bluuebunny/crossref_metadata_2025 huggingface dataset:
Design-Rules for Stapled Alpha-Helical Peptides with On-Target In Vivo Activity: Application to Mdm2/X dual antagonists
Authors: Chandramohan Arun , Josien Hubert , Yuen Tsz Ying , Duggal Ruchia , Spiegelberg Diana , Yan Lin , Angela Juang Yu-Chi , Ge Lan , Aronica Pietro , Kaan Kristal , Lim Yee Hwee , Peier Andrea , Sherborne Brad , Hochman Jerome , Lin Songnian , Biswas Kaustav , Henry Brian , Nestor Marika , Verma Chandra S , Lane David , Sawyer Tomi , Garbaccio Robert , Kannan Srinivasaraghavan , Kannan Srinivasaraghavan , Brown Christopher J. , Johannes Charles W , Partridge Anthony William
Published: February 2023

Stapled α-helical peptides can bind to and modulate historically intractable targets while addressing the traditional liabilities associated with peptide therapeutics. However, their pipeline advancement has been impeded by the challenges of identifying peptides with sufficient cellular uptake to engage the target protein while lacking off-target toxicities. Here, we advance the field to arrive at a workflow for identifying advanced stapled peptide lead molecules with on-target in vivo activity with no off-target cell proliferation effects. Specifically, we generated a >350-member library based on ATSP-7041, a stapled peptide Mdm2(X) antagonist with validated on-target cellular effects but with significant off-target activity. Key insights from library analysis include 1) a clear correlation between lipophilicity and permeability, 2) removal of positive charge to avoid off-target toxicities, 3) judicious placement of anionic residues to enhance peptide solubility/behavior, 4) optimization of C-terminal length and helicity to enhance cell activity, 5) optimization of staple type/number to avoid polypharmacology. Incorporation of one or more of these attributes led to molecules with improved in vitro and in vivo activities (up to a >292x improved cell proliferation EC50). A subset of peptides were devoid of off-target cell proliferation effects in cell lines lacking wild-type p53 protein (up to a >3800x on-target index). This latter improvement contrasted with clinical Mdm2 antagonistic molecules. Application of these ‘design rules’ to a distinct Mdm2(X) peptide series resulted in rapid improvement in cellular activity (>150x) and removal of off-target toxicities. Overall, the detailed workflow outlined here should help researchers identify stapled α-helical peptides for therapeutic impact.
The ancestral shape of the access proton path of mitochondrial ATP synthases revealed by a split subunit-a
Authors: Wong Jonathan E. , Zíková Alena , Gahura Ondřej
Published: February 2023

The passage of protons across membranes through F1Fo-ATP synthases spins their rotors and drives synthesis of ATP. While the principle of torque generation by proton transfer is known, the mechanisms and routes of proton access and release and their evolution are not fully understood. Here, we show that the entry site and path of protons in the lumenal half-channel of mitochondrial ATP synthases are largely defined by a short N-terminal α-helix of subunit-a. InTrypanosoma bruceiand other Euglenozoa, the α-helix is part of another polypeptide chain that is a product of subunit-a gene fragmentation. This α-helix and other elements forming the proton pathway are widely conserved across eukaryotes and in Alphaproteobacteria, the closest extant relatives of mitochondria, but not in other bacteria. The α-helix blocks one of two proton routes found inEscherichia coli, resulting in the single proton entry site in mitochondrial and alphaproteobacterial ATP synthases. Thus, the shape of the access half-channel predates eukaryotes and originated in the lineage from which mitochondria evolved by endosymbiosis.
Investigation of co-encapsulation of pancreatic beta cells and curcumin within alginate microcapsules
Authors: Hosseinzadeh Zahra , Alemzadeh Iran , Vossoughi Manouchehr
Published: February 2023

1.

Cell encapsulation is an ideal approach for the replacement of pancreatic function in Type 1 diabetes. Poor biocompatibility of microcapsules generates an inflammatory response in the implantation site and induces fibrosis infiltration, which causes microencapsulated cell death and graft failure. To prevent inflammation after implantation, composite microcapsules which exhibit anti-inflammatory properties were designed. This study is about co-encapsulating beta cells and curcumin within 1.5% alginate by the jet-breaking regime of the syringe pump. The microcapsules size distribution and rate of the alginate solution were characterized to find uniform particles. Micro-size particles were attained at a rate of 25 ml/min. Uniform spherical microcapsules (200–300 μm) were created in large amounts in a short period. Microcapsule breakage was less than 3% during 7 days and demonstrated the stability of the encapsulation method. Insulin secretion and cell viability assays were performed 1, 3, and 7 days after microencapsulation by GSIS and MTT assays. No significant differences in the amount of insulin secretion and beta cell viability were observed among free cells, alginate microcapsules, and curcumin-alginate microcapsules during 7 days (P > 0.05). Therefore, curcumin and alginate membrane did not show any harmful impacts on the function and survival of the beta cells.
Task shifting healthcare services in the post-COVID world: A scoping review
Authors: Das Shukanto , Grant Liz
Published: February 2023

Task shifting (TS) redistributes services from specialised to less-qualified providers. Need for TS was intensified during COVID-19 pandemic. We locate evidences of TS across all health conditions to answer: (A) What role has TS played in services delivery since the onset of the pandemic? (B) How has the pandemic impacted strategies of TS globally? We searched five databases in October 2022: Medline, CINHAL Plus, Elsevier, Global Health and Google Scholar. 35 citations were selected. Data was analysed thematically and reported as per PRSIMA-ScR. We used WHO health systems framework and emergent themes to discuss findings. TS was observed in countries of all income-levels. 63% (n=22) articles discussed what impact TS had in COVID-19 care, mental healthcare, care for HIV, sexual and reproductive health, nutrition and rheumatoid diseases. Others (n=13) highlight how pandemic altered TS strategies in mental healthcare, HIV services, hypertension and diabetes and emergency services. Studies varied in reporting TS; majority using terms “task shifting”, followed by “task sharing”, “task shifting and sharing” and “task delegation”. TS affected every block of health system. TS to non-specialists and non-healthcare staff improved services. Modifying roles through training and collaboration strengthened workforce. TS diagnostics increased access to medicines and technologies. Strategic leadership was key. Research on financing TS during pandemics is required. Stakeholders generally accepted TS. Shifting staff between programs led to unintended service incapacities. Pandemic affected strategies of TS. Training, providing care, follow-ups and consultations went digital. Virtually-delivered interventions improved outcomes. Accessibility to digital technology presented barriers. COVID-19 modified health-seeking behaviour. Patients preferred teleconsultations and online-symptom checkers. Organisations altered operating procedures and patient-flow pathways and added precautions to protect staff. Risks of spreading COVID-19 prompted facilities to reconsider TS. TS improved outcomes by filling workforce gaps and increasing access. We recommend TS to improve services delivery during the pandemic and beyond.
MsPBRsP: Multi-scale Protein Binding Residues Prediction Using Language Model
Authors: Li Yuguang , Lu Shuai , Nan Xiaofei , Zhang Shoutao , Zhou Qinglei
Published: February 2023

Accurate prediction of protein binding residues (PBRs) from sequence is important for the understanding of cellular activity and helpful for the design of novel drug. However, experimental methods are time-consuming and expensive. In recent years, a lot of computational predictors based on machine learning and deep learning models are proposed to reduce such consumption. But those methods often use MSA tools such as PSI-BLAST or NetSurfP to generate some statistical features and enter them into predictive models as necessary supplementary input. The input generation process normally takes long time, and there is no standard to specify which and how many statistic results should be provided to a prediction model. In addition, prediction of PBRs relies on residue local context, but the most appropriate scale is undetermined. Most works pre-selected certain residue features as input and a scale size based on expertise for certain type of PBRs. In this study, we propose a general tool-free end-to-end framework that can be applied to all types of PBRs, Multiscale Protein Binding Residues Prediction using language model (MsPBRsP). We adopt a pre-trained language model ProtTrans to save the large consumption caused by MSA tools, and use protein sequence alone as input to our model. To ease scale size uncertainty, we construct multi-size windows in attention layer and multi-size kernels in convolutional layer. We test our framework on various benchmark datasets including PBRs from protein-protein, protein-nucleotide, protein-small ligand, heterodimer, homodimer and antibody-antigen interactions. Compared with existing state-of-the-art methods, MsPBRsP achieves superior performance with less running time and higher prediction rates on every PBRs prediction task. Specifically, we boost F1 score by 27.1% and AUPRC score by 7.6% on NSP448 dataset and decrease running time from over 10 minutes to under 0.1s on average. The source code and datasets are available at https://github.com/biolushuai/MsPBRsP-for-multiple-PBRsprediction.
Mode-based morphometry: A multiscale approach to mapping human neuroanatomy
Authors: Cao Trang , Pang James C. , Segal Ashlea , Chen Yu-Chi , Aquino Kevin M. , Breakspear Michael , Fornito Alex
Published: February 2023

Voxel-based morphometry (VBM) and surface-based morphometry (SBM) are two widely used neuroimaging techniques for investigating brain anatomy. These techniques rely on statistical inferences at individual points (voxels or vertices), clusters of points, or a priori regions-of-interest. They are powerful tools for describing brain anatomy, but offer little insights into the generative processes that shape a particular set of findings. Moreover, they are restricted to a single spatial resolution scale, precluding the opportunity to distinguish anatomical variations that are expressed across multiple scales. Drawing on concepts from classical physics, here we develop an approach, called mode-based morphometry (MBM), that can describe any empirical map of anatomical variations in terms of the fundamental, resonant modes––eigenmodes––of brain anatomy, each tied to a specific spatial scale. Hence, MBM naturally yields a multiscale characterization of the empirical map, affording new opportunities for investigating the spatial frequency content of neuroanatomical variability. Using simulated and empirical data, we show that the validity and reliability of MBM are either comparable or superior to classical vertex-based SBM for capturing differences in cortical thickness maps between two experimental groups. Our approach thus offers a robust, accurate, and informative method for characterizing empirical maps of neuroanatomical variability that can be directly linked to a generative physical process.
Multiscale Multimodal Characterization and Simulation of Structural Alterations in Failed Bioprosthetic Heart Valves
Authors: Tsolaki Elena , Corso Pascal , Zboray Robert , Avaro Jonathan , Appel Christian , Liebi Marianne , Bertazzo Sergio , Heinisch Paul Philipp , Carrel Thierry , Obrist Dominik , Herrmann Inge K.
Published: February 2023

Calcific degeneration is the most frequent type of heart valve failure, with rising incidence due to the ageing population. The gold standard treatment to date is valve replacement. Unfortunately, calcification oftentimes re-occurs in bioprosthetic substitutes, with the governing processes remaining poorly understood. Here, we present a multiscale, multimodal analysis of disturbances and extensive mineralisation of the collagen network in failed bioprosthetic bovine pericardium valve explants with full histoanatomical context. In addition to highly abundant mineralized collagen fibres and fibrils, calcified micron-sized particles previously discovered in native valves were also prevalent on the aortic as well as the ventricular surface of bioprosthetic valves. The two mineral types (fibers and particles) were detectable even in early-stage mineralisation, prior to any macroscopic calcification. Based on multiscale multimodal characterisation and high-fidelity simulations, we demonstrate that mineral occurrence coincides with regions exposed to high haemodynamic and biomechanical indicators. These insights obtained by multiscale analysis of failed bioprosthetic valves may serve as groundwork for the evidence-based development of more durable alternatives.

Graphical Abstract
Network-Level Changes in the Brain Underlie Fear Memory Strength
Authors: Haubrich Josue , Nader Karim
Published: February 2023

The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using c-fos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.
2019-20 H1N1 clade A5a.1 viruses have betterin vitroreplication compared with the co-circulating A5a.2 clade
Authors: Swanson Nicholas J , Marinho Paula , Dziedzic Amanda , Jedlicka Anne , Liu Hsuan , Fenstermacher Katherine , Rothman Richard , Pekosz Andrew
Published: February 2023

Surveillance for emerging human influenza virus clades is important for identifying changes in viral fitness and assessing antigenic similarity to vaccine strains. While fitness and antigenic structure are both important aspects of virus success, they are distinct characteristics and do not always change in a complementary manner. The 2019-20 Northern Hemisphere influenza season saw the emergence of two H1N1 clades: A5a.1 and A5a.2. While several studies indicated that A5a.2 showed similar or even increased antigenic drift compared with A5a.1, the A5a.1 clade was still the predominant circulating clade that season. Clinical isolates of representative viruses from these clades were collected in Baltimore, Maryland during the 2019-20 season and multiple assays were performed to compare both antigenic drift and viral fitness between clades. Neutralization assays performed on serum from healthcare workers pre- and post-vaccination during the 2019-20 season show a comparable drop in neutralizing titers against both A5a.1 and A5a.2 viruses compared with the vaccine strain, indicating that A5a.1 did not have antigenic advantages over A5a.2 that would explain its predominance in this population. Plaque assays were performed to investigate fitness differences, and the A5a.2 virus produced significantly smaller plaques compared with viruses from A5a.1 or the parental A5a clade. To assess viral replication, low MOI growth curves were performed on both MDCK-SIAT and primary differentiated human nasal epithelial cell cultures. In both cell cultures, A5a.2 yielded significantly reduced viral titers at multiple timepoints post-infection compared with A5a.1 or A5a. Receptor binding was then investigated through glycan array experiments which showed a reduction in receptor binding diversity for A5a.2, with fewer glycans bound and a higher percentage of total binding attributable to the top three highest bound glycans. Together these data indicate that the A5a.2 clade had a reduction in viral fitness, including reductions in receptor binding, that may have contributed to the limited prevalence observed after emergence.
Improving retinal vascular endothelial cell tropism through rational rAAV capsid design
Authors: Periasamy Ramesh , Patel Dwani D. , Boye Sanford L. , Boye Shannon E. , Lipinski Daniel M.
Published: February 2023

Vascular endothelial cells (VEC) are essential for retinal homeostasis and their dysfunction underlies pathogenesis in diabetic retinopathy (DR) and exudative age-related macular degeneration (AMD). Studies have shown that recombinant adeno-associated virus (rAAV) vectors are effective at delivering new genetic material to neural and glial cells within the retina, but targeting VECs remains challenging. To overcome this limitation, herein we developed rAAV capsid mutant vectors with improved tropism towards retinal VEC. rAAV2/2, 2/2[QuadYF-TV], and rAAV2/9 serotype vectors (n=9, capsid mutants per serotype) expressing GFP were generated by inserting heptameric peptides (7AA) designed to increase endothelial targeting at positions 588 (2/2 and 2/2[QuadYF-TV] or 589 (2/9) of the virus protein (VP 1-3). The packaging and transduction efficiency of the vectors were assessed in HEK293T and bovine VECs using Fluorescence microscopy and flow cytometry, leading to the identification of one mutant, termed EC5, that showed improved endothelial tropism when inserted into all three capsid serotypes. Intra-ocular and intravenous administration of EC5 mutants in C57Bl/6j mice demonstrated moderately improved transduction of the retinal vasculature, particularly surrounding the optic nerve head, and evidence of sinusoidal endothelial cell transduction in the liver. Most notably, intravenous administration of the rAAV2/2[QuadYF-TV] EC5 mutant led to a dramatic and unexpected increase in cardiac muscle transduction.
Coordinated growth of linked epithelia is mediated by the Hippo pathway
Authors: Friesen Sophia , Hariharan Iswar K.
Published: February 2023

An epithelium in a living organism seldom develops in isolation. Rather, most epithelia are tethered to other epithelial or non-epithelial tissues, necessitating growth coordination between layers. We investigated how two tethered epithelial layers of theDrosophilalarval wing imaginal disc, the disc proper (DP) and the peripodial epithelium (PE), coordinate their growth. DP growth is driven by the morphogens Hedgehog (Hh) and Dpp, but regulation of PE growth is poorly understood. We find that the PE adapts to changes in growth rates of the DP, but not vice versa, suggesting a “leader and follower” mechanism. Moreover, PE growth can occur by cell shape changes, even when proliferation is inhibited. While Hh and Dpp pattern gene expression in both layers, growth of the DP is exquisitely sensitive to Dpp levels, while growth of the PE is not; the PE can achieve an appropriate size even when Dpp signaling is inhibited. Instead, both the growth of the PE and its accompanying cell shape changes require the activity of two components of the mechanosensitive Hippo pathway, the DNA-binding protein Scalloped (Sd) and its co-activator (Yki), which could allow the PE to sense and respond to forces generated by DP growth. Thus, an increased reliance on mechanically-dependent growth mediated by the Hippo pathway, at the expense of morphogen-dependent growth, enables the PE to evade layer-intrinsic growth control mechanisms and coordinate its growth with the DP. This provides a potential paradigm for growth coordination between different components of a developing organ.
Methodology for inference of intercellular gene interactions
Authors: Modi Saurabh , Zurakowski Ryan , Gleghorn Jason P.
Published: February 2023

To govern organ size, shape, and function, cell-secreted diffusible molecules called morphogens spatially pattern cell differentiation, gene expression, and proliferation. Local morphogen concentration governs cell differentiation through gene regulatory networks (GRN). Previous inference methodologies tackle intercellular GRN inference between cells of one type. This is insufficient, as many developmental systems consist of cells of different types interacting with each other. Inference methodologies of GRNs between different cell types assume knowledge of diffusible morphogen identity and concentration. This makes their applicability limited in real biological systems. Here, we develop a computational methodology to infer the intercellular GRN derived from experiments that use fluorescence from reporter proteins for gene expression measurements. For validation, we demonstrate the methodologyin silicousing three case studies based on developmental and synthetic biology. The results show that, barring practical identifiability limitations, the methodology successfully infers the intercellular GRNs.
Stochastic bounds of aggregation dynamics distinguish near-wild-type from wild-type strains in social bacteria
Authors: Asp Merrill E. , Caro Eduardo A. , Welch Roy D. , Patteson Alison E.
Published: February 2023

The genotype-to-phenotype problem (G2P) for multicellular development asks how genetic inputs control collective phenotypic outputs. It is a difficult problem even to observe. On the genotype side, the phenotypic impact of mutation is often subtle due at least partly to gene redundancy and myriad other factors. On the phenotype side, biological and even technical developmental replicates can display significant phenotypic variation due at least in part to stochasticity, again with other factors. We attempt to partially resolve the G2P inputs and outputs from the obfuscating effects of factors like redundancy and stochasticity. As a model organism, we selected the biofilm-forming speciesMyxococcus xanthus, a motile self-organizing bacterium that forms three-dimensional cell aggregates that grow and mature into spore-filled fruiting bodies when under starvation stress. We developed data acquisition tools and analysis and visualization methods that can produce a topological map ofM. xanthusdevelopment. We demonstrate that even subtle effects on developmental dynamics caused by mutation can be identified, discriminated, characterized, and given statistical significance.
Tipping points emerge from weak mutualism in metacommunities
Authors: Denk Jonas , Hallatschek Oskar
Published: February 2023

The coexistence of obligate mutualists is often precariously close to tipping points where small environmental changes can drive catastrophic shifts in species composition. For example, microbial ecosystems can collapse by the decline of a strain that provides an essential resource on which other strains cross-feed. Here, we show that tipping points, ecosystem collapse, bistability and hysteresis arise even with very weak (non-obligate) mutualism provided the population is spatially structured. Based on numeric solutions of a metacommunity model and mean-field analyses, we demonstrate that weak mutualism lowers the minimal dispersal rate necessary to avoid stochastic extinction, while species need to overcome a mean threshold density to survive in this low dispersal rate regime. Moreover, we show that, starting with a randomly interacting species pool, metapopulation structure tends to select for an ecosystem with mutualistic interactions. Bistable metacommunities could, therefore, be a natural outcome of evolutionary dynamics in structured ecosystems.
The Kinase Module of the Mediator regulates cell cycle re-entry and transcriptional response following DNA damage
Authors: Memişoğlu Gönen , Bohn Stefan , Krogan Nevan , Haber James E. , Ruthenburg Alexander J.
Published: February 2023

When faced with a DNA double strand break, cells activate an elaborate signaling cascade called the DNA damage response to protect genomic integrity. To identify novel factors that modulate the DNA damage response to DNA double strand breaks, we performed an epistatic miniarray profile (E-MAP) analysis of Mec1 and Rad53, two essential kinases that coordinate the DNA damage response in budding yeast. Through this analysis, we discovered a genetic interaction between the kinase module (CKM) of the Mediator of transcription and Rad53. We find that all four subunits of the CKM, as well as CKM’s kinase activity are critical for cell cycle re-entry following a DNA break, whereas the core Mediator subunits are dispensable. Notably, CKM mutants do not impair DNA repair by homologous recombination or confer sensitivity to DNA damaging reagents, suggesting that CKM specifically impinges on DNA damage signaling. In support of this, we find that Rad53 and CKM physically interact in response to DNA damage. Following the induction of a DNA break, CKM is a critical regulator of global transcription inhibition. In addition to this global effect, we illustrate that CKM functions locally at DNA breaks together with the core Mediator. In the absence of catalytically active CKM, the CKM-Mediator complexes at DNA breaks are replaced by RNAPII. Taken together, our results reveal a previously uncharacterized role for CKM in the DNA damage response.
Acetylcholine engages distinct amygdala microcircuits to gate internal theta rhythm
Authors: Bratsch-Prince Joshua X. , Warren James W. , Jones Grace C. , McDonald Alexander J. , Mott David D.
Published: February 2023

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in basolateral amygdala (BLA) underlie emotional memory, yet their mechanism remains unclear. Using brain slice electrophysiology in mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potential that depend upon activation of cholecystokinin (CCK) interneurons (INs). Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, gating BLA theta. ACh-induced theta activity is more readily evoked in BLA over cortex or hippocampus, suggesting preferential activation of BLA during high ACh states. These data reveal a SOM-CCK IN circuit in BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.
Active maintenance of CD8+T cell naïvety through regulation of global genome architecture
Authors: Russ Brendan E. , Tsyganov Kirril , Quon Sara , Yu Bingfei , Li Jasmine , Lee Jason K. C. , Olshansky Moshe , He Zhaohren , Harrison Paul F. , Barugahare Adele , See Michael , Nussing Simone , Morey Alison E. , Udupa Vibha A. , Bennett Taylah .J , Kallies Axel , Murre Cornelis , Collas Phillipe , Powell David , Goldrath Ananda W. , Turner Stephen J.
Published: February 2023

The differentiation of naïve CD8+cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8+T cells. We observed that the architecture of the naive CD8+T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naïve chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naïve CD8+T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naïve chromatin state.

One Sentence Summary

CD8+T cell naïvety is actively maintained by transcription factors that enforce a distinct, naïve chromatin architecture.

Highlights

CD8+T cell differentiation states are underscored by distinct chromatin looping architectures.

Chromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes.

Effector and memory CTLs have similar genome architectures, explaining rapid memory recall.

CTL differentiation is restrained by BACH2 and SATB1, which enforce a naïve loop architecture.
Multiscale networks in multiple sclerosis
Authors: Kennedy Keith E , Kerlero de Rosbo Nicole , Uccelli Antonio , Cellerino Maria , Ivaldi Federico , Contini Paola , De Palma Raffaele , Harbo Hanne H , Berge Tone , Bos Steffan D , Høgestøl Einar A , Brune-Ingebretsen Synne , de Rodez Benavent Sigrid , Paul Friedemann , Brandt Alexander U , Bäcker-Koduah Priscilla , Behrens Janina , Kuchling Joseph , Asseyer Susana E , Scheel Michael , Chien Claudia , Zimmermann Hanna , Motamedi Seyedamirhosein , Kauer-Bonin Josef , Saez-Rodriguez Julio , Rinas Melani , Alexopoulos Leonidas , Andorra Magi , Llufriu Sara , Saiz Albert , Blanco Yolanda , Martinez-Heras Eloy , Solana Elisabeth , Pulido-Valdeolivas Irene , Martinez-Lapiscina Elena H , Garcia-Ojalvo Jordi , Villoslada Pablo
Published: February 2023

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information, and Boolean simulations identified paths within and among all layers. The path more commonly found from the boolean simulations connects MP2K, with Th17 cells, the retinal nerve fiber layer (RNFL) thickness and the age related MS severity score (ARMSS). Combinations of several proteins (HSPB1, MP2K1, SR6, KS6B1, SRC, MK03, LCK and STAT6)) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level.
Whole genome sequencing ofBorrelia burgdorferiisolates reveals linked clusters of plasmid-borne accessory genome elements associated with virulence
Authors: Lemieux Jacob E. , Huang Weihua , Hill Nathan , Cerar Tjasa , Freimark Lisa , Hernandez Sergio , Luban Matteo , Maraspin Vera , Bogovic Petra , Ogrinc Katarina , Ruzic-Sabljic Eva , Lapierre Pascal , Lasek-Nesselquist Erica , Singh Navjot , Iyer Radha , Liveris Dionysios , Reed Kurt D. , Leong John M. , Branda John A. , Steere Allen C. , Wormser Gary P. , Strle Franc , Sabeti Pardis C. , Schwartz Ira , Strle Klemen
Published: February 2023

Lyme disease is the most common vector-borne disease in North America and Europe. The clinical manifestations of Lyme disease vary based on the genospecies of the infectingBorrelia burgdorferispirochete, but the microbial genetic elements underlying these associations are not known. Here, we report the whole genome sequence (WGS) and analysis of 299 patient-derivedB. burgdorferisensu stricto (Bbss) isolates from patients in the Eastern and Midwestern US and Central Europe. We develop a WGS-based classification ofBbssisolates, confirm and extend the findings of previous single- and multi-locus typing systems, define the plasmid profiles of human-infectiousBbssisolates, annotate the core and strain-variable surface lipoproteome, and identify loci associated with disseminated infection. A core genome consisting of ∼800 open reading frames and a core set of plasmids consisting of lp17, lp25, lp36, lp28-3, lp28-4, lp54, and cp26 are found in nearly all isolates. Strain-variable (accessory) plasmids and genes correlate strongly with phylogeny. Using genetic association study methods, we identify an accessory genome signature associated with dissemination and define the individual plasmids and genes that make up this signature. Strains within the RST1/WGS A subgroup, particularly a subset marked by the OspC type A genotype, are associated with increased rates of dissemination. OspC type A strains possess a unique constellation of strongly linked genetic changes including the presence of lp56 and lp28-1 plasmids and a cluster of genes that may contribute to their enhanced virulence compared to other genotypes. The patterns of OspC type A strains typify a broader paradigm acrossBbssisolates, in which genetic structure is defined by correlated groups of strain-variable genes located predominantly on plasmids, particularly for expression of surface-exposed lipoproteins. These clusters of genes are inherited in blocks through strain-specific patterns of plasmid occupancy and are associated with the probability of invasive infection.
Characteristic differences in tibial subchondral bone changes in the post-traumatic knee osteoarthritis model
Authors: Arakawa Kohei , Takahata Kei , Usami Yuna , Kokubun Takanori
Published: February 2023

Objective

Meniscus degeneration and subchondral bone changes contribute to the development and progression of knee OA. The purpose of this study was to reveal the relationship between medial meniscus degeneration and characteristics of subchondral bone changes in different models

Design

We used the anterior cruciate ligament transection (ACL-T) model, destabilization of the medial meniscus (DMM) model, controlled abnormal tibial translation (CATT) model and a controlled abnormal tibial rotation (CATR) model with different mechanical stresses. We performed histological analysis and micro computed tomography analysis, at 4 and 6 weeks. In addition, we divided the tibial subchondral bone into four compartments and set the regions of interest

Results

Meniscus degeneration was observed in all groups, but there was no significant difference. The ACL-T group showed posterior displacement of the contact area, and the DMM and CATR groups showed lateral deviation of the medial meniscus. The region-specific subchondral bone changes in each model showed that changes in mechanical stress due to ACL and meniscus dysfunction, as well as changes in the contact area, affect the bony structure of the subchondral bone differently in each region.

Conclusions

Subchondral bone changes in different models of mechanical stress were different in each region. In particular, changes in the contact area and increased compressive stress due to meniscus dysfunction were suggested to promote bone formation. The results of this study indicate that changes in alignment and contact area in the PTOA model may cause region-specific characteristics of the subchondral bone changes.
Automated quantification of lipophagy in Saccharomyces cerevisiae from fluorescence and cryo-soft X-ray microscopy data using deep learning
Authors: Egebjerg Jacob Marcus , Szomek Maria , Thaysen Katja , Juhl Alice Dupont , Werner Stephan , Pratsch Christoph , Schneider Gerd , Röttger Richard , Wüstner Daniel
Published: February 2023

Lipophagy is a form of autophagy by which lipid droplets (LDs) become digested to provide nutrients as a cellular response to starvation. Lipophagy is often studied in yeast,Saccharomyces cerevisiae, in which LDs become internalized into the vacuole. There is a lack of tools to quantitatively assess lipophagy in intact cells with high resolution and throughput. Here, we combine soft X-ray tomography (SXT) with fluorescence microscopy and use a deep learning computational approach to visualize and quantify lipophagy in yeast. We focus on yeast homologs of mammalian Niemann Pick type C proteins, whose dysfunction leads to Niemann Pick type C disease in humans, i.e., NPC1 (named NCR1 in yeast) and NPC2. We developed a convolutional neural network (CNN) model which classifies ring-shaped versus lipid-filled or fragmented vacuoles containing ingested LDs in fluorescence images from wild-type yeast and from cells lacking NCR1 (Δncr1cells) or NPC2 (Δnpc2cells). Using a second CNN model, which performs automated segmentation of LDs and vacuoles from high-resolution reconstructions of X-ray tomograms, we can obtain 3D renderings of LDs inside and outside of the vacuole in a fully automated manner and additionally measure droplet volume, number, and distribution. We find that cells lacking functional NPC proteins can ingest LDs into vacuoles normally but show compromised degradation of LDs and accumulation of lipid vesicles inside vacuoles. This phenotype is most severe inΔnpc2cells. Our new method is versatile and allows for automated high-throughput 3D visualization and quantification of lipophagy in intact cells.
Dopamine dysregulation in Parkinson’s disease flattens the pleasurable urge to move to musical rhythms
Authors: Pando-Naude Victor , Matthews Tomas Edward , Højlund Andreas , Jakobsen Sebastian , Østergaard Karen , Johnsen Erik , Garza-Villarreal Eduardo A. , Witek Maria A. G. , Penhune Virginia , Vuust Peter
Published: February 2023

The pleasurable urge to move to music (PLUMM) elicits activity in motor and reward areas of the brain and is thought to be driven by predictive processes. Dopamine within motor and limbic cortico-striatal networks is implicated in the predictive processes underlying beat-based timing and music-induced pleasure, respectively. This suggests a central role of cortico-striatal dopamine in PLUMM. This study tested this hypothesis by comparing PLUMM in Parkinson’s disease patients, healthy age-matched, and young controls. Participants listened to musical sequences with varying rhythmic and harmonic complexity (low, medium, high), and rated their experienced pleasure and urge to move to the rhythm. In line with previous results, healthy younger participants showed an inverted U-shaped relation between rhythmic complexity and ratings, with a preference for medium complexity rhythms, while age-matched controls showed a similar, but weaker, inverted U-shaped response. Conversely, PD patients showed a significantly flattened response for both the urge to move and pleasure. Crucially, this flattened response could not be attributed to differences in rhythm discrimination and did not reflect an overall decrease in ratings. Together, these results support the role of dopamine within cortico-striatal networks in the predictive processes that form the link between the perceptual processing of rhythmic patterns, and the affective and motor responses to rhythmic music.
Complex hierarchical structures in single-cell genomics data unveiled by deep hyperbolic manifold learning
Authors: Tian Tian , Zhong Cheng , Lin Xiang , Wei Zhi , Hakonarson Hakon
Published: February 2023

With the advances in single-cell sequencing techniques, numerous analytical methods have been developed for delineating cell development. However, most are based on Euclidean space, which would distort the complex hierarchical structure of cell differentiation. Recently, methods acting on hyperbolic space have been proposed to visualize hierarchical structures in single-cell RNA-seq (scRNA-seq) data and have been proven to be superior to methods acting on Euclidean space. However, these methods have fundamental limitations and are not optimized for the highly sparse single-cell count data. To address these limitations, we propose scDHMap, a model-based deep learning approach to visualize the complex hierarchical structures of scRNA-seq data in low-dimensional hyperbolic space. The evaluations on extensive simulation and real experiments show that scDHMap outperforms existing dimensionality-reduction methods in various common analytical tasks as needed for scRNA-seq data, including revealing trajectory branches, batch correction, and denoising the count matrix with high dropout rates. In addition, we extend scDHMap to visualize single-cell ATAC-seq data.
Correction of rhodopsin serial crystallography diffraction intensities for a lattice-translocation defect
Authors: Rodrigues Matthew J. , Casadei Cecilia M. , Weinert Tobias , Panneels Valerie , Schertler Gebhard F. X.
Published: February 2023

Rhodopsin is a G-protein-coupled receptor that detects light and initiates the intracellular signalling cascades that underpin vertebrate vision. Light sensitivity is achieved by covalent linkage to 11-cis retinal, which isomerizes upon photo-absorption. Serial femtosecond crystallography data collected from rhodopsin microcrystals grown in the lipidic cubic phase were used to solve the room-temperature structure of the receptor. Although the diffraction data showed high completeness and good consistency to 1.8 Å resolution, prominent electron-density features remained unaccounted for throughout the unit cell after model building and refinement. A deeper analysis of the diffraction intensities uncovered the presence of a lattice-translocation defect (LTD) within the crystals. The procedure followed to correct the diffraction intensities for this pathology enabled the building of an improved resting-state model. The correction was essential to both confidently model the structure of the unilluminated state and interpret the light-activated data collected after photo-excitation of the crystals. It is expected that similar cases of LTD will be observed in other serial crystallography experiments and that correction will be required in a variety of systems.
Business and management research trends of sustainability assessment in the food sector
Authors: Nicolas Carolina , Geldres-Weiss Valeska V.
Published: February 2023

Purpose

This study aimed to identify research trends and topics in sustainability assessment in the food sector within the scope of economics, business and management research.

Design/methodology/approach

The authors conducted a bibliometric analysis by applying a rigid and systematic research protocol, employing bibliometric techniques and a keyword co-occurrence network. Further, the Visualization of Similarities viewer software was used to analyse publications between 1994 and 2021.

Findings

The knowledge trends regarding “sustainability assessment” in the research area of business economics demonstrated a notable evolution of the topics analysed, ranging from indicators and policy analyses in agriculture and fishery sectors, to the topic of sustainability life cycle assessment (LCA) and management systems. In business and management research areas, the main theoretical frameworks used for sustainability assessment in the food sector included the triple-bottom line (TBL) and the LCA, and the main research topics were food chain logistics, bio-based products, retailers, consumption patterns and crop-based biodiesel options.

Research limitations/implications

This study employed only the WoS database and future studies could incorporate other scientific databases. Regarding future research, more emphasis could be laid on food retailers given their prevalence as demonstrated by the study and past research.

Practical implications

The findings can help all participants in the food global value chain to make better decisions to guide their sustainability efforts and assessment. Moreover, this research reveals that companies need to be actively engaged with their stakeholders and pay special attention to consumer patterns and perceptions.

Originality/value

The bibliometric research focus on business and management research areas using the Web of Sciences categories, starting from the research area of business economics to the analysis of the food sector's sustainability assessment.
Called to stay? The moderating roles of feedback from others and role clarity in the relationship between experiencing a calling and organizational embeddedness
Authors: Muehlhausen Julia , Spurk Daniel , Hirschi Andreas , Sandmeier Anita
Published: February 2023

Purpose

Organizational embeddedness of employees who are experiencing their work as a calling is of high relevance. Understanding what promotes staying in organizations can provide benefits for individuals with a calling while at the same time helping organizations to retain those valuable employees. Therefore, the purpose of this study was to investigate how and when experiencing work as a calling relates to organizational embeddedness (OE). Based on assumptions from the theory of work adjustment (TWA), the authors hypothesized a conditional effects model with feedback from others and role clarity as moderating variables.

Design/methodology/approach

For this longitudinal study, the authors collected data at two measurement time points (N = 553). To tests the hypotheses, the authors performed hierarchical regression analysis. Additionally, the authors conducted simple slope tests to calculate the effects of calling on OE, depending on the different levels of the moderators.

Findings

The results indicated that higher levels of experiencing a calling are associated with higher levels of OE 18 months later while controlling for the initial levels of OE. Additionally, the moderation analysis revealed that feedback from others and role clarity strengthened the relationship between experiencing a calling and OE. Interestingly, for individuals with low feedback from others and low role clarity, experiencing a calling was not related to OE.

Originality/value

Addressing recent research calls that highlight more research on boundary conditions and diverse theoretical perspectives, this study contributes to the literature on calling and organizational retention and provides a more individual and career-related view of potential predictors of OE.
Do SEC filings indicate any trends? Evidence from the sentiment distribution of forms 10-K and 10-Q with FinBERT
Authors: Kim Hyogon , Lee Eunmi , Yoo Donghee
Published: February 2023

Purpose

This study quantified companies' views on the COVID-19 pandemic with sentiment analysis of US public companies' disclosures. The study aims to provide timely insights to shareholders, investors and consumers by exploring sentiment trends and changes in the industry and the relationship with stock price indices.

Design/methodology/approach

From more than 50,000 Form 10-K and Form 10-Q published between 2020 and 2021, over one million texts related to the COVID-19 pandemic were extracted. Applying the FinBERT fine-tuned for this study, the texts were classified into positive, negative and neutral sentiments. The correlations between sentiment trends, differences in sentiment distribution by industry and stock price indices were investigated by statistically testing the changes and distribution of quantified sentiments.

Findings

First, there were quantitative changes in texts related to the COVID-19 pandemic in the US companies' disclosures. In addition, the changes in the trend of positive and negative sentiments were found. Second, industry patterns of positive and negative sentiment changes were similar, but no similarities were found in neutral sentiments. Third, in analyzing the relationship between the representative US stock indices and the sentiment trends, the results indicated a positive relationship with positive sentiments and a negative relationship with negative sentiments.

Originality/value

Performing sentiment analysis on formal documents like Securities and Exchange Commission (SEC) filings, this study was differentiated from previous studies by revealing the quantitative changes of sentiment implied in the documents and the trend over time. Moreover, an appropriate data preprocessing procedure and analysis method were presented for the time-series analysis of the SEC filings.