bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical-like bistable dynamics in the resting-state human brain
Authors: Wang Sheng H. , Arnulfo Gabriele , Myrov Vladislav , Siebenhühner Felix , Nobili Lino , Breakspear Michael , Palva Satu , Palva J. Matias 
Published: January 2022

AbstractBrain activity exhibits scale-free avalanche dynamics and power-law long-range temporal correlations (LRTCs) across the nervous system. This has been thought to reflect “brain criticality”, i.e., brains operating near a critical phase transition between disorder and excessive order. Neuronal activity is, however, metabolically costly and may be constrained by activity-limiting mechanisms and resource depletion, which could make the phase transition discontinuous and bistable. Observations of bistability in awake human brain activity have nonetheless remained scarce and its functional significance unclear. First, using computational modelling where bistable synchronization dynamics emerged through local positive feedback, we found bistability to occur exclusively in a regime of critical-like dynamics. We then assessed bistability in vivo with resting-state magnetoencephalography and stereo-encephalography. Bistability was a robust characteristic of cortical oscillations throughout frequency bands from δ (3-7 Hz) to high-γ (100-225 Hz). As predicted by modelling, bistability and LRTCs were positively correlated. Importantly, while moderate levels of bistability were positively correlated with executive functioning, excessive bistability was associated with epileptic pathophysiology and predictive of local epileptogenicity. Critical bistability is thus a salient feature of spontaneous human brain dynamics in awake resting-state and is both functionally and clinically significant. These findings expand the framework of brain criticality and show that critical-like neuronal dynamics in vivo involves both continuous and discontinuous phase transitions in a frequency-, neuroanatomy-, and state-dependent manner.
High-throughput direct screening of restriction endonuclease using microfluidic fluorescence-activated drop sorter based on SOS response in E. coli
Authors: Zhang Yizhe , Agresti Jeremy J. , Zheng Yu , Weitz David A. 
Published: January 2022

ABSTRACTA restriction endonuclease (RE) is an enzyme that can recognize a specific DNA sequence and cleave that DNA into fragments with double-stranded breaks. This sequence-specific cleaving ability and its ease of use have made REs commonly used tools in molecular biology since their first isolation and characterization in 1970s. While artificial REs still face many challenges in large-scale synthesis and precise activity control for practical use, searching for new REs in natural samples remains a viable route for expanding the RE pool for fundamental research and industrial applications. In this paper, we propose a new strategy to search for REs in an efficient fashion. Briefly, we construct a host bacterial cell to link the RE genotype to the phenotype of β-galactosidase expression based on the bacterial SOS response, and use a high-throughput microfluidic platform to isolate, detect and sort the REs. We employ this strategy to screen for the XbaI gene from constructed libraries of varied sizes. In single round of sorting, a 30-fold target enrichment was obtained within 1 h. The direct screening approach we propose shows potential for efficient search of desirable REs in natural samples compared to the conventional RE-screening method, and is amenable to being adapted to high-throughput screening of other genotoxic targets.
PCR-free, label-free detection of sequence-specific DNA with single-molecule sensitivity using in vitro N-hybrid system in microfluidic drops
Authors: Zhang Yizhe , Weitz David A. 
Published: January 2022

AbstractWe propose a novel method that can detect DNA with high specificity at the single-molecule level by employing the in vitro N-hybrid strategy realized in sub-picoliter microfluidic drops. It detects target DNA based on the specific interactions of the target-encoded proteins with their partner molecules, and achieves single-molecule sensitivity via signal-transduction and signal-amplification during gene-expression processes in a sub-picoliter droplet, therefore effectively avoiding complicated procedures in labeling-based methods or biases and artifacts in PCR-based methods.
Two subsets of circulating Ly6Clo monocytes distinguished by CD138 (syndecan-1) expression and Nr4a1 dependence in pristane-treated mice
Authors: Han Shuhong , Zhuang Haoyang , Arja Rawad Daniel , Reeves Westley H. 
Published: January 2022

AbstractChronic peritoneal inflammation following pristane injection induces lupus with diffuse alveolar hemorrhage (DAH) and pulmonary capillaritis in C57BL/6 mice. The pathogenesis involves pristane-induced microvascular lung injury. BALB/c mice are resistant to endothelial injury and DAH. Lung disease in C57BL/6 mice is abolished by depleting monocytes/macrophages. The objective of this study was to define the role of myeloid subsets in DAH. Hemorrhage and vasculitis were abolished in Ccr2-/- mice, indicating involvement of bone marrow-derived monocytes/macrophages. Along with Ly6Chi monocytes, we found two subsets of circulating Ly6Clo monocytes: one CD138- and a novel CD138+ subset. Nr4a1-dependent patrolling Ly6Clo monocytes maintain vascular integrity after endothelial injury. Circulating Ly6CloCD138+ monocytes were associated with DAH and were absent in mice without DAH. They also were absent in Nr4a1-/- mice, whereas Ly6CloCD138- monocytes were unaffected. However, Nr4a1-/- mice were susceptible to pristane-induced DAH and lung vasculitis, suggesting that disease onset does not require Ly6CloCD138- monocytes. Peritoneal Ly6CloCD138+ Mϕ were unchanged in Nr4a1-/- mice, indicating that they are not derived from Ly6CloCD138+ monocytes. We conclude that pristane-induced lung microvascular lung injury stimulates a wave of Nr4h1-dependent Ly6CloCD138+ patrolling monocytes in an ineffectual effort to maintain vascular integrity in the face of ongoing endothelial damage.
Differential response ofCandidaspecies morphologies and isolates to fluconazole and boric acid
Authors: Salama Ola E. , Gerstein Aleeza C. 
Published: January 2022

AbstractCandida albicansis the most prevalent cause of vulvovaginal candidiasis (‘yeast infection’) and recurrent vulvovaginal candidiasis, though the incidence of non-albicans yeast species is increasing. The azole fluconazole is the primary antifungal drug used to treat R/VVC yet isolates from some species have intrinsic resistance to fluconazole, and recurrent infection can occur even with fluconazole-susceptible populations. The second-line broad-spectrum antimicrobial drug, boric acid, is an alternative treatment that has been found to successfully treat complicated VVC infections. Far less is known about how boric acid inhibits growth of yeast isolates in different morphologies compared to fluconazole. We found significant differences in drug resistance and drug tolerance (the ability of a subpopulation to grow slowly in high levels of drug) betweenC. albicans, C. glabrata, andC. parapsilosisisolates, with the specific relationships dependent on both drug and phenotype. Population-level variation for both susceptibility and tolerance was broader for fluconazole than boric acid in all species. Unlike fluconazole, which neither prevented hyphal formation nor disrupted mature biofilms, boric acid inhibitedC. albicanshyphal formation and reduced mature biofilm biomass and metabolic activity in all isolates in a dose-dependent manner. Variation in planktonic response did not generally predict biofilm phenotypes. Overall, our findings illustrate that boric acid is broadly effective at inhibiting growth across many isolates and morphologies, which could explain why it is an effective treatment for R/VVC.
Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis
Authors: Di Stefano Leon , Ogburn Elizabeth L. , Ram Malathi , Scharfstein Daniel O. , Li Tianjing , Khanal Preeti , Baksh Sheriza N. , McBee Nichol , Gruber Joshua , Gildea Marianne R. , Clark Megan R. , Goldenberg Neil A. , Bennani Yussef , Brown Samuel M. , Buckel Whitney R. , Clement Meredith E. , Mulligan Mark J. , O’Halloran Jane A. , Rauseo Adriana M. , Self Wesley H. , Semler Matthew W. , Seto Todd , Stout Jason E. , Ulrich Robert J. , Victory Jennifer , Bierer Barbara E. , Hanley Daniel F. , Freilich Daniel 
Published: January 2022

AbstractBackgroundResults from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients.MethodsWe searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions.ResultsEight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively).ConclusionsThe findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.
Plasma SARS-CoV-2 RNA levels as a biomarker of lower respiratory tract SARS-CoV-2 infection in critically ill patients with COVID-19
Authors: Jacobs Jana L. , Naqvi Asma , Shah Faraaz A. , Boltz Valerie F. , Kearney Mary F. , McVerry Bryan J. , Ray Prabir , Schaefer Caitlin , Fitzpatrick Meghan , Methé Barbara , Lee Janet , Morris Alison , Mellors John W. , Kitsios Georgios D. , Bain William 
Published: January 2022

AbstractPlasma SARS-CoV-2 viral RNA (vRNA) levels are predictive of COVID-19 outcomes in hospitalized patients, but whether plasma vRNA reflects lower respiratory tract (LRT) vRNA levels is unclear. We compared plasma and LRT vRNA levels in simultaneously collected longitudinal samples from mechanically-ventilated patients with COVID-19. LRT and plasma vRNA levels were strongly correlated at first sampling (r=0.83, p<10−8) and then declined in parallel except in non-survivors who exhibited delayed vRNA clearance in LRT samples. Plasma vRNA measurement may offer a practical surrogate of LRT vRNA burden in critically ill patients, especially early in severe disease.
Medical domain knowledge in domain-agnostic generative AI
Authors: Kather Jakob Nikolas , Laleh Narmin Ghaffari , Foersch Sebastian , Truhn Daniel 
Published: January 2022

AbstractThe text-guided diffusion model GLIDE (Guided Language to Image Diffusion for Generation and Editing) is the state of the art in text-to-image generative artificial intelligence (AI). GLIDE has rich representations, but medical applications of this model have not been systematically explored. If GLIDE had useful medical knowledge, it could be used for medical image analysis tasks, a domain in which AI systems are still highly engineered towards a single use-case. Here we show that the publicly available GLIDE model has reasonably strong representations of key topics in cancer research and oncology, in particular the general style of histopathology images and multiple facets of diseases, pathological processes and laboratory assays. However, GLIDE seems to lack useful representations of the style and content of radiology data. Our findings demonstrate that domain-agnostic generative AI models can learn relevant medical concepts without explicit training. Thus, GLIDE and similar models might be useful for medical image processing tasks in the future - particularly with additional domain-specific fine-tuning.
Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma
Authors: Thind Amarinder S. , Ashford Bruce , Strbenac Dario , Gupta Ruta , Clark Jonathan R , Iyer N. Gopalakrishna , Mitchell Jenny , Lee Jenny , Mueller Simon A , Minaei Elahe , Perry Jay R. , Ranson Marie 
Published: January 2022

ABSTRACTMetastatic cutaneous squamous cell carcinoma (cSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy that is associated with reduced overall survival. Yet compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic cSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic cSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic cSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 cSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic cSCC.In the noncoding genome, 3’UTR regions ofEVC(48% of specimens),PPP1R1A(48% of specimens) andABCA4(20% of specimens) along with the tumor-suppressing lncRNA LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential noncoding biomarkers of cSCC. Recurrent copy number loss in the tumor suppressor genePTPRDwas observed. Gene amplification was much less frequent and few genes were recurrently amplified. Single nucleotide variants driver analyses from 3 tools confirmedTP53andCDKN2Aas recurrently mutated genes but also identifiedC9as potential novel driver in this disease. Further, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID 9 has previously been shown to have no association with skin melanoma, unlike ID 13 and 8, suggesting a novel pattern of indel variation in metastatic cSCC. The enrichment analysis of various genetically altered candidates shows enrichment of ‘TGF-beta regulation of extracellular matrix’ and ‘Cell cycle G1 to S check points’. These enriched terms are associated with genetic instability, cell proliferation, and migration providing mechanisms of genomic drivers of metastatic cSCC.
Recognition of HIV-1 Capsid Licenses Innate Immune Response to Viral Infection
Authors: Yoh Sunnie M , Mamede João I. , Lau Derrick , Ahn Narae , Sánchez-Aparicio Maria T , Temple Joshua , Tuckwell Andrew , Fuchs Nina V. , Cianci Gianguido C. , Riva Laura , Curry Heather , Yin Xin , Gambut Stéphanie , Simons Lacy M. , Hultquist Judd F. , König Renate , Xiong Yong , García-Sastre Adolfo , Böcking Till , Hope Thomas J. , Chanda Sumit K. 
Published: January 2022

SUMMARYCyclic GMP-AMP synthase (cGAS) is a primary sensor of aberrant DNA that governs an innate immune signaling cascade, leading to the induction of the type-I interferon response. We have previously identified polyglutamine binding protein 1, PQBP1, as an adaptor molecule required for cGAS-mediated innate immune response of lentiviruses, including the human immunodeficiency virus 1 (HIV-1), but dispensable for the recognition of DNA viruses. HIV-1- encoded DNA is synthesized as a single copy from its RNA genome, and is subsequently integrated into the host chromatin. HIV-1 then produces progeny through amplification and packaging of its RNA genome, thus, in contrast to DNA viruses, HIV-1 DNA is both transient and of low abundance. However, the molecular basis for the detection and verification of this low abundance HIV-1 DNA pathogen-associated molecular pattern (PAMP) is not understood. Here, we elucidate a two-factor authentication strategy that is employed by the innate immune surveillance machinery to selectively respond to the low concentration of PAMP, while discerning these species from extranuclear DNA molecules. We find that, upon HIV-1 infection, PQBP1 decorates intact viral capsid, which serves as a primary verification step for the viral nucleic acid cargo. As the reverse transcription and capsid disassembly initiate, cGAS protein is then recruited to the capsid in a PQBP1-dependent manner, enabling cGAS molecules to be co-positioned at the site of PAMP generation. Thus, these data indicate that PQBP1 recognition of the HIV-1 capsid sanctions a robust cGAS-dependent response to a limited abundance and short-lived DNA PAMP. Critically, this illuminates a molecular strategy wherein the modular recruitment of co-factors to germline encoded pattern recognition receptors (PRRs) serves to enhance repertoire of pathogens that can be sensed by the innate immune surveillance machinery.
Potent protease inhibitors of deadly lagoviruses: rabbit hemorrhagic disease virus and European brown hare syndrome virus
Authors: Perera Krishani Dinali , Johnson David , Lovell Scott , Groutas William , Chang Kyeong-Ok , Kim Yunjeong 
Published: January 2022

AbstractRabbit hemorrhagic disease (RHD) and European brown hare syndrome (EBHS) are highly contagious diseases caused by lagoviruses in theCaliciviridaefamily and mainly affect rabbits and hares, respectively. These infectious diseases are associated with high mortality and a serious threat to domesticated and wild rabbits and hares, including endangered species such as Riparian brush rabbits. In the US, only isolated cases of RHD had been reported until Spring 2020. However, RHD caused by RHD type 2 virus (RHDV2) was unexpectedly reported in April 2020 in New Mexico and has subsequently spread to several US states infecting wild rabbits and hares, making it highly likely that RHD will become endemic in the US. Vaccines are available for RHD, however, there is no specific treatment for these diseases. RHDV and EBHSV encode a 3C-like protease (3CLpro), which is essential for virus replication and a promising target for antiviral drug development. We have previously generated focused small molecule libraries of 3CLpro inhibitors and demonstrated thein vitropotency andin vivoefficacy of some protease inhibitors against viruses that encode 3CLpro including caliciviruses and coronaviruses. Here we established the enzyme and cell-based assays for these uncultivable viruses to determine thein vitroactivity of 3CLpro inhibitors, including GC376, a protease inhibitor being developed for feline infectious peritonitis, and identified potent inhibitors of RHDV1 and 2 and EBHSV. In addition, structure-activity relationship study and homology modelling of the 3CLpros and inhibitors revealed that lagoviruses share similar structural requirements for 3CLpro inhibition with other caliciviruses.
The Salmonella transmembrane effector SteD hijacks AP1-mediated vesicular trafficking for delivery to antigen-loading MHCII compartments
Authors: Godlee Camilla , Cerny Ondrej , Liu Mei , Blundell Samkeliso , Gallagher Alanna E. , Shahin Meriam , Holden David W. 
Published: January 2022

AbstractSteD is a transmembrane effector of the Salmonella SPI-2 type III secretion system that inhibits T cell activation by reducing the amounts of at least three proteins – major histocompatibility complex II (MHCII), CD86 and CD97 – from the surface of antigen-presenting cells. SteD specifically localises at the trans-Golgi network (TGN) and MHCII compartments; however, the targeting, membrane integration and trafficking of SteD are not understood. Using systematic mutagenesis, we identify distinct regions of SteD that are required for these processes. We show that SteD integrates into membranes of the ER/Golgi through a two-step mechanism of membrane recruitment from the cytoplasm followed by integration. SteD then migrates to and accumulates within the TGN. From here it hijacks the host adaptor protein (AP)1-mediated trafficking pathway from the TGN to MHCII compartments. AP1 binding and post-TGN trafficking require a short sequence in the N-terminal cytoplasmic tail of SteD that resembles the AP1-interacting dileucine sorting signal, but in inverted orientation, suggesting convergent evolution.
Live imaging of Yersinia translocon formation and immune recognition in host cells
Authors: Rudolph Maren , Carsten Alexander , Aepfelbacher Martin , Wolters Manuel 
Published: January 2022

AbstractYersinia enterocolitica employs a type three secretion system (T3SS) to translocate immunosuppressive effector proteins into host cells. To this end, the T3SS assembles a translocon/pore complex composed of the translocator proteins YopB and YopD in host cell membranes serving as an entry port for the effectors. The translocon is formed in a Yersinia-containing pre-phagosomal compartment that is connected to the extracellular space. As the phagosome matures, the translocon and the membrane damage it causes are recognized by the cell-autonomous immune system. We infected cells in the presence of fluorophore-labeled ALFA-tag-binding nanobodies with a Y. enterocolitica strain expressing YopD labeled with an ALFA-tag. Thereby we could record the integration of YopD into translocons and its intracellular fate in living host cells. YopD was integrated into translocons around 2 min after uptake of the bacteria into a phosphatidylinositol-4,5-bisphosphate enriched pre-phagosomal compartment and remained there for 27 min on average. Damaging of the phagosomal membrane as visualized with recruitment of GFP-tagged galectin-3 occurred in the mean around 14 min after translocon formation. Shortly after recruitment of galectin-3, guanylate-binding protein 1 (GBP-1) was recruited to phagosomes, which was accompanied by a decrease in the signal intensity of translocons, suggesting their degradation. In sum, we were able for the first time to film the spatiotemporal dynamics of Yersinia T3SS translocon formation and degradation and its sensing by components of the cell-autonomous immune system.
Privacy-Preserving Federated Neural Network Learning for Disease-Associated Cell Classification
Authors: Sav Sinem , Bossuat Jean-Philippe , Troncoso-Pastoriza Juan R. , Claassen Manfred , Hubaux Jean-Pierre 
Published: January 2022

ABSTRACTTraining accurate and robust machine learning models requires a large amount of data that is usually scattered across data-silos. Sharing or centralizing the data of different healthcare institutions is, however, unfeasible or prohibitively difficult due to privacy regulations. In this work, we address this problem by using a novel privacy-preserving federated learning-based approach, PriCell, for complex machine learning models such as convolutional neural networks. PriCell relies on multiparty homomorphic encryption and enables the collaborative training of encrypted neural networks with multiple healthcare institutions. We preserve the confidentiality of each institutions’ input data, of any intermediate values, and of the trained model parameters. We efficiently replicate the training of a published state-of-the-art convolutional neural network architecture in a decentralized and privacy-preserving manner. Our solution achieves an accuracy comparable to the one obtained with the centralized solution, with an improvement of at least one-order-of-magnitude in execution time with respect to prior secure solutions. Our work guarantees patient privacy and ensures data utility for efficient multi-center studies involving complex healthcare data.