Miracle-dz/UniFAR-FTUs huggingface dataset:
Measuring thermodynamic preferences to form non-native conformations in nucleic acids using melting experiments reveals a rich sequence-specific DNA conformational landscape

Thermodynamic preferences to form non-native conformations are crucial for understanding how nucleic acids fold and function. However, they are difficult to measure experimentally because this requires accurately determining the population of minor low-abundance (<10%) conformations in a sea of other conformations. Here we show that melting experiments enable facile measurements of thermodynamic preferences to adopt non-native conformations in DNA and RNA. The key to this ‘delta-melt’ approach is to use chemical modifications to render specific minor non-native conformations the major state. The validity and robustness of delta-melt is established for four different non-native conformations under various physiological conditions and sequence contexts through independent measurements of thermodynamic preferences using NMR. delta-melt is fast, simple, cost-effective, and enables thermodynamic preferences to be measured for exceptionally low-populated conformations. Using delta-melt, we obtained rare insights into conformational cooperativity, obtaining evidence for significant cooperativity (1.0-2.5 kcal/mol) when simultaneously forming two adjacent Hoogsteen base pairs. We also measured the thermodynamic preferences to form G-C+ and A-T Hoogsteen and A-T base open states for nearly all sixteen trinucleotide sequence contexts and found distinct sequence-specific variations on the order of 2-3 kcal/mol. This rich landscape of sequence-specific non-native minor conformations in the DNA double helix may help shape the sequence-specificity of DNA biochemistry. Thus, melting experiments can now be used to access thermodynamic information regarding regions of the free energy landscape of biomolecules beyond the native folded and unfolded conformations. Significance Statement Thermodynamic preferences of nucleic acids to adopt non-native conformations are crucial for understanding how they function but prove difficult to measure experimentally. As a result, little is known about how these thermodynamic preferences vary with sequence and structural contexts, physiological conditions, and chemical modifications. Here, we show that modifications stabilizing non-native conformations and rendering them the major state, in conjunction with melting experiments, enable facile measurements of thermodynamic preferences to form various non-native conformations in DNA and RNA. delta-melt provided rare insights into the cooperativity of forming tandem Hoogsteen base pairs and revealed large and distinct sequence-specific preferences to form G-C+ and A-T Hoogsteen and A-T base open conformations in DNA, which may contribute to sequence-specific DNA biochemistry.
Understanding Determinants of Hunting Trip Productivity in an Arctic Community

We examine factors underlying hunting productivity among Inuit in Ulukhaktok, Northwest Territories, Canada. Specifically, we focus on the role of gasoline use as the main variable of interest—commonly cited as a crucial determinant of hunting participation. Over the course of 12 months, 10 hunters recorded their on-the-land activities using a GPS tracking system, participatory mapping sessions, and bi-weekly interviews. A multivariable linear regression model (MvLRM) was applied to assess whether factors such as consumables used (i.e. heating fuel, gasoline, oil, food), distances traveled, or the number of companions on a trip were associated with the mass of edible foods returned to the community. Results indicate that, despite being positively associated with hunting trip productivity when assessed through a univariable linear regression model, gasoline is not a statistically significant determinant of standalone trip yield when adjusting for other variables in a multivariable linear regression. Instead, factors relating to seasonality, number of companions, and days on the land emerged as more significant and substantive drivers of productivity while out on the land. The findings do not suggest that access to, or the availability of, gasoline does not affect whether a hunting trip commences or is planned, nor that an increase in the amount of gasoline available to a hunter might increase the frequency of trips (and therefore annual productivity). Rather, this work demonstrates that the volume of gasoline used by harvesters on standalone hunting trips represent a poor a priori predictor of the edible weight that harvesters are likely to return to the community.
Validation and Prediction of the School Psychological Capital Among Chinese College Students

This study validated the school psychological capital (PsyCap) scale in the Chinese context and examined the predictive effect of PsyCap resources on academic engagement and achievement emotions. Self-report data for PsyCap resources, student engagement, enjoyment, anxiety, and boredom toward English learning were collected from 1,000 sophomores. Item-level analyses and confirmatory factor analysis were used to verify the validity of the school PsyCap scale, and structural equation modeling was applied to reveal the predictive effect of school PsyCap resources on academic engagement and achievement emotions. Results showed that the school PsyCap scale retained superior psychometric properties. Besides, PsyCap resources were demonstrated to have a positive relationship to academic engagement and enjoyment, and a negative relationship to anxiety and boredom. The effectiveness of the school PsyCap scale was verified among Chinese college students, and besides the traditional predictors, school PsyCap is also critically important for students’ academic engagement and achievement emotions. Limitations and implications are discussed.
Auto-Antibody Production During Experimental Atherosclerosis in ApoE-/- Mice

Current models stipulate that B cells and antibodies function during atherosclerosis in two distinct ways based on antibody isotype, where IgM is protective and IgG is inflammatory. To examine this model, we generated ApoE-/- Aid-/- mice, which are unable to produce IgG antibodies due to the absence of activation-induced deaminase (AID) but maintain high plasma cholesterol due to the absence of apolipoprotein E (APOE). We saw a dramatic decrease in plaque formation in ApoE-/- Aid-/- mice compared to ApoE-/- mice. Rigorous analysis of serum antibodies revealed both ApoE-/- and ApoE-/- Aid-/- mice had substantially elevated titers of IgM antibodies compared to C57BL/6J controls, suggesting a more complex dynamic than previously described. Analysis of antigen specificity demonstrated that ApoE-/- Aid-/- mice had elevated titers of antibodies specific to malondialdehyde-oxidized low density lipoprotein (MDA-oxLDL), which has been shown to block macrophage recruitment into plaques. Conversely, ApoE-/- mice showed low levels of MDA-oxLDL specificity, but had antibodies specific to numerous self-proteins. We provide evidence for a hierarchical order of antibody specificity, where elevated levels of MDA-oxLDL specific IgM antibodies inhibit plaque formation. If the level of MDA-oxLDL specific IgM is insufficient, self-reactive IgM and IgG antibodies are generated against debris within the arterial plaque, resulting in increased inflammation and further plaque expansion.
The Distributional Characteristics of Multiple Sclerosis Lesions on Quantitative Susceptibility Mapping and Their Correlation With Clinical Severity

Background: Multiple sclerosis (MS) patients have a wide spectrum of severity and responses to therapy; the personalization of treatment relies on sensitive and specific biomarkers. Previous studies have suggested that susceptibility contrast in demyelinated plaques is associated with iron-related pathology in multiple sclerosis which may indicate clinical severity. The aims of this study were to characterize the spatial distribution of MS lesions with different iron patterns by using quantitative susceptibility mapping and to explore neuroradiological findings that correlate with poor clinical outcome. Methods: Twenty-six patients with relapsing–remitting MS [14 men, 12 women; mean age, 29 ± 8 (standard deviation) years; age range, 21–52 years] were included in this study. Differences in lesion number, T2 volume, and susceptibility were compared among lesions subcategorized by location and by the presence or absence of a hyperintense rim on quantitative susceptibility mapping. Associations between these imaging features and clinical outcomes including Expanded Disability Status Scale scores and annual relapse rates were investigated. Results: A total of 811 unifocal MS lesions were included, and their QSM patterns were nodular hyperintensity with no rim (rim–, 540, 67%) or with a hyperintense rim on the edge (rim+, 172, 21%) and nodular isointensity (99, 12%). Rim+ lesions had significantly larger volume (115 ± 142 vs. 166 ± 185 mm3, p < 0.001) and lower susceptibility (4 ± 15 vs. 8 ± 16 ppb, p < 0.05) than rim– lesions. More rim+ lesions were found in periventricular areas [median, 45%; interquartile range (IQR), 36%], whereas a larger proportion of rim– lesions were distributed in juxtacortical (median, 32%; IQR, 21%) and deep white matter (median, 38%; IQR, 22%) areas. The annual relapse rate was positively correlated with the proportion of periventricular rim+ lesions (p < 0.001, r = 0.65) and the proportion of subtentorial rim+ lesions (p < 0.05, r = 0.40). Additionally, a significant association was found between the burden of periventricular rim+ lesions (β = 0.64, p < 0.001) and the burden of subtentorial rim– lesions (β = 0.36, p < 0.05). Conclusions: A high number or lesion burden of periventricular rim+ lesions or subtentorial lesions is associated with frequent clinical relapses.
Modern Pollen Assemblages in Typical Agro-Pastoral Ecotone in the Eastern Tibetan Plateau and Its Implications for Anthropogenic Activities

Long-term evolution of human-environment interaction in the Qinghai-Tibetan Plateau (QTP) has been discussed intensively in recent years. The identification of human-related pollen types may help explore the coupled process of climate change, ecological response and anthropogenic activities on the QTP. The aim of this study is to evaluate the impact of anthropogenic activities on surface pollen assemblages and identify pollen indicators associated with grazing and cultivation in typical agro-pastoral ecotone of the eastern QTP. Totally 84 surface samples were analyzed from five vegetational communities in the eastern QTP, which are identifiable based on surface pollen assemblages. Principal component analysis of 29 pollen types and two supplementary variables of human influences were used to assess the impact of anthropogenic activities on surface pollen assemblages in eastern QTP. Severe grazing led to increase of Rosaceae, Ranunculaceae, Fabaceae, Taraxacum-Type, Aster-type and Saussurea-Type in pollen assemblages. Highland agricultural cultivation can be identified by the content and morphological characteristic of Brassicaceae and Cerealia Poaceae pollen. The aerial dispersed distances of Brassicaceae and Cerealia Poaceae pollen are very short, and domesticated herbivores are important factors, which disperse the Cerealia Poaceae pollen into pastures in agro-pastoral ecotone of the QTP. Modern pollen indicators of cultivation and grazing activity will provide precise references for fossil pollen study of prehistoric human activities in the QTP.
The Heart in the Mind: A Systematic Review and Meta-Analysis of the Association Between Theory of Mind and Cardiac Vagal Tone

Theory of mind (ToM) is the human ability to infer the mental states of others in order to understand their behaviors and plan own actions. In the past decades, accumulating evidence has shown that heart rate variability (HRV), an index of parasympathetic control of the heart, is linked to behavioral regulation, social competence, and social cognition abilities, all implicated—to some extent—in ToM. This study aims to systematically review and meta-analyze the available studies, investigating the relation between ToM and HRV in typically developing people. Six studies were eligible for the meta-analysis, yielding a significant association between HRV and ToM of a small-to-medium effect size (g = 0.44). This result was not influenced by publication bias. Due to the small number of studies eligible for the meta-analysis, it was not possible to test for the effect of categorical moderators. The moderating role of sex and quality of the studies was examined by meta-regression analysis. Moderation analysis did not yield any significant effect; however, at a descriptive level, studies yielding the largest effect size were characterized by the use of high frequency-HRV assessment at rest and the Reading the Mind in the Eyes Test to evaluate ToM abilities. The results preliminarily suggest that tonic HRV might be used as an indicator of the ability to understand the content of mind of others.
Global Causes, Drivers, and Prevention Measures for Lost Fishing Gear

Abandoned, Lost or otherwise discarded fishing gear (ALDFG) comprises a significant part of global marine plastic pollution, with adverse consequences for fishers, the seafood industry, and marine wildlife and habitats. To effectively prevent and reduce ALDFG at source, an understanding of the major causes of and drivers behind fishing gear losses is required. We interviewed 451 fishers from seven countries around the world (Belize, Iceland, Indonesia, Morocco, New Zealand, Peru, and the United States of America) representing five key fishing gear types (gillnets, purse seine nets, trawl nets, longlines, and pots and traps) about why and under what circumstances they lose their gear. We also asked them their views on the most effective interventions to reduce gear losses. Across all major gear types and countries where interviews were undertaken, bad weather was the most common cause of gear loss, followed by interactions with wildlife (identified as a cause for loss by 81% and 65% of all fishers interviewed, respectively). Snagging gear on a bottom obstruction was a major cause of loss for gears that contact the seafloor, along with conflicts with other fishers, often via gear and vessel interactions, for gillnet and pot and trap fishers. Operational and behavioral characteristics such as gear type, trip length, and the party responsible to pay for gear repairs and replacements all significantly influenced gear losses. Gear maintenance was the most effective gear loss prevention measure across all gear types and countries reported by fishers, followed by training crew in gear management (identified as an effective prevention measure by 95% and 82% of all fishers interviewed, respectively). Actions available to fishers, managers and port operators to effectively prevent fishing gear losses include: gear maintenance; reducing active gear interactions with wildlife; reducing financial and administrative burdens for port reception facilities; reducing trip lengths; and targeting education and gear stewardship programs to fishers with limited ALDFG awareness, particularly those in low income fisheries and countries.
Alpha-Synuclein as a Biomarker of Parkinson’s Disease: Good, but Not Good Enough

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.
Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells

The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.
Body Composition Variables as Radiographic Biomarkers of Clinical Outcomes in Metastatic Renal Cell Carcinoma Patients Receiving Immune Checkpoint Inhibitors

Background Immune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Biomarkers for mRCC patients treated with ICI are limited, and body composition is underutilized in mRCC. We investigated the association between body composition and clinical outcomes in ICI-treated mRCC patients. Methods We performed a retrospective analysis of 79 ICI-treated mRCC patients at Winship Cancer Institute from 2015-2020. Baseline CT images were collected at mid-L3 and segmented using SliceOMatic v5.0 (TomoVision). Density of skeletal muscle (SM), subcutaneous fat, inter-muscular fat, and visceral fat were measured and converted to indices by dividing by height(m)2 (SMI, SFI, IFI, and VFI, respectively). Total fat index (TFI) was defined as the sum of SFI, IFI, and VFI. Patients were characterized as high versus low for each variable at gender-specific optimal cuts using overall survival (OS) as the primary outcome. A prognostic risk score was created based on the beta coefficient from the multivariable Cox model after best subset variable selection. Body composition risk score was calculated as IFI + 2*SM mean + SFI and patients were classified as poor (0-1), intermediate (2), or favorable risk (3-4). Kaplan-Meier method and Log-rank test were used to estimate OS and PFS and compare the risk groups. Concordance statistics (C-statistics) were used to measure the discriminatory magnitude of the model. Results Most patients were male (73%) and most received ICI as first (35%) or second-line (51%) therapy. The body composition poor-risk patients had significantly shorter OS (HR: 6.37, p<0.001), PFS (HR: 4.19, p<0.001), and lower chance of CB (OR: 0.23, p=0.044) compared to favorable risk patients in multivariable analysis. Patients with low TFI had significantly shorter OS (HR: 2.72, p=0.002), PFS (HR: 1.91, p=0.025), and lower chance of CB (OR: 0.25, p=0.008) compared to high TFI patients in multivariable analysis. The C-statistics were higher for body composition risk groups and TFI (all C-statistics ≥ 0.598) compared to IMDC and BMI. Conclusions Risk stratification using the body composition variables IFI, SM mean, SFI, and TFI may be prognostic and predictive of clinical outcomes in mRCC patients treated with ICI. Larger, prospective studies are warranted to validate this hypothesis-generating data.
Cardiac, Macro-, and Micro-Circulatory Abnormalities in Association With Individual Metabolic Syndrome Component: The Northern Shanghai Study

Objective: This study investigated the association of metabolic syndrome (MS) and its components with cardiac, macro-, and micro-circulatory abnormalities in an elderly Chinese population. Methods: This cross-sectional study was conducted using data for 1,958 participants from the Northern Shanghai Study aged over 65 years without a history of cardiovascular disease. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III in 2005 (NCEPIII 2005). Asymptomatic cardiovascular impairment parameters, including the left ventricle mass index (LVMI), peak transmitral pulsed Doppler velocity/early diastolic tissue Doppler velocity (E/Ea), carotid-femoral pulse wave velocity (cf-PWV), ankle-brachial index (ABI), carotid intima-media thickness (CIMT), arterial plaque, and urinary albumin–creatinine rate (UACR), were evaluated. Results: LVMI, E/Ea, cf-PWV, and the proportion of UACR > 30 mg/g exhibited increasing trends while ABI exhibited a decreasing trend according to the number of MS components (all p for trend < 0.01). Logistic regression analysis revealed that MS was significantly associated with LV hypertrophy (LVH), LV diastolic dysfunction, arteriosclerosis, and microalbuminuria (all p < 0.001). Central obesity and high blood pressure were associated with all cardiovascular abnormalities (all p < 0.05), whereas elevated plasma glucose was associated with arteriosclerosis and microalbuminuria (both p < 0.001). In addition, high triglyceride levels were associated with microalbuminuria (p < 0.05). Conclusions: MS is significantly associated with cardiac, macro-, and micro-circulatory abnormalities in elderly Chinese. Moreover, the presence of individual MS components may have specific prognostic significance.