significant advance over tools that limit imaging to a few representative tissue sections. The spatial distribution of drugs, targets, and biomarkers can help inform relationships between exposure at the site of action, efficacy, and safety during drug discovery. We demonstrate the use of LSFM to investigate distribution of an oncolytic virus (OV) and vasculature in xenograft tumors, as well as brain Aβ pathology in an Alzheimer’s disease (AD) mouse model. Machine learning-based image analysis tools developed to segment vasculature in tumors showed that random forest and deep learning methods provided superior segmentation accuracy vs intensity-based thresholding. Sub-cellular resolution enabled detection of punctate and diffuse intracellular OV distribution profiles. LSFM investigation in the brain in a TgCRND8 AD mouse model at 6.5 months of age enabled evaluation of Aβ plaque density in different brain regions. The utility of LSFM data to support quantitative systems pharmacology (QSP) and physiology-based pharmacokinetics (PBPK) modeling to inform drug development are also discussed. In summary, we showcase how LSFM can expand our understanding of macromolecular drug and biomarker distribution to advance drug discovery and development.
Poly-basic peptides and polymers as new drug candidate againstPlasmodium falciparum
Authors: Sivakumar Roshan , Floyd Katherine , Jessey Erath , Kim Kim Jenny , Bayguinov Peter O. , Fitzpatrick James A.J. , Goldfrab Dennis , Jovanovic Marko , Tripathi Abhai , Djuranovic Sergej , Pavlovic-Djuranovic Slavica 
Published: September 2023

AbstractPlasmodium falciparum, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs like lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite’s growing resistance to existing therapies. Our study shows that a common characteristic of theP. falciparumproteome – stretches of poly-lysine residues such as those found in proteins related to adhesion and pathogenicity – can serve as an effective peptide treatment for infected erythrocytes. A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytesin vitrowith minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 hours. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers further increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, our affinity pull-downs and mass-spectrometry identifyP. falciparum’souter membrane proteins as likely targets for polybasic peptide medications. Since poly-lysine dendrimers are already FDA-approved for drug delivery, their adaptation as antimalarial drugs presents a promising new therapeutic strategy.One-Sentence SummaryOur study demonstrates that poly-lysine peptides, particularly those modified through PEG-ylation or in the form of poly-lysine dendrimers, can effectively reducePlasmodium falciparum,the causative agent of malaria, in human erythrocytesin vitro,with potential for use as a promising new antimalarial therapy.
Theory on the power-law distribution of the Michaelis-Menten enzyme kinetic parameters
Authors: Murugan Rajamanickam 
Published: September 2023

ABSTRACTWe show on the biophysical basis that the observed enzyme kinetic parameters related to the substrate binding, product turnover and catalytic efficiency follow power-law type density functions. These finding are validated with the available datasets on various enzymes across different substrates. The product turnover rates and catalytic efficiencies seems to follow a bimodal type density functions in line with the single molecule experiments on enzyme catalysis which can be explained by a sum of two different power-law type density functions. The curve geometry of the density functions is decided by the underlying biophysical factors and the location of the peak is dictated by the natural selection pressure.
Evaluating the effectiveness of artifact correction and rejection in event-related potential research
Authors: Zhang Guanghui , Garrett David R. , Simmons Aaron M. , Kiat John E. , Luck Steven J. 
Published: September 2023

AbstractEyeblinks and other large artifacts can create two major problems in event-related potential (ERP) research, namely confounds and increased noise. Here, we developed a method for assessing the effectiveness of artifact correction and rejection methods at minimizing these two problems. We then used this method to assess a common artifact minimization approach, in which independent component analysis (ICA) is used to correct ocular artifacts, and artifact rejection is used to reject trials with extreme values resulting from other sources (e.g., movement artifacts). This approach was applied to data from five common ERP components (P3b, N400, N170, mismatch negativity, and error-related negativity). Four common scoring methods (mean amplitude, peak amplitude, peak latency, and 50% area latency) were examined for each component. We found that eyeblinks differed systematically across experimental conditions for several of the components. We also found that artifact correction was reasonably effective at minimizing these confounds, although it did not usually eliminate them completely. In addition, we found that the rejection of trials with extreme voltage values was effective at reducing noise, with the benefits of eliminating these trials outweighing the reduced number of trials available for averaging. For researchers who are analyzing similar ERP components and participant populations, this combination of artifact correction and rejection approaches should minimize artifact-related confounds and lead to improved data quality. Researchers who are analyzing other components or participant populations can use the method developed in this study to determine which artifact minimization approaches are effective in their data.
The Atlantic Forest of South America: spatiotemporal dynamics of remaining vegetation and implications for conservation
Authors: Vancine Maurício Humberto , Muylaert Renata L. , Niebuhr Bernardo Brandão , Oshima Júlia Emi de Faria , Tonetti Vinicius , Bernardo Rodrigo , De Angelo Carlos , Rosa Marcos Reis , Grohmann Carlos Henrique , Ribeiro Milton Cezar 
Published: September 2023

AbstractThe Atlantic Forest in South America (AF) is one of the world’s most diverse and threatened biodiversity hotspots. We present a comprehensive spatiotemporal analysis of 34 years of AF landscape change between 1986-2020. We analyzed landscape metrics of forest vegetation only (FV), forest plus other natural vegetation (NV), and investigated the sensitivity of metrics to linear infrastructure. Currently, remnants comprise about 23% of FV and 36% of NV, and have decreased by 2.4% and 3.6% since 1986, respectively. Linear infrastructure negatively affected large fragments (>500,000 ha) by breaking them apart. Our findings suggest that AF protection legislation adopted in mid-2005 has taken effect: between 1986-2005, there was a loss of FV and NV (3% and 3.45%) and a decrease in the number of FV and NV fragments (8.6% and 8.3%). Between 2005-2020, there was a relative recovery of FV (1 Mha; 0.6%), slight loss of NV (0.25 Mha; 0.15%) and increase in the number of FV and NV fragments (12% and 9%). Still, 97% of the vegetation fragments are small (<50 ha), with an average fragment size between 16 and 26 ha. Furthermore, 50-60% of the vegetation is <90 m from its edges, and the isolation between fragments is high (250-830 m). Alarmingly, protected areas and indigenous territories cover only 10% of the AF and are very far from any fragments (>10 km). Our work highlights the importance of legislation and landscape dynamics analysis to help monitor and keep track of AF biodiversity conservation and restoration programs in the future.HighlightsThere is 23% forest and 36% natural vegetation cover remaining in the Atlantic Forest.Between 1986-2020, native forest cover decreased by 2.4% and natural vegetation by 3.6%.Since 2005, there has been a 1 Mha increase in forest area by small fragments (1 ha).Roads and railways reduced by 56%-89% fragment size, especially on large fragments.Alarmingly, 97% of fragments are small (<50 ha) and 60% are under edge effect (<90 m).
Early life stress impairs VTA coordination of BLA network and behavioral states
Authors: Stone Bradly T. , Antonoudiou Pantelis , Teboul Eric , Scarpa Garrett , Weiss Grant , Maguire Jamie L. 
Published: September 2023

AbstractMotivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states – and whether ELS impacts VTA-mediated network communication – remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and mPFC activity, and that ELS weakens the ability of the VTA to coordinate BLA network states, likely due to ELS-induced impairments in dopamine signaling between the VTA and BLA. Consequently, ELS mice exhibit increased social avoidance, which can be recapitulated in control mice by inhibiting VTA-BLA communication. These data suggest that ELS impacts social reward via the VTA-BLA dopamine network.
Surprising Features of Nuclear Receptor Interaction Networks Revealed by Live Cell Single Molecule Imaging
Authors: Dahal Liza , Graham Thomas GW , Dailey Gina M , Heckert Alec , Tjian Robert , Darzacq Xavier 
Published: September 2023

AbstractType 2 Nuclear Receptors (T2NRs) require heterodimerization with a common partner, the Retinoid X Receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and over-expression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged retinoid X receptor (RXR) and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
Hallmark molecular and pathological features of POLG disease are recapitulated in cerebral organoids
Authors: Chen Anbin , Yangzom Tsering , Hong Yu , Lundberg Bjørn Christian , Sullivan Gareth John , Tzoulis Charalampos , Bindoff Laurence A. , Liang Kristina Xiao 
Published: September 2023

AbstractIn our research, we developed a 3D brain organoid model to study POLG-related encephalopathy, a mitochondrial disease stemming fromPOLGgene mutations. We utilized induced pluripotent stem cells (iPSCs) derived from patients with these mutations to generate cortical organoids, which exhibited typical POLG disease features, such as altered morphology, neuronal loss, and mtDNA depletion. We also identified significant dysregulation in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK-STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory DA GLU neurons. This novel model effectively mirrors both the molecular and pathological attributes of POLG disease, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG-related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.HighlightsWe have successfully developed cortical organoid model that represents POLG-related disease.This model effectively replicates both histological and molecular signatures seen in the brains of patients.The cortical organoid model displays a range of features common in POLG-related disease, including neurodegeneration, mtDNA depletion, and neuronal complex I deficiency.The use of metformin supplementation in this model improved mitochondria protein and reduced cell death.
Gene regulatory network inference from CRISPR perturbations in primary CD4+ T cells elucidates the genomic basis of immune disease
Authors: Weinstock Joshua S. , Arce Maya M. , Freimer Jacob W. , Ota Mineto , Marson Alexander , Battle Alexis , Pritchard Jonathan K. 
Published: September 2023

AbstractThe effects of genetic variation on complex traits act mainly through changes in gene regulation. Although many genetic variants have been linked to target genes incis, the trans-regulatory cascade mediating their effects remains largely uncharacterized. Mapping trans-regulators based on natural genetic variation, including eQTL mapping, has been challenging due to small effects. Experimental perturbation approaches offer a complementary and powerful approach to mapping trans-regulators. We used CRISPR knockouts of 84 genes in primary CD4+ T cells to perturb an immune cell gene network, targeting both inborn error of immunity (IEI) disease transcription factors (TFs) and background TFs matched in constraint and expression level, but without a known immune disease association. We developed a novel Bayesian structure learning method called Linear Latent Causal Bayes (LLCB) to estimate the gene regulatory network from perturbation data and observed 211 directed edges among the genes which could not be detected in existing CD4+ trans-eQTL data. We used LLCB to characterize the differences between the IEI and background TFs, finding that the gene groups were highly interconnected, but that IEI TFs were much more likely to regulate immune cell specific pathways and immune GWAS genes. We further characterized nine coherent gene programs based on downstream effects of the TFs and linked these modules to regulation of GWAS genes, finding that canonical JAK-STAT family members are regulated byKMT2A, a global epigenetic regulator. These analyses reveal the trans-regulatory cascade from upstream epigenetic regulator to intermediate TFs to downstream effector cytokines and elucidate the logic linking immune GWAS genes to key signaling pathways.