bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recurrence of cancer cell states across diverse tumors and their interactions with the microenvironment
Authors: Barkley Dalia , Moncada Reuben , Pour Maayan , Liberman Deborah A. , Dryg Ian , Werba Gregor , Wang Wei , Baron Maayan , Rao Anjali , Xia Bo , França Gustavo S. , Weil Alejandro , Delair Deborah F. , Hajdu Cristina , Lund Amanda W. , Osman Iman , Yanai Itai 
Published: December 2021

ABSTRACTWhile genetic tumor heterogeneity has long been recognized, recent work has revealed significant variation among cancer cells at the epigenetic and transcriptional levels. Profiling tumors at the single-cell level in individual cancer types has shown that transcriptional heterogeneity is organized into cancer cell states, implying that diverse cell states may represent stable and functional units with complementary roles in tumor maintenance and progression. However, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Furthermore, the role of cancer cell states in tumor progression and their specific interactions with cells of the tumor microenvironment remain to be elucidated. Here, we perform a pan-cancer single-cell RNA-Seq analysis across 15 cancer types and identify a catalog of 16 gene modules whose expression defines recurrent cancer cell states, including ‘stress’, ‘interferon response’, ‘epithelial-mesenchymal transition’, ‘metal response’, ‘basal’ and ‘ciliated’. Using mouse models, we find that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Moreover, spatial transcriptomic analysis further links the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance, and metastasis.
Light-induced Patterning of Electroactive Bacterial Biofilms
Authors: Zhao Fengjie , Chavez Marko S. , Naughton Kyle L. , Cole Christina M. , Gralnick Jeffrey A. , El-Naggar Mohamed Y. , Boedicker James Q. 
Published: December 2021

AbstractElectroactive bacterial biofilms can function as living biomaterials that merge the functionality of living cells with electronic components. However, the development of such advanced living electronics has been challenged by the inability to control the geometry of electroactive biofilms relative to solid-state electrodes. Here, we developed a lithographic strategy to pattern conductive biofilms of Shewanella oneidensis by controlling aggregation protein CdrAB expression with a blue light-induced genetic circuit. This controlled deposition enabled S. oneiensis biofilm patterning on transparent electrode surfaces and measurements demonstrated tunable biofilm conduction dependent on pattern size. Controlling biofilm geometry also enabled us, for the first time, to quantify the intrinsic conductivity of living S. oneidensis biofilms and experimentally confirm predictions based on simulations of a recently proposed collision-exchange electron transport mechanism. Overall, we developed a facile technique for controlling electroactive biofilm formation on electrodes, with implications for both studying and harnessing bioelectronics.
A role for CD4 helper cells in HIV control and progression
Authors: Rouzine Igor M. 
Published: December 2021

It remains unclear why HIV persists in most untreated individuals, and why a small minority of individuals can control the virus, either spontaneously or after an early treatment. The present work motivated by the striking differences in the functional avidity of CD4 T cells discovered between patient cohorts in a recent study [1] offers an experimentally–testable mathematical model that explains the diverse outcome of infection. The model predicts an arms race between viral dissemination and the proliferation of HIV-specific CD4 helper cells leading to one of two states: a low-viremia state or a high-viremia state. Helper CD4 cells with a higher avidity favor virus control. The parameter segregating spontaneous and post-treatment controllers is the infectivity asymmetry between activated and resting CD4 T cells. The predictions are found to be consistent with the data from [1] and with data on the avidity CD8 T cells [2]. I also analyze the alternative explanation of T cell exhaustion previously proposed to explain the diverse patient cohorts and demonstrate that it does not explain these and some other experimental data.ImportanceWhy HIV persists in most untreated individuals, and why a minority can control the virus, either spontaneously or after short treatment, remains unknown. The present study offers a mathematical model of the immune response that explains the differences between the patient cohorts as a result of the arms race between viral dissemination and the proliferation of HIV-specific CD4 T cells. It offers testable predictions and personalized adjustment of early ART to a patient.
Transmission dynamics and control of Sporotrichosis in domestic felines
Authors: Araújo Aurélio A , Codeço Cláudia , Freitas Dayvison F S , de Macedo Priscila M , Pereira Sandro A , Gremião Isabella D F , Coelho Flávio C. 
Published: December 2021

AbstractSporotrichosis is a subcutaneous mycosis with a global distribution, also known as “rose gardener’s disease”. Brazil is experiencing a rapid spread of the zoonotic transmission of of Sporothrix brasiliensis, the main etiological agent of this disease in this country, affecting domestic felines. Cost-effective interventions need to be developed to control this emergent public health problem. To allow for the comparison of alternative control strategies, we propose in this paper, a mathematical model representing the transmission of S. brasiliensis among cats, stratified by age and sex. Analytical properties of the model are derived and simulations show possible strategies for reducing the endemic levels of the disease in the cat population, with a positive impact on human health. The scenarios included mass treatment of infected cats and mass implementation of contact reduction practices, such as neutering. The results indicate that mass treatment can reduce substantially the disease prevalence, and this effect is potentialized when combined with neutering or other contact-reduction interventions. On the other hand, contact-reduction methods alone are not sufficient to reduce prevalence.Author summarySporotrichosis, as a neglected tropical mycosis, has in domestic cats a very important reservoir for Sporothrix sp., its pathogen. Infected cats can easily transmit the fungus to other cats and also to humans by means of scratching and biting.Here we propose a mathematical model incorporating all forms of transmission of Sporothrix within a cat population, taking into account age and sex-related behavioral differences which can affect the transmission dynamics.The model also includes a treated compartment, which facilitates the exploration of pharmacological interventions to reduce the prevalence of the disease. We derive the next-generation matrix for the model, which allows the calculation of the disease’s basic reproduction number under different scenarios.Using the model, we explore different control scenarios involving treatment of the disease, but also the contribution of neutering of cats to the reduction of transmission through changes induced by neutering, of the cat’s social interactions.
Control-based continuation: a new approach to prototype synthetic gene networks
Authors: de Cesare Irene , Salzano Davide , di Bernardo Mario , Renson Ludovic , Marucci Lucia 
Published: December 2021

AbstractControl-Based Continuation (CBC) is a general and systematic method to carry out the bifurcation analysis of physical experiments. CBC does not rely on a mathematical model and thus overcomes the uncertainty introduced when identifying bifurcation curves indirectly through modelling and parameter estimation. We demonstrate, in silico, CBC applicability to biochemical processes by tracking the equilibrium curve of a toggle switch which includes additive process noise and exhibits bistability. We compare results obtained when CBC uses a model-free and model-based control strategy and show that both can track stable and unstable solutions, revealing bistability. We then demonstrate CBC in conditions more representative of a real experiment using an agent-based simulator describing cells growth and division, cell-to-cell variability, spatial distribution, and diffusion of chemicals. We further show how the identified curves can be used for parameter estimation and discuss how CBC can significantly accelerate the prototyping of synthetic gene regulatory networks.
The origin and evolution of loqs2: a gene encoding an antiviral dsRNA binding protein in Aedes mosquitoes
Authors: Estevez-Castro Carlos F. , Rodrigues Murillo F. , Babarit Antinéa , Ferreira Flávia Viana , Marois Eric , Cogni Rodrigo , Marques João Trindade , Olmo Roenick Proveti 
Published: December 2021

AbstractMosquito borne viruses such as dengue, Zika, yellow fever and Chikungunya cause millions of infections every year. These viruses are mostly transmitted by two urban-adapted mosquito species, Aedes aegypti and Aedes albopictus, that appear to be more permissive to arbovirus infections compared to closely related species, although mechanistic understanding remains unknown. Aedes mosquitoes may have evolved specialized antiviral mechanisms that potentially contribute to the low impact of viral infection. Recently, we reported the identification of an Aedes specific double-stranded RNA binding protein (dsRBP), named Loqs2, that is involved in the control of infection by dengue and Zika viruses in Ae. aegypti. Loqs2 interacts with two important co-factors of the RNA interference (RNAi) pathway, Loquacious (Loqs) and R2D2, and seems to be a strong regulator of the antiviral defense. However, the origin and evolution of loqs2 remains unclear. Here, we describe that loqs2 likely originated from two independent duplications of the first dsRNA binding domain (dsRBD) of loquacious that occurred before the radiation of the Aedes Stegomyia subgenus. After its origin, our analyses suggest that loqs2 evolved by relaxed positive selection towards neofunctionalization. In fact, loqs2 is evolving at a faster pace compared to other RNAi components such as loquacious, r2d2 and Dicer-2 in Aedes mosquitoes. Unlike loquacious, transcriptomic analysis showed that loqs2 expression is tightly regulated, almost restricted to reproductive tissues in Ae. aegypti and Ae. albopictus. Transgenic mosquitoes engineered to ubiquitously express loqs2 show massive dysregulation of stress response genes and undergo developmental arrest at larval stages. Overall, our results uncover the possible origin and neofunctionalization of a novel antiviral gene, loqs2, in Aedes mosquitoes that ultimately may contribute to their effectiveness as vectors for arboviruses.
Molecular features underlying Pseudomonas aeruginosa persistence in human plasma
Authors: Janet-Maitre Manon , Pont Stéphane , Masson Frerich , Sleiman Serena , Trouillon Julian , Robert-Genthon Mylène , Gallet Benoît , Dumestre-Perard Chantal , Elsen Sylvie , Moriscot Christine , Bardoel Bart , Rooijakkers Suzan , Cretin François , Attrée Ina 
Published: December 2021

AbstractPseudomonas aeruginosa, an opportunistic Gram-negative pathogen, is a leading cause of bacteremia with a high mortality rate. We recently reported that P. aeruginosa forms a persister-like sub-population of evaders in human plasma and blood. However, the molecular mechanisms underlying the formation of evaders remained unknown. Here, using a gain-of-function genetic screen, we examined the molecular determinants of P. aeruginosa persistence in plasma. We found that, among other factors, ATP and biotin availability greatly influence bacterial survival in plasma; mutants in pur and bio genes display higher tolerance and persistence, respectively. Electron microscopy combined with energy-dispersive X-ray spectroscopy (EDX) revealed the formation of polyphosphate granules upon incubation in plasma in several clinical strains, implying the bacterial response to a low-energy stress signal. Indeed, mutants with transposon insertions in ppk genes were eliminated in the plasma. Analysis of several steps of the complement cascade and exposure to an outer-membrane-impermeable drug, nisin, suggested that the mutants impede membrane attack complex (MAC) activity per se. Through this study, we shed light on P. aeruginosa response to the plasma conditions and discovered the multifactorial origin of bacterial resilience to MAC that provides a comprehensive picture of the complex interplay between P. aeruginosa and the human complement system.Author summaryPersistence of bacterial pathogens is a main cause of treatment failure and establishment of chronic bacterial infection. Despite innate immune responses, some bacteria may persist in human blood and plasma. Here we used a genome-wide screen to investigate the molecular determinants influencing Pseudomonas aeruginosa persistence in human plasma facing the complement system. Alongside a multifactorial strategy, we found intracellular levels of ATP and biotin to significantly influence bacterial capacity to deal with membrane attack complex (MAC)-dependent killing. These results underline the need to understand the complex interplay between bacterial pathogens and the human immune system when seeking to develop efficient antibacterial strategies.
Popeye Domain-Containing Protein 1 Scaffolds a Complex of Adenylyl Cyclase 9 and the Two-Pore-Domain Potassium Channel TREK-1 in Heart
Authors: Baldwin Tanya A. , Li Yong , Marsden Autumn , Schindler Roland F.R. , Zhang Musi , Carbajal Anibal Garza , Garcia Mia A. , Venna Venugopal Reddy , Brand Thomas , Dessauer Carmen W. 
Published: December 2021

ABSTRACTThe establishment of macromolecular complexes by scaffolding proteins such as A-kinase anchoring proteins is key to the local production of cAMP by anchored adenylyl cyclase (AC) and the subsequent cAMP signaling necessary for many cardiac functions. We have identified herein a novel AC scaffold, the Popeye domain-containing (POPDC) protein. Unlike other AC scaffolding proteins, POPDC1 binds cAMP with high affinity. The POPDC family of proteins are important for cardiac pacemaking and conduction, due in part to their cAMP-dependent binding and regulation of TREK-1 potassium channels. TREK-1 binds the AC9:POPDC1 complex and co-purifies in a POPDC1-dependent manner with AC9-associated activity in heart. Although the interaction of AC9 and POPDC1 is cAMP independent, TREK-1 association with AC9 and POPDC1 is reduced in an isoproterenol-dependent manner, requiring an intact cAMP binding Popeye domain and AC activity within the complex. We show that deletion of Adcy9 (AC9) gives rise to bradycardia at rest and stress-induced heart rate variability. The phenotype for deletion of Adcy9 is milder than previously observed upon loss of Popdc1, but similar to loss of Kcnk2 (TREK-1). Thus, POPDC1 represents a novel scaffolding protein for AC9 to regulate heart rate control.ONE-SENTENCE SUMMARYAdenylyl cyclase type 9 binds in an isoproterenol-dependent manner to the POPDC1:TREK-1 complex regulating heart rate.
HSP70-binding motifs function as protein quality control degrons
Authors: Abildgaard Amanda B. , Voutsinos Vasileios , Petersen Søren D. , Larsen Fia B. , Kampmeyer Caroline , Johansson Kristoffer E. , Stein Amelie , Ravid Tommer , Andréasson Claes , Jensen Michael K. , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus 
Published: December 2021

AbstractProtein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and PQC-linked degradation therefore overlaps in specificity with chaperone binding. This sheds new light on how the PQC system has evolved to exploit the intrinsic capacity of chaperones to recognize misfolded proteins, thereby placing them at the nexus of protein folding and degradation.Significance StatementIt is broadly accepted that misfolded proteins are often rapidly degraded by the ubiquitin-proteasome system, but how cells specifically recognize this immensely diverse group of proteins is largely unknown. Here we show that upon uncoupling of protein folding from protein degradation, a canonical chaperone-binding motif doubles as a degradation signal (degron), and that within the context of a Hsp70-binding region, many sequences are compatible with degron function. We find that degradation is correlated with the number of Hsp70-binding sites within a protein, and that the number of exposed Hsp70-binding sites in the yeast proteome correlates with more rapid degradation.
Implications of AlphaFold2 for crystallographic phasing by molecular replacement
Authors: McCoy Airlie J. , Sammito Massimo D. , Read Randy J. 
Published: December 2021

The AlphaFold2 results in the 14th edition of Critical Assessment of Structure Prediction (CASP14) showed that accurate (low root-mean-square deviation) in silico models of protein structure domains are on the horizon, whether or not the protein is related to known structures through high-coverage sequence similarity. As highly accurate models become available, generated by harnessing the power of correlated mutations and deep learning, one of the aspects of structural biology to be impacted will be methods of phasing in crystallography. Here, the data from CASP14 are used to explore the prospects for changes in phasing methods, and in particular to explore the prospects for molecular-replacement phasing using in silico models.
Understanding reporting boundaries in annual reports: a conceptual framework
Authors: Bayne Lyndie 
Published: December 2021

PurposeThe purpose of this paper is to enhance conceptual understanding of reporting boundaries in corporate annual reports by developing a conceptual framework of the rules and principles, referred to here as dimensions, underlying boundaries. A total of nine contemporary regulations/guidelines are compared in terms of the boundary dimensions identified to illustrate similarities and differences in boundary concepts.Design/methodology/approachTo develop a conceptual framework of reporting boundary dimensions, academic and industry literature were analysed to identify boundary dimensions. Thereafter, nine contemporary regulations/guidelines were compared in terms of these dimensions. A qualitative approach was taken including document analysis and content analysis.FindingsA total of 10 key boundary dimensions were identified through analysis of academic and industry literature. Each dimension represents a continuum along which regulations/guidelines can position themselves. Taken together, the 10 dimensions provide a comprehensive description of the chosen boundary concept.Originality/valueThe paper contributes to accounting theory by providing a holistic conceptual framework of dimensions relating to reporting boundaries, thus answering calls for more conceptual development of the boundary construct. The conceptual framework and comparison of contemporary regulations/guidelines adds to scarce literature considering financial and non-financial boundaries simultaneously, which is relevant for annual reports. From a practical perspective, the paper brings renewed visibility to boundaries with implications for preparers, users, standard setters and auditors of annual reports.
Parametric and V&V study in a fundamental CFD process: revisiting the lid-driven cavity flow
Authors: Ge Mingming , Zhang Xin-Lei , Brookshire Kaleb , Coutier-Delgosha Olivier 
Published: December 2021

Purpose
The openings on aircraft structures can be modeled from an aerodynamical point of view as lid-driven cavities (LDC). This paper aims to show the primary verification and validation (V&V) process in computational fluid dynamics (CFD, and to investigate the influences of numerical settings on the efficiency and accuracy for solving the LDC problem.

Design/methodology/approach
To dig into the details of CFD approaches, this paper outlines the design, implementation, V&V and results of an efficient explicit algorithm. The parametric study is performed thoroughly focusing on various iteration methods, grid density discretization terms and Reynolds number effects.

Findings
This study parameterized the numerical implementation which provides empirical insights into how computational accuracy and efficiency are affected by changing numerical settings. At a low Reynolds number (not over 1,000), the time-derivative preconditioning is necessary, and k = 0.1 can be the optimal value to guarantee the efficiency, as well as the stability. A larger artificial viscosity (c = 1/16) would relieve the calculating oscillation issue but proportionally increase the discretization error. Furthermore, the iteration method and the mesh quality are two key factors that affect the convergence efficiency, thus need to be selected “wisely”.

Practical implications
The study shows how numerical implementation can enhance an accurate and efficient solution. This workflow can be used to determine the best parameter settings whenever CFD researchers applying this LDC problem as a complementary design tool for testing newly developed solvers.

Originality/value
The studied LDC problem is representative of CFD analysis in real aircraft structures. These numerical simulations provide a cost-effective and convenient tool to understand the parameter sensitivity, solution receptivity and physics of the CFD process.