bluuebunny/crossref_metadata_2025_split huggingface dataset:
Additive interaction and mediation-interaction decomposition: DNA methylation age acceleration, education, and cognitive impairment in the Health and Retirement Study
Authors: Ware Erin B. , Higgins Cesar , Harris Sean , Fisher Jonah D. , Bakulski Kelly M. 
Published: December 2022

AbstractImportanceDementia represents a significant and increasing public health burden. DNA methylation age acceleration may be associated with dementia and dementia risk factors, such as education, but investigating their impact on dementia is necessary.ObjectiveTo evaluate the association of educational attainment on dementia and cognitive impairment through DNA methylation age acceleration, while accommodating exposure-mediator interaction effects.DesignIn the 2016 Health and Retirement Study wave, we evaluated six epigenetic clocks, including GrimAge, with Langa-Weir classified dementia, cognitive impairment non-dementia, and normal cognition. Age acceleration was the residual between chronological age of participants and DNA methylation clock, dichotomized at zero. To understand the joint association of low education (≤12 years) and DNA methylation age acceleration in relation to cognitive impairment, we used weighted logistic regression and calculated interaction on the additive scale adjusting for chronological age, sex, race/ethnicity, and cell type composition. We performed four-way mediation and interaction decomposition analysis to estimate the: 1) controlled direct effect of education on cognition, 2) interaction reference, 3) interaction mediation, and 4) the pure indirect effect of DNA methylation age acceleration on cognition.SettingAnalysis was conducted on a subsample of Health and Retirement Study participants in the 2016 Venous Blood Study (N=3,724).ResultsBoth GrimAge acceleration (OR=1.6 95%CI 1.3 – 2.1) and low educational attainment (OR=2.4 95%CI 1.9 – 3.0) were associated with higher odds of cognitive impairment, non-dementia in a mutually adjusted logistic model. We found additive interaction associations between low education and GrimAge acceleration on dementia. We observed that 6-8% of the association of education on dementia was mediated through GrimAge acceleration. While mediation effects were small, the portion of the association of education due to additive interaction with GrimAge acceleration was between 23.6 and 29.2%.Conclusions and RelevanceAccelerated DNA methylation age was associated with increased odds of cognitive impairment and we observed more than additive interaction effects between education and age acceleration on dementia. These results support the interplay of social disadvantage and biological aging processes on impaired cognition.
An allelic series rare variant association test for candidate gene discovery
Authors: McCaw Zachary R , O’Dushlaine Colm , Somineni Hari , Bereket Michael , Klein Christoph , Karaletsos Theofanis , Casale Francesco Paolo , Koller Daphne , Soare Thomas W 
Published: December 2022

AbstractAllelic series are of candidate therapeutic interest due to the existence of a dose-response relationship between the functionality of a gene and the degree or severity of a phenotype. We define an allelic series as a gene in which increasingly deleterious mutations lead to increasingly large phenotypic effects, and develop a gene-based rare variant association test specifically targeted for the identification of allelic series. Building on the well-known burden and sequence kernel association (SKAT) tests, we specify a variety of association models, covering different genetic architectures, and integrate these into a COding-variant Allelic Series Test (COAST). Through extensive simulations, we confirm that COAST maintains the type I error and improves power when the pattern of coding-variant effect sizes increases monotonically with mutational severity. We applied COAST to identify allelic series for 4 circulating lipid traits and 5 cell count traits among 145,735 subjects with available whole exome sequencing data from the UK Biobank. Compared with optimal SKAT (SKAT-O), COAST identified 29% more Bonferroni significant associations with circulating lipid traits, on average, and 82% more with cell count traits. All of the gene-trait associations identified by COAST have corroborating evidence either from rare-variant associations in the full cohort (Genebass,N= 400K), or from common variant associations in the GWAS catalog. In addition to detecting many gene-trait associations present in Genebass using only a fraction (36.9%) of the sample, COAST detects associations, such asANGPTL4with triglycerides, that are absent from Genebass but which have clear common variant support.
Determinants of Motor Neuron Functional Subtypes Important for Locomotor Speed
Authors: D’Elia Kristen P. , Hameedy Hanna , Goldblatt Dena , Frazel Paul , Kriese Mercer , Zhu Yunlu , Hamling Kyla R. , Kawakami Koichi , Liddelow Shane A. , Schoppik David , Dasen Jeremy S. 
Published: December 2022

ABSTRACTLocomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally-distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes, and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily-conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss ofprdm16ormecomcauses fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.
Spatiotemporal profiling of a dominant coral’s photo-endosymbiotic assemblage indicates that acclimation is supported by phenotypic plasticity of single cells
Authors: Anthony CJ , Lock C , Taylor BM , Bentlage B 
Published: December 2022

AbstractCoral-associated dinoflagellates (Symbiodiniaceae) are photosynthetic endosymbionts that influence coral acclimation and adaptation, as indicated by photo-physiological plasticity (phenotypic variance) in response to environmental change. Symbiont shuffling (shifts in endosymbiont community composition), changes in endosymbiont cell density, and phenotypic plasticity have all been proposed as mechanisms to adjust to environmental change. However, few studies have been able to partition which of the three strategies were responsible for observed phenotypic variance. Therefore, we quantified the biodiversity, cell density, and phenotypic variance of single cells forAcropora pulchra-associated Symbiodiniaceae assemblages. Using a combination of metabarcoding and flow cytometry, we simultaneously characterized Symbiodiniaceae assemblages at the community (biodiversity), population (cell density), and individual level (phenotype) under natural environmental conditions to determine whether phenotypic variation of Symbiodiniaceae communities is concomitant with either symbiont shuffling, changes in cell density, or phenotypic plasticity. Symbiodiniaceae assemblages displayed season-specific phenotypic variance, while biodiversity was geographically structured and cell density showed limited data structure. Based on these patterns, we reveal that phenotypic plasticity of individual Symbiodiniaceae cells is the source of a phenotypic variation, thus indicating that phenotypic plasticity is a mechanism for rapid acclimation to mild environmental change.
Genomics of turions from the Greater Duckweed reveal its pathways for dormancy and reemergence strategy
Authors: Pasaribu Buntora , Acosta Kenneth , Aylward Anthony , Liang Yuanxue , Abramson Bradley W. , Colt Kelly , Nolan T. Hartwick , Shanklin John , Michael Todd P. , Lam Eric 
Published: December 2022

SummaryOver 15 families of aquatic plants are known to use a strategy of developmental switching upon environmental stress to produce dormant propagules called turions. However, few molecular details for turion biology have been elucidated due to the difficulties in isolating high-quality nucleic acids from this tissue. We successfully developed a new protocol to isolate high-quality transcripts and carried out RNA-seq analysis of mature turions from the Greater DuckweedSpirodela polyrhiza. Comparison of turion transcriptome to that of fronds, the actively growing leaf-like tissue, were carried out.Bioinformatic analysis of high confidence, differentially expressed transcripts between frond and mature turion tissues revealed major pathways related to stress tolerance, starch and lipid metabolism, and dormancy that are mobilized to reprogram frond meristems for turion differentiation.We identified the key genes that are likely to drive starch and lipid accumulation during turion formation, as well as in pathways for starch and lipid utilization upon turion germination. Comparison of genome-wide cytosine methylation levels also revealed evidence for epigenetic changes in the formation of turion tissues.Similarities between turions and seeds provided evidence that key regulators for seed maturation and germination have been retooled for their function in turion biology.
Extrapolating Heterogeneous Time-Series Gene Expression Data using Sagittarius
Authors: Woicik Addie , Zhang Mingxin , Chan Janelle , Ma Jianzhu , Wang Sheng 
Published: December 2022

AbstractUnderstanding the temporal dynamics of gene expression is crucial for developmental biology, tumor biology, and biogerontology. However, some timepoints remain challenging to measure in the lab, particularly during very early or very late stages of a biological process. Here we propose Sagittarius, a transformer-based model that can accurately simulate gene expression profiles at timepoints outside of the range of times measured in the lab. The key idea behind Sagittarius is to learn a shared reference space for time series measurements, thereby explicitly modeling unaligned timepoints and conditional batch effects between time series, and making the model widely applicable to diverse biological settings. We show Sagittarius’s promising performance when extrapolating mammalian developmental gene expression, simulating drug-induced expression at unmeasured dose and treatment times, and augmenting datasets to accurately predict drug sensitivity. We also used Sagittarius to extrapolate mutation profiles for early-stage cancer patients, which enabled us to discover a gene set connected to the Hedgehog signaling pathway that may be related to tumorigenesis in sarcoma patients, includingPTCH1,ARID2, andMYCBP2. By augmenting experimental temporal datasets with crucial but difficult-to-measure extrapolated datapoints, Sagittarius enables deeper insights into the temporal dynamics of heterogeneous transcriptomic processes and can be broadly applied to biological time series extrapolation.
Difference in determinants and changing patterns of plant community composition with and without grazing across semi-arid and arid regions in Mongolian steppe
Authors: Ishii Naohiro I. , Nishimura Issei , Qi Yulan , Batdelger Gantsetseg , Kagami Maiko , Takimoto Gaku , Sasaki Takehiro 
Published: December 2022

AbstractAridity, edaphic variables related to aridity, and livestock grazing are major drivers of plant community composition across dryland grasslands. With accounting these factors, little is known about differences in determinants and changing patterns along aridity gradients with different average of aridity. Thus, the comparative investigations of communities without and with grazing in semi-arid and arid regions are suitable to clarify the difference in compositional responses along aridity gradients between potential vegetations and degraded ones with grazing. We investigated compositional changes of communities without/with grazing in semi-arid (north) /arid (south) regions across Mongolia. The compositional changes based on Bray-Curtis dissimilarity were investigated by generalized dissimilarity modeling, including geographic distance, aridity, soil pH, and sand and clay contents as independent variables. The determinants and changing patterns of community composition were compared among the four groups. Aridity had significant impacts on community composition regardless of the regions and the absence/presence of grazing. However, without the dependency on grazing, the difference in response patterns was observed between the regions. The compositional change was steeper especially at the upper edge of aridity rather than the lower edge in the arid region. This indicates the vulnerability of plant communities to aridity shifts due to future climate change in desert steppe of Mongolia. In addition, regardless of the regions, the effects of soil pH on community composition were eliminated by grazing. Because soil pH indirectly affected by aridity shifts can have impacts on community composition of potential vegetations without grazing, the long-term monitoring of vegetation dynamics needs observations of both of communities without and with grazing.
Ca2+and cAMP open differentially dilating synaptic fusion pores
Authors: Bulgari Dinara , Cavolo Samantha L. , Schmidt Brigitte F. , Buchan Katherine , Bruchez Marcel P. , Deitcher David L. , Levitan Edwin S. 
Published: December 2022

ABSTRACTNeuronal dense-core vesicles (DCVs) contain neuropeptides and much larger proteins that affect synaptic growth and plasticity. Rather than using full collapse exocytosis that is common in endocrine cells, DCVs at a native intact synapse, theDrosophilaneuromuscular junction, release their contents via fusion pores formed by kiss and run exocytosis. Here fluorogen activating protein (FAP) imaging reveals the permeability range of synaptic DCV fusion pores and then shows that this constraint is circumvented by cAMP-induced extra fusions with dilating pores that result in DCV emptying. These Ca2+-independent full fusions require PKA-R2, a PKA phosphorylation site on the fusion clamp protein complexin and the acute presynaptic function of Rugose/Neurobeachin, a PKA-R2 anchor implicated in learning and autism. Therefore, localized Ca2+-independent cAMP signaling opens dilating fusion pores to release large cargo proteins that cannot pass through the narrower fusion pores that normally dominate spontaneous and Ca2+-evoked synaptic protein release. Hence, two independent exocytosis triggers (Ca2+and cAMP) vary the composition of released proteins at the synapse by differentially adjusting DCV fusion pores.
An apicomplexan bromodomain, TgBDP1 associates with diverse epigenetic factors to regulate essential transcriptional processes inToxoplasma gondii
Authors: Fleck Krista , McNutt Seth , Chu Feixia , Jeffers Victoria 
Published: December 2022

AbstractThe protozoan pathogenToxoplasma gondiirelies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms ofToxoplasmaand related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation forToxoplasmain both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the chromatin pathway that influences transcriptional regulation in response to the modification is unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein TgBDP1 which is conserved amongst Apicomplexa and within the Alveolata superphylum, is essential forToxoplasmaasexual proliferation. Using CUT&TAG we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodelling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in theToxoplasmatachyzoite.SummaryHistone acetylation is critical for proper regulation of gene expression in the single celled eukaryotic pathogenToxoplasma gondii. Bromodomain proteins are “readers” of histone acetylation and may link the modified chromatin to transcription factors. Here, we show that the bromodomain protein TgBDP1 is essential for parasite survival and that loss of TgBDP1 results in global dysregulation of gene expression. TgBDP1 is recruited to the promoter region of a large proportion of parasite genes, forms a core complex with two other bromodomain proteins and interacts with different transcriptional regulatory complexes. We conclude that TgBDP1 is a key factor for sensing specific histone modifications to influence multiple facets of transcriptional regulation inToxoplasma gondii.
Folic acid-loaded chitosan nanoparticles: Cytotoxicity, acute and sub-acute oral toxicity and bioavailability in Wistar rats
Authors: Fathima Eram , Kumar Shashank , Patil M M , Khanum Farhath , Anand T 
Published: December 2022

AbstractThe study aims to develop folic acid-loaded chitosan nanoparticles (FA-Chi-NPs) as the vitamin is sensitive to heat and light and to investigate the safety of FA-Chi-NPsin vitroandin vivo. The prepared formulation showed an average diameter of 191.7 ± 2 nm with a zeta potential of + 52 ± 4 mV and PDI of 0.195 ± 0.03. The encapsulation efficiency was found to be 80%.In vitrocytotoxicity assays revealed that FA-Chi-NPs had no cytotoxic effect on Caco-2 cells. Acute-toxicity and subacute-toxicity of FA-Chi-NPs (0.4, 2, and 4 mg/kg body weight) revealed no mortality, and no gross morphological abnormalities were noticed. There were no dose-dependent toxic effects of free folic acid (FA) and FA-Chi-NPs in haematological, histological, plasma biochemical indices, oxidative stress enzymes, or other parameters when compared to the control group(s). The plasma and tissue levels of FA from FA-Chi-NPs were significantly higher. Results demonstrated enhanced bioavailability of FA from FA-Chi-NPs with no toxicity.Practical applicationsIn the current study, nanoencapsulation is used as a potential approach to enhance folic acid bioavailability. The results showed that encapsulating folic acid in chitosan improved bioavailability with no apparent adverse effects, and thus chitosan could be a promising polymer for safe folic acid delivery.
Blood meals from ‘dead-end’ vertebrate hosts enhance transmission potential of malaria-infected mosquitoes
Authors: Pathak Ashutosh K. , Shiau Justine C. , de Freitas Cury Rafael Sadock , Kyle Dennis E. 
Published: December 2022

ABSTRACTIngestion of an additional blood meal(s) by mosquitoes can accelerate parasite migration to the salivary glands in infected mosquitoes. Most studies, however, offer blood from the same vertebrate host species as the original challenge (for e.g., human for primary and additional blood meals). Here, we show a second blood meal from bovine and canine hosts can also enhance sporozoite migration inAnopheles stephensimosquitoes infected with the human- and rodent-restrictedPlasmodium falciparumandP. bergheirespectively. The extrinsic incubation period (time to sporozoite appearance in salivary glands) showed more consistent reductions with blood from human and bovine donors than canine blood, although the latter’s effect may be confounded by the toxicity, albeit non-specific, associated with the anticoagulant used to collect whole blood from donors. The complex patterns of enhancement highlight the limitations of a laboratory system but are nonetheless reminiscent of parasite host-specificity and mosquito adaptations, and the genetic predisposition ofAn. stephensifor bovine blood. We suggest that in natural settings, a blood meal from any vertebrate host could accentuate the risk of human infections byP. falciparum, although our observations should also be applicable to other species ofPlasmodiumand indeed other vector-borne diseases such as arboviruses for instance.Graphical AbstractHIGHLIGHTSPlasmodium falciparumandP. bergheicause malaria in humans and rodents, respectively.They are vectored byAnophelesspecies that can also imbibe blood from other vertebrate species.Parasite development is enhanced after another blood meal, usually from the same host (e.g., human).Here, bovine, and canine blood also enhanced development ofPlasmodiumspecies inAn. stephensi.In natural settings, blood from any host could enhance development of vector transmitted parasites.
Targeting riboswitches with beta-axial substituted cobalamins
Authors: Lennon Shelby R. , Wierzba Aleksandra J. , Siwik Shea H. , Gryko Dorota , Palmer Amy E. , Batey Robert T. 
Published: December 2022

AbstractRNA-targeting small molecule therapeutics an emerging field hindered by an incomplete understanding of the basic principles governing RNA-ligand interactions. One way to advance our knowledge in this area is to study model systems where these interactions are better understood, such as riboswitches. Riboswitches bind a wide array of small molecules with high affinity and selectivity, providing a wealth of information on how RNA recognizes ligands through diverse structures. The cobalamin-sensing riboswitch is a particularly useful model system as similar sequences show highly specialized binding preferences for different biological forms of cobalamin. This riboswitch is also widely dispersed across bacteria and therefore holds strong potential as an antibiotic target. Many synthetic cobalamin forms have been developed for various purposes including therapeutics, but their interaction with cobalamin riboswitches is yet to be explored. In this study, we characterize the interactions of eleven cobalamin derivatives with three representative cobalamin riboswitches usingin vitrobinding experiments (both chemical footprinting and a fluorescence-based assay) and a cell-based reporter assay. The derivatives show productive interactions with two of the three riboswitches, demonstrating simultaneously plasticity and selectivity within these RNAs. The observed plasticity is partially achieved through a novel structural rearrangement within the ligand binding pocket, providing insight into how similar RNA structures can be targeted in the future. As the derivatives also showin vivofunctionality, they serve as several potential lead compounds for further drug development.
PROSTATA: Protein Stability Assessment using Transformers
Authors: Umerenkov Dmitriy , Shashkova Tatiana I. , Strashnov Pavel V. , Nikolaev Fedor , Sindeeva Maria , Ivanisenko Nikita V. , Kardymon Olga L. 
Published: December 2022

AbstractAccurate prediction of change in protein stability due to point mutations is an attractive goal that remains unachieved. Despite the high interest in this area, little consideration has been given to the transformer architecture, which is dominant in many fields of machine learning. In this work, we introduce PROSTATA, a predictive model built in knowledge transfer fashion on a new curated dataset. PROSTATA demonstrates superiority over existing solutions based on neural networks. We show that the large margin of improvement is due to both the architecture of the model and the quality of the new training data set. This work opens up opportunities for developing new lightweight and accurate models for protein stability assessment. PROSTATA is available athttps://github.com/AIRI-Institute/PROSTATA.