bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physical behaviours and their association with type 2 diabetes risk in urban South African middle-aged adults: An isotemporal substitution approach
Authors: Kufe Clement N. , Goedecke Julia H. , Masemola Maphoko , Chikowore Tinashe , Soboyisi Melikhaya , Smith Antonia , Westgate Kate , Brage Soren , Micklesfield Lisa K. 
Published: February 2022

AbstractIntroductionTo examine the associations between physical behaviours and type 2 diabetes mellitus (T2DM) risk in middle-aged South African men and women.Research design and methodsThis cross-sectional study included middle-aged men (n=403; age: median [IQR], 53.0 [47.8–58.8] years) and women (n=324; 53.4 [49.1–58.1] years) from Soweto, South Africa. Total movement volume (average movement in milli-g) and time (minutes/day) spent in different physical behaviours, including awake sitting/lying, standing, light intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA), were determined by combining the signals from two triaxial accelerometers worn simultaneously on the hip and thigh. All participants completed an oral glucose tolerance test, from which indicators of diabetes risk were derived. Associations between physical behaviours and T2DM risk were adjusted for sociodemographic factors and body composition.ResultsTotal movement volume was inversely associated with measures of fasting and 2-h glucose and directly associated with insulin sensitivity, basal insulin clearance, beta-cell function, but these associations were not independent of fat mass, except for basal insulin clearance in women. In men, replacing 30 minutes of sitting/lying, standing or LPA with the same amount of MVPA time was associated with 1.2–1.4 mmol/L lower fasting glucose and 12.3–13.4 mgl2/mUmin higher insulin sensitivity. In women, substituting sitting/lying with the same amount of standing time or LPA was associated with 0.5–0.8 mmol/L lower fasting glucose. Substituting 30 minutes sitting/lying with the same amount of standing time was also associated with 3.2 mgl2/mUmin higher insulin sensitivity, and substituting 30 minutes of sitting/lying, standing or LPA with the same amount of MVPA time was associated with 0.25-0.29 ng/mIU higher basal insulin clearance in women.ConclusionMVPA is important in reducing T2DM risk in men and women but LPA appears to be important in women only. Recommendations for PA may differ by sex.
Where is Omicron? Comparison of SARS-CoV-2 RT-PCR and Antigen Test Sensitivity at Commonly Sampled Anatomic Sites Over the Course of Disease
Authors: Lin Jessica , Frediani Jennifer K , Damhorst Gregory L , Sullivan Julie A , Westbrook Adrianna , McLendon Kaleb , Baugh Tyler J , O’Sick William H , Roback John D , Piantadosi Anne L , Waggoner Jesse J , Bassit Leda , Rao Anuradha , Greenleaf Morgan , O’Neal Jared W , Swanson Seegar , Pollock Nira R , Martin Greg S , Lam Wilbur A , Levy Joshua M 
Published: February 2022

BackgroundUpper respiratory samples for SARS-CoV-2 detection include the gold standard nasopharyngeal (NP) swab, and mid-turbinate (MT) nasal swabs, oropharyngeal (OP) swabs, and saliva. Following the emergence of the omicron (B.1.1.529) variant, limited preliminary data suggest that OP swabs or saliva samples may be more sensitive than nasal swabs, highlighting the need to understand differences in viral load across different sites.MethodsMT, OP, and saliva samples were collected from symptomatic individuals presenting for evaluation in Atlanta, GA, in January 2022. Longitudinal samples were collected from a family cohort following COVID-19 exposure to describe detection of viral targets over the course of infection.ResultsSARS-CoV-2 RNA and nucleocapsid antigen measurements demonstrated a nares-predominant phenotype in a familial cohort. A consistent dominant location for SARS-CoV-2 was not found among 54 individuals. Positive percent agreement for virus detection in MT, OP and saliva specimens were 66.7 [54.1–79.2], 82.2 [71.1–93.4], and 72.5 [60.3–84.8] by RT-PCR, respectively, and 46.2 [32.6–59.7], 51.2 [36.2–66.1], and 72.0 [59.6–84.4] by ultrasensitive antigen assay. The composite of positive MT or OP assay was not significantly different than either alone for both RT-PCR and antigen assay (PPA 86.7 [76.7–96.6] and 59.5 [44.7–74.4], respectively).ConclusionsOur data suggest that SARS-CoV-2 nucleocapsid and RNA exhibited similar kinetics and diagnostic yield in three upper respiratory sample types across the duration of symptomatic disease. Collection of OP or combined nasal and OP samples does not appear to increase sensitivity versus validated nasal sampling for rapid detection of viral antigen.
Early tetrapod diversification under neutral theory
Authors: Dunne Emma M. , Thompson Samuel E. D. , Butler Richard J. , Rosindell James , Close Roger A. 
Published: February 2022

AbstractEstimates of deep-time biodiversity typically rely on statistical methods to mitigate the impacts of sampling biases in the fossil record. However, these methods are limited by the spatial and temporal scale of the underlying data. Here we use a spatially explicit mechanistic model, based on neutral theory, to test hypotheses of early tetrapod diversity change during the late Carboniferous and early Permian, critical intervals for the diversification of vertebrate life on land. Our neutral simulations suggest, in contrast to previous studies, that increases in early tetrapod diversity were not driven by local endemism following the ‘Carboniferous Rainforest Collapse’. We show that apparent changes in face-value diversity can instead be explained by variation in sampling intensity through time. Our results further demonstrate the importance of accounting for sampling biases in analyses of the fossil record and demonstrate the vast potential of mechanistic models, including neutral models, for testing hypotheses in palaeobiology.
Integrating region- and network-level contributions to episodic recollection using multilevel structural equation modeling
Authors: Kurkela Kyle A. , Cooper Rose A. , Ryu Ehri , Ritchey Maureen 
Published: February 2022

AbstractThe brain is composed of networks of interacting brain regions that support higher order cognition. For instance, a posterior medial (PM) network appears to support recollection and other forms of episodic construction. Past research has focused largely on the roles of individual brain regions in recollection or on their mutual engagement as part of an integrated network. Yet the relationship between these region- and network-level contributions remains poorly understood. Here we applied multilevel structural equation modeling (SEM) to examine the functional organization of the PM network and its relationship to episodic memory outcomes. We evaluated two aspects of functional heterogeneity in the PM network: first, the organization of individual regions into subnetworks, and second, the presence of regionally-specific contributions while accounting for network-level effects. The results suggest that the PM network is composed of ventral and dorsal subnetworks, with the ventral subnetwork making a unique contribution to recollection, and that memory-related activity in individual regions is well accounted for by these network-level effects. These findings highlight the importance of considering both region and network levels of analysis when studying brain-behavior relationships.
Not all noise-reduction methods for fMRI preprocessing are created equal
Authors: Hoeppli M.E. , Garenfeld M.A. , Mortensen C.K. , Nahman-Averbuch H. , King C.D. , Coghill R.C. 
Published: February 2022

AbstractPreprocessing fMRI data requires striking a fine balance between conserving signals of interest and removing noise. Typical steps of preprocessing include motion correction, slice timing correction, spatial smoothing, and high-pass filtering. However, these standard steps do not remove many sources of noise. Thus, noise-reduction techniques such as CompCor and FIX have been developed to further improve the ability to draw meaningful conclusions from the data. The ability of these techniques to minimize noise while conserving signals of interest has been tested almost exclusively in resting-state fMRI datasets and, only rarely, in task-related fMRI datasets. Application of noise-reduction techniques to task-related fMRI is particularly important given that such procedures have been shown to reduce false positive rates. However, little remains known about the impact of different noise reduction techniques on the retention of signal, particularly during tasks that may be associated with systemic physiological changes. In this paper, we compared two noise-reduction techniques, i.e. FIX and CompCor, in an fMRI dataset including noxious heat stimulation and non-noxious auditory stimulation.Results show that preprocessing including FIX noise-reduction technique conserves significantly more signal than a preprocessing protocol including CompCor noise-reduction technique in both noxious heat and non-noxious auditory stimulations, while removing only slightly less noise. These results suggest that FIX might be the most appropriate technique to achieve the balance between conserving signals of interest and removing noise.
An explainable unsupervised framework for alignment-free protein classification using sequence embeddings
Authors: Yeung Wayland , Zhou Zhongliang , Mathew Liju , Gravel Nathan , Taujale Rahil , Venkat Aarya , Lanzilotta William , Li Sheng , Kannan Natarajan 
Published: February 2022

ABSTRACTProtein classification is a cornerstone of biology that relies heavily on alignment-based comparison of primary sequences. However, the systematic classification of large protein superfamilies is impeded by unique challenges in aligning divergent sequence datasets. We developed an alignment-free approach for sequence analysis and classification using embedding vectors generated from pre-trained protein language models that capture underlying protein structural-functional properties from unsupervised training on millions of biologically-observed sequences. We constructed embedding-based trees (with branch support) which depict hierarchical clustering of protein sequences and infer fast/slow evolving sites through interpretable sequence projections. Applied towards diverse protein superfamilies, embedding tree infers Casein Kinase 1 (CK1) as the basal protein kinase clade, identifies convergent functional motifs shared between divergent phosphatase folds, and infers evolutionary relationships between diverse radical S-Adenosyl-L-Methionine (SAM) enzyme families. Overall results indicate that embedding trees effectively capture global data structures, functioning as a general unsupervised approach for visualizing high-dimensional manifolds.
Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal – medial prefrontal cortex circuit during natural sleep in AppNL-G-Fmice
Authors: Brady Erica S , Griffiths Jessica , Andrianova Lilya , Saito Takashi , Saido Takaomi C , Randall Andrew D , Tamagnini Francesco , Witton Jonathan , Craig Michael T 
Published: February 2022

AbstractIn the early stages of Alzheimer’s disease (AD), the accumulation of the peptide amyloid-β (Aβ) damages synapses and disrupts neuronal activity and leads to disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-Fmouse model used in the present study. These mice appear to model the early stages of Aβ-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-Fmice, we analysed neuronal oscillations found in the hippocampal – medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the amplitude of mPFC spindles and decrease in the power of hippocampal SWRs was identified. The former was associated with a decrease in the density of mPFC PV-expressing interneurons and the latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+imaging. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.
Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation
Authors: Dufour Damien , Dumontet Typhanie , Sahut-Barnola Isabelle , Onzon Meline , Pussard Eric , Wilmouth James , Olabe Julie , Lucas Cecily , Levasseur Adrien , Soubeyrand-Damon Christelle , Pointud Jean-Christophe , Roucher-Boulez Florence , Tauveron Igor , Bossis Guillaume , Yeh Edward T. , Breault David T. , Val Pierre , Lefrançois-Martinez Anne-Marie , Martinez Antoine 
Published: February 2022

AbstractSUMOylation is a dynamic posttranslational modification, that provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, an emblematic endocrine organ that mediates adaptation to physiological demands, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress. Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by ACTH/PKA signalling within the zona Fasciculata (zF), we generated mice with adrenal-specific Senp2 loss to address these questions. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zF, a blunted reponses to ACTH and isolated glucocorticoid deficiency. Mechanistically, overSUMOylation resulting from SENP2 loss shifts the balance between ACTH/PKA and WNT/β-catenin signalling leading to repression of PKA activity and ectopic activation of β-catenin. At the cellular level, this blocks transdifferentiation of β-catenin-positive zona Glomerulosa cells into zF cells and sensitises them to premature apoptosis. Our findings indicate that the SUMO pathway is critical for adrenal homeostasis and stress responsiveness.
PDR6-mediated camalexin efflux and disease resistance are regulated through direct phosphorylation by the kinases OXI1 and AGC2-2
Authors: Miao Guopeng , Han Juan , Liu Chang-xin , Liu Jian , Wang Cheng-run , Wang Shun-chang 
Published: February 2022

AbstractPlant immune signaling largely relies on post-translational modifications to establish a rapid and appropriate defense response to different pathogen types and infection pressure. Specific pleiotropic drug resistance (PDR) transporters can transport secondary metabolites to contribute to pathogen invasion resistance. However, the establishment of the post-translational regulation of PDR transporters that efflux secondary metabolites is unclear. In this study, by detecting the camalexin contents on the leaf surfaces of mutants and overexpression lines, two AGC kinases, namely, OXI1 and its closest homologue AGC2-2, were found to be related to extracellular camalexin secretion. The overexpression of OXI1 or AGC2-2 resulted in an increase in camalexin contents on the leaf surface and a decrease in camalexin contents in the leaf interior. These effects increased the resistance of the transgenic lines to surface-inoculated Pseudomonas syringae and Botrytis cinerea. Through in vitro kinase assay and in vivo phosphorylation level detection, we confirmed that the two kinases were related to the phosphorylation modification of PDR6. Pull-down assays, bimolecular fluorescence complementation, and rapamycin-dependent delocalization assays indicated the existence of direct protein–protein interaction between the two kinases and PDR6. By using LC–MS/MS, we also identified the PDR6 phosphorylation sites that were modified by the two kinases in vitro. Through the expression of the dephosphorylated variants of PDR6 in the mutant background, the action site S31 of OXI1 and the action sites S33 and S827 of AGC2-2 were found to have positive effects on the efflux activity of PDR6. In addition, T832, the action site of OXI1, may contribute to the stability of PDR6 on the plasma membrane.
The Requirement of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in Mouse Ovarian Development and Fertility
Authors: Woodman Morgan F. , Ozcan Meghan C.H. , Gura Megan A. , De La Cruz Payton , Gadson Alexis K. , Grive Kathryn J. 
Published: February 2022

ABSTRACTUbiquitin C-Terminal Hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme enriched in neuronal and gonadal tissues known to regulate the cellular stores of mono-ubiquitin and protein turnover. While its function in maintaining proper motor neuron function is well-established, investigation into its role in the health and function of reproductive processes is only just beginning to be studied. Single-cell-sequencing analysis of all ovarian cells from the murine perinatal period revealed that Uchl1 is very highly expressed in the developing oocyte population, an observation which was corroborated by high levels of oocyte-enriched UCHL1 protein expression in oocytes of all stages throughout the mouse reproductive lifespan. To better understand the role UCHL1 may be playing in oocytes, we utilized a UCHL1-deficient mouse line, finding reduced number of litters, reduced litter sizes, altered folliculogenesis, morphologically abnormal oocytes, disrupted estrous cyclicity and apparent endocrine dysfunction in these animals compared to their wild-type and heterozygous littermates. These data reveal a novel role of UCHL1 in female fertility as well as overall ovarian function, and suggest a potentially essential role for the ubiquitin proteasome pathway in mediating reproductive health.Summary sentenceUbiquitin C-Terminal Hydrolase L1 (UCHL1) is required for proper ovarian folliculogenesis, estrous cyclicity, and fertility in the female mouse.
Fused in sarcoma undergoes cold denaturation: Implications on phase separation
Authors: Félix Sara S. , Laurents Douglas V. , Oroz Javier , Cabrita Eurico J. 
Published: February 2022

AbstractThe mediation of fused in sarcoma (FUS) protein liquid-liquid phase separation (LLPS) is generally attributed to the low-complexity and disordered domains, while the role of its folded domains remains unknown. In this work we questioned the role of the folded domains on the full-length (FL) FUS LLPS and studied the influence of several metabolites, ions and overall conditions on the LLPS process using turbidity assays, differential interference contrast microscopy and nuclear magnetic resonance spectroscopy. We demonstrate that FL FUS LLPS is highly responsive to the surrounding conditions, and that overall intrinsic disorder is crucial for LLPS. To promote such disorder, we reveal that the FUS RNA-recognition domain (RRM) and the zinc-finger motif (ZnF) undergo cold denaturation above 0ºC, at a temperature that is determined by the conformational stability of the ZnF domain. We hypothesize that, in cold shock conditions, cold denaturation might provide a pathway that exposes additional residues to promote FUS self-assembly. Such findings mark the first evidence that FUS globular domains may have an active role in stress granule formation in cold stress.
A parvocellular-magnocellular functional gradient in human visual cortex
Authors: Ibarbia-Garate Maddi , Paz-Alonso Pedro M. 
Published: February 2022

ABSTRACTThe magnocellular and parvocellular systems are major visual recognition pathways, with distinct histological and physiological properties. Despite their critical role, there is limited evidence on the specific contributions these visual pathways make to visual recognition in general and to word reading in particular. Using a multimodal functional MRI approach and individual-subject analyses, here we investigate the involvement of visual cortex regions in the recognition of magnocellular- and parvocellular-biased words and images. Our results reveal a functional gradient in the activation profile of both left and right visual cortex: posterior regions are more strongly recruited for processing parvocellular-biased, while anterior regions are more involved in processing magnocellular-biased stimuli. Furthermore, functional connectivity analyses show clustering in the strength of functional coupling among visual cortex regions as a function of the distance between regions, with greater coupling within and less coupling across posterior and anterior regions. Finally, we found minimal differences in lateralization for word and image recognition in these visual cortical regions. These results were replicated in a retest session with a subset of participants. Our findings underscore a functional division of labor in the visual cortex as a function determined by a parvocellular or magnocellular bias in properties of the stimuli and further reveal that in this context the visual cortex is not particularly biased towards words or images.
Membrane binding of pore-forming γ-hemolysin components studied at different lipid compositions
Authors: Tarenzi Thomas , Lattanzi Gianluca , Potestio Raffaello 
Published: February 2022

AbstractMethicillin-resistant Staphylococcus aureus is is among those pathogens currently posing the highest threat to public health. Its host immune evasion strategy is mediated by pore-forming toxins (PFTs), among which the bicomponent γ-hemolysin is one of the most common. The complexity of the porogenesis mechanism by γ-hemolysin poses difficulties in the development of antivirulence therapies targeting PFTs from S. aureus, and sparse and apparently contrasting experimental data have been produced. Here, through a large set of molecular dynamics simulations at different levels of resolution, we investigate the first step of pore formation, and in particular the effect of membrane composition on the ability of γ-hemolysin components, LukF and Hlg2, to steadily adhere to the lipid bilayer in the absence of proteinaceous receptors. Our simulations are in agreement with experimental data of γ-hemolysin pore formation on model membranes, which are here explained on the basis of the bilayer properties. Our computational investigation suggests a possible rationale to explain experimental data on phospholipid binding to the LukF component, and to hypothesise a mechanism by which, on purely lipidic bilayers, the stable anchoring of LukF to the cell surface facilitates Hlg2 binding, through the exposure of its N-terminal region. We expect that further insights on the mechanism of transition between soluble and membrane bound-forms and on the role played by the lipid molecules will contribute to the design of antivirulence agents with enhanced efficacy against methicillin-resistant S. aureus infections.Graphical AbstractHighlightsThe presence of cholesterol and unsaturated phospholipid tails facilitates the binding of γ-hemolysin components, LukF and Hlg2, on model membranes.Coarse-grained simulations show that the two components have different absorption capabilities, with LukF undergoing the most stable binding.The spontaneous docking of LukF on the membrane is mediated by two distant phosphatidylcholine binding sites.