bluuebunny/crossref_metadata_2025_split huggingface dataset:
An immunocompetent human kidney on-a-chip model to study renal inflammation and immune-mediated injury
Authors: Gijzen Linda , Bokkers Marleen , Hanamsagar Richa , Olivier Thomas , Burton Todd P. , Tool Laura M. , Rahman Mouly F. , Lowman John , Savova Virginia , Means Terry K. , Lanz Henriette L. 
Published: June 2024

AbstractKidney damage and dysfunction is an emerging health issue worldwide resulting in high morbidity and mortality rates. Numerous renal diseases are recognized to be driven by the immune system. Despite this recognition, the development of targeted therapies has been challenging as knowledge of the underlying mechanism and complex interactions remains insufficient. Recent advancements in the field offer promising avenues for exploring the interplay between renal cells and immune cells and their role in the development of renal inflammation and diseases. This study describes the establishment of a human immunocompetent 3Din vitroco-culture model of the proximal tubule in a high-throughput microfluidic platform that can be used to study renal functionality and inflammatory processes.The model incorporated RPTEC in the top compartment and HUVECs in the bottom compartment cultured under flow and in direct contact with a collagen-I ECM gel resulting in the formation of polarized tubular structures. As an immune component, human primary monocytes of different donors were added to the lumen of the endothelium. Renal inflammation was successfully induced using complement activated serum (CAS) as evident by epithelial morphological changes, increased expression of adhesion molecules, release of pro-inflammatory cytokines, and reduced epithelial viability. Realtime migratory behavior of monocytes showed increased extravasation and migration towards the ECM and Renal compartment upon exposure to CAS with donor-to-donor differences observed. Finally, immune modulatory compounds showed efficacious inhibition of monocyte migration under inflammatory conditions in the microfluidic co-culture model.A successful co-culture model was established and can be applied to study renal functionality in health and disease but also for drug screening due to the compatibility of the platform with automation and relatively high throughput. Overall, the described proximal tubule model has high potential to fill the gap that currently exists to study renal inflammation preclinically.
Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia
Authors: Tian Zhengming , Li Yuning , Jin Feiyang , Xu Zirui , Gu Yakun , Guo Mengyuan , Shao Qianqian , Liu Yingxia , Luo Hanjiang , Wang Yue , Zhang Suyu , Yang Chenlu , Liu Xin , Ji Xunming , Liu Jia 
Published: June 2024

AbstractHypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell-cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transferin vitro, clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. And we found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
The umbrella cell keratin network: organization as a tile-like mesh, formation of a girded layer in response to bladder filling, and dependence on the plectin cytolinker
Authors: Ruiz Wily G. , Clayton Dennis R. , Parakala-Jain Tanmay , Dalghi Marianela G. , Franks Jonathan , Apodaca Gerard 
Published: June 2024

ABSTRACTThe keratin cytoskeleton and associated desmosomes contribute to the mechanical stability of epithelial tissues, but their organization in bladder umbrella cells and their responses to bladder filling are poorly understood. Using super-resolution confocal microscopy, along with 3D image reconstruction and platinum replica electron microscopy, we observed that the apical keratin network of umbrella cells was organized as a dense tile-like mesh comprised of tesserae bordered on their edges by cortical actin filaments, filled with woven keratin filaments, and crosslinked by plectin. A band of keratin was also observed at the cell periphery that was linked to the junction-associated actin ring by plectin. During bladder filling, the junction-localized desmosomal necklace expanded, and a subjacent girded layer was formed that linked the keratin network to desmosomes, including those at the umbrella cell-intermediate cell interface. Disruption of plectin led to focal keratin network dissolution, loss of the junction-associated band of keratin, perturbation of tight junction continuity, and loss of cell-cell cohesion. Our studies reveal a novel tile-like organization of the umbrella cell keratin cytoskeleton that is dependent on plectin, that reorganizes in response to bladder filling, and that likely serves to maintain umbrella cell continuity in the face of mechanical distension.
Actinomycin D and bortezomib disrupt protein homeostasis in Wilms tumor
Authors: Tiburcio Patricia D.B. , Chen Kenian , Xu Lin , Chen Kenneth S. 
Published: June 2024

ABSTRACTWilms tumor is the most common kidney cancer in children, and diffuse anaplastic Wilms tumor is the most chemoresistant histological subtype. Here, we explore how Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell cycle progression. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Based on these findings, we tested whether the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment. Indeed, we found that the combination induces apoptosis bothin vitroandin vivoand prolongs survival in xenograft models. Lastly, we show that increased levels of proteasome components are associated with anaplastic histology and worse prognosis in Wilms tumor patients. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.
FoldToken2: Learning compact, invariant and generative protein structure language
Authors: Gao Zhangyang , Tan Cheng , Li Stan Z. 
Published: June 2024

AbstractThe equivariant nature of 3D coordinates has posed long term challenges in protein structure representation learning, alignment, and generation. Can we create a compact and invariant language that equivalently represents protein structures? Towards this goal, we propose FoldToken2 to transfer equivariant structures into discrete tokens, while maintaining the recoverability of the original structures. From FoldToken1 to FoldToken2, we improve three key components: (1) invariant structure encoder, (2) vector-quantized compressor, and (3) equivariant structure decoder. We evaluate FoldToken2 on the protein structure reconstruction task and show that it outperforms previous FoldToken1 by 20% in TMScore and 81% in RMSD. FoldToken2 is likely the first method that works well for both single-chain and multi-chain protein structure quantization. We believe that FoldToken2 will inspire further improvement in protein structure representation, alignment, and generation tasks. Online example is available atColab.
Percutaneous aspiration for shortening time to blood cultures sterilization in right-sided infective endocarditis and vegetations
Authors: Polo Francisco Tirado , Nakhle Asaad , Gnall Eric , Rozenbaum Zach 
Published: June 2024

AbstractBackgroundSurgical intervention is associated with earlier clearance of bacteremia in infective endocarditis (IE).AimWe hypothesized that vegetectomies using percutaneous aspiration shortens time to sterilization of blood cultures in patients with right-sided IE and vegetations.ResultsThe cohort included 37 patients, 23 treated conservatively, and 14 underwent percutaneous vegetectomy. The median time to blood culture sterilization among patients with bacteremia over 7 days, was 16.5 (IQR 9.75-29) for patients treated conservatively and 11.5 (IQR 8.5-11.5) for those who underwent vegetectomy. The 2 patients who required mechanical ventilation were among the vegetectomy group, and the single patient who died during the same admission was treated conservatively. There were no complications in the vegetectomy group.ConclusionThese data are hypothesis-generating, suggesting that utilizing percutaneous aspiration in patients with right-sided IE and vegetations shortens time to sterilization of blood cultures, and possibly improves outcomes.
Characterizing hepatitis B virus infection in children in the Democratic Republic of Congo to inform elimination efforts
Authors: Morgan CE , Powers KA , Edwards JK , Devkota U , Biju S , Lin FC , Schmitz JL , Cloherty G , Muwonga J , Mboyo A , Tshiamala P , Kashamuka MM , Tshefu A , Emch M , Yotebieng M , Becker-Dreps S , Parr JB , Thompson P 
Published: June 2024

AbstractObjectiveDespite global reductions in hepatitis B virus (HBV) prevalence, an estimated 6.2 million children are infected, two-thirds of whom live in the WHO Africa region. We sought to characterize childhood HBV to inform elimination efforts in the Democratic Republic of Congo (DRC), one of the largest and most populous African countries.MethodsUsing the most recent (2013–14) nationally representative Demographic and Health Survey in the DRC, we analyzed HBV surface antigen (HBsAg) on dried blood spots and associated survey data from children aged 6-59 months. We estimated HBsAg-positivity prevalence nationally, regionally, and by potential correlates of infection. We evaluated spatial variation in HBsAg-positivity prevalence, overall and by age, sex, and vaccination status.FindingsUsing data from 5,679 children, we found national HBsAg-positivity prevalence was 1.3% (95% CI: 0.9%-1.7%), but ranged from 0.0% in DRC’s capital city province, Kinshasa, to 5.6% in northwestern Sud-Ubangi Province. Prevalence among boys (1.8%, 95% CI: 1.2%-2.7%) was double that among girls (0.7%, 95%CI: 0.4%-1.3%). Tetanus antibody-negativity, rurality, and lower household wealth were also significantly associated with higher HBsAg-positivity prevalence. We observed no difference in prevalence by age. Children had higher HBsAg-positivity odds if living with ≥1 HBsAg-positive adult household member (OR: 2.3, 95%CI: 0.7-7.8), particularly an HBsAg-positive mother (OR: 7.2, 95%CI:1.6-32.2).ConclusionIn the largest national survey of HBV among children and household contacts in the DRC, we found that childhood HBV prevalence was 10-60 times the global target of 0.1%. We highlight specific regions and populations for further investigation and focused prevention efforts.
Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database
Authors: Gudmundsson Sanna , Singer-Berk Moriel , Stenton Sarah L. , Goodrich Julia K. , Wilson Michael W. , Einson Jonah , Watts Nicholas A ,   Genome Aggregation Database Consortium, Lappalainen Tuuli , Rehm Heidi L. , MacArthur Daniel G. , O’Donnell-Luria Anne 
Published: June 2024

ABSTRACTIncomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants (pLoF) in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. We identified explanations for the presumed lack of disease manifestation in 701 of the variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders rarely occur, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
Fluorescein-Based SynNotch Adaptors for Regulating Gene Expression Responses to Diverse Extracellular Cues
Authors: Tran Jeremy C. , Kuffner Christopher J. , Marzilli Alexander M. , Miller Ryan Emily , Silfen Zachary E. , McMahan Jeffrey B. , Sloas D. Christopher , Chen Christopher S. , Ngo John T. 
Published: June 2024

ABSTRACTWe introduce an adaptor-based strategy for regulating fluorescein-binding synthetic Notch (SynNotch) receptors using ligands based on conjugates of fluorescein isomers and analogs. To develop a versatile system, we evaluated the surface expression and activities of multiple constructs containing distinct extracellular fluorescein-binding domains. Using an optimized receptor, we devised ways to regulate signaling via fluorescein-based chemical transformations, including an approach based on a bio-orthogonal chemical ligation and a spatially controllable strategy via the photo-patterned uncaging of ano-nitrobenzyl-caged fluorescein conjugate. We further demonstrate that fluorescein-conjugated extracellular matrix (ECM)-binding peptides can regulate SynNotch activity depending on the folding state of collagen-based ECM networks. Treatment with these conjugates enabled cells to distinguish between folded versus denatured collagen proteins and enact dose-dependent gene expression responses depending on the nature of the signaling adaptors presented. To demonstrate the utility of these tools, we applied them to control the myogenic conversion of fibroblasts into myocytes with spatial and temporal precision and in response to denatured collagen-I, a biomarker of multiple pathological states. Overall, we introduce an optimized fluorescein-binding SynNotch as a versatile tool for regulating transcriptional responses to extracellular ligands based on the widely used and clinically-approved fluorescein dye.
Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity
Authors: Dalit Lennard , Tan Chin Wee , Sheikh Amania A. , Munnings Ryan , Alvarado Carolina , Hussain Tabinda , Zaini Aidil , Cooper Lucy , Kirn Alana , Hailes Lauren , Nguyen Angela , Mackay Laura , Harris Nicola , Zaph Colby , La Gruta Nicole L. , Nutt Stephen L. , Good-Jacobson Kim L. , Davis Melissa J , Bryant Vanessa L. , Groom Joanna R. 
Published: June 2024

SUMMARYAdaptive immune responses protect against multiple classes of pathogens, including viral, bacterial, fungal, and helminth infections. In all these settings, CD4+T follicular helper (Tfh) cells tailor high-affinity class-switched B cells responses. How Tfh lineage sovereignty is established while allowing for this context-specific functional heterogeneity is unclear. Here, we identify Tfh transcriptional networks in response to diverse infections. While Bcl-6 is the transcriptional linchpin of the core Tfh signature, this is overlayed with pathogen-specific transcriptional modules that shape Tfh function. Cytokine-transcriptional Tfh programing in mouse and human lymphoid tissue demonstrated that type I interferon and TGFβ signaling direct individual Tfh subpopulations to instruct B cell output. Here, we provide a transcriptional map and cell surface resource to interrogate Tfh diversity in humans and mice. This resource can be leveraged to further understand the origins of immune flexibility, perform immune monitoring in infection and antibody-mediated diseases and to develop context-specific vaccines.ONE-SENTENCE SUMMARYDalit, Tan and colleagues provide a resource that functionally and transcriptionally profiles T follicular helper cells (Tfh) during diverse pathogen responses to reveal a blueprint for transcriptional flexibility and new tools to interrogate Tfh heterogeneity in mice and humans.
A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43
Authors: Mackness Brian C. , Morgan Brittany R. , Deveau Laura M. , Kathuria Sagar V. , Zitzewitz Jill A. , Massi Francesca 
Published: June 2024

AbstractFolding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.
Spaceflight Shifts in Community rRNA Copy Number in the Salivary Microbiome of Astronauts
Authors: Williamson Mark R. 
Published: June 2024

AbstractThe oral microbiome is stable, easily sampled, and can indicate disease. Using metagenomic data from GeneLab, I examined the effects of spaceflight on the human salivary microbiome using a composite community measure, average rRNA copy number. A higher copy number is associated with a faster growth rate and primary microbial succession. I found a significant increase in community weighted mean copy number between pre-spaceflight and during-spaceflight samples (p=0.0082). Furthermore, changes in abundance suggest a greater impact on individual species rather than phyla-level changes. Finally, a robustness analysis highlighted the importance of accurate copy number estimates and species-level identification.Graphical Abstract
Acquisition, Evolution, and Diversification of Genomic Islands: A Case Study of a Virulence Gene Cluster inPseudomonas syringae
Authors: de Oliveira Luiz Orlando , Rody Hugo Vianna Silva , Aguilera Selene , Murillo Jesús 
Published: June 2024

AbstractGenomic islands are widely distributed among bacteria, facilitating the dissemination of genes relevant to human, animal, and plant health. Herein, we explore the evolutionary history of a genomic island (Tox island) composed of a novel mobile genetic element (GInt) carrying an ∼25 kb gene cluster (Pht cluster) responsible for the biosynthesis of the phytotoxin phaseolotoxin, a virulence factor of the plant pathogenPseudomonas syringae. The Pht cluster has been acquired, either naked or associated with a GInt, on seven independent occasions by four phylogroups ofP. syringaeand the distant rhizobacteriumPseudomonassp. JAI115. The Pht cluster was independently captured by three distinct GInt elements, suggesting specific mechanisms for gene capture. Once acquired, the Tox island tends to be stably maintained, evolving with the genome. An array of molecular analyses delineated the likely evolutionary trajectory of the Pht cluster withinP. syringaepv. actinidiae (Psa) andP. amygdalipv. phaseolicola (Pph), involving: 1) acquisition by Pph; 2) transfer of haplotype G to Psa biovar 1; 3) acquisition or replacement by a haplotype of haplogroup D in Psa biovar 1; 4) acquisition of haplotype C by Psa biovar 6; and 5) replacement of the Tox island in Pph by a distantly related GInt. These findings underscore the potential role of phaseolotoxin in bacterial fitness and contribute to our understanding of virulence evolution in plant pathogens. Furthermore, GInts provide a model for studying the evolutionary dynamics of mobile genetic elements and the dissemination of adaptive genes among bacterial pathogens.
Anatomically distinct cortical tracking of music and speech by slow (1-8Hz) and fast (70-120Hz) oscillatory activity
Authors: Osorio Sergio , Assaneo M. Florencia 
Published: June 2024

AbstractMusic and speech encode hierarchically organized structural complexity at the service of human expressiveness and communication. Previous research has shown that populations of neurons in auditory regions track the envelope of acoustic signals within the range of slow and fast oscillatory activity. However, the extent to which cortical tracking is influenced by the interplay between stimulus type, frequency band, and brain anatomy remains an open question. In this study, we reanalyzed intracranial recordings from thirty subjects implanted with electrocorticography (ECoG) grids in the left cerebral hemisphere, drawn from an existing open-access ECoG database. Participants passively watched a movie where visual scenes were accompanied by either music or speech stimuli. Cross-correlation between brain activity and the envelope of music and speech signals, along with density-based clustering analyses and linear mixed effect modeling, revealed both anatomically overlapping and functionally distinct mapping of the tracking effect as a function of stimulus type and frequency band. We observed widespread left-hemisphere tracking of music and speech signals in the Slow Frequency Band (SFB, band-passed filtered low-frequency signal between 1-8Hz), with near zero temporal lags. In contrast, cortical tracking in the High Frequency Band (HFB, envelope of the 70-120Hz band-passed filtered signal) was higher during speech perception, was more densely concentrated in classical language processing areas, and showed a frontal-to-temporal gradient in lag values that was not observed during perception of musical stimuli. Our results highlight a complex interaction between cortical region and frequency band that shapes temporal dynamics during processing of naturalistic music and speech signals.