bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adverse childhood experiences and severity levels of inflammation and depression from childhood to young adulthood: a longitudinal cohort study
Authors: Iob Eleonora , Lacey Rebecca , Giunchiglia Valentina , Steptoe Andrew 
Published: March 2022

AbstractAdverse childhood experiences (ACEs) are associated with depression and systemic inflammation in adults. However, limited longitudinal research has tested these relationships in children and young people, and it is unclear whether inflammation is an underlying mechanism through which ACEs influence depression. We examined the longitudinal associations of several ACEs across different early-life periods with longitudinal patterns of early-life inflammation and depression in young adulthood and assessed the mediating role of inflammation. The data came from the Avon Longitudinal Study of Parents and Children (N = 3931). ACEs from the prenatal period through to adolescence were operationalised using cumulative scores, single adversities, and dimensions derived through factor analysis. Inflammation (C-reactive protein) was measured on three occasions (9–18 years) and depressive symptoms were ascertained on four occasions (18–23 years). Latent class growth analysis was employed to delineate group-based trajectories of inflammation and depression. The associations between ACEs and the inflammation/depression trajectories were tested using multinomial logistic regression analysis. Most types of ACEs across all early-life periods were associated with elevated depression trajectories, with larger associations for threat-related adversities compared with other ACEs. Bullying victimisation and sexual abuse in late childhood/adolescence were associated with elevated CRP trajectories, while other ACEs were unrelated to inflammation. Inflammation was also unrelated to depression and did not mediate the associations with ACEs. These results suggest that ACEs are consistently associated with depression, whereas the associations of inflammation with ACEs and depression are weak in young people. Interventions targeting inflammation in this population might not offer protection against depression.
Seasonal variability of ocean circulation near the Dotson Ice Shelf, Antarctica
Authors: Yang H. W. , Kim T.-W. , Dutrieux Pierre , Wåhlin A. K. , Jenkins Adrian , Ha H. K. , Kim C. S. , Cho K.-H. , Park T. , Lee S. H. , Cho Y.-K. 
Published: March 2022

AbstractRecent rapid thinning of West Antarctic ice shelves are believed to be caused by intrusions of warm deep water that induce basal melting and seaward meltwater export. This study uses data from three bottom-mounted mooring arrays to show seasonal variability and local forcing for the currents moving into and out of the Dotson ice shelf cavity. A southward flow of warm, salty water had maximum current velocities along the eastern channel slope, while northward outflows of freshened ice shelf meltwater spread at intermediate depth above the western slope. The inflow correlated with the local ocean surface stress curl. At the western slope, meltwater outflows followed the warm influx along the eastern slope with a ~2–3 month delay. Ocean circulation near Dotson Ice Shelf, affected by sea ice distribution and wind, appears to significantly control the inflow of warm water and subsequent ice shelf melting on seasonal time-scales.
A multi-factor trafficking site on the spliceosome remodeling enzyme BRR2 recruits C9ORF78 to regulate alternative splicing
Authors: Bergfort Alexandra , Preußner Marco , Kuropka Benno , Ilik İbrahim Avşar , Hilal Tarek , Weber Gert , Freund Christian , Aktaş Tuğçe , Heyd Florian , Wahl Markus C. 
Published: March 2022

AbstractThe intrinsically unstructured C9ORF78 protein was detected in spliceosomes but its role in splicing is presently unclear. We find that C9ORF78 tightly interacts with the spliceosome remodeling factor, BRR2, in vitro. Affinity purification/mass spectrometry and RNA UV-crosslinking analyses identify additional C9ORF78 interactors in spliceosomes. Cryogenic electron microscopy structures reveal how C9ORF78 and the spliceosomal B complex protein, FBP21, wrap around the C-terminal helicase cassette of BRR2 in a mutually exclusive manner. Knock-down of C9ORF78 leads to alternative NAGNAG 3′-splice site usage and exon skipping, the latter dependent on BRR2. Inspection of spliceosome structures shows that C9ORF78 could contact several detected spliceosome interactors when bound to BRR2, including the suggested 3′-splice site regulating helicase, PRPF22. Together, our data establish C9ORF78 as a late-stage splicing regulatory protein that takes advantage of a multi-factor trafficking site on BRR2, providing one explanation for suggested roles of BRR2 during splicing catalysis and alternative splicing.
Single-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Authors: Liu Xiangjun , Jin Shanzhao , Hu Simeng , Li Ruoyan , Pan Haihao , Liu Yi , Lai Pan , Xu Deshu , Sun Jingru , Liu Ziyang , Gao Yumei , Zhao Yifan , Liu Fengjie , Xiao Yu , Li Yingyi , Wen Yujie , Chen Zhuojing , Xu Bufang , Lin Yuchieh , Ran Menglong , Li Qianxi , Yang Shuxia , Li Hang , Tu Ping , Haniffa Muzlifah , Teichmann Sarah A. , Bai Fan , Wang Yang 
Published: March 2022

AbstractCutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the TCyEM group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the TCM group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8+ reactive T cells, B cells and Tregs with suppressive activities. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.
Precision of morphogen gradients in neural tube development
Authors: Vetter Roman , Iber Dagmar 
Published: March 2022

AbstractMorphogen gradients encode positional information during development. How high patterning precision is achieved despite natural variation in both the morphogen gradients and in the readout process, is still largely elusive. Here, we show that the positional error of gradients in the mouse neural tube has previously been overestimated, and that the reported accuracy of the central progenitor domain boundaries in the mouse neural tube can be achieved with a single gradient, rather than requiring the simultaneous readout of opposing gradients. Consistently and independently, numerical simulations based on measured molecular noise levels likewise result in lower gradient variabilities than reported. Finally, we show that the patterning mechanism yields progenitor cell numbers with even greater precision than boundary positions, as gradient amplitude changes do not affect interior progenitor domain sizes. We conclude that single gradients can yield the observed developmental precision, which provides prospects for tissue engineering.
Cryo-EM structure of a SARS-CoV-2 omicron spike protein ectodomain
Authors: Ye Gang , Liu Bin , Li Fang 
Published: March 2022

AbstractThe omicron variant of SARS-CoV-2 has been spreading rapidly across the globe. The virus-surface spike protein plays a critical role in the cell entry and immune evasion of SARS-CoV-2. Here we determined the 3.0 Å cryo-EM structure of the omicron spike protein ectodomain. In contrast to the original strain of SARS-CoV-2 where the receptor-binding domain (RBD) of the spike protein takes a mixture of open (“standing up”) and closed (“lying down”) conformations, the omicron spike molecules are predominantly in the open conformation, with one upright RBD ready for receptor binding. The open conformation of the omicron spike is stabilized by enhanced inter-domain and inter-subunit packing, which involves new mutations in the omicron strain. Moreover, the omicron spike has undergone extensive mutations in RBD regions where known neutralizing antibodies target, allowing the omicron variant to escape immune surveillance aimed at the original viral strain. The stable open conformation of the omicron spike sheds light on the cell entry and immune evasion mechanisms of the omicron variant.
Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations
Authors: Yehia Lamis , Ni Ying , Sadler Tammy , Frazier Thomas W. , Eng Charis 
Published: March 2022

AbstractPTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, has been associated with organ-specific cancers and autism spectrum disorder (ASD) and/or developmental delay (DD). Predicting precise clinical phenotypes in any one PHTS individual remains impossible. We conducted an untargeted metabolomics study on an age- and sex-matched series of PHTS individuals with ASD/DD, cancer, or both phenotypes. Using agnostic metabolomic-analyses from patient-derived lymphoblastoid cells and their spent media, we found 52 differentially abundant individual metabolites, 69 cell/media metabolite ratios, and 327 pair-wise metabotype (shared metabolic phenotype) ratios clearly distinguishing PHTS individuals based on phenotype. Network analysis based on significant metabolites pointed to hubs converging on PTEN-related insulin, MAPK, AMPK, and mTOR signaling cascades. Internal cross-validation of significant metabolites showed optimal overall accuracy in distinguishing PHTS individuals with ASD/DD versus those with cancer. Such metabolomic markers may enable more accurate risk predictions and prevention in individual PHTS patients at highest risk.
Green flexible electronics based on starch
Authors: Xiang Huacui , Li Zhijian , Liu Hanbin , Chen Tao , Zhou Hongwei , Huang Wei 
Published: March 2022

AbstractFlexible electronics (FEs) with excellent flexibility or foldability may find widespread applications in the wearable devices, artificial intelligence (AI), Internet of Things (IoT), and other areas. However, the widely utilization may also bring the concerning for the fast accumulation of electronic waste. Green FEs with good degradability might supply a way to overcome this problem. Starch, as one of the most abundant natural polymers, has been exhibiting great potentials in the development of environmental-friendly FEs due to its inexpensiveness, good processability, and biodegradability. Lots of remarks were made this field but no summary was found. In this review, we discussed the preparation and applications of starch-based FEs, highlighting the role played by the starch in such FEs and the impacts on the properties. Finally, the challenge was discussed and the outlook for the further development was also presented.
Haemagglutinin antigen selectively targeted to chicken CD83 overcomes interference from maternally derived antibodies in chickens
Authors: Shrestha Angita , Meeuws Rick , Sadeyen Jean-Remy , Chang Pengxiang , Van Hulten Marielle , Iqbal Munir 
Published: March 2022

AbstractMaternally derived antibodies (MDAs) are important for protecting chickens against pathogens in the neonatal stage however, they often interfere with vaccine performance. Here, we investigated the effects of MDAs on a targeted antigen delivery vaccine (TADV), which is developed by conjugating H9 subtype avian influenza virus haemagglutinin (HA) antigen to single chain fragment variable (scFv) antibodies specific for the chicken antigen presenting cell receptor CD83. Groups of 1-day-old chickens carrying high levels of MDAs (MDA++) and 14-day old chickens carrying medium levels of MDAs (MDA+) were immunised with TADV (rH9HA-CD83 scFv), untargeted rH9HA or inactivated H9N2 vaccines. Immunogenicity in these vaccinated chickens was compared using haemagglutination inhibition (HI) and enzyme-linked immunosorbent assays (ELISA). The results showed that the TADV (rH9HA-CD83 scFv) induced significantly higher levels of H9HA-specific antibody titres compared to the untargeted rH9HA and inactivated H9N2 vaccines in MDA++ and MDA+ chickens. Overall, the data demonstrates immune responses induced by TADV are not affected by the MDA in chickens.
Antibody evasion properties of SARS-CoV-2 Omicron sublineages
Authors: Iketani Sho , Liu Lihong , Guo Yicheng , Liu Liyuan , Chan Jasper F.-W. , Huang Yiming , Wang Maple , Luo Yang , Yu Jian , Chu Hin , Chik Kenn K.-H. , Yuen Terrence T.-T. , Yin Michael T. , Sobieszczyk Magdalena E. , Huang Yaoxing , Yuen Kwok-Yung , Wang Harris H. , Sheng Zizhang , Ho David D. 
Published: March 2022

AbstractThe identification of the Omicron (B.1.1.529.1 or BA.1) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Botswana in November 20211 immediately caused concern owing to the number of alterations in the spike glycoprotein that could lead to antibody evasion. We2 and others3–6 recently reported results confirming such a concern. Continuing surveillance of the evolution of Omicron has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K alteration (BA.1+R346K, also known as BA.1.1) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike alterations and lacking 13 spike alterations found in BA.1. Here we extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.1 (refs. 2,3,5,6). These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab)7, which had retained appreciable activity against BA.1 and BA.1+R346K (refs. 2–4,6). This finding shows that no authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant, except for the recently authorized LY-CoV1404 (bebtelovimab).
Designing sensitive viral diagnostics with machine learning
Authors: Metsky Hayden C. , Welch Nicole L. , Pillai Priya P. , Haradhvala Nicholas J. , Rumker Laurie , Mantena Sreekar , Zhang Yibin B. , Yang David K. , Ackerman Cheri M. , Weller Juliane , Blainey Paul C. , Myhrvold Cameron , Mitzenmacher Michael , Sabeti Pardis C. 
Published: March 2022

AbstractDesign of nucleic acid-based viral diagnostics typically follows heuristic rules and, to contend with viral variation, focuses on a genome’s conserved regions. A design process could, instead, directly optimize diagnostic effectiveness using a learned model of sensitivity for targets and their variants. Toward that goal, we screen 19,209 diagnostic–target pairs, concentrated on CRISPR-based diagnostics, and train a deep neural network to accurately predict diagnostic readout. We join this model with combinatorial optimization to maximize sensitivity over the full spectrum of a virus’s genomic variation. We introduce Activity-informed Design with All-inclusive Patrolling of Targets (ADAPT), a system for automated design, and use it to design diagnostics for 1,933 vertebrate-infecting viral species within 2 hours for most species and within 24 hours for all but three. We experimentally show that ADAPT’s designs are sensitive and specific to the lineage level and permit lower limits of detection, across a virus’s variation, than the outputs of standard design techniques. Our strategy could facilitate a proactive resource of assays for detecting pathogens.
Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells
Authors: Balboa Diego , Barsby Tom , Lithovius Väinö , Saarimäki-Vire Jonna , Omar-Hmeadi Muhmmad , Dyachok Oleg , Montaser Hossam , Lund Per-Eric , Yang Mingyu , Ibrahim Hazem , Näätänen Anna , Chandra Vikash , Vihinen Helena , Jokitalo Eija , Kvist Jouni , Ustinov Jarkko , Nieminen Anni I. , Kuuluvainen Emilia , Hietakangas Ville , Katajisto Pekka , Lau Joey , Carlsson Per-Ola , Barg Sebastian , Tengholm Anders , Otonkoski Timo 
Published: March 2022

AbstractTransplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.
Transcriptional kinetics and molecular functions of long noncoding RNAs
Authors: Johnsson Per , Ziegenhain Christoph , Hartmanis Leonard , Hendriks Gert-Jan , Hagemann-Jensen Michael , Reinius Björn , Sandberg Rickard 
Published: March 2022

AbstractAn increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene’s transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.
Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial
Authors: Chu Laurence , Vrbicky Keith , Montefiori David , Huang Wenmei , Nestorova Biliana , Chang Ying , Carfi Andrea , Edwards Darin K. , Oestreicher Judy , Legault Holly , Dutko Frank J. , Girard Bethany , Pajon Rolando , Miller Jacqueline M. , Das Rituparna , Leav Brett , McPhee Roderick 
Published: March 2022

AbstractRising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6–8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 (NCT04405076). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2.
Modeling energy depletion in rat livers using Nash equilibrium metabolic pathway analysis
Authors: Lucia Angelo , Ferrarese Emily , Uygun Korkut 
Published: March 2022

AbstractThe current gold standard of Static Cold Storage (SCS), which is static cold storage on ice (about + 4 °C) in a specialized media such as the University of Wisconsin solution (UW), limits storage to few hours for vascular and metabolically active tissues such as the liver and the heart. The liver is arguably the pinnacle of metabolism in human body and therefore metabolic pathway analysis immediately becomes very relevant. In this article, a Nash Equilibrium (NE) approach, which is a first principles approach, is used to model and simulate the static cold storage and warm ischemia of a proposed model of liver cells. Simulations of energy depletion in the liver in static cold storage measured by ATP content and energy charge are presented along with comparisons to experimental data. In addition, conversion of Nash Equilibrium iterations to time are described along with an uncertainty analysis for the parameters in the model. Results in this work show that the Nash Equilibrium approach provides a good match to experimental data for energy depletion and that the uncertainty in model parameters is very small with percent variances less than 0.1%.