bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond target-decoy competition: stable validation of peptide and protein identifications in mass spectrometry-based discovery proteomics
Authors: Couté Yohann , Bruley Christophe , Burger Thomas 
Published: September 2019

AbstractIn bottom-up discovery proteomics, target-decoy competition (TDC) is the most popular method for false discovery rate (FDR) control. Despite unquestionable statistical foundations, this method has drawbacks, including its hitherto unknown intrinsic lack of stabilityvis-à-vispractical conditions of application. Although some consequences of this instability have already been empirically described, they may have been misinter-preted. This article provides evidence that TDC has become less reliable as the accuracy of modern mass spectrometers improved. We therefore propose to replace TDC by a totally different method to control the FDR at spectrum, peptide and protein levels, while benefiting from the theoretical guarantees of the Benjamini-Hochberg framework. As this method is simpler to use, faster to compute and more stable than TDC, we argue that it is better adapted to the standardization and throughput constraints of current proteomic platforms.
Polarity protein distribution on the metaphase furrow regulates hexagon dominated plasma membrane organization in syncytialDrosophilaembryos
Authors: Dey Bipasha , Mitra Debasmita , Das Tirthasree , Sherlekar Aparna , Balaji Ramya , Rikhy Richa 
Published: September 2019

AbstractEpithelial cells have a polarised distribution of protein complexes on the lateral membrane and are present as a polygonal array dominated by hexagons. Metazoan embryogenesis enables the study of temporal formation of the polygonal array and mechanisms that regulate its distribution. The plasma membrane of the syncytialDrosophilablastoderm embryo is organized as a polygonal array during cortical division cycles with an apical membrane and lateral furrow in between adjacent nuclei. We find that polygonal plasma membrane organization arises in syncytial division cycle 11 and hexagon dominance occurs with increase in furrow length in cycle 12. This is coincident with DE-cadherin and Bazooka enrichment at edges and the septin, Peanut enrichment at vertices of the base of the furrow. DE-cadherin depletion leads to loss of hexagon dominance. Bazooka and Peanut depletion leads to a delay in occurrence of hexagon dominance from nuclear cycle 12 to 13. Hexagon dominance in Bazooka and Peanut mutants occurs with furrow extension and correlates with increase in DE-cadherin in syncytial cycle 13. We conclude that a change in polarity complex distribution leads to loss of furrow stability thereby changing the polygonal organization of the blastoderm embryo.Highlight Summary for TOCMetazoan embryogenesis starts with the formation of polygonal epithelial-like cells. We show that hexagon dominance in polygonal epithelial-like plasma membrane organization occurs in nuclear cycle 12 in the syncytial blastodermDrosophilaembryo. DE-cadherin and Bazooka distribution along the lateral furrow regulates this hexagon dominance.
Rare Variants in theOTOGGene Are a Frequent Cause of Familial Meniere’s Disease
Authors: Roman-Naranjo Pablo , Gallego-Martinez Alvaro , Soto-Varela Andrés , Aran Ismael , Moleon Maria del Carmen , Espinosa-Sanchez Juan Manuel , Amor-Dorado Juan Carlos , Batuecas-Caletrio Angel , Perez-Vazquez Paz , Lopez-Escamez Jose A. 
Published: September 2019

AbstractObjectivesMeniere’s disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo and tinnitus. Familial MD has been reported in 6-9% of sporadic cases, and few genes includingFAM136A, DTNA, PRKCB, SEMA3DandDPThave been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD.DesignExome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis (SRVA) and a gene burden analysis (GBA) were conducted in the dataset selecting one patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls.ResultsA total of 5136 single nucleotide variants in hearing loss genes were considered for SRVA in familial MD cases, but only one heterozygous variant in theOTOGgene (rs552304627) was found in two unrelated families. The GBA found an enrichment of rare missense variants in theOTOGgene in familial MD. So, 15/46 families (33%) showed at least one rare missense variant in theOTOGgene, suggesting a key role in familial MD.ConclusionsThe authors found an enrichment of multiplex rare missense variants in theOTOGgene in familial MD. This finding supportsOTOGas a relevant gene in familial MD and set the groundwork for genetic testing in MD.
Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank
Authors: Parker Margaret M. , Ticau Simina , Butler James , Erbe David , Merkel Madeline , Aldinc Emre , Hinkle Gregory , Nioi Paul 
Published: September 2019

AbstractBackgroundDestabilized transthyretin (TTR) can result in the progressive, fatal disease transthyretin-mediated (ATTR) amyloidosis. A stabilizingTTRmutation, T119M, is the basis for a therapeutic strategy to reduce destabilized TTR. Recently, T119M was associated with extended lifespan and lower risk of cerebrovascular disease in a Danish cohort. We aimed to determine whether this finding could be replicated in the UK Biobank.MethodsTTRT119M carriers were identified in the UK Biobank, a large prospective cohort of ∼500,000 individuals. Association between T119M genotype and inpatient diagnosis of vascular disease, cardiovascular disease, cerebrovascular disease, and mortality was analyzed.ResultsFrequency of T119M within the white UK Biobank population (n=337,148) was 0.4%. Logistic regression comparing T119M carriers to non-carriers found no association between T119M and vascular disease (odds ratio [OR]=1.08;p=.27), cardiovascular disease (OR=1.08;p=.31), cerebrovascular disease (OR=1.1;p=.42), or death (OR=1.2;p=.06). Cox proportional hazards regression showed similar results (hazard ratio>1,p>.05). Age at death and vascular disease diagnosis were similar between T119M carriers and non-carriers (p=.12 andp=.38, respectively).ConclusionsThere was no association between theTTRT119M genotype and risk of vascular disease or death in a large prospective cohort study, indicating that TTR tetramer stabilization through T119M is not protective in this setting.
A simple, versatile and robust centrifugation-based filtration protocol for the isolation and quantification of α-synuclein monomers, oligomers and fibrils: towards improving experimental reproducibility in α-synuclein research
Authors: Kumar Senthil T. , Donzelli Sonia , Chiki Anass , Syed Muhammed Muazzam Kamil , Lashuel Hilal A. 
Published: September 2019

AbstractIncreasing evidence suggests that the process of alpha-synuclein (aSyn) aggregation from monomers into amyloid fibrils via oligomeric intermediates plays an essential role in the pathogenesis of different synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy and dementia with Lewy bodies. However, the nature of the toxic species and the mechanisms by which they contribute to neurotoxicity and disease progression remain elusive. Over the past two decades, significant efforts and resources have been invested in studies aimed at identifying the putative toxic species along the pathway of aSyn fibrillization, and to develop small molecule drugs or antibodies that target toxic aSyn oligomeric intermediates. Although this approach has helped to advance the field and provide insights into the biological properties and toxicity of different aSyn species, many of the fundamental questions regarding the role of aSyn aggregation in PD remain unanswered, and no therapeutic compounds targeting aSyn oligomers have passed clinical trials. Several factors have contributed to this slow progress, including the complexity of the aggregation pathways and the heterogeneity and dynamic nature of aSyn aggregates. In the majority of experiment, the aSyn samples used contain mixtures of aSyn species that exist in an equilibrium and their ratio changes upon modifying experimental conditions. The failure to quantitatively account for the distribution of different aSyn species in different studies has contributed not only to experimental irreproducibility but also to misinterpretation of results and misdirection of valuable resources. Towards addressing these challenges and improving experimental reproducibility in Parkinson’s research, we describe here a simple centrifugation-based filtration protocol for the isolation, quantification and assessment of the distribution of of aSyn monomers, oligomers and fibrils, in heterogeneous aSyn samples of increasing complexity. The protocol is simple, does not require any special instrumentation and can be performed rapidly on multiple samples using small volumes. Here, we present and discuss several examples that illustrate the applications of this protocol and how it could contribute to improving the reproducibility of experiments aimed at elucidating the structural basis of aSyn aggregation, seeding activity, toxicity and pathology spreading. This protocol is applicable, with slight modifications, to other amyloid-forming proteins.Table of Content Figure
The Curli Accessory Protein CsgF Influences the Aggregation of Human Islet Amyloid Polypeptide
Authors: Meza-Barajas Osmar , Aranda Isamar , Binmahfooz Ashwag , Newell Alliosn , Jayasinghe Sajith 
Published: September 2019

AbstractGram-negative bacteria, such as E. coli and Salmonella, contain proteinaceous, hair-like, cell surface filaments known as curli. Curli serve to facilitate cell-cell interactions and are essential for host cell colonization. Curli assembly involves six proteins, CsgA, CsgB, CsgC, CsgE, CsgF, and CsgG. CsgE and CsgF are thought to act as chaperones to help prevent the premature aggregation of CsgA and/or CsgB, and to help transport these proteins, through the outer-membrane protein CsgG, to the cell surface where they assemble to form Curli. It has been observed that CsgF is able to inhibit the aggregation of CsgA, the major protein component of Curli. This article describes CsgF’s ability to influence the aggregation of human islet amyloid polypeptide (hIAPP), an amyloidogenic polypeptide that is unrelated to Curli. In the presence of CsgF no increase in Thioflavin T fluorescence was observed for freshly solubilized hIAPP monitored as a function of time, suggesting that CsgF prevents the aggregation of hIAPP during the time period of observation. An analog of CsgF lacking the N-terminal unstructured region retained the ability to inhibit the aggregation of hIAPP. The nature of the CsgF-hIAPP interaction was probed via fluorescence quenching using a series of single cysteine mutants of CsgF labeled via the individual cysteine side chains with the fluorophore IAEDANS. In the presence of hIAPP, but not in the presence of the non-amyloidogenic rat islet amyloid polypeptide, the fluorophore attached to position of 23 of CsgF was found to be less exposed the quencher acrylamide suggesting that the interaction of hIAPP changes the solvent exposure of the N-terminus of CsgF. Taken together these data suggest that the structured region of CsgF, between residues 66 and 128, is involved in the protein’s interaction with hIAPP and that upon interaction structural changes make the N-terminus less solvent exposed.
Perceptual metacognition of human faces is causally supported by function of the lateral prefrontal cortex
Authors: Lapate Regina C. , Samaha Jason , Rokers Bas , Postle Bradley R. , Davidson Richard J. 
Published: September 2019

AbstractMetacognitive visual awareness—the ability to know that one is having a particular visual experience—is thought to optimally guide behavior and help us accurately navigate our complex social environments. Yet the neural underpinnings of visual metacognition continue to be the subject of vigorous debate: While prior work identified correlations between perceptual metacognitive ability and the structure and function of lateral prefrontal cortex (LPFC), evidence for a causal role of this region in promoting metacognition is controversial—in fact, some question whether the prefrontal cortex plays any role in supporting conscious visual experiences. Moreover, whether LPFC function promotes metacognitive awareness of perceptual and emotional features of complex, yet ubiquitous socio-emotional face stimuli is unknown. Using model-based analyses following a causal intervention to LPFC in humans, we demonstrate that LPFC promotes metacognitive awareness of the orientation of emotional faces—although not of their emotional expressions. Effects were specific to metacognition, as LPFC perturbation did not alter stimulus discrimination performance. Collectively, these data support the causal involvement of the prefrontal cortex in metacognitive awareness, and indicate that the role of LPFC function in metacognition encompasses perceptual experiences of naturalistic social stimuli.
Structural requirements of the phytoplasma effector protein SAP54 for causing homeotic transformation of floral organs
Authors: Aurin Marc-Benjamin , Haupt Michael , Görlach Matthias , Rümpler Florian , Theißen Günter 
Published: September 2019

SummaryPhytoplasmas are intracellular bacterial plant pathogens that cause devastating diseases in crops and ornamental plants by the secretion of effector proteins. One of these effector proteins, termed SECRETED ASTER YELLOWS-WITCHES’ BROOM PROTEIN 54 (SAP54), leads to the degradation of a specific subset of floral homeotic proteins of the MIKC-type MADS-domain family via the ubiquitin-proteasome pathway. In consequence, the developing flowers show the homeotic transformation of floral organs into vegetative leaf-like structures. The molecular mechanism of SAP54 action involves physical binding to the keratin-like K-domain of MIKC-type proteins, and to some RAD23 proteins, which translocate ubiquitylated substrates to the proteasome. The structural requirements and specificity of SAP54 function are poorly understood, however. Here we report, based on biophysical and molecular biological analyses, that SAP54 folds into α-helical structures. We also show that the insertion of helix-breaking mutations disrupts correct folding of SAP54, which interferes with the ability of SAP54 to bind to its target proteins and to cause disease phenotypesin vivo. Surprisingly, dynamic light scattering data together with electrophoretic mobility shift assays suggest that SAP54 preferentially binds to multimeric complexes of MIKC-type proteins rather than to dimers or monomers of these proteins. Together with literature data this finding suggests that MIKC-type proteins and SAP54 constitute multimeric α-helical coiled-coils, possibly also involving other partners such as RAD23 proteins. Our investigations clarify the structure-function relationship of an important phytoplasma effector protein and thus may ultimately help to develop treatments against some devastating plant diseases.SIGNIFICANCE STATEMENTPhytoplasmas are bacterial plant pathogens that cause devastating diseases in crops and ornamental plants by the secretion of effector proteins such as SAP54, which leads to the degradation of some floral homeotic proteins. Our study clarifies the structural requirements of SAP54 function and illuminates the molecular mode of interaction and thus may ultimately help to develop treatments against some devastating plant diseases.
Reduction of spontaneous cortical beta bursts in Parkinson’s disease is linked to symptom severity
Authors: Vinding Mikkel C. , Tsitsi Panagiota , Waldthaler Josefine , Oostenveld Robert , Ingvar Martin , Svenningsson Per , Lundqvist Daniel 
Published: September 2019

AbstractParkinson’s disease is characterized by a gradual loss of dopaminergic neurons, which are associated with altered neuronal activity in the beta band (13-30 Hz). Assessing beta band activity typically involves transforming the time-series to get the power of the signal in the frequency-domain. Such transformation assumes that the time-series can be reduced to a combination of steady-state sine-and cosine waves. However, recent studies have suggested that this approach masks relevant biophysical features in the beta band activity—for example, that the beta band exhibits transient bursts of high-amplitude activity.In an exploratory study we used magnetoencephalography (MEG) to record cortical beta band activity to characterize how spontaneous cortical beta bursts manifest in Parkinson’s patients ON and OFF dopaminergic medication, and compare this to matched healthy controls. From three minutes of MEG data, we extracted the time-course of beta band activity from the sensorimotor cortex and characterized high-amplitude epochs in the signal to test if they exhibited burst like properties. We then compared the rate, duration, inter-burst interval, and peak amplitude of the high-amplitude epochs between the Parkinson’s patients and healthy controls.Our results show that Parkinson’s patients OFF medication had a 6-17% lower beta bursts rate compared to healthy controls, while both the duration and the amplitude of the bursts were the same for Parkinson’s patients and healthy controls and medicated state of the Parkinson’s patients. These data thus support the view that beta bursts are fundamental underlying features of beta band activity, and show that changes in cortical beta band power in PD can be explained primarily by changes in the underlying burst rate. Importantly, our results also revealed a relationship between beta bursts rate and motor symptom severity in PD: a lower burst rate scaled with increased in severity of bradykinesia and postural/kinetic tremor. Beta burst rate might thus serve as neuromarker for Parkinson’s disease that can help in the assessment of symptom severity in Parkinson’s disease or evaluate treatment effectiveness.
The effects of e-cigarette vapor exposure on the transcriptome and virulence of Streptococcus pneumoniae
Authors: Bagale Kamal , Paudel Santosh , Cagle Hayden , Sigel Erin , Kulkarni Ritwij 
Published: September 2019

AbstractThe effects of e-cigarette vapor (EV) exposure on the physiology of respiratory microflora are not fully defined. We analyzed the effects of exposure to vapor from nicotine-containing and nicotine-free e-liquid formulations on virulence and transcriptome of Streptococcus pneumoniae strain TIGR4, a pathogen that asymptomatically colonizes human nasopharyngeal mucosa. TIGR4 was pre-exposed for 2h to nicotine-containing EV extract (EVE+NIC), nicotine-free EV extract (EVE−NIC), cigarette smoke extract (CSE), or nutrient-rich TS broth (control). The differences in the treatment and control TIGR4 were explored using transcriptome sequencing, in vitro virulence assays, and in vivo mouse model of acute pneumonia. The analysis of RNASeq profiles revealed modest changes in the expression of 14 genes involved in sugar transport and metabolism in EVE−NIC pre-exposed TIGR4 compared to the control. While, EVE+NIC or CSE exposure altered expression of 264 and 982 genes, respectively, most of which were involved in metabolism and stress response. Infection in a mouse model of acute pneumonia with control TIGR4 or with TIGR4 pre-exposed to EVE+NIC, EVE−NIC, or CSE did not show significant differences in disease parameters, such as bacterial organ burden and respiratory cytokine response. Interestingly, TIGR4 exposed to CSE or EVE+NIC (but not EVE−NIC) exhibited moderate induction of biofilm formation. However, none of the treatment groups showed significant alterations in pneumococcal hydrophobicity or epithelial cell adherence. In summary, our study reports that exposure to EV significantly alters the S. pneumoniae transcriptome in a nicotine-dependent manner without affecting pneumococcal virulence.ImportanceWith the increasing popularity of e-cigarettes amongst cigarette smoking and non-smoking adults and children, and the recent reports of vaping related lung illnesses and deaths, further analysis of the adverse health effects of e-cigarette vapor (EV) exposure is warranted. Since pathogenic bacteria such as Streptococcus pneumoniae can colonize the human nasopharynx as commensals, they may be affected by the exposure to bioactive chemicals in EV. Hence in this study we examined the effects of EV exposure on the physiology of S. pneumoniae strain TIGR4. In order to differentiate between the effects of nicotine and non-nicotine components, we specifically compared RNASeq profiles and virulence of TIGR4 exposed to vapor from nicotine-containing and nicotine-free e-liquid formulations. We observed that nicotine-containing EV augmented TIGR4 biofilms and altered expression of TIGR4 genes predominantly involved in metabolism and stress response. However, neither nicotine-containing nor nicotine-free EV affected TIGR4 virulence in a mouse model.
Active transcription and Orc1 drive chromatin association of the AAA+ ATPase Pch2 during meiotic G2/prophase
Authors: da Silva Richard Cardoso , Villar-Fernández María Ascensión , Vader Gerben 
Published: September 2019

AbstractPch2 is an AAA+ protein that controls DNA break formation, recombination and checkpoint signaling during meiotic G2/prophase. Chromosomal association of Pch2 is linked to these processes, and several factors influence the association of Pch2 to euchromatin and the specialized chromatin of the ribosomal (r)DNA array of budding yeast. Here, we describe a comprehensive mapping of Pch2 localization across the budding yeast genome during meiotic G2/prophase. Within non-rDNA chromatin, Pch2 associates with a subset of actively RNA Polymerase II (RNAPII)-dependent transcribed genes. Chromatin immunoprecipitation (ChIP)- and microscopy-based analysis reveals that active transcription is required for chromosomal recruitment of Pch2. Similar to what was previously established for association of Pch2 with rDNA chromatin, we find that Orc1, a component of the Origin Recognition Complex (ORC), is required for the association of Pch2 to these euchromatic, transcribed regions, revealing a broad connection between chromosomal association of Pch2 and Orc1/ORC function. Ectopic mitotic expression is insufficient to drive recruitment of Pch2, despite the presence of active transcription and Orc1/ORC in mitotic cells. This suggests meiosis-specific ‘licensing’ of Pch2 recruitment to sites of transcription, and accordingly, we find that the synaptonemal complex (SC) component Zip1 is required for the recruitment of Pch2 to transcription-associated binding regions. Interestingly, Pch2 binding patterns are distinct from meiotic axis enrichment sites (as defined by Red1, Hop1 and Rec8). This suggests that although Pch2 is linked to axis/SC-directed recruitment and function, the chromosomal population of Pch2 described here is not directly associated with chromosomal axis sites. In line with this observation, interfering with the pool of Pch2 that associates with active RNAPII transcription does not lead to effects on the chromosomal abundance of Hop1, a known axial client of Pch2. We thus report characteristics and dependencies for Pch2 recruitment to meiotic chromosomes, and reveal an unexpected link between Pch2, SC formation, chromatin and active transcription.