bluuebunny/crossref_metadata_2025 huggingface dataset:
An efficient algorithm for Nash equilibria when harvesting interacting living resources
Authors: Del Santo O’Neill T. J. , Rossberg A. G. , Thorpe R. B.
Published: January 2023

Natural ecological communities exhibit complex mixtures of interspecific biological interactions, which makes finding optimal yet sustainable exploitation rates challenging. Most fisheries management advice is at present based on applying the Maximum Sustainable Yield (MSY) target to each species in a community by modelling it as if it was a monoculture. Such application of single-species MSY policies to strongly interacting populations can result in tragic overexploitation. However, the idea of “maximising the yield from each species separately” can be extended to take into account species interactions using a multispecies or ecosystem model and determining a Nash Equilibrium (NE), where the yields of each species taken in isolation are simultaneously maximised. Here we present ‘nash’, anRpackage that streamlines the computation of NE reference points for fisheries and other systems represented by a user-defined multispecies or ecosystem model. We present two real-world fisheries management applications alongside performance benchmarks. Satisfactorily search results are shown across models with an approximate factor 15 increase in performance when compared to the expensive round-robbing sequential optimisation algorithms used by other authors in the literature. We believe that thenashpackage can play an instrumental role in fully implementing ecosystem-based management policies worldwide.

Open Research statement

This submission uses novel code, which is provided, per our requirements, in an external repository to be evaluated during the peer review process via the following linkhttps://github.com/ThomasDelSantoONeill/nash
Impact of structural sampling, coupling scheme and state of interest on the energy transfer in CP29
Authors: Petry S. , Tremblay J. C. , Götze J. P.
Published: January 2023

The Qyand Bxexcitation energy transfer (EET) in the minor light harvesting complex CP29 (LHCII B4.1) antenna complex ofPisum sativumwas characterized using a computational approach. We applied Förster theory (FRET) and the transition density cube (TDC) method estimating the Coulombic coupling, based on a combination of classical molecular dynamics and QM/MM calculations.

Employing TDC instead of FRET mostly affects the EET between chlorophylls (Chls) and carotenoids (Crts), as expected due to the Crts being spatially more challenging for FRET. Only between Chls, effects are found to be small (about only 0.1 EET efficiency change when introducing TDC instead of FRET). Effects of structural sampling were found to be small, illustrated by a small average standard deviation for the Qystate coupling elements (FRET/TDC: 0.97/0.94 cm−1). Due to the higher flexibility of the Bxstate, the corresponding deviations are larger (FRET/TDC between Chl-Chl pairs: 17.58/22.67 cm−1, between Crt-Chl pairs: 62.58/31.63 cm−1). In summary, it was found for the Q band that the coupling between Chls varies only slightly depending on FRET or TDC, resulting in a minute effect on EET acceptor preference. In contrast, the coupling in the B band spectral region is found to be more affected. Here, the S2(1Bu) states of the spatially challenging Crts may act as acceptors in addition to the Chl B states. Depending on FRET or TDC, several Chls show different Chl-to-Crt couplings. Interestingly, the EET between Chls or Crts in the B band is found to often outcompete the corresponding decay processes. The individual efficiencies for B band EET to Crts vary however strongly with the chosen coupling scheme (e.g., up to 0.29/0.99 FRET/TDC efficiency for the Chla604/neoxanthin pair). Thus, the choice of coupling scheme must involve a consideration of the state of interest.
Heterogeneity of the group B streptococcal type VII secretion system and influence on colonization of the female genital tract
Authors: Spencer Brady L. , Job Alyx M. , Robertson Clare M. , Hameed Zainab A. , Serchejian Camille , Wiafe-Kwakye Caitlin S. , Mendonça Jéssica C. , Apolonio Morgan A. , Nagao Prescilla E. , Neely Melody N. , Korotkova Natalia , Korotkov Konstantin V. , Patras Kathryn A. , Doran Kelly S.
Published: January 2023

Type VIIb secretion systems (T7SSb) in Gram-positive bacteria facilitate physiology, interbacterial competition, and/or virulence via EssC ATPase-driven secretion of small ɑ-helical proteins and toxins. Recently, we characterized T7SSb in group BStreptococcus(GBS), a leading cause of infection in newborns and immunocompromised adults. GBS T7SS comprises four subtypes based on variation in the C-terminus of EssC and the repertoire of downstream effectors; however, the intra-species diversity of GBS T7SS and impact on GBS-host interactions remains unknown. Bioinformatic analysis indicates that GBS T7SS loci encode subtype-specific putative effectors, which have low inter-species and inter-subtype homology but contain similar domains/motifs and therefore may serve similar functions. We further identify orphaned GBS WXG100 proteins. Functionally, we show that GBS T7SS subtype I and III strains secrete EsxAin vitroand that in subtype I strain CJB111,esxA1appears to be differentially transcribed from the T7SS operon. Further, we observe subtype-specific effects of GBS T7SS on host colonization, as subtype I but not subtype III T7SS promotes GBS vaginal persistence. Finally, we observe that T7SS subtypes I and II are the predominant subtypes in clinical GBS isolates. This study highlights the potential impact of T7SS heterogeneity on host-GBS interactions.
Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome
Authors: Healy Michael D. , McNally Kerrie E. , Butkovic Rebeka , Chilton Molly , Kato Kohji , Sacharz Joanna , McConville Calum , Moody Edmund R.R. , Shaw Shrestha , Planelles-Herrero Vicente J. , Yadav Sathish K.N. , Ross Jennifer , Borucu Ufuk , Palmer Catherine S. , Chen Kai-En , Croll Tristan I. , Hall Ryan J. , Caruana Nikeisha J. , Ghai Rajesh , Nguyen Thi H.D. , Heesom Kate J. , Saitoh Shinji , Berger Imre , Schaffitzel Christiane , Williams Tom A. , Stroud David A. , Derivery Emmanuel , Collins Brett M. , Cullen Peter J.
Published: January 2023

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed of VPS35L, VPS26C and VPS29, and the CCC complex which contains ten subunits COMMD1-COMMD10 and two coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy andin silicopredictions we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilised by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a sixteenth subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.
Distinct mechanisms underlie value-driven modulation of visual cortex by previously rewarded visual and auditory stimuli
Authors: Antono Jesssica Emily , Dang Shilpa , Auksztulewicz Ryszard , Pooresmaeili Arezoo
Published: January 2023

Past reward associations may be signaled by stimuli from different sensory modalities, however it remains unclear how different types of reward-associated stimuli modulate perception. In this human fMRI study, we employed a paradigm involving a visual discrimination task, where a visual target was simultaneously presented with either an intra-(visual) or a cross-modal (auditory) cue that was previously associated with rewards. We hypothesized that depending on the sensory modality of the cues distinct neural pathways underlie the value-driven modulation of visual areas. Two steps of analyses were conducted: first, using a multivariate approach, we confirmed that previously reward-associated cues enhanced the target representation in the early visual areas. Then, using effective connectivity analysis, we tested three possible patterns of communication across the brain regions that could underlie the modulation of visual cortex: a direct pathway from the frontal valuation areas to the visual areas, a mediated pathway through the attention-related areas, and a mediated pathway that additionally involved distinct sensory association areas for auditory and visual rewards. We found evidence for the third model and demonstrate that reward-related information is communicated across the valuation and attention-related brain regions such as the intraparietal sulcus across for both visual and auditory cues. Additionally, the long-range communication of reward information also involved the superior temporal areas in case of auditory reward-associated stimuli. These results suggest that in the presence of previously rewarded stimuli from different sensory modalities, a combination of domain-general and domain-specific mechanisms are recruited across the brain to adjust visual processing.
Longitudinal study of functional brain networks for processing infant directed and adult directed speech during the first year
Authors: Háden Gábor P. , Tóth Brigitta , Winkler István
Published: January 2023

In most cultures infant directed speech (IDS) is used to communicate with young children. The main role IDS plays in parent-child interactions appears to change over time from conveying emotion to facilitating language acquisition. There is EEG evidence for the discrimination of IDS form adult directed speech (ADS) at birth, however, less is known about the development of brain networks responsible for differentially processing IDS and ADS. The current study compared topological characteristics of functional brain networks obtained from 49 healthy infants at the age of 0, 6, and 9 months listening to the same fairy tale presented by the same speaker in IDS and ADS speech. Brain connectivity was assessed by the phase lag synchronization index in 6 frequency bands (delta, theta, low alpha, high alpha, beta, gamma). The topology of the large scale network organization was quantified using minimum spanning tree graphs, separately for each band. The delta band cortical network’s organization was found to be significantly more hierarchical and had a more cost-efficient organization during listening to ID compared to listening to AD. This network organization changes with age as nodes over the frontal cortex become more central within the network. The general picture emerging from the results is that with development the speech processing network becomes more integrated and its focus is shifting towards the left hemisphere. Our results suggest that ID speech specific differences in network topology are related to changes in the role of IDS during the first year of life.

Highlights

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Multiple stages of maturation are reflected by different EEG bands, occurring in parallel, but with different timing.

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Networks processing infant directed speech changes during the first year of life reflecting the change in the role infant directed speech plays in development.

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Speech processing networks are shifting towards the left hemisphere with age.

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Longitudinal study of speech perception using functional networks on a large sample
A Distinct Phenotype of Polarized Memory B cell holds IgE Memory
Authors: Koenig Joshua F.E. , Knudsen Niels Peter H , Phelps Allyssa , Bruton Kelly , Hoof Ilka , Lund Gitte , Libera Danielle Della , Lund Anders , Christensen Lars Harder , Glass David R. , Walker Tina , Fang Allison , Waserman Susan , Jordana Manel , Andersen Peter S
Published: January 2023

Allergen-specific IgE antibodies mediate allergic pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. We report a population of type 2 polarized MBCs defined as CD23hi, IL-4Rαhi, CD32lowat the transcriptional and surface protein levels. These “MBC2s” are enriched in IgG1 and IgG4-expressing cells, while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. MBC2s generated allergen specific-IgE during sublingual immunotherapy, thereby identifying these cells as the primary reservoir of IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases, but which could be beneficial in protection against venoms and helminths.

One-Sentence Summary

Identification of a novel memory B cell subset which holds allergen specific IgE memory.
The worldwide invasion history of a pest ambrosia beetle inferred using population genomics
Authors: Urvois T. , Perrier C. , Roques A. , Sauné L. , Courtin C. , Kajimura H. , Hulcr J. , Cognato A.I. , Auger-Rozenberg M.-A. , Kerdelhué C.
Published: January 2023

Xylosandrus crassiusculus, a fungus-farming wood borer native to Southeastern Asia, is the most rapidly spreading invasive ambrosia species worldwide. Previous studies focusing on its genetic structure suggested the existence of cryptic genetic variation in this species. Yet, these studies used different genetic markers, focused on different geographical areas, and did not include Europe. Our first goal was to determine the worldwide genetic structure of this species based on both mitochondrial and genomic markers. Our second goal was to studyX. crassiusculus’ invasion history on a global level and identify the origins of the invasion in Europe. We used a COI and RAD sequencing design to characterize 188 and 206 specimens worldwide, building the most comprehensive genetic dataset for any ambrosia beetle to date. The results were largely consistent between markers. Two differentiated genetic clusters were invasive, albeit in different regions of the world. The two markers were inconsistent only for a few specimens found exclusively in Japan. Mainland USA could have acted as a source for further expansion to Canada and Argentina through stepping-stone expansion and bridgehead events. We showed that Europe was only colonized by Cluster 2 through a complex invasion history including several arrivals from multiple origins in the native area, and possibly including bridgehead from the USA. Our results also suggested that Spain was colonized directly from Italy through intracontinental dispersion. It is unclear whether the mutually exclusive allopatric distribution of the two Clusters is due to neutral effects or due to different ecological requirements.
In-situ metagenomics: A platform for rapid sequencing and analysis of metagenomes in less than one day
Authors: Tamames Javier , Jiménez Diego , Redondo Álvaro , Martínez-García Sandra , de los Rios Asunción
Published: January 2023

We present here a complete system for metagenomic analysis that allows performing the sequencing and analysis of a medium-size metagenome in less than one day. This unprecedented development was possible due to the conjunction of state-of-the art experimental and computational advances: a portable laboratory suitable for DNA extraction and sequencing with nanopore technology; the powerful metagenomic analysis pipeline SqueezeMeta, capable to provide a complete analysis in a few hours and using scarce computational resources; and tools for the automatic inspection of the results via a graphical user interface, that can be coupled to a web server to allow remote visualization of data (SQMtools and SQMxplore). We have tested the feasibility of our approach in the sequencing of the microbiota associated to volcanic rocks in La Palma, Canary Islands. Also, we did a two-day sampling campaign of marine waters in which the results obtained the first day guided the experimental design of the second day. This system offers the possibility of prospecting any habitat in a quick way, obtaining both taxonomic and functional information about the target microbiome.
Predicted and Experimental NMR Chemical Shifts at Variable Temperatures: The Effect of Protein Conformational Dynamics
Authors: Yi Xu , Zhang Lichirui , Friesner Richard A. , McDermott Ann
Published: January 2023

NMR chemical shifts provide a sensitive probe of protein structure and dynamics. Prediction of shifts, and therefore interpretation of shifts, particularly for the frequently measured amidic15N sites, remains a tall challenge. We demonstrate that protein15N chemical shift prediction from QM/MM predictions can be improved if conformational variation is included via MD sampling, focusing on the antibiotic target,E. coliDihydrofolate reductase (DHFR). Variations of up to 25 ppm in predicted15N chemical shifts are observed over the trajectory. For solution shifts the average of fluctuations on the low picosecond timescale results in a superior prediction to a single optimal conformation. For low temperature solid state measurements, the histogram of predicted shifts for locally minimized snapshots with specific solvent arrangements sampled from the trajectory explains the heterogeneous linewidths; in other words, the conformations and associated solvent are ‘frozen out’ at low temperatures and result in inhomogeneously broadened NMR peaks. We identified conformational degrees of freedom that contribute to chemical shift variation. Backbone torsion angles show high amplitude fluctuations during the trajectory on the low picosecond timescale. For a number of residues, including I60, ψ varies by up to 60º within a conformational basin during the MD simulations, despite the fact that I60 (and other sites studied) are in a secondary structure element and remain well folded during the trajectory. Fluctuations in ψ appear to be compensated by other degrees of freedom in the protein, including φ of the succeeding residue, resulting in “rocking” of the amide plane with changes in hydrogen bonding interactions. Good agreement for both room temperature and low temperature NMR spectra provides strong support for the specific approach to conformational averaging of computed chemical shifts.
Hydrogels with stiffness-degradation spatial patterns control anisotropic 3D cell response
Authors: Garrido Claudia A. , Garske Daniela S. , Thiele Mario , Amini Shahrouz , Real Samik , Duda Georg N. , Schmidt-Bleek Katharina , Cipitria Amaia
Published: January 2023

In nature, tissues are patterned, but most biomaterials used in human applications are not. Patterned biomaterials offer the opportunity to mimic spatially segregating biophysical and biochemical properties found in nature. Engineering such properties allows to study cell-matrix interactions in anisotropic matrices in great detail. Here, we developed alginate-based hydrogels with patterns in stiffness and degradation, composed of distinct areas of soft non-degradable (Soft-NoDeg) and stiff degradable (Stiff-Deg) material properties. The hydrogels exhibit emerging patterns in stiffness and degradability over time, taking advantage of dual Diels-Alder covalent crosslinking and UV-mediated peptide crosslinking. The materials were mechanically characterized using rheology for single-phase and surface micro-indentation for patterned materials. 3D encapsulated mouse embryonic fibroblasts (MEFs) allowed to characterize the anisotropic cell-matrix interaction in terms of cell morphology by employing a novel image-based quantification tool. Live/dead staining showed no differences in cell viability but distinct patterns in proliferation, with higher cell number in Stiff-Deg materials at day 14. Patterns of projected cell area became visible already at day 1, with larger values in Soft-NoDeg materials. This was inverted at day 14, when larger projected cell areas were identified in Stiff-Deg. This shift was accompanied by a significant decrease in cell circularity in Stiff-Deg. The control of anisotropic cell morphology by the material patterns was also confirmed by a significant increase in filopodia number and length in Stiff-Deg materials. The novel image-based quantification tool was useful to spatially visualize and quantify the anisotropic cell response in 3D hydrogels with stiffness-degradation spatial patterns. Our results show that patterning of stiffness and degradability allows to control cell anisotropic response in 3D and can be quantified by image-based strategies. This allows a deeper understanding of cell-matrix interactions in a multicomponent material.
Unlocking the Power of R: A High-Accuracy Method for Measuring DAB Staining on Immunohistochemical Slides
Authors: Amine Fares Mohamed , Tarek Khenenou , Eddine Rahmoun Djallal
Published: January 2023

The current research aimed to establish a method for measuring the percentage of diaminobenzidine (DAB) staining on immunohistochemical slides with high accuracy and efficiency. The R programming language was utilized in this endeavor. A total of 50 slides were collected from various types of tissue, and were stained using an anti-cytokeratin antibody and the DAB detection method. These slides were then scanned using a high-resolution scanner, and the resulting images were analyzed using R, a custom script was specifically developed to segment the tissue and DAB-positive areas, and calculate the percentage of DAB staining on the slide. The results were then compared to manual measurements of DAB staining performed by a trained technician. The R-based method was found to be highly accurate, with a mean absolute error of only 0.76 % compared to manual measurements, this study provides evidence that the use of R for DAB quantification is a fast and reliable alternative to manual methods, enabling the analysis of large numbers of slides in a short period of time. It offers a valuable tool for researchers and technicians in the field of histopathology, enabling them to quickly and accurately analyze DAB staining on immunohistochemical slides, which is essential for the diagnosis and treatment of various diseases.
Engineering synthetic CopT/A-based genetic circuits for miRNA imaging and functional gene regulation
Authors: Zhang Chuanxian , Shi Xiaorui , Tang Chu , Du Yarong , Shu Wenjie , Wang Fu
Published: January 2023

Synthetic genetic circuits that can operate at the transcriptional and translation levels have been widely applied in the control of cellular behaviors and functions. However, the regulation of genetic circuits is often accompanied by the introduction of exogenous substances or the endogenous generation of inhibitory products, which would bring uncontrollable hazards for biological safety and reduce the efficiency of the system. Here, we described a miRNA-responsive CopT-CopA (miCop) genetic circuit system to realize real-time monitoring the intracellular expression of miRNA-124a during neurogenesis or miRNA-122 under the stimulation of extracellular drugs in living cells and animals. Furthermore, to prove the modularity of the system, we engineered this mipCop to tune the expression of DTA (diphtheria toxin A) gene, and showed the powerful capacity of killing cancer cells by inducing apoptosis and cell cycle arrest based on miRNA response. This study provides an effective means to couple miRNA sensing with miRNA-responsive gene modulation, which may open up new diagnostic or therapeutic applications.
The Evolution of Local Energetic Frustration in Protein Families
Authors: Freiberger Maria I. , Ruiz-Serra Victoria I. , Pontes Camila , Romero-Durana Miguel , Galaz-Davison Pablo , Ramírez-Sarmiento Cesar , Schuster Claudio D. , Marti Marcelo A. , Wolynes Peter G. , Ferreiro Diego U. , Parra R. Gonzalo , Valencia Alfonso
Published: January 2023

Energetic local frustration offers a biophysical perspective to interpret the effects of sequence variability on protein families. Here we present a methodology to analyze local frustration patterns within protein families that allows us to uncover constraints related to stability and function, and identify differential frustration patterns in families with a common ancestry. We have analyzed these signals in very well studied cases such as PDZ, SH3,αandβglobins and RAS families. Recent advances in protein structure prediction make it possible to analyze a vast majority of the protein space. An automatic and unsupervised proteome-wide analysis on the SARS-CoV-2 virus demonstrates the potential of our approach to enhance our understanding of the natural phenotypic diversity of protein families beyond single protein instances. We have applied our method to modify biophysical properties of natural proteins based on their family properties, as well as perform unsupervised analysis of large datasets to shed light on the physicochemical signatures of poorly characterized proteins such as emergent pathogens.
Genome Skimming with Nanopore Sequencing Precisely Determines Global and Transposon DNA Methylation in Vertebrates
Authors: Faulk Christopher
Published: January 2023

Genome skimming is defined as low-pass sequencing below 0.05X coverage and is typically used for mitochondrial genome recovery and species identification. Long read nanopore sequencers enable simultaneous reading of both DNA sequence and methylation and can multiplex samples for low-cost genome skimming. Here I present nanopore sequencing as a highly precise platform for global DNA methylation and transposon assessment. At coverage of just 0.001X, or 30 Mb of reads, accuracy is sub-1%. Biological and technical replicates validate high precision. Skimming 40 vertebrate species reveals conserved patterns of global methylation consistent with whole genome bisulfite sequencing and an average mapping rate above 97%. Genome size directly correlates to global DNA methylation, explaining 44% of its variance. Accurate SINE and LINE transposon methylation in both mouse and primates can be obtained with just 0.0001X coverage, or 3 Mb of reads. Sample multiplexing, field portability, and the low price of this instrument combine to make genome skimming for DNA methylation an accessible method for epigenetic assessment from ecology to epidemiology, and by low resource groups.
LY6E protects mice from pathogenic effects of murine coronavirus and SARS-CoV-2
Authors: Mar Katrina B. , Van Dyke Marley C. , Lopez Alexandra H. , Eitson Jennifer L. , Fan Wenchun , Hanners Natasha W. , Evers Bret M. , Shelton John M. , Schoggins John W.
Published: January 2023

LY6E is an antiviral protein that inhibits coronavirus entry. Its expression in immune cells allows mice to control murine coronavirus infection. However, it is not known which immune cell subsets mediate this control or whether LY6E protects mice from SARS-CoV-2. In this study, we used tissue-specific Cre recombinase expression to ablateLy6ein distinct immune compartments or in all epiblast-derived cells, and bone marrow chimeras to target Ly6e in a subset of radioresistant cells. Mice lackingLy6einLyz2-expressing cells and radioresistantVav1-expressing cells were more susceptible to lethal murine coronavirus infection. Mice lackingLy6eglobally developed clinical disease when challenged with the Gamma (P.1) variant of SARS-CoV-2. By contrast, wildtype mice and mice lacking type I and type III interferon signaling had no clinical symptoms after SARS-CoV-2 infection. Transcriptomic profiling of lungs from SARS-CoV-2-infected wildtype andLy6eknockout mice revealed a striking reduction of secretory cell-associated genes in infected knockout mice, includingMuc5b, an airway mucin-encoding gene that may protect against SARS-CoV-2-inflicted respiratory disease. Collectively, our study reveals distinct cellular compartments in which Ly6e confers cell intrinsic antiviral effects, thereby conferring resistance to disease caused by murine coronavirus and SARS-CoV-2.
Characterizing the Interactions of Cell Membrane-Disrupting Peptides with Lipid-Functionalized Single-Walled Carbon Nanotube Systems for Antimicrobial Screening
Authors: Yadav Anju , Kelich Payam , Kallmyer Nathaniel E. , Reuel Nigel F. , Vuković Lela
Published: January 2023

Lipid-functionalized single-walled carbon nanotubes (SWNTs) have garnered significant interest for their potential use in a wide range of biomedical applications. In this work, we used molecular dynamics simulations to study the equilibrium properties of SWNTs surrounded by the phosphatidylcholine (POPC) corona phase, and their interactions with three cell membrane disruptor peptides: colistin, TAT peptide, and crotamine-derived peptide. Our results show that SWNTs favor asymmetrical positioning within the POPC corona, so that one side of the SWNT, covered by the thinnest part of the corona, comes in contact with charged and polar functional groups of POPC and water. We also observed that colistin and TAT insert deeply into POPC corona, while crotamine-derived peptide only adsorbs to the corona surface. Compared to crotamine-derived peptide, colistin and TAT also induce larger perturbations in the thinnest region of the corona, by allowing more water molecules to directly contact the SWNT surface. In separate simulations, we show that three examined peptides exhibit similar insertion and adsorption behaviors when interacting with POPC bilayers, confirming that peptide-induced perturbations to POPC in conjugates and bilayers are similar in nature and magnitude. Furthermore, we observed correlations between the peptide-induced structural perturbations and the near-infrared emission of the lipid-functionalized SWNTs, which suggest that the optical signal of the conjugates transduces the morphological changes in the lipid corona. Overall, our findings indicate that lipid-functionalized SWNTs could serve as simplified cell membrane model systems for pre-screening of new antimicrobial compounds that disrupt cell membranes.
Individual Differences in Delay Discounting are Associated with Dorsal Prefrontal Cortex Connectivity in Youth
Authors: Mehta Kahini , Pines Adam , Adebimpe Azeez , Larsen Bart , Bassett Dani S. , Calkins Monica E. , Baller Erica , Gell Martin , Patrick Lauren M. , Gur Raquel E. , Gur Ruben C. , Roalf David R. , Romer Daniel , Wolf Daniel H. , Kable Joseph W. , Satterthwaite Theodore D.
Published: January 2023

Delay discounting is a measure of impulsive choice relevant in adolescence as it predicts many real-life outcomes, including substance use disorders, obesity, and academic achievement. However, the functional networks underlying individual differences in delay discounting during youth remain incompletely described. Here we investigate the association between multivariate patterns of functional connectivity and individual differences in impulsive choice in a large sample of youth. A total of 293 youth (9-23 years) completed a delay discounting task and underwent resting-state fMRI at 3T. A connectome-wide analysis using multivariate distance-based matrix regression was used to examine whole-brain relationships between delay discounting and functional connectivity was then performed. These analyses revealed that individual differences in delay discounting were associated with patterns of connectivity emanating from the left dorsal prefrontal cortex, a hub of the default mode network. Delay discounting was associated with greater functional connectivity between the dorsal prefrontal cortex and other parts of the default mode network, and reduced connectivity with regions in the dorsal and ventral attention networks. These results suggest that delay discounting in youth is associated with individual differences in relationships both within the default mode network and between the default mode and networks involved in attentional and cognitive control.
scTOP: physics-inspired order parameters for cellular identification and visualization
Authors: Yampolskaya Maria , Herriges Michael , Ikonomou Laertis , Kotton Darrell , Mehta Pankaj
Published: January 2023

Advances in single-cell RNA-sequencing (scRNA-seq) provide an unprecedented window into cellular identity. The increasing abundance of data requires new theoretical and computational frameworks for understanding cell fate determination, accurately classifying cell fates from expression data, and integrating knowledge from cell atlases. Here, we present single-cell Type Order Parameters (scTOP): a statistical-physics-inspired approach for constructing “order parameters” for cell fate given a reference basis of cell types. scTOP can quickly and accurately classify cells at a single-cell resolution, generate interpretable visualizations of developmental trajectories, and assess the fidelity of engineered cells. Importantly, scTOP does this without using feature selection, statistical fitting, or dimensional reduction (e.g., UMAP, PCA, etc.). We illustrate the power of scTOP utilizing a wide variety of human and mouse datasets (bothin vivoandin vitro). By reanalyzing mouse lung alveolar development data, we characterize a transient perinatal hybrid alveolar type 1/alveolar type 2 (AT1/AT2) cell population that disappears by 15 days post-birth and show that it is transcriptionally distinct from previously identified adult AT2-to-AT1 transitional cell types. Visualizations of lineage tracing data on hematopoiesis using scTOP confirm that a single clone can give rise to as many as three distinct differentiated cell types. We also show how scTOP can quantitatively assess the transcriptional similarity between endogenous and transplanted cells in the context of murine pulmonary cell transplantation. Finally, we provide an easy-to-use Python implementation of scTOP. Our results suggest that physics-inspired order parameters can be an important tool for understanding development and characterizing engineered cells.
Rapid engineering of SARS-CoV-2 therapeutic antibodies to increase breadth of neutralization including XBB.1.5 and BQ.1.1
Authors: Entzminger Kevin C. , Fleming Jonathan K. , Entzminger Paul D. , Espinosa Lisa Yuko , Samadi Alex , Hiramoto Yuko , Okumura CJ , Maruyama Toshiaki
Published: January 2023

An antibody panel that broadly neutralizes currently circulating Omicron variants was obtained byin vitroaffinity maturation using phage display. Starting from a single parent clone, antibody engineering was performed in iterative stages in real time as variants emerged using a proprietary technology called STage-Enhanced Maturation (STEM). Humanized from a rabbit antibody, the parent clone showed undetectable neutralization of later Omicron variants, while an early stage IgG possessing only an engineered light chain potently neutralizes some BA.2 but not BA.4/BA.5 lineage variants. However, the final heavy and light chain engineered mAbs show potent neutralization of XBB.1.5 and BQ.1.1 by surrogate virus neutralization test, and biolayer interferometry shows pM KDaffinity for both variants. Our work not only details novel therapeutic candidates but also validates a unique general strategy to create broadly neutralizing mAbs to current and future SARS-CoV-2 variants.
Label-Free Mammalian Cell Tracking Enhanced by Precomputed Velocity Fields
Authors: Han Yue , Lei Yang , Shkolnikov Viktor , Xin Daisy , Barcelo Steven , Allebach Jan , Delp Edward J.
Published: January 2023

Label-free cell imaging, where the cell is not “labeled” or modified by fluorescent chemicals, is an important research area in the field of biology. It avoids altering the cell’s properties which typically happens in the process of chemical labeling. However, without the contrast enhancement from the label, the analysis of label-free imaging is more challenging than label-based imaging. In addition, it provides few human interpretable features, and thus needs machine learning approaches to help with the identification and tracking of specific cells. We are interested in label-free phase contrast imaging to track cells flowing in a cell sorting device where images are acquired at 500 frames/s. Existing Multiple Object Tracking (MOT) methods face four major challenges when used for tracking cells in a microfluidic sorting device: (i) most of the cells have large displacements between frames without any overlap; (ii) it is difficult to distinguish between cells as they are visually similar to each other; (iii) the velocities of cells vary with the location in the device; (iv) the appearance of cells may change as they move in and out of the focal plane of the imaging sensor that observes the isolation process. In this paper, we introduce a method for tracking cells in a predefined flow in the sorting device via phase contrast microscopy. Our proposed method is based on DeepSORT and YOLOv4 and exploits prior knowledge of a cell’s velocity to assist tracking. We modify the Kalman filter in DeepSORT to accommodate a non-constant velocity motion model and integrate a representative velocity field obtained from fluid dynamics into the Kalman filter. The experimental results show that our proposed method outperforms several MOT methods for tracking cells in the sorting device.
Serum soluble urokinase plasminogen activator receptor as a biomarker for distinguishing Kawasaki disease from infections in febrile children
Authors: Alsuwaidi Ahmed R. , George Junu A. , Narchi Hassib
Published: January 2023

Background

The soluble form of the urokinase plasminogen activator receptor (SuPAR) is a potential biomarker in various inflammatory, infectious, and autoimmune conditions.

Objectives

In this stusy, we aimed to evaluate its diagnostic utility in febrile children to distinguish between Kawasaki disease (KD) and infections, and to investigate any association with the development of coronary artery aneurysms (CAA) KD.

Methods

In this retrospective observational cohort study we enrolled 17 children with fever lasting more than 5 days and without suggestive diagnostic signs on admission to hospital. Serum SuPAR concentrations were measured on admission and compared between children with confirmed KD and those with infections, as well as between children with KD who did or did not develop CAA.

Results

KD was later confirmed in seven children (median age 25 months), and febrile infections in 10. There was no significant difference in suPAR concentrations between both groups: 5.35 ± 2.76 ng/mL in KD, and 5.57 ± 1.69 ng/mL in febrile infections (p=0.84). The best cut-off value for suPAR, ≥ 7.74 ng/mL, was the best to correctly classify 64.7% of the cases, with a sensitivity of 28.6% and specificity of 90%. However, it had a low diagnostic performance (Youden index 18.6%, area under the curve curve 60%), and therefore failed to differentiate between KD and infections. In the seven children with KD, only one child developed CAA (SuPAR 4.69 ng/mL) while six other did not (SuPAR 5.47 ± 1.04 ng/mL) but the statistical significance could not be computed.

Conclusion

In febrile children, serum suPAR concentrations failed to distinguish between KD and infections, and were not associated with the development of CAA in KD. Therefore, SuPAR is not a useful biomarker in the diagnosis or prognosis of KD.
Potential for High Dynamic Range Sedia Limiting Antigen Antibody Assay to Support Viral Load monitoring during Antiretroviral Therapy
Authors: Sempa Joseph B. , Welte Alex
Published: January 2023

Introduction

Viral Load (VL) monitoring is a crucial component of patient care during antiretroviral therapy (ART) but is not routinely available in many resource-constrained settings, where millions of patients will require care for decades to come. We hypothesise a serologic ‘recent infection’ test (Sedia LAg assay) which has a high dynamic range for detecting antigen-driven antibody response can provide informative proxies for VL trajectories.

Methods

We analysed data linked via specimens in a well-described repository for recent infection test benchmarking (CEPHIA collaboration). Patient panels were comprised of 1) observations straddling ART start; 2) observations from a period of stable viral suppression; 3) observations straddling rebound after a period of viral suppression. We analysed an individual’s Sedia LAg ELISA normalised optical density (ODn) trends within these categories. Using groups 2) and 3) we evaluated the specificity and sensitivity of a proposed proxy for “the latest observation is at a time of VL rebound”; proxy was defined as follows: we estimated patient-specific mean-previous-ODn for all observations with at least two preceding virally suppressed observations. We considered various thresholds to define both “VL suppression” and “ODn uptick”.

Results

In regression analysis by category: 1) ODn gradients are statistically significantly negative just after ART-start (p=0.010); 2) During periods of stable viral suppression, ODn tended to decline, but not statistically significantly, for a range of clinically meaningful “VL suppression” thresholds; 3) comparing ODn values just before, versus at, “VL rebound”, ODn changes were statistically significantly increasing at rebound (p= 0.001). In the analysis comparing groups 2) and 3), at a Z score threshold of 0.8, the proposed proxy for a first viral rebound had an observed specificity and sensitivity both close to 90%.

Conclusion

The high dynamic range of serological tests previously investigated for defining ‘recent infection’ has potential, as demonstrated using the Sedia LAg ELISA, to provide meaningful information about the success of ART, during treatment initiation, at times of stable suppression, and to flag possible viral rebound. It should be investigated how this can be combined with patient management workflows and (clinical and) other data, to provide efficiencies in long-term monitoring viral control in resource-limited settings.
Wengen, a Tumour Necrosis Factor Receptor, regulates the Fibroblast Growth Factor pathway by an unconventional mechanism
Authors: Letizia Annalisa , Espinàs Maria Lluisa , Llimargas Marta
Published: January 2023

Unveiling the molecular mechanisms of receptor activation has led to much understanding of development as well as the identification of important drug targets. We use theDrosophilatracheal system to study the activity of two families of widely used and conserved receptors, the TNFRs and the RTK-FGFRs. Breathless, an FGFR, is known to respond to ligand by activating the differentiation program of the tracheal terminal cell. Here we show that Wengen, a TNFR, acts independently of both its canonical ligand and its downstream pathway genes to repress terminal cell differentiation. In contrast to Breathless, Wengen does not stably localise at the membrane and is instead internalised — a trafficking that seems essential for activity. We find that Wengen forms a complex with Breathless, and both colocalise in intracellular vesicles. Furthermore, Wengen regulates Breathless accumulation, likely regulating Breathless intracellular trafficking and degradation. We propose that, in the tracheal context, Wengen interacts with Breathless to regulate its activity in terminal cell differentiation. We suggest that such unconventional mechanism, involving binding by TNFRs to unrelated proteins, may be a general strategy of TNFRs activity.
Purification and structure of luminal domain C of human Niemann–Pick C1 protein
Authors: Odongo Laura , Zadrozny Kaneil K. , Diehl William E. , Luban Jeremy , White Judith M. , Ganser-Pornillos Barbie K. , Tamm Lukas K. , Pornillos Owen
Published: January 2023

Niemann–Pick C1 protein (NPC1) is a membrane protein that primarily resides in late endosomes and lysosomes, and plays an important role in cholesterol homeostasis in the cell. The second luminal domain of NPC1 (NPC1-C) serves as the intracellular receptor for Ebola and Marburg viruses. Here, the recombinant production of nonglycosylated and glycosylated NPC1-C and a new crystal form of the nonglycosylated protein are reported. The crystals belonged to space group P21 and diffracted to 2.3 Å resolution. The structure is similar to other reported structures of NPC1-C, with differences observed in the protruding loops when compared with NPC1-C in complex with Ebola virus glycoprotein or NPC2.
3-(2-Bromoethyl)-5,5-diphenylimidazolidine-2,4-dione
Authors: Guerrab Walid , El Moutaouakil Ala Allah Abderrazzak , Alsubari Abdulsalam , Mague Joel T. , Ramli Youssef
Published: January 2023

The imidazolidine ring in the title molecule, C17H15BrN2O2, is slightly ruffled [r.m.s. deviation = 0.0192 Å], while the attached phenyl rings at the C atom at the position between the amine and carbonyl centres are rotated well out of its mean plane [dihedral angles with the imidazolidine ring = 63.60 (8) and 76.4 (1)°]. In the crystal, a three-dimensional network features N—H...O and C—H...O hydrogen bonds together with C—H...π(ring) interactions.
Assessing graduates' transversal competences through an adapted MMI model: confidant interview vs stress interview
Authors: Freire Carla , Barbosa Iris
Published: January 2023

Purpose

The purpose of this article is to compare graduates' score rates in two multiple mini-interview (MMI) stations designed to assess graduates from several academic areas: confidant vs stress interview and synchronous vs asynchronous. This relates to three transversal competences (TCs) (learning to learn [LL], positive professional attitude [PPA] and market orientation [MO]) and analyses the impact of global performance during interviews, in the context of the hypothetical hiring decision.

Design/methodology/approach

The paired samples t-test was employed to compare the scores obtained by 130 graduates in two assessment exercises, which were designed to evaluate the same set of TCs. Multiple linear regression models were estimated to model the effect of global performance during the interview on the hypothetical hiring decision.

Findings

Results indicate a significant difference in averages between the graduates' TCs scores in confidant interviews, when compared with stress interviews. However, this is only observed in synchronous evaluations. In both interviews, the assessment of the participant's global performance has a significant effect on the hypothetical hiring decision.

Research limitations/implications

In the confidant interview, the interviewer was also the synchronous evaluator, which may have affected their focus on the evaluation process. The order in which graduates participated in the confidant and stress interviews varied, thus possibly influencing their performance.

Practical implications

The results are relevant for HEIs, graduates and employers involved in the evaluation of TCs.

Originality/value

The article derives from a broader research project which adapted the MMI model to other academic areas. It considers two instruments to evaluate graduates' TCs and two assessment circumstances.