bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omicron neutralizing antibody response following booster vaccination compared with breakthrough infection
Authors: Curlin Marcel E. , Bates Timothy A. , Guzman Gaelen , Schoen Devin , McBride Savannah K. , Carpenter Samuel D. , Tafesse Fikadu G. 
Published: April 2022

ABSTRACTThe rapid spread of the vaccine-resistant Omicron variant of SARS-CoV-2 presents a renewed threat to both unvaccinated and fully vaccinated individuals, and accelerated booster vaccination campaigns are underway to mitigate the ongoing wave of Omicron cases. The degree of immunity provided by standard vaccine regimens, boosted regimens, and immune responses elicited by the combination of vaccination and natural infection remain incompletely understood. The relative magnitude, quality and durability of serological responses, and the likelihood of neutralizing protection against future SARS-CoV-2 variants following these modes of exposure are unknown but are critical to the future trajectory of the COVID-19 pandemic. In this study of 99 vaccinated adults, we find that compared with responses after two doses of an mRNA regimen, the immune responses three months after a third vaccine dose and one month after breakthrough infection due to prior variants show dramatic increases in magnitude, potency, and breadth, including increased antibody dependent cellular phagocytosis and robust neutralization of the recently circulating Omicron variant. These results suggest that as the number of Omicron cases rise and as global vaccination and booster campaigns continue, an increasing proportion of the world’s population will acquire potent immune responses that may be protective against future SARS-CoV-2 variants.
Workplace Infection Prevention Control Measures and Work Engagement During the COVID-19 Pandemic among Japanese Workers: A Prospective Cohort Study
Authors: Ikegami Kazunori , Ando Hajime , Fujino Yoshihisa , Eguchi Hisashi , Muramatsu Keiji , Nagata Tomohisa , Tateishi Seiichiro , Tsuji Mayumi , Ogami Akira ,   the CORoNaWork project
Published: April 2022

AbstractObjectivesIt has been widely reported that the COVID-19 pandemic may have a psychological influence on people. Thus, it could be important to note how workplace infection prevention and control (IPC) measures for COVID-19 contribute to positive mental health among workers. We hypothesized that if workplace IPC measures are adequately implemented, they would have a positive effect on employees’ work engagement.MethodsWe conducted an internet-based prospective cohort study from December 2020 (baseline) to December 2021 (follow-up after one year) using self-administered questionnaires. At baseline, 27,036 workers completed the questionnaires, while 18,560 (68.7%) participated in the one-year follow-up. After excluding the 6,578 participants who changed jobs or retired during the survey period, or telecommuted more than four days per week, 11,982 participants were analyzed. We asked participants about the implementation of workplace IPC measures at baseline and conducted a nine-item version of the Utrecht Work Engagement Scale (UWES-9) at follow-up.ResultsFour groups were created according to the number of workplace IPC measures implemented. The mean (SD) UWES-9 score of the “0–2” group was the lowest at 18.3 (13.2), while that of the “8” group was the highest at 22.6 (12.6). The scores of the “3– 5,” “6–7,” and “8” groups were significantly higher than that of the “0–2” group (all, p<0.001). The p trend of the four groups was also significant (p<0.001).ConclusionsPromoting workplace IPC measures improves workers’ work engagement, and a dose-response relationship exists between workplace IPC measures and work engagement.
Scalable production of recombinant three-finger proteins: from inclusion bodies to high quality molecular probes
Authors: Xu Jiang , Lei Xiao , Li Ao , Li Jun , Li Shuxing , Chen Lin 
Published: April 2022

AbstractWe introduce a working pipeline for expression, purification and validation of disulfide-bond rich three-finger proteins using E. coli as the expression host. With this pipeline, we have successfully obtained highly purified and bioactive recombinant α-Bungarotoxin, k-Bungarotoxin, Hannalgesin, Mambalgin-1, α-Cobratoxin, MTα, Slurp1, Pate B etc. Milligrams to hundreds of milligrams of recombinant three finger proteins were obtained within weeks in the lab. The recombinant proteins showed specificity in binding assay and six of them were crystallized and structurally validated using X-ray diffraction protein crystallography. As many three finger proteins have attractive therapeutic or research interests and due to the extremely high quality of the recombinant three finger proteins we obtained, our method provides a competitive alternative to either their native counterparts or chemically synthetic ones, and should facilitate related research and applications.
Speech prosody supports speaker selection and auditory stream segregation in a multi-talker situation
Authors: Kovács Petra , Tóth Brigitta , Honbolygó Ferenc , Szalárdy Orsolya , Kohári Anna , Mády Katalin , Magyari Lilla , Winkler István 
Published: April 2022

AbstractTo process speech in a multi-talker environment, listeners need to segregate the mixture of incoming speech streams and focus their attention on one of them. Potentially, speech prosody could aid the segregation of different speakers, the selection of the desired speech stream, and detecting targets within the attended stream. For testing these issues, we recorded behavioral responses and extracted event-related potentials and functional brain networks from electroencephalographic signals recorded while participants listened to two concurrent speech streams, performing a lexical detection and a recognition memory task in parallel. Prosody manipulation was applied to the attended speech stream in one group of participants and to the ignored speech stream in another group. Naturally recorded speech stimuli were either intact, synthetically F0-flattened, or suppressed by the speaker. Results show that prosody – especially the parsing cues mediated by speech rate – facilitates stream selection, while playing a smaller role in auditory stream segmentation and target detection.
Base editor scanning charts the DNMT3A activity landscape
Authors: Lue Nicholas Z. , Garcia Emma M. , Ngan Kevin C. , Lee Ceejay , Doench John G. , Liau Brian B. 
Published: April 2022

AbstractDNA methylation is critical for regulating gene expression, necessitating its accurate placement by enzymes such as the DNA methyltransferase DNMT3A. Dysregulation of this process is known to cause aberrant development and oncogenesis, yet how DNMT3A is regulated holistically by its three domains remains challenging to study. Here we integrate base editing with a DNA methylation reporter to perform in situ mutational scanning of DNMT3A in cells. We identify mutations throughout the protein that perturb function, including ones at an interdomain interface that block allosteric activation. Unexpectedly, we also find mutations in the PWWP domain, a histone reader, that modulate enzyme activity despite preserving histone recognition and protein stability. These effects arise from altered PWWP domain DNA affinity, which we show is a noncanonical function required for full activity in cells. Our findings highlight mechanisms of interdomain crosstalk and demonstrate a generalizable strategy to probe sequence-activity relationships of nonessential chromatin regulators.
Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment
Authors: Barefoot Megan E. , Loyfer Netanel , Kiliti Amber J. , Schmidt Marcel O. , Shabi-Porat Sapir , Jain Sidharth , Roth Sarah Martinez , McDeed A. Patrick , Shahrour Nesreen , Ballew Elizabeth , Lin Yun-Tien , Li Heng-Hong , Mays Anne Deslattes , Rudra Sonali , Riegel Anna T. , Unger Keith , Kaplan Tommy , Wellstein Anton 
Published: April 2022

AbstractRadiation therapy is an effective cancer treatment although damage to healthy tissues is common. Here we characterize the methylomes of healthy human and mouse tissues to establish sequencing-based, cell-type specific reference DNA methylation atlases. Identified cell-type specific DNA blocks were mostly hypomethylated and located within genes intrinsic to cellular identity. Cell-free DNA fragments released from dying cells into the circulation were captured from serum samples by hybridization to CpG-rich DNA panels. The origins of the circulating DNA fragments were inferred from mapping to the established DNA methylation atlases. Thoracic radiation-induced tissue damages in a mouse model were reflected by dose-dependent increases in lung endothelial, cardiomyocyte and hepatocyte methylated DNA in serum. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type specific effects of radiation and provide a quantitative measure of the biologically effective radiation dose received by healthy tissues.Graphical Abstract
Long-term balancing selection and the genetic load linked to the self-incompatibility locus inArabidopsis halleriandA. lyrata
Authors: Le Veve Audrey , Burghgraeve Nicolas , Genete Mathieu , Lepers-Blassiau Christelle , Takou Margarita , De Meaux Juliette , Mable Barbara K. , Durand Eléonore , Vekemans Xavier , Castric Vincent 
Published: April 2022

AbstractBalancing selection is a form of natural selection maintaining diversity at the sites it targets and at linked nucleotide sites. Due to selection favouring heterozygosity, it has the potential to facilitate the accumulation of a “sheltered” load of tightly linked recessive deleterious mutations. However, precisely evaluating the extent of these effects has remained challenging. Taking advantage of plant self-incompatibility as one of the best-understood examples of long-term balancing selection, we provide a highly resolved picture of the genomic extent of balancing selection on the sheltered genetic load. We used targeted genome resequencing to reveal polymorphism of the genomic region flanking the self-incompatibility locus in three sample sets in each of the two closely related plant speciesArabidopsis halleriandA. lyrata, and used 100 control regions from throughout the genome to factor out differences in demographic histories and/or sample structure. Nucleotide polymorphism increased strongly around theS-locus in all sample sets, but only over a limited genomic region, as it became indistinguishable from the genomic background beyond the first 25-30kb. Genes in this chromosomal interval exhibited no excess of mutations at 0-fold degenerated sites relative to putatively neutral sites, hence revealing no detectable weakening of the efficacy of purifying selection even for these most tightly linked genes. Overall, our results are consistent with the predictions of a narrow genomic influence of linkage to theS-locus, and clarify how natural selection in one genomic region affects the evolution of the adjacent genomic regions.
Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease
Authors: Svedružić Željko M. , Jengić Vesna Šendula , Ostojić Lucija 
Published: April 2022

AbstractSignificancepathogenic changes in γ-secretase activity, and its response to different drugs, can be greatly affected by changes in saturation of γ-secretase with its substrate. The molecular mechanism is unclear.Resultsmultiscale molecular dynamics studies show that saturation of γ-secretase with its substrate can result in parallel binding of different substrate molecules at the docking site and the active site. C-terminal domain of the second substrate can bind at cytosolic end of presenilin subunit while γ-secretase is still processing its first substrate. Such interactions can disrupt dynamic presenilin structures that regulate proteolytic steps. Similar disruptions in dynamic presenilin structures can be produced by different drugs and by different disease-causing mutations. Thus, the presented two-substrate mechanism, can explain toxic inhibition of γ-secretase activity and toxic increase in production of the longer, more hydrophobic, Aβ-proteins. Toxic aggregation between N-terminal domains of the two substrates is controlled by nicastrin ectodomain. Such aggregation is more likely to happen with C99-βCTF-APP than with C83-αCTF-APP substrate, which can explain, why β-secretase path is more pathogenic than α-secretase path. The binding of C99-βCTF-APP substrate to γ-secretase can be controlled by substrate-channeling between nicastrin ectodomain and β-secretase.ConclusionsThe presented two-substrate mechanism can explain why different studies consistently show that increase in saturation of γ-secretase with its substrate can support pathogenic changes in different sporadic and familiar cases of the disease. Future drug-development strategies can target different physiological mechanisms that control the balance between cellular levels of γ-secretase activity and the total amyloid metabolism.
Monitoring extracellular ion and metabolite dynamics with recombinant nanobody-fused biosensors
Authors: Burgstaller Sandra , Wagner Teresa R. , Bischof Helmut , Bueckle Sarah , Padamsey Aman , Frecot Desiree I. , Kaiser Philipp D. , Skrabak David , Malli Roland , Lukowski Robert , Rothbauer Ulrich 
Published: April 2022

ABSTRACTThe tumor microenvironment (TME) consists of different cell types that secrete proteins and also control the extracellular concentration of ions and metabolites. Changes in these intra-tumoral analytes and conditions, including K+, glucose, and pH, have been described to alter the metabolic activity of cancer cells, promote tumor cell growth, and impair anti-tumor immunity. However, the mechanisms regulating ion and metabolite levels and their effects on certain characteristics of the TME are still poorly understood. Therefore, accurate determination and visualization of analyte or state changes in real time within the TME is desired.In this study, we genetically combined FRET-based fluorescent biosensors with nanobodies (Nbs) and used them for targeted visualization and monitoring of extracellular changes in K+, pH, and glucose on cell surfaces. We demonstrated that these recombinant biosensors quantitatively visualize extracellular K+ alterations on multiple cancer and non-cancer cell lines and primary neurons. By implementing a HER2 specific Nb, we generated K+ and pH sensors, which retain their functionality and specifically stained HER2 positive breast cancer cells. Based on the successful technical development of several Nb-biosensor combinations, we anticipate that this approach can be easily extended to design other targeted biosensors. Such versatile probes will open new possibilities for the reliable study of extracellular analytes in advanced 3D cell models or even in vivo systems.
Representation of illusory shapes within the topographic areas of the posterior parietal cortex
Authors: Arsenovic Ana , Ischebeck Anja , Zaretskaya Natalia 
Published: April 2022

AbstractThe human visual system consists of multiple topographic maps that extend from the early visual cortex along the dorsal and ventral processing streams. Responses to illusory shapes within these maps have been demonstrated in the ventral stream areas, in particular the lateral occipital complex. Recently, the intraparietal sulcus of the dorsal stream has been linked to the processing of illusory shapes defined by motion. It therefore remains unclear whether the topographically organized parietal areas also respond to static illusory shapes, which would suggest their generic role in representing illusory content. Here we measured brain responses using fMRI while human participants observed flickering inducers around the fixation task. The inducers either formed an illusory diamond in the center, a triangle in the left or in the right hemifield, or were inverted such that no illusory figure was formed. We compared responses of parietal regions IPS0-IPS5 and SPL1 to each illusory figure with the non-illusory condition. To determine the role of attention in illusory shape responses we manipulated the difficulty of the fixation task. Our results show that all IPS areas responded to illusory shapes. The more posterior areas IPS0-IPS3 additionally displayed a preference towards the contralateral shapes, while the more anterior areas IPS4 and IPS5 showed response attenuation with increased task difficulty. We suggest that the IPS can represent illusory content irrespective of the perceptual mechanism that generated it. These responses may serve as a potential feedback signal that drives illusory shape responses in early and ventral visual areas.Significance statementThe traditional view of the ventral visual pathway being solely responsible for representation of objects has recently been challenged by demonstrating illusory shape representation within the dorsal visual pathway with moving bistable stimuli. Our results provide evidence for the dorsal stream contribution to representing not only moving, but also static illusory shapes. Our results also show a functional subdivision along the topographic maps, with spatially specific shape responses in the more posterior, and attention-dependent responses in the more anterior areas. IPS areas of the dorsal stream should thus be considered in the theoretical accounts and neural models of how subjective content is generated in the brain.
Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5
Authors: Clasen Sara J. , Bell Michael E. W. , Lee Du-Hwa , Henseler Zachariah M. , Borbón Andrea , de la Cuesta-Zuluaga Jacobo , Parys Katarzyna , Zou Jun , Youngblut Nicholas D. , Gewirtz Andrew T. , Belkhadir Youssef , Ley Ruth E. 
Published: April 2022

AbstractFlagellin, the protein unit of the bacterial flagellum, stimulates the innate immune receptor Toll-like receptor (TLR)5 following pattern recognition, or evades TLR5 through lack of recognition. This binary response fails to explain the weak agonism of flagellins from commensal bacteria, raising the question of how TLR5 response is tuned. Here, we describe a novel class of flagellin-TLR5 interaction, termed silent recognition. Silent flagellins are weak agonists despite high affinity binding to TLR5. This dynamic response is tuned by TLR5-flagellin interaction distal to the site of pattern recognition. Silent flagellins are produced primarily by the abundant gut bacteria Lachnospiraceae and are enriched in non-Western populations. These findings provide a mechanism for the innate immune system to tolerate commensal-derived flagellins.One-Sentence SummaryTLR5 sensitively recognizes, but responds weakly to, flagellins from gut commensal bacteria.
Melatonin suppression does not automatically alter sleepiness, vigilance, sensory processing, or sleep
Authors: Blume Christine , Niedernhuber Maria , Spitschan Manuel , Slawik Helen C. , Meyer Martin P. , Bekinschtein Tristan A. , Cajochen Christian 
Published: April 2022

AbstractPre-sleep exposure to short-wavelength light suppresses melatonin and decreases sleepiness with activating effects extending to sleep. This has mainly been attributed to melanopic effects, but mechanistic insights are missing. Thus, we investigated whether two light conditions only differing in the melanopic effects (123 vs. 59 lux melanopic EDI) differentially affect sleep besides melatonin. Additionally, we studied whether the light differentially modulates sensory processing during wakefulness and sleep.Twenty-nine healthy volunteers (18-30 years, 15 women) were exposed to two metameric light conditions (high-vs. low-melanopic, ≈60 photopic lux) for 1 hour ending 50 min prior to habitual bed time. This was followed by an 8-h sleep opportunity with polysomnography. Objective sleep measurements were complemented by self-report. Salivary melatonin, subjective sleepiness, and behavioural vigilance were sampled at regular intervals. Sensory processing was evaluated during light exposure and sleep on the basis of neural responses related to violations of expectations in an oddball paradigm.We observed suppression of melatonin by ≈14 % in the high-compared to the low-melanopic condition. However, conditions did not differentially affect sleep, sleep quality, sleepiness, or vigilance. A neural mismatch response was evident during all sleep stages, but not differentially modulated by light.Suppression of melatonin by light targeting the melanopic system does not automatically translate to acutely altered levels of vigilance or sleepiness or to changes in sleep, sleep quality, or basic sensory processing. Given contradicting earlier findings and the retinal anatomy, this may suggest that an interaction between melanopsin and cone-rod signals needs to be considered.Statement of SignificanceMetameric light allows to mechanistically investigate the contribution of one specific retinal receptor. Using this approach, we here investigated the effects of high-vs. low-melanopic light for 1 hour in the evening at ecologically valid screen illuminance (≈60 photopic lux). Going beyond earlier research, we also investigated effects on sleep. We found that despite significant suppression of melatonin, other endpoints including sleep and sleep quality were not differentially affected. This underlines that melatonin suppression does not automatically translate to alterations of sleep, sleepiness, or vigilance. Further, it suggests that melanopsin effects may need to be studied in the context of cone-rod signals. Future research should thus investigate the relevance of such an interaction, which may vary between endpoints.
Expanding adult tubular microvessels on stiff substrates with endothelial cells and pericytes from the same tissue
Authors: Song Xiuyue , Yu Yali , Mu Jie , Wang Zihan , Leng Yu , Xu Yalan , Zhu Hai , Qiu Xuefeng , Li Peifeng , Li Jing , Wang Dong 
Published: April 2022

AbstractMicrovessels are essential for tissue engineering and regeneration. In current methods, endothelial cells are usually cultured in commercially available media and form a monolayer of cell sheets on stiff substrates and a tubular structure when cultured with soft hydrogels. To mimic the microvessels in vivo, researchers usually coculture the endothelial cells and pericytes from different adult tissues or derived from pluripotent stem cells in a three-dimensional hydrogel. However, there is a challenge for these models to reflect tissue-specific characteristics due to the vascular heterogeneity throughout the body. Here, we established a culture model for expanding adult tubular microvessels on stiff substrates with endothelial cells and pericytes derived from the same tissue. We isolated microvessels from adult rat subcutaneous soft connective tissue and cultured them on regular plastic dishes. We performed a series of screenings and formulated a custom-made medium (Medium-X), containing mainly antioxidants and three small molecules, Chir99021, A83-01, and Y27632. Medium-X significantly promoted adult microvessel growth while maintaining their characteristic tubular morphology up to 8 weeks in vitro, contrary to the monolayer of endothelial cell sheets in the commercially available medium EGM2MV. Transcriptomic analysis showed that Medium-X maintained the tubular morphology of microvessels by promoting angiogenesis and vascular remodeling while suppressing oxidation and lipid metabolic pathways. The model presented in this study can be applied to other organs for expanding organ-specific microvessels for tissue engineering and vascular regeneration.