bluuebunny/crossref_metadata_2025_split huggingface dataset:
The structural context of PTMs at a proteome wide scale
Authors: Bludau Isabell , Willems Sander , Zeng Wen-Feng , Strauss Maximilian T. , Hansen Fynn M. , Tanzer Maria C. , Karayel Ozge , Schulman Brenda A. , Mann Matthias 
Published: February 2022

AbstractThe recent revolution in computational protein structure prediction provides folding models for entire proteomes, which can now be integrated with large-scale experimental data. Mass spectrometry (MS)-based proteomics has identified and quantified tens of thousands of post-translational modifications (PTMs), most of them of uncertain functional relevance. In this study, we determine the structural context of these PTMs and investigate how this information can be leveraged to pinpoint potential regulatory sites. Our analysis uncovers global patterns of PTM occurrence across folded and intrinsically disordered regions. We found that this information can help to distinguish regulatory PTMs from those marking improperly folded proteins. Interestingly, the human proteome contains thousands of proteins that have large folded domains linked by short, unstructured regions that are strongly enriched in regulatory phosphosites. These include well-known kinase activation loops that induce protein conformational changes upon phosphorylation. This regulatory mechanism appears to be widespread in kinases but also occurs in other protein families such as solute carriers. It is not limited to phosphorylation but includes ubiquitination and acetylation sites as well. Furthermore, we performed three-dimensional proximity analysis which revealed examples of spatial co-regulation of different PTM types and potential PTM crosstalk. To enable the community to build upon these first analyses, we provide tools for 3D visualization of proteomics data and PTMs as well as python libraries for data accession and processing.
Distinct glycerophospholipids potentiate Gsα-activated adenylyl cyclase activity
Authors: Seth Anubha , Landau Marius , Shevchenko Andrej , Traikov Sofia , Schultz Anita , Elsabbagh Sherif , Schultz Joachim E. 
Published: February 2022

AbstractNine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical membrane domains which are isoform-specifically conserved. Previously we proposed that these membrane domains are orphan receptors (10.7554/eLife.13098; 10.1016/j.cellsig.2020.109538). Lipids extracted from fetal bovine serum at pH 1 inhibited several mAC activities. Guided by a lipidomic analysis we tested glycerophospholipids as potential ligands. Contrary to expectations we surprisingly discovered that 1-stearoyl-2-docosahexaenoyl-phosphatidic acid (SDPA) potentiated Gsα-activated activity of human AC isoform 3 seven-fold. The specificity of fatty acyl esters at glycerol positions 1 and 2 was rather stringent. 1-Stearoyl-2-docosahexaenoyl-phosphatidylserine and 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine significantly potentiated several Gsα-activated mAC isoforms to different extents. SDPA appears not interact with forskolin activation of AC isoform 3. SDPA enhanced Gsα-activated AC activities in membranes from mouse brain cortex. The action of SDPA was reversible. Unexpectedly, SDPA did not affect cAMP generation in HEK293 cells stimulated by isoproterenol, PGE2 and adenosine, virtually excluding a role as an extracellular ligand and, instead, suggesting an intracellular role. In summary, we discovered a new dimension of intracellular AC regulation by chemically defined glycerophospholipids.
Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor
Authors: Oliveira A. Sofia F. , Bermudez Isabel , Gallagher Timothy , Wonnacott Susan , Ciccotti Giovanni , Sessions Richard B. , Mulholland Adrian J. 
Published: February 2022

AbstractDespite decades of study, the structural mechanisms underpinning agonist efficacy in pentameric ligand-gated ion channels remain poorly understood. Here, a combination of extensive equilibrium and dynamical-nonequilibrium molecular dynamics simulations was used to obtain a detailed description of the structural and dynamic changes induced within the human α4β2 nicotinic acetylcholine receptor by a full and a partial agonist, namely acetylcholine and nicotine, and map how these rearrangements propagate within this receptor. These simulations reveal how the agonists modulate the patterns associated with intra and inter-domain communication and the evolution of the agonist-specific structural rearrangements. For the first time, we show that full and partial agonists, although generally using similar routes for through-receptor signal transmission, induce different amplitudes of conformational rearrangements in key functional motifs, thus impacting the rates of signal propagation within the protein. The largest agonist-induced conformational differences are located in the Cys loop, loops C and α1-β1 in the α4 subunit, loops F and β1-β2 in the β2 subunit and in the extracellular selectivity filter.
Sporulation activated via σW protects Bacillus from a Tse1 peptidoglycan hydrolase T6SS effector
Authors: Pérez-Lorente Alicia I. , Molina-Santiago Carlos , de Vicente Antonio , Romero Diego 
Published: February 2022

AbstractBacterial communities constantly interact with various community members employing diverse offensive and defensive tools to reach coexistence. The extracellular matrix and sporulation are defensive mechanisms used by Bacillus cells when they interact with Pseudomonas strains expressing a type VI secretion system (T6SS). Here, we define Tse1 as the main toxin mobilized by the Pseudomonas T6SS that triggers sporulation in Bacillus. We characterize Tse1 as a peptidoglycan hydrolase that indirectly alters the dynamics and functionality of the Bacillus cell membrane. We also delineate the response of Bacillus cells to Tse1, which through the coordinated actions of the extracellular sigma factor σW and the cytoplasmic histidine kinases KinA and KinB, culminates in activation of the sporulation cascade. We propose that this cellular developmental response is conserved in Bacilli to defend against the toxicity of T6SS-mobilized Tse1 effector.
Resistance of Dickeya solani strain IPO 2222 to lytic bacteriophage vB_Dsol_D5 (ΦD5) results in fitness tradeoffs for the bacterium during infection
Authors: Bartnik Przemyslaw , Lewtak Kinga , Fiołka Marta , Czaplewska Paulina , Narajczyk Magdalena , Czajkowski Robert 
Published: February 2022

AbstractResistance to bacteriophage infections protects bacteria in phage-full environments, allowing them to survive and multiply in the presence of their viral predators. However, such resistance may cause direct costs for strains linked with the ecological fitness expressed as reduced competitiveness for resources or reduced virulence or both. Unfortunately, limited knowledge exists about such costs paid by phage-resistant plant pathogenic bacteria in their natural environments. This study analyzed the costs of phage resistance paid by broad host phytopathogenic pectinolytic bacterium Dickeya solani both in vitro and in potato (Solanum tuberosum L.) plants. Thirteen D. solani IPO 2222 Tn5 mutants were identified that exhibited resistance to infection caused by lytic bacteriophage vB_Dsol_D5 (ΦD5). The genes disrupted in these 13 mutants encoded proteins involved in the synthesis of the bacterial envelope components (viz. LPS, EPS and capsule). The ability of ΦD5-resistant D. solani mutants to colonize and cause symptoms on potato plants as well as other phenotypes that are known to contribute to the ecological fitness of D. solani in-plant environment, including growth rate, production of effectors, swimming and swarming motility, use of various carbon and nitrogen sources and biofilm formation were assessed. Although phage resistance did not affect most of the phenotypes of ΦD5-resistant D. solani evaluated in vitro, all phage resistant mutants were significantly compromised in their ability to survive on and colonize and cause disease symptoms in potato plants. This study is, to our knowledge, one of few to show the direct link between phage resistance and the fitness of plant pathogenic bacteria and the first one to assess phage-host associations for D. solani.
The extracellular sialidase NEU3 induces neutrophil priming
Authors: Kirolos Sara A. , Gomer Richard H. 
Published: February 2022

AbstractSome extracellular glycoconjugates have sialic acid as the terminal sugar, and sialidases are enzymes that remove this sugar. Mammals have four sialidases, but their biological functions are unclear. In this report, we show that incubation of human neutrophils with the human sialidase NEU3, but not NEU1, NEU2 or NEU4, inducess human male and female neutrophils to change from a round to a more amoeboid morphology, causes the primed neutrophil markers CD66, CD11B, and CD18 to localize to the cell cortex, and decreases the localization of the unprimed neutrophil markers CD43 and CD62L at the cell cortex. NEU3, but not the other 3 sialidases, also causes human male and female neutrophils to increase their F-actin content. The inhibition of NEU3 by the NEU3 inhibitor 2-acetylpyridine attenuated the NEU3 effect on neutrophil morphology, indicating that the effect of NEU3 is dependent on its enzymatic activity. Together, these results indicate that NEU3 can prime human male and female neutrophils, and that NEU3 is a potential regulator of inflammation.
Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites
Authors: Maury Eduardo A. , Jones Attila , Seplyarskiy Vladimir , Rosenbluh Chaggai , Bae Taejong , Wang Yifan , Abyzov Alexej , Khoshkoo Sattar , Chahine Yasmine ,   Brain Somatic Mosaicism Network, Park Peter J. , Akbarian Schahram , Lee Eunjung Alice , Sunyaev Shamil R. , Walsh Christopher A. , Chess Andrew 
Published: February 2022

AbstractSchizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process “skiagenesis” (from the Greekskia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset (∼13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes.Skiagenesisprovides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.
ATPase activity of DFCP1 controls selective autophagy
Authors: Nähse Viola , Raiborg Camilla , Tan Kia Wee , Mørk Sissel , Torgersen Maria Lyngaas , Wenzel Eva Maria , Nager Mireia , Salo Veijo T. , Johansen Terje , Ikonen Elina , Schink Kay Oliver , Stenmark Harald 
Published: February 2022

AbstractCellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1. Autophagosomes can assemble in specialized cup-shaped regions of the endoplasmic reticulum (ER) known as omegasomes, which are characterized by the presence of the ER protein DFCP1/ZFYVE1. The function of DFCP1 is unknown, as are the mechanisms of omegasome formation and constriction. Here, we demonstrate that DFCP1 is an ATPase that dimerizes in an ATP-dependent fashion. Whereas depletion of DFCP1 had a minor effect on bulk autophagic flux, DFCP1 was required to maintain the autophagic flux of p62 under both fed and starved conditions, and this was dependent on its ability to bind and hydrolyse ATP. While DFCP1 mutants defective in ATP binding or hydrolysis localized to forming omegasomes, these omegasomes failed to constrict. Consequently, the release of nascent autophagosomes from omegasomes was markedly delayed. DFCP1 was found to associate with ubiquitinated proteins, and degradation of ubiquitinated cargoes such as protein aggregates, mitochondria and micronuclei was strongly inhibited when DFCP1 was knocked out or mutated. Thus, DFCP1 mediates ATPase-driven constriction of omegasomes to release autophagosomes for selective autophagy.
QTL analysis reveals an oligogenic architecture of a rapidly adapting trait during the European invasion of common ragweed
Authors: Prapas Diana , Scalone Romain , Lee Jacqueline , Nurkowski Kristin A , Bou-assi Sarah , Rieseberg Loren , Battlay Paul , Hodgins Kathryn A 
Published: February 2022

AbstractBiological invasions offer a unique opportunity to investigate evolution over contemporary time-scales. Rapid adaptation to local climates during range expansion can be a major determinant of invasion success, yet fundamental questions remain about its genetic basis. This study sought to investigate the genetic basis of climate adaptation in invasive common ragweed (Ambrosia artemisiifolia). Flowering time adaptation is key to this annual species’ invasion success, so much so that it has evolved repeated latitudinal clines in size and phenology across its native and introduced ranges despite high gene flow among populations. Here, we produced a high-density linkage map (4,493 SNPs) and paired this with phenotypic data from an F2 mapping population (n=336) to identify one major and two minor quantitative trait loci (QTL) underlying flowering time and height differentiation in this species. Within each QTL interval, several candidate flowering time genes were also identified. Notably, the major flowering time QTL detected in this study was found to overlap with a previously identified haploblock (putative inversion). Multiple genetic maps of this region identified evidence of suppressed recombination in specific genotypes, consistent with inversions. These discoveries support the expectation that a concentrated genetic architecture with fewer, larger and more tightly-linked alleles should underlie rapid local adaptation during invasion, particularly when divergently-adapting populations experience high-levels of gene flow.
AIMP1-derived peptide secreted from hair follicle stem cells activates dermal papilla cells to promote hair growth
Authors: Kim YounHa , Lee Ho , Kim Doyeun , Bak Soon Sun , Yoon Ina , Paus Ralf , Cho Seongmin , Jeong Seung Jae , Jeon Yoon , Park Min Chul , Oh Ji Won , Park Jung Min , Kim Sang Bum , Sung Young Kwan , Kim Sunghoon 
Published: February 2022

ABSTRACTHair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) are crucial in the biogenesis and maintenance of hair follicles (HFs). In this study, a fragment derived from aminoacyl-tRNA synthetase-interacting multifunctional protein1 (AIMP1) was secreted from HFSCs to activate DPCs to maintain hair follicle homeostasis. A histological analysis revealed that AIMP1 levels in hair follicles decreased with hair loss. Hair regrowth in AIMP1-induced mice was faster than that in non-induced mice. Deletion mapping revealed 41 amino acids (TN41, aa 6-46) as the active region of AIMP1. The N-terminal peptide fragment of AIMP1 generated by MMP1 was secreted from Wnt-treated HFSCs to activate DPCs via FGFR2. TN41 activated Akt and ERK, increased β-catenin, and enhanced DPCs activation. TN41 also promoted hair shaft elongation in cultured human hair follicles and improved the hair-inducing activity of cultured DPC spheroids. In summation, the AIMP1 fragment secreted from HFSCs appears to stimulate active hair regrowth through activating DPCs.
Nr2f1a maintains atrial nkx2.5 expression to repress pacemaker identity within venous atrial cardiomyocytes
Authors: Martin Kendall E. , Ravisankar Padmapriyadarshini , Beerens Manu E. M. , MacRae Calum A. , Waxman Joshua S. 
Published: February 2022

AbstractMaintenance of cardiomyocyte identity is vital for normal heart development and function. However, our understanding of cardiomyocyte plasticity remains incomplete. Here, we show that sustained expression of the zebrafish transcription factor (TF) Nr2f1a prevents the progressive acquisition of ventricular cardiomyocyte (VC) and pacemaker cardiomyocyte (PC) identities within distinct regions of the atrium. Transcriptomic analysis of isolated atrial cardiomyocytes (ACs) from nr2f1a mutant zebrafish embryos showed increased VC marker gene expression and altered expression of core PC regulatory genes, including decreased expression of nkx2.5, a critical repressor of PC differentiation. At the arterial pole of the atrium in nr2f1a mutants, cardiomyocytes resolve to VC identity within the expanded atrioventricular canal. However, at the venous pole, there is a progressive wave of AC transdifferentiation into PCs across the atrium toward the arterial pole. Restoring Nkx2.5 is sufficient to repress PC identity in nr2f1a mutant atria and analysis of chromatin accessibility identified a Nr2f1a-dependent nkx2.5 enhancer expressed in the atrial myocardium directly adjacent to PCs, supporting that Nr2f1a limits PC differentiation within venous ACs via maintaining nkx2.5 expression. The Nr2f-dependent maintenance of AC identity within discrete atrial compartments may provide insights into the molecular etiology of concurrent structural congenital heart defects and associated arrhythmias.
Dynamic performance development of entrepreneurial ecosystem in the agricultural sector
Authors: Hosseinzadeh Mahnaz , Samadi Foroushani Marzieh , Sadraei Razieh 
Published: February 2022

PurposeThe study aims to identify the dynamic complexities and development points of the entrepreneurial ecosystem (EE) in the agricultural sector of Iran to improve production factors' productivity, including arable land, water resources and human capital.Design/methodology/approachFirst, the EE of the agricultural sector in Iran was designed following Isenberg's framework. Then, the main variables and interrelationships of the variables in each context of the ecosystem, called subsystems, were formulated using the system dynamics (SD) approach. Next, the model was simulated and validated. Afterward, different policy options were identified, embedded into the model structure and simulated. Finally, the best policy group was selected.FindingsAccording to Isenberg's EE model, three groups of policies were identified and evaluated, including “entrepreneurship development financing and investment policy,” “agricultural ecosystem's supportive services development policy” and “production factors productivity development policy.” According to the simulation results, the best combination of the solution strategies was recognized. The presented SD-EE model has a generic nature in the agricultural sector and could be modified to be applied in different regions for policy-making purposes.Originality/valueThe main contribution of the study is twofold. First, Isenberg's EE framework is applied to structure the main subsystems and interrelationships of the subsystems in the agricultural sector that has previously received limited attention. Second, the research is the first to operationalize the basic theory of Isenberg's EE in practice applying a robust systemic modeling methodology like SD.
Current status of research support services in university libraries of Pakistan
Authors: Awan Muhammad Hanif , Richardson Joanna , Ahmed Shamshad 
Published: February 2022

Purpose
Research support services (RSS) is an emerging and popular area in university libraries, whose increasing importance has been well documented since the early 2010s. This study aims to identify the status of RSS provided in the university libraries of Pakistan and to compare the results with relevant international studies. The research also reports on the perception of librarians regarding the application of RSS in Pakistani university libraries.

Design/methodology/approach
A quantitative survey was conducted of the chief librarians/head librarians working in the 175 university libraries of Pakistan. A structured questionnaire was designed and pre-tested with national and international research experts, faculty members and library professionals. SPSS was used to calculate descriptive statistics. Results of the study were compared with previous literature from an international perspective.

Findings
Results of the study indicated that most of the university libraries are providing basic RSS and that they have good collections of both general and subject-specific works to meet the needs of researchers. Most respondents not only were interested in providing RSS but also emphasized that libraries should upgrade their collection to meet researchers’ requirements. However, results of the study also indicated that there was noticeably less support for both the more advanced and newer research support services.

Practical implications
Because the delivery of RSS enables libraries to help meet a university’s strategic research goals, the findings will be of interest to university library and information science executives, policymakers and administration. The suggested recommendations highlight those service areas which are most in need of improvement.

Originality/value
This research provides an updated perspective on the delivery of research support services by university libraries in Pakistan.