bluuebunny/crossref_metadata_2025 huggingface dataset:
Systems-Level Proteomics Evaluation of Microglia Response to Tumor-Supportive Anti-inflammatory Cytokines
Authors: Ahuja Shreya , Lazar Iulia M.
Published: February 2021

Background

Microglia safeguard the CNS against injuries and pathogens by inducing an inflammatory response. When exposed to anti-inflammatory cytokines, these cells possess the ability to switch from an inflammatory to an immunosuppressive phenotype. Cancer cells exploit this property to evade the immune system, and elicit an anti-inflammatory microenvironment that facilitates tumor attachment and growth.

Objective

The tumor-supportive biological processes that are activated in microglia cells in response to anti-inflammatory cytokines released from cancer cells were explored with mass spectrometry and proteomic technologies.

Methods

Serum-depleted and non-depleted human microglia cells (HMC3) were treated with a cocktail of IL-4, IL-13, IL-10, TGFβ, and CCL2. The cellular protein extracts were analyzed by LC-MS/MS. Using functional annotation clustering tools, statistically significant proteins that displayed a change in abundance between cytokine-treated and non-treated cells were mapped to their biological networks and pathways.

Results

The proteomic analysis of HMC3 cells enabled the identification of ∼10,000 proteins. Stimulation with anti-inflammatory cytokines resulted in the activation of distinct, yet integrated clusters of proteins that trigger downstream a number of tumor-promoting biological processes. The observed changes could be classified into four major categories, i.e., mitochondrial gene expression, ECM remodeling, immune response, and impaired cell cycle progression. Intracellular immune activation was mediated mainly by the transducers of MAPK, STAT, TGFβ, NFKB, and integrin signaling pathways. Abundant collagen formation along with the expression of additional receptors, matrix components, growth factors, proteases and protease inhibitors, enabled ECM remodeling processes supportive of cell-cell and cell-matrix adhesion. Overexpression of integrins and their modulators was reflective of signaling processes that correlated ECM reorganization with cytoskeletal re-arrangements supportive of cell migration. Antigen processing/presentation was represented by HLA class I histocompatibility antigens, and correlated with upregulated proteasomal subunits, and vesicular/viral transport and secretory processes. Immunosuppressive and proangiogenic chemokines were detectable in low abundance. Pronounced pro-inflammatory, chemotactic or phagocytic trends were not observed, however, the expression of certain receptors and ECM proteins indicated the presence of such capabilities.

Conclusions

Comprehensive proteomic profiling of HMC3 cells stimulated with anti-inflammatory cytokines revealed a microglia phenotype that provides novel insights into the tumor microenvironment-driven mechanisms that fuel cancer development in the brain.
Automatic Landmark Detection of Human Back Surface from Depth Images via Deep Learning
Authors: Delgarmi Masumeh , Heravi Hamed , Jounghani Ali Rahimpour , Shahrezaie Abdullah , Ebrahimi Afshin , Shamsi Mousa
Published: February 2021

Studying human postural structure is one of the challenging issues among scholars and physicians. The spine is known as the central axis of the body, and due to various genetic and environmental reasons, it could suffer from deformities that cause physical dysfunction and correspondingly reduce people’s quality of life. Radiography is the most common method for detecting these deformities and requires monitoring and follow-up until full treatment; however, it frequently exposes the patient to X-rays and ionization and as a result, cancer risk is increased in the patient and could be highly dangerous for children or pregnant women. To prevent this, several solutions have been proposed using topographic data analysis of the human back surface. The purpose of this research is to provide an entirely safe and non-invasive method to examine the spiral structure and its deformities. Hence, it is attempted to find the exact location of anatomical landmarks on the human back surface, which provides useful and practical information about the status of the human postural structure to the physician.

In this study, using Microsoft Kinect sensor, the depth images from the human back surface of 105 people were recorded and, our proposed approach - Deep convolution neural network-was used as a model to estimate the location of anatomical landmarks. In network architecture, two learning processes, including landmark position and affinity between the two associated landmarks, are successively performed in two separate branches. This is a bottom-up approach; thus, the runtime complexity is considerably reduced, and then the resulting anatomical points are evaluated concerning manual landmarks marked by the operator as the benchmark. Our results showed that 86.9% of PDJ and 80% of PCK. According to the results, this study was more effective than other methods with more than thousands of training data.
Modeling ex vivo tumor-infiltrating lymphocyte expansion from established solid malignancies
Authors: Knochelmann HM , Rivera-Reyes AM , Wyatt MM , Smith AS , Chamness R , Dwyer CJ , Bobian M , Rivera GO Rangel , Horton JD , Lilly M , Rubinstein MP , Neskey DM , Paulos CM
Published: February 2021

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) elicits the regression of metastatic malignancies, yet a low proportion of patients achieve complete durable responses. The high incidence of relapse in these patients highlights the need to better understand mechanisms of tumor escape from T cell control. While melanoma has provided the foundation for developing TIL therapy, much less is known about TIL efficacy and relapse in other malignancies. We sought to investigate TIL characteristics in mouse tumors which have not been studied in this setting. Here, we expanded murine TILex vivoin IL-2 from fragments of multiple tumor models, including oral cavity cancer models of varying immunogenicity. Additionally, TIL was expanded from pmel-1 mice bearing B16 melanoma, yielding an enriched population of tumor-infiltrating TCR transgenic T cells. Murine TILs are similar to human TIL in that they express high levels of inhibitory receptors (PD-1, Tim-3, etc.) and can be expandedex vivoin IL-2 extensively. Of clinical relevance, we draw parallels between murine and patient TIL, evaluating relationships between PD-1, Lag-3, and Tim-3 on TILs from a cohort of oral cavity cancer patients. This platform can be used by labs even in the absence of clinical specimens or clean cell facilities and will be important to more broadly understand TIL phenotypes across many different malignancies.
Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer
Authors: Behrenbruch Corina , Foroutan Momeneh , Lind Phoebe , Smith Jai , Grandin Mélodie , Cooper Benjamin , Shembrey Carolyn , Ramm Susanne , Cowley Karla , Nikolic Iva , Luu Jennii , Cursons Joseph , Millen Rosie , Patch Ann-Marie , Huntington Nicholas D. , Puisieux Alain , Michael Michael , Knowles Brett , Thomson Benjamin NJ. , Ramsay Robert G. , Grimmond Sean M. , Simpson Kaylene , Heriot Alexander G. , Hollande Frédéric
Published: February 2021

Patients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion of them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt to enable successful surgical removal of their metastases and to reduce the risk of recurrence. Yet, the majority of patients progress during treatment or recur following surgery, and molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Here, using a combination of phenotypic, transcriptomic and genomic analyses of both tumor samples derived from patients with metastatic CRC and matching patient-derived tumor organoids (PDTOs), we characterize a novel FOLFOX resistance mechanism and identify inhibitors that target this mechanism to resensitize metastatic organoids to FOLFOX. Resistant PDTOs, identified afterin vitroexposure to FOLFOX, exhibited elevated expression of E2F pathway, S phase, G2/M and spindle assembly checkpoints (SAC) genes. Similar molecular features were detected in CRLM from patients with progressive disease while under neoadjuvant FOLFOX treatment, highlighting the relevance of this finding. FOLFOX resistant PDTOs displayed inactivating mutations of TP53 and exhibited transcriptional features of P53 pathway downregulation. We found that they accumulated in early S-phase and underwent significant DNA damage during FOLFOX exposure, thereafter arresting in G2/M while they repaired their DNA after FOLFOX withdrawal. In parallel, results of a large kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G2M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during treatment with FOLFOX. Corroborating this finding, CHK1 and WEE1 inhibitors were found to synergize with FOLFOX and sensitize previously resistant PDTOs. Additionally, targeting the SAC master regulator MPS1 using empesertib after exposure to FOLFOX, when cells accumulate in G2M, was also very effective to kill FOLFOX-resistant PDTOs. Our results indicate that targeted and timely inhibition of specific cell cycle checkpoints shows great potential to improve response rates to FOLFOX in patients with metastatic CRC, for whom therapeutic alternatives remain extremely limited.
Nitroxoline as a promising alternative drug for the treatment of Lyme disease based on anin-vitrostudy
Authors: Alvarez-Manzo Hector S. , Zhang Yumin , Shi Wanliang , Zhang Ying
Published: February 2021

Lyme disease (LD) is the most common vector-borne disease in USA and Europe and is caused byBorrelia burgdorferi. Despite proper treatment, approximately one fifth of patients will develop post-treatment LD syndrome (PTLDS), a condition which is poorly understood. One of the possible causes is thought to be due to persister forms ofB. burgdorferithat are not effectively killed by the current Lyme antibiotics. In this study, we evaluated nitroxoline, an antibiotic used to treat urinary tract infections, for its activity against a stationary-phase culture enriched with persister forms of B. burgdorferi. Nitroxoline was found to be equivalent in activity againstB. burgdorferito cefuroxime (standard Lyme antibiotic) in different experiments. Moreover, we found that the three-drug combination cefuroxime + nitroxoline + clarithromycin eradicated 98.3% of stationary phase bacteria in the drug-exposure experiment and prevented the regrowth in the subculture study after drug exposure, as well as two-drug combinations cefuroxime + nitroxoline and clarithromycin + nitroxoline. These drug combinations should be further evaluated in a LD mouse model to assess if eradication of persister forms of B. burgdorferiin-vivois possible and if so, whether nitroxoline could be repurposed as an alternative drug for the treatment of LD.
A theoretical approach to coupling the epithelial-mesenchymal transition (EMT) to extracellular matrix (ECM) stiffness via LOXL2
Authors: Deng Youyuan , Chakraborty Priyanka , Jolly Mohit Kumar , Levine Herbert
Published: February 2021

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as ECM (extracellular matrix) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state.
Inference of genome 3D architecture by modeling overdispersion of Hi-C data
Authors: Varoquaux Nelle , Noble William S. , Vert Jean-Philippe
Published: February 2021

We address the challenge of inferring a consensus 3D model of genome architecture from Hi-C data. Existing approaches most often rely on a two step algorithm: first convert the contact counts into distances, then optimize an objective function akin to multidimensional scaling (MDS) to infer a 3D model. Other approaches use a maximum likelihood approach, modeling the contact counts between two loci as a Poisson random variable whose intensity is a decreasing function of the distance between them. However, a Poisson model of contact counts implies that the variance of the data is equal to the mean, a relationship that is often too restrictive to properly model count data.

We first confirm the presence of overdispersion in several real Hi-C data sets, and we show that the overdispersion arises even in simulated data sets. We then propose a new model, called Pastis-NB, where we replace the Poisson model of contact counts by a negative binomial one, which is parametrized by a mean and a separate dispersion parameter. The dispersion parameter allows the variance to be adjusted independently from the mean, thus better modeling overdispersed data. We compare the results of Pastis-NB to those of several previously published algorithms: three MDS-based methods (ShRec3D, ChromSDE, and Pastis-MDS) and a statistical methods based on a Poisson model of the data (Pastis-PM). We show that the negative binomial inference yields more accurate structures on simulated data, and more robust structures than other models across real Hi-C replicates and across different resolutions.

A Python implementation of Pastis-NB is available athttps://github.com/hiclib/pastisunder the BSD license

Supplementary information is available athttps://nellev.github.io/pastisnb/
Mathematical model reveals that heterogeneity in the number of ion transporters regulates the fraction of mouse sperm capacitation
Authors: Aguado-García Alejandro , Priego-Espinosa Daniel A. , Aldana Andrés , Darszon Alberto , Martínez-Mekler Gustavo
Published: February 2021

Capacitation is a complex maturation process mammalian sperm must undergo in the female genital tract to be able to fertilize an egg. This process involves, amongst others, physiological changes in flagellar beating pattern, membrane potential, intracellular ion concentrations and protein phosphorylation. Typically, in a capacitation medium, only a fraction of sperm achieve this state. The cause for this heterogeneous response is still not well understood and remains an open question. Here, one of our principal results is to develop a discrete regulatory network, with mostly deterministic dynamics in conjunction with some stochastic elements, for the main biochemical and biophysical processes involved in the early events of capacitation. The model criterion for capacitation requires the convergence of specific levels of a select set of nodes. Besides reproducing several experimental results and providing some insight on the network interrelations, the main contribution of the model is the suggestion that the degree of variability in the total amount and individual number of ion transporters among spermatozoa regulates the fraction of capacitated spermatozoa. This conclusion is consistent with recently reported experimental results. Based on this mathematical analysis, experimental clues are proposed for the control of capacitation levels. Furthermore, cooperative and interference traits that become apparent in the modelling among some components also call for future theoretical and experimental studies.

Author summary

Fertilization is one of the fundamental processes for the preservation of life. In mammals, sperm undergo a complex process during their passage through the female tract known as capacitation, which enables them for fertilization. At the present time, it is accepted from experimental observation, though not understood, that only a fraction of the sperm is capacitated. In this work, by means of a network mathematical model for regulatory sperm intracellular signaling processes involved in mice capacitation, we find that the variability in the distribution of the number of ion transporters intervenes in the regulation of the capacitation fraction. Experimental verification of this suggestion could open a line of research geared to the regulation of the degree of heterogeneity in the number of ion transporters as a fertility control. The model also uncovers, throughin silicooveractivation and loss of function of network nodes, synergetic traits which again call for experimental verification.
LncRNA SNHG1 suppresses LPS-induced acute lung injury by regulating miR-421/TIMP3 axis
Authors: Jiang Zeyu , Tan Jinyi , Yuan Yan , Shen Jiang , Chen Yan
Published: February 2021

Extensive evidence has revealed the crucial roles of long non-coding RNAs (lncRNAs) in acute lung injury (ALI). This study aimed to explore the mechanism of lncRNA SNHG1 in lipopolysaccharides (LPS)-induced ALI. RT-qPCR was employed to test the levels of SNHG1, miR-421 and TIMP3 in A549 cells. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. ELISA assay was adopted to examine the levels of inflammatory-related cytokines, including IL-1β, IL-6 and TNF-α. The binding sequences of miR-421 and SNHG1 or TIMP3 were predicted using starBase software. Then dual-luciferase reporter and RIP assays were adopted to verify the interaction between miR-421 and SNHG1 or TIMP3. The protein level of TIMP3 was measured by western blotting. It was found that LPS stimulation downregulated SNHG1 level and SNHG1 addition decreased viability, and induced apoptosis as well as promoted inflammatory responses in LPS-treated A549 cells. SNHG1 could sponge miR-421 and SNHG1 protected A549 cells from LPS-induced injury via inhibiting miR-421. Moreover, TIMP3 was a target of miR-421. MiR-421 silence protected A549 cells against the LPS-triggered inhibition in viability, and promotion in apoptosis and inflammatory responses. SNHG1 could upregulate TIMP3 through acting as a ceRNA of miR-421 in A549 cells. Altogether, the present study elaborated that SNHG1 inhibited LPS-stimulated ALI by modulating the miR-421/TIMP3 axis.
Little evidence the standard genetic code is optimized for resource conservation
Authors: Rozhoňová Hana , Payne Joshua L.
Published: February 2021

Selection for resource conservation can shape the coding sequences of organisms living in nutrient-limited environments. Recently, it was proposed that selection for resource conservation, specifically for nitrogen and carbon content, has also shaped the structure of the standard genetic code, such that the missense mutations it allows tend to cause small increases in the number of nitrogen and carbon atoms in amino acids. Moreover, it was proposed that this optimization is not confounded by known optimizations of the standard genetic code, such as for polar requirement or hydropathy. We challenge these claims. We show the proposed optimization for nitrogen conservation is highly sensitive to choice of null model and the proposed optimization for carbon conservation is confounded by the known conservative nature of the standard genetic code with respect to the molecular volume of amino acids. There is therefore little evidence the standard genetic code is optimized for resource conservation.
A partially nested cortical hierarchy of neural states underlies event segmentation in the human brain
Authors: Geerligs Linda , Gözükara Dora , Oetringer Djamari , Campbell Karen , van Gerven Marcel , Güçlü Umut
Published: February 2021

A fundamental aspect of human experience is that it is segmented into discrete events. This may be underpinned by transitions between distinct neural states. Using an innovative data-driven state segmentation method, we investigate how neural states are organized across the cortical hierarchy and where in the cortex neural state boundaries and perceived event boundaries overlap. Our results show that neural state boundaries are organized in a temporal cortical hierarchy, with short states in primary sensory regions, and long states in lateral and medial prefrontal cortex. State boundaries are shared within and between groups of brain regions that resemble well-known functional networks. Perceived event boundaries overlap with neural state boundaries across large parts of the cortical hierarchy, particularly when those state boundaries demarcate a strong transition or are shared between brain regions. Taken together, these findings suggest that a partially nested cortical hierarchy of neural states forms the basis of event segmentation.
What The Brain Does As We Speak
Authors: Forseth KJ , Pitkow X , Fischer-Baum S , Tandon N
Published: February 2021

Abstract

Language is a defining human behavior and is dependent on networks interactions amongst broadly distributed neuronal substrates. Transient dynamics between language regions that underpin speech production have long been postulated, yet have proven challenging to evaluate empirically. We used direct intracranial recordings during single word production to create a finely resolved spatiotemporal atlas (134 patients, 25810 electrodes, 40278 words) of the entire language-dominant cortex and used this to derive single-trial state-space sequences of network motifs. We derived 5 discrete neural states during the production of each word, distinguished by unique patterns of distributed cortical interaction. This interactive model was significantly better than a model of the same design but lacking interactions between regions in explaining observed activity. Our results eschew strict functional attribution to localized cortical populations, supporting instead the idea that cognitive processes are better explained by distributed metastable network states.
Ancient genomes reveal hybridisation between extinct short-faced bears and the extant spectacled bear (Tremarctos ornatus)
Authors: Salis Alexander T , Gower Graham , Schubert Blaine W. , Soibelzon Leopoldo H. , Heiniger Holly , Prieto Alfredo , Prevosti Francisco J. , Meachen Julie , Cooper Alan , Mitchell Kieren J.
Published: February 2021

Two genera and multiple species of short-faced bear from the Americas went extinct during or toward the end of the Pleistocene, and all belonged to the endemic New World subfamily Tremarctinae [1-7]. Two of these species were giants, growing in excess of 1,000 kg [6, 8, 9], but it remains uncertain how these extinct bears were related to the sole surviving short-faced bear: the spectacled bear (Tremarctos ornatus). Ancient mitochondrial DNA has recently suggested phylogenetic relationships among these lineages that conflict with interpretations based on morphology [1, 10-12]. However, widespread hybridisation and incomplete lineage sorting among extant bears mean that the mitochondrial phylogeny frequently does not reflect the true species tree [13, 14]. Here we present ancient nuclear genome sequences from representatives of the two extinct short-faced bear genera,ArctotheriumandArctodus. Our new data support a third hypothesis for the relationships among short-faced bears, which conflicts with existing mitochondrial and morphological data. Based on genome-wide D-statistics, we suggest that the extant spectacled bear derives substantial ancestry from Pleistocene hybridisation with an extinct short-faced bear lineage, resulting in a discordant phylogenetic signal between the mitochondrion and portions of the nuclear genome.
LevioSAM: Fast lift-over of alternate reference alignments
Authors: Mun Taher , Chen Nae-Chyun , Langmead Ben
Published: February 2021

Motivation

As more population genetics datasets and population-specific references become available, the task of translating (“lifting”) read alignments from one reference coordinate system to another is becoming more common. Existing tools generally require a chain file, whereas VCF files are the more common way to represent variation. Existing tools also do not make effective use of threads, creating a post-alignment bottleneck.

Results

LevioSAM is a tool for lifting SAM/BAM alignments from one reference to another using a VCF file containing population variants. LevioSAM uses succinct data structures and scales efficiently to many threads. When run downstream of a read aligner, levioSAM completes in less than 13% the time required by an aligner when both are run with 16 threads.

Availability

https://github.com/alshai/levioSAM

Contact

tmun1@jhu.edu,langmea@cs.jhu.edu
Cell Rearrangement Generates Pattern Emergence as a Function of Temporal Morphogen Exposure
Authors: Fulton Timothy , Spiess Kay , Thomson Lewis , Wang Yuxuan , Clark Bethan , Hwang Seongwon , Paige Brooks , Verd Berta , Steventon Benjamin
Published: February 2021

As tissues elongate, cell rearrangement alters positional information in manner that must be accounted for to generate gene expression pattern. How this is achieved during paraxial mesoderm elongation is unknown. By reverse-engineering gene regulatory networks that predict single cell expression trajectories across the tissue, we find a network capable of recapitulating the full range of dynamic differentiation profiles observed bothin vivoandin vitro. Simulating gene expression profiles onin totocell tracking data sets reveal that temporal exposure to Wnt and FGF is generated by cell movement. The absence of reversal in gene expression towards a more premature gene expression state predicts the generation of aberrant tbx6 expression in the posterior progenitor zone that we then confirm by quantitative single cell imaging. Taken together, these results demonstrate cell rearrangement tunes the dynamics of mesoderm progenitor differentiation to generate pattern emergence as a function of temporal Wnt and FGF exposure.
Multiple dimensions underlying the functional organisation of the language network
Authors: Hodgson Victoria J. , Ralph Matthew A. Lambon , Jackson Rebecca L.
Published: February 2021

Understanding the different neural networks that support human language is an ongoing challenge for cognitive neuroscience. Which divisions are capable of distinguishing the functional significance of regions across the language network? A key separation between semantic cognition and phonological processing was highlighted in early meta-analyses, yet these seminal works did not formally test this proposition. Moreover, organisation by domain is not the only possibility. Regions may be organised by the type of process performed, as in the separation between representation and control processes proposed within the Controlled Semantic Cognition framework. The importance of these factors was assessed in a series of activation likelihood estimation meta-analyses that investigated which regions of the language network are consistently recruited for semantic and phonological domains, and for representation and control processes. Whilst semantic and phonological processing consistently recruit many overlapping regions, they can be dissociated (by differential involvement of bilateral anterior temporal lobes and superior temporal gyri) only when using both formal analysis methods and sufficient data. Both semantic and phonological regions are further dissociable into control and representation regions, highlighting this as an additional, distinct dimension on which the language network is functionally organised. Furthermore, some of these control regions overlap with multiple-demand network regions critical for control beyond the language domain, suggesting the relative level of domain-specificity is also informative. Multiple, distinct dimensions are critical to understand the role of language regions. Here we present a proposal as to the core principles underpinning the functional organisation of the language network.

SIGNIFICANCE STATEMENT

Traditional theories of the organisation of the cortical language network separate areas based on the type of information processed, such as distinct regions representing the meaning of words or their sounds. Here, we re-analyse and update a seminal study, to directly compare these networks. This differentiates some language regions, yet a high degree of overlap is found, suggesting this division alone, does not provide a full mapping of the language network. Additional dimensions, reflecting different kinds of information, are demonstrated to underlie the functional organisation of the language network. First, representation and control processes engage distinct regions in each subdomain. Secondly, comparison outside of language highlights the importance of a ‘domain-specificity’ dimension, distinguishing subdomain-specific semantic control and domain-general control regions.
Defining the role of the polyasparagine repeat domain of theS. cerevisiaetranscription factor Azf1p
Authors: Stewart Taylor , Wolfe Benjamin E. , Fuchs Stephen M.
Published: February 2021

Across eukaryotes, homopolymeric repeats of amino acids are enriched in regulatory proteins such as transcription factors and chromatin remodelers. These domains play important roles in signaling, binding, prion formation, and functional phase separation. Azf1p is a prion-forming yeast transcription factor that contains two homorepeat domains, a polyglutamine and a polyasparagine domain. In this work, we report a new phenotype for Azf1p and identify a large set of genes that are regulated by Azf1p during growth in glucose. We show that the polyasparagine (polyN) domain plays a subtle role in transcription but is dispensable for Azf1p localization and prion formation. Genes upregulated upon deletion of the polyN domain are enriched in functions related to carbon metabolism and storage. This domain may therefore be a useful target for engineering yeast strains for fermentation applications and small molecule production. We also report that both the polyasparagine and polyglutamine domains vary in length across strains ofS. cerevisiaeand propose a model for how this variation may impact protein function.
Catching SARS-CoV-2 by sequence hybridization: a comparative analysis
Authors: Rehn Alexandra , Braun Peter , Knüpfer Mandy , Wölfel Roman , Antwerpen Markus H. , Walter Mathias C.
Published: February 2021

Controlling and monitoring the still ongoing SARS-CoV-2 pandemic regarding geographical distributions, evolution and emergence of new mutations of the SARS-CoV-2 virus is only possible due to continuous next-generation sequencing (NGS) and worldwide sequence data sharing. Efficient sequencing strategies enabling the retrieval of the maximum number of high quality, full-length genomes are hence indispensable. Here, we describe for the first time a combined approach of digital droplet PCR (ddPCR) and NGS to evaluate five commercially available sequence capture panels targeting SARS-CoV-2. In doing so, we were not only able to determine the most sensitive and specific capture panel, but to discriminate their mode of action and number of read pairs needed to recover a high quality full length genome. Thereby, we are providing essential information for all sequencing laboratories worldwide striving for maximizing the sequencing output and simultaneously minimizing time, costs and sequencing resources.
Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals
Authors: Kliesmete Zane , Wange Lucas Esteban , Vieth Beate , Esgleas Miriam , Radmer Jessica , Huelsmann Matthias , Geuder Johanna , Richter Daniel , Ohnuki Mari , Goetz Magdalena , Hellmann Ines , Enard Wolfgang
Published: February 2021

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it can control proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (ω) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay (MPRA) and identify one CRE that co-evolves with cortical folding in Old World Monkeys and Apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species.
Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Authors: Dampalla Chamandi S. , Zhang Jian , Perera Krishani Dinali , Wong Lok-Yin Roy , Meyerholz David K. , Nguyen Harry Nhat , Kashipathy Maithri M. , Battaile Kevin P. , Lovell Scott , Kim Yunjeong , Perlman Stanley , Groutas William C. , Chang Kyeong-Ok
Published: February 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and was proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 hr post infection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.
SSNA1 stabilizes dynamic microtubules and detects microtubule damage
Authors: Lawrence EJ , Arnaiz C , Arpag G , Zanic M
Published: February 2021

Sjögren’s Syndrome Nuclear Autoantigen 1 (SSNA1/NA14) is a microtubule-associated protein with important functions in cilia, dividing cells and developing neurons. However, the direct effects of SSNA1 on microtubules are not known. We employedin vitroreconstitution with purified proteins and TIRF microscopy to investigate the activity of human SSNA1 on dynamic microtubule ends and lattices. We find that SSNA1 modulates all parameters of microtubule dynamic instability – slowing down the rates of growth, shrinkage and catastrophe, and promoting rescue. SSNA1 accumulation on dynamic microtubule ends correlates with the growth rate slow-down. Furthermore, SSNA1 prevents catastrophe when soluble tubulin is removed or sequestered by Op18/Stathmin. Finally, SSNA1 detects spastin-induced damage and inhibits spastin’s severing activity. Therefore, SSNA1 is both a potent microtubule stabilizing protein and a sensor of microtubule damage; activities that likely underlie SSNA1’s cellular functions.
Mechanically Transduced Immunosorbent Assay To Measure Protein-Protein Interactions
Authors: Petell Christopher J. , Randene Kathyrn , Pappas Michael , Sandoval Diego , Strahl Brian D. , Harrison Joseph S. , Steimel Joshua P.
Published: February 2021

Measuring protein-protein interaction (PPI) affinities is fundamental to biochemistry. Yet, conventional methods rely upon the law of mass action and cannot measure many PPIs due to a scarcity of reagents and limitations in the measurable affinity ranges. Here we present a novel technique that leverages the fundamental concept of friction to produce a mechanical signal that indicates binding. The mechanically transduced immunosorbent (METRIS) assay utilizes rolling magnetic probes to measure PPI interaction affinities. METRIS measures the translational displacement of protein-coated particles on a protein-functionalized substrate. The translational displacement scales with the effective friction induced by a PPI, thus producing a mechanical signal when a binding event occurs. The METRIS assay uses as little as 20 pmols of reagents to measure a wide range of affinities while exhibiting a high resolution and sensitivity. Here we use METRIS to measure several PPIs that were previously inaccessible using traditional methods, providing new insights into epigenetic recognition.
Mindfulness in ethical consumption: the mediating roles of connectedness to nature and self-control
Authors: Li Yiyan , Wei Liyuan , Zeng Xiaohua , Zhu Jianjun
Published: February 2021

Purpose

Ethical consumption is an integral component for the sustainable development in the world and is especially challenging in the Western consumer society. This research demonstrates that mindfulness, a Buddhism-based notion, is associated with two related and distinctive approaches of ethical consumption: refinement and reduction. It examines the psychological mechanisms underlying the effects of mindfulness on these two approaches of ethical consumption.

Design/methodology/approach

Self-report data were collected through an online survey with consumers from western societies (N = 523).

Findings

The findings show (1) that the significance of mindfulness on both approaches of ethical consumption and (2) that the contrast between the different mechanisms underlying them. Specifically, the mindfulness–consumption refinement link is fully mediated by connectedness-to-nature whereas the mindfulness–consumption reduction link is fully mediated by connectedness-to-nature and self-control. A series of supplementary studies further confirmed the proposed model.

Research limitations/implications

It demonstrates the multifaceted and complex nature of ethical consumption, which is positively associated with mindfulness but through distinctive psychological mechanisms.

Practical implications

The multifaceted and complex nature of ethical consumption and its underlying drivers need special attention. Mindfulness can be an effective means to boost ethical consumption behavior. Meanwhile, nurturing the sense of connectedness to nature and self-control capability facilitates the path-through of the positive impacts of mindfulness

Social implications

The findings can be adopted to enhance the effectiveness of mindfulness practice in promoting ethical consumption towards achieving the Sustainable Consumption goal, especially in the West.

Originality/value

The paper makes original contribution by conceptualizing two interrelated and distinctive approaches of ethical consumption and shows how mindfulness promotes both through different mediating pathways. Overall, this study paints a clearer picture how mindfulness relates to ethical consumption.
Artificial intelligence and robots in individuals' lives: how to align technological possibilities and ethical issues
Authors: Liang Ting-Peng , Robert Lionel , Sarker Suprateek , Cheung Christy M.K. , Matt Christian , Trenz Manuel , Turel Ofir
Published: February 2021

Purpose

This paper reports the panel discussion on the topic of artificial intelligence (AI) and robots in our lives. This discussion was held at the Digitization of the Individual (DOTI) workshop at the International Conference on Information Systems in 2019. Three scholars (in alphabetical order: Ting-Peng Liang, Lionel Robert and Suprateek Sarker) who have done AI- and robot-related research (to varying degrees) were invited to participate in the panel discussion. The panel was moderated by Manuel Trenz.

Design/methodology/approach

This paper introduces the topic, chronicles the responses of the three panelists to the questions the workshop chairs posed and summarizes their responses, such that readers can have an overview of research on AI and robots in individuals' lives and insights about future research directions.

Findings

The panelists discussed four questions with regard to their research experiences on AI- and robot-related topics. They expressed their viewpoints on the underlying nature, potential and effects of AI in work and personal life domains. They also commented on the ethical dilemmas for research and practice and provided their outlook for future research in these emerging fields.

Originality/value

This paper aggregates the panelists' viewpoints, as expressed at the DOTI workshop. Crucial ethical and theoretical issues related to AI and robots in both work and personal life domains are addressed. Promising research directions to these cutting-edge research fields are also proposed.
Performance measurement embedded in organizational project management of general contractors operating in Poland
Authors: Głodziński Eryk
Published: February 2021

Purpose

The purpose of this paper is to discuss contemporary knowledge relevant to the application of performance measurement (PMe) in the concept of OPM and to compare findings from a literature review with solutions recommended for utilization by managers from general contractors operating in Poland. There are few studies related to the mentioned topic, much fewer describing the geographical area of Eastern Europe.

Design/methodology/approach

Triangulation of research methods was selected. First literature review, next desk research and finally descriptive statistical analysis and interview were conducted. The research methods were applied in three steps whose beginnings overlapped and the mid-term findings from one study complemented others.

Findings

PMe should be focused on management and governance issues. Its evaluation is related to various organizational levels (permanent organization, portfolio, program, project, construction site and supply chain), most of them are under valuated by practitioners. The conducted study pointed out that there are numerous supporting tools and measures applicable in organizational project management (OPM). The managers recommend combining various tools in one comprehensive OPM system, to limit multiple manual incorporations of the same data to the various databases. The managers call to increase the practical usefulness of researchers’ proposals, to educate the construction managers in the application of complex performance systems and to promote portfolio thinking.

Originality/value

The comparison of performance measurement solutions proposed by academia with experience collected from Polish construction managers could support the better application of theoretical ideas in practice.
Shade‐growing practices lessen the impact of coffee plantations on multiple dimensions of ant diversity
Authors: Ibarra‐Isassi Javier , Handa Ira Tanya , Arenas‐Clavijo Anderson , Escobar‐Ramírez Selene , Armbrecht Inge , Lessard Jean‐Philippe
Published: February 2021

Land use management influence changes in biodiversity beyond the targeted species. Management practices in coffee plantations have shifted from coffee growing below accompanying (shade) trees, to intensified monocultures in which coffee grows fully exposed to the sun. Anthropogenic disturbance causes changes in species composition relative to adjacent natural patches and reduces their biotic heterogeneity. Here, we assessed the impact of coffee plantation management practices on the taxonomical, phylogenetic and functional composition of ant communities, an ecologically dominant group and crucial biological pest controller in these agroecosystems. We hypothesized that shade‐grown coffee plantations would harbour ant communities similar to those of nearby forest patches, but dissimilar to those of intensified monocultures.

We surveyed ant diversity in eight shade‐grown coffee farms, eight intensive coffee monocultures and eight forest patches. We used a combination of active and passive sampling methods over two field campaigns spanning 6 months.

Our results support our hypothesis for all diversity dimensions. Additionally, ant communities in intensified monocultures were taxonomically and functionally, but not phylogenetically, more homogeneous than those found in forest patches and shade‐grown plantations.

Synthesis and applications. Our findings support the idea that practices in shade‐grown coffee plantations buffer the impoverishment of multiple diversity dimensions after forest conversion. Additionally, we identified that leaf‐litter depth and number of twigs mitigate ant diversity loss which, in turn, can favour the presence of potential biocontrol agents. By assessing and integrating multiple biodiversity dimensions into management strategies, farmers and interested parties can minimize future biodiversity and ecosystem service loss.
Impacts of multiple pollutants on pollinator activity in road verges
Authors: Phillips Benjamin B. , Bullock James M. , Gaston Kevin J. , Hudson‐Edwards Karen A. , Bamford Meg , Cruse Dave , Dicks Lynn V. , Falagan Carmen , Wallace Claire , Osborne Juliet L.
Published: February 2021

To tackle pollinator declines, there is a major need to increase the quantity of flower‐rich habitats. Road verges offer one such opportunity but are exposed to diverse forms of pollution from roads and road traffic.

We carried out a broad initial assessment to establish if and how pollution affects the quality of road verges as pollinator foraging environments. We assessed the spatial distribution of pollution, flowers and pollinators in road verges, then used field experiments to simulate and measure the impacts of four ubiquitous and little studied forms of road pollution (noise, turbulence, dust and metals) on pollinator densities and foraging behaviour.

We found that pollinators in road verges were exposed to noise, turbulence, dust and metal pollution, which decreased with distance from the road edge but, with the exception of turbulence, extended more than 8 m into road verges.

Pollinator densities were lower closer to the road edge—particularly within first 2 m (55% lower than at 7–9 m)—where pollution is greatest. This was despite a similar density and species richness of flowers.

Simulated turbulence deterred pollinators by causing intermittent disturbance (reducing visit duration by up to 54%), and some pollinator taxa preferentially avoided concentrations of metals that were more frequently found in flowers within 2 m of roads (resulting in up to 75% fewer visits), while noise and dust had no apparent effect.

Synthesis and applications. Pollinators in road verges are exposed to many forms of pollution, and we found impacts of roadside‐realistic levels of turbulence and metals on pollinator densities and foraging behaviour. Although the findings suggest that road verges are largely suitable for pollinator conservation, management enhancements should prioritise areas more than 2 m from the road edge, and verges along roads with relatively lower traffic densities.