julilili42/papers huggingface dataset:
Illusory traits: Wrong but sometimes useful
2023-11-23

Psychological measures frequently show trait-like properties, and the ontological status of stable psychological traits has been discussed for decades. We argue that these properties can emerge from causal dynamics of time-varying processes, which are omitted from the analysis model, potentially leading to the estimation of traits that are, at least in part, illusory. Theories positing the importance of a large set of dynamic psychological causes across development are consistent with the existence of illusory traits. We show via simulation that even a linear system with many processes can generate a covariance matrix with trait-like properties. We then attempt to examine how illusory traits affect our conclusions drawn from a common statistical model which assumes stable traits to analyze longitudinal panel data—a random-intercept cross-lagged panel model (RI-CLPM). We find that the RI-CLPM sometimes falsely detects the existence of traits in the presence of omitted processes, even when the data generating model does not include any traits. However, in this scenario, the RI-CLPM estimates less causally biased autoregressive and cross-lagged effects than an analysis model which does not assume traits (i.e., the cross-lagged panel model). Results indicate that the detection of trait variance should not be inferred as strong evidence for the existence of time-invariant trait causes. On the other hand, even when traits are illusory, statistical models assuming stable traits may sometimes be useful for causal inference.
Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders
2023-11-23

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
Paralog-specific TTC30 regulation of Sonic hedgehog signaling
2023-11-23

The intraflagellar transport (IFT) machinery is essential for cilia assembly, maintenance, and trans-localization of signaling proteins. The IFT machinery consists of two large multiprotein complexes, one of which is the IFT-B. TTC30A and TTC30B are integral components of this complex and were previously shown to have redundant functions in the context of IFT, preventing the disruption of IFT-B and, thus, having a severe ciliogenesis defect upon loss of one paralog. In this study, we re-analyzed the paralog-specific protein complexes and discovered a potential involvement of TTC30A or TTC30B in ciliary signaling. Specifically, we investigated a TTC30A-specific interaction with protein kinase A catalytic subunit α, a negative regulator of Sonic hedgehog (Shh) signaling. Defects in this ciliary signaling pathway are often correlated to synpolydactyly, which, intriguingly, is also linked to a rare TTC30 variant. For an in-depth analysis of this unique interaction and the influence on Shh, TTC30A or B single- and double-knockout hTERT-RPE1 were employed, as well as rescue cells harboring wildtype TTC30 or the corresponding mutation. We could show that mutant TTC30A inhibits the ciliary localization of Smoothened. This observed effect is independent of Patched1 but associated with a distinct phosphorylated PKA substrate accumulation upon treatment with forskolin. This rather prominent phenotype was attenuated in mutant TTC30B. Mass spectrometry analysis of wildtype versus mutated TTC30A or TTC30B uncovered differences in protein complex patterns and identified an impaired TTC30A–IFT57 interaction as the possible link leading to synpolydactyly. We could observe no impact on cilia assembly, leading to the hypothesis that a slight decrease in IFT-B binding can be compensated, but mild phenotypes, like synpolydactyly, can be induced by subtle signaling changes. Our systematic approach revealed the paralog-specific influence of TTC30A KO and mutated TTC30A on the activity of PRKACA and the uptake of Smoothened into the cilium, resulting in a downregulation of Shh. This downregulation, combined with interactome alterations, suggests a potential mechanism of how mutant TTC30A is linked to synpolydactyly.
Precursor deconvolution error estimation: The missing puzzle piece in false discovery rate in top‐down proteomics
2023-11-23

Abstract Top‐down proteomics (TDP) directly analyzes intact proteins and thus provides more comprehensive qualitative and quantitative proteoform‐level information than conventional bottom‐up proteomics (BUP) that relies on digested peptides and protein inference. While significant advancements have been made in TDP in sample preparation, separation, instrumentation, and data analysis, reliable and reproducible data analysis still remains one of the major bottlenecks in TDP. A key step for robust data analysis is the establishment of an objective estimation of proteoform‐level false discovery rate (FDR) in proteoform identification. The most widely used FDR estimation scheme is based on the target‐decoy approach (TDA), which has primarily been established for BUP. We present evidence that the TDA‐based FDR estimation may not work at the proteoform‐level due to an overlooked factor, namely the erroneous deconvolution of precursor masses, which leads to incorrect FDR estimation. We argue that the conventional TDA‐based FDR in proteoform identification is in fact protein‐level FDR rather than proteoform‐level FDR unless precursor deconvolution error rate is taken into account. To address this issue, we propose a formula to correct for proteoform‐level FDR bias by combining TDA‐based FDR and precursor deconvolution error rate.
Feeling the Truth: Emotions and Digital Truth-making within Right-wing Populist Networks on Twitter/X
2023-11-23

Based on an investigation of how everyday users participate in right-wing populist discourse on social media platforms, this article explores the emotional practices that shape and legitimise purported truths about the threat posed by Islam to the Western world. The article builds on the findings of an online ethnography of a right-wing community of users on Twitter. Drawing on a practice theory approach of emotions that considers the properties of social media platforms, we argue that right-wing populist claims to truth do not function in a linear way. The emotions mobilised in this context do not solely focus on rejection and exclusion. Rather, right-wing populist truth-making is a complex process in which emotional practices of inclusion and exclusion are interwoven.&amp;nbsp;
Leaving no one behind: successful ageing at the intersection of ageism and ableism
2023-11-24

Abstract Background The concept of ‘successful ageing’ has been a prominent focus within the field of gerontology for several decades. However, despite the widespread attention paid to this concept, its intersectional implications have not been fully explored yet. This paper aims to address this gap by analyzing the potential ageist and ableist biases in the discourse of successful ageing through an intersectional lens. Method A critical feminist perspective is taken to examine the sensitivity of the discourse of successful ageing to diversity in societies. The paper analyzes how ageist and ableist biases can manifest in the ways we conceptualize ageing, drawing on examples in the context of mental health. Results We argue that the conventional approach to successful ageing is limited in its ability to account for the experiences of people who have faced intersectional discrimination throughout their lives. Drawing on examples in the context of mental health, we explore among others the link between depression and disabilities. Furthermore, we shed light on the negative impact of ageist and ableist attitudes concerning the diagnosis and treatment of dementia. Discussion We demonstrate how diversity is often overlooked in discussions of ageing well, and how ageist and ableist biases can manifest in the ways we conceptualize ageing. We argue that focusing solely on the health status as a means of achieving success fails to adequately counter ageism for all people. We further emphasize the role of structural factors, such as ageist attitudes, in shaping the experience of ageing and exacerbating health inequalities. Conclusion Overall, our findings emphasize the need for a more nuanced and inclusive understanding of ageing and therefore an intersectional approach to conceptions of ageing well that recognizes and addresses the biases and limitations of current discourses. Thereby, this paper offers valuable insights into the complex intersections between age and disabilities from a bioethical perspective, highlighting the need for a more inclusive and intersectional approach to ageing.
Recurrentde-novo gain-of-functionmutation inSPTLC2confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis
2023-11-24

Background Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS . SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. Methods We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in SPTLC2 . The de-novo status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry. Results Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel de-novo SPTLC2 mutation, c.203T&gt;G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells. Conclusions Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.
Invasive Staphylococcus epidermidis uses a unique processive wall teichoic acid glycosyltransferase to evade immune recognition
2023-11-24

Staphylococcus epidermidis expresses glycerol phosphate wall teichoic acid (WTA), but some health care–associated methicillin-resistant S. epidermidis (HA-MRSE) clones produce a second, ribitol phosphate (RboP) WTA, resembling that of the aggressive pathogen Staphylococcus aureus . RboP-WTA promotes HA-MRSE persistence and virulence in bloodstream infections. We report here that the TarM enzyme of HA-MRSE [TarM(Se)] glycosylates RboP-WTA with glucose, instead of N -acetylglucosamine (GlcNAc) by TarM(Sa) in S. aureus . Replacement of GlcNAc with glucose in RboP-WTA impairs HA-MRSE detection by human immunoglobulin G, which may contribute to the immune-evasion capacities of many invasive S. epidermidis . Crystal structures of complexes with uridine diphosphate glucose (UDP-glucose), and with UDP and glycosylated poly(RboP), reveal the binding mode and glycosylation mechanism of this enzyme and explain why TarM(Se) and TarM(Sa) link different sugars to poly(RboP). These structural data provide evidence that TarM(Se) is a processive WTA glycosyltransferase. Our study will support the targeted inhibition of TarM enzymes, and the development of RboP-WTA targeting vaccines and phage therapies.
Application of 2D shape analysis to study Epigravettian lithic assemblages: assessing its analytical potential
2023-11-24

In this paper, we apply a two-dimensional (2D) Geometric morphometric analysis to a sample of Epigravettian lithic artefacts with the aim of assessing the potential of such an approach to study Epigravettian lithic assemblages. The lithic sample comes from layer 9c2 (Evolved Epigravettian, Upper Palaeolithic, about 18,000-19,000 years ago) of Grotta Paglicci (Apulia, southern Italy). After extracting the outline coordinates from high-resolution images using the software DiaOutline, we conduct Elliptic Fourier Analysis, Principal Component Analysis, and Linear Discriminant Analysis in the R package Momocs to investigate the internal variability of the sample. Shape analysis confirms that 1) the production of microbladelets was not linked to a dedicated reduction sequence and 2) the modification of blanks into backed points followed a rather standardised stone tool design. The result opens interesting perspectives for the routine implementation of 2D shape analyses complementary to the classical technological ones.
Multi-purpose pots: Reconstructing early farmer behaviour at Lydenburg Heads site, South Africa, using organic residue analysis
2023-11-24

About 2000 years ago, Bantu-speaking people introduced an agro-pastoral lifeway into southern Africa and lived in northern and eastern lowland parts of the region by 700 CE. Also defined as the 'southern African Iron Age', pottery is the most common and diagnostic artefact category. The soil chemistry of several farming sites resulted in poor faunal preservation and especially within Mpumalanga Province, South Africa, the possibilities for dietary reconstructions based on bone assemblages is very limited. Furthermore, the majority of ceramic research on early farming communities (ca. 200–900 CE) has focused on typology and ethnoarchaeological interpretations. This study represents the first application of Organic Residue Analysis (ORA) applied to southern African early farming pottery to gain a deeper understanding of past human behaviour and subsistence patterns. We investigate the potential and evaluate future prospects of applying this method to southern African early farming pottery. A combined lipid biomarker (GC-MS) and compound specific isotope approach (GC-C-IRMS) was applied to pottery sherds (n = 40) from the Lydenburg Heads site (LHS), dating to the 7th century CE (Mzonjani facies) and 9th to 11th centuries CE (Doornkop facies), to test for lipid preservation, trace possible vessel use and dietary changes through time and embed the research data within the faunal and botanical record available. Our study provides first evidence for the processing of dairy products by early farmers in southern Africa. Both facies imply multi-purpose functionality of the ceramics tested, demonstrated by the mixing of animal fats and plant oils. The obtained ORA data from LHS confirms the processing of ruminant carcass fats within both occupation facies, likely representing domestic animal fats, as well as the processing of wild non-ruminant carcass fats within the earlier Mzonjani facies. The identification of ricinoleic acid in two vessels of the Doornkop facies, provides evidence for potential medicinal use. Preliminary data also indicate that dung could have been involved in different forms of pottery sealing and/or mending during both occupation facies. In this study, we begin to explore biomolecular evidence for dietary choices made by early farmers in southern Africa, shedding light on previously unexplored key products.
The Iconography of Children as Cultic Characters in Mediterranean tophet Precincts
2023-11-24

Abstract Within the range of Phoenician artisanal production of stone votive markers in the central Mediterranean, specifically cippi and stelae from tophet precincts, this paper offers a preliminary exploration of some iconographic and stylistic aspects of anthropomorphic representations in general, and those of children in particular. It provides an overview of traditional craftmanship at different centers of production, the ritual function of stelae in archaeological contexts, and their relevance in the social sphere as “talking monuments.” It also analyses certain specific figural elements (e. g., the so-called “bottle-idol”) and their developments over time. The main aim is to propose tentative interpretations for images of children, given the specific rituals of the sanctuary and their ideological meanings.
The impact of cooperation under climate constraints: an Agent-Based Model for exploring Paleolithic behavioral adaptations in the Inner Asian Mountain Corridor
2023-11-24

Modern humans dispersed throughout the entire world during the Pleistocene, completing an important part of our evolutionary history. One of the most difficult territories to be colonized by humans was Central Asia, a region characterized by cold and arid climates and by stark geographic contrasts, such as high mountains flanked by deserts. Central Asia therefore offers an ideal context for testing hypotheses about the role of human behavior in dispersals under adverse conditions. We introduce here an evolutionary theoretical Agent-Based Model exploring the effect of cooperation on dispersal under different climate constraints in two study sub-regions, the Altai and Tian Shan Mountains. The model uses an evolutionary framework to test cooperation dilemmas within four theoretical climate scenarios. These are based on the average temperature during glacial and interglacial periods. We compare how extreme climate scenarios affect human cooperation depending on the regions and climates in which hominins are found. We show that: a) population size can significantly influence pressure on the group, such that a higher population implies more pressure to cooperate; b) cooperative behaviors are needed for survival in the harshest conditions and c) if the initial probability of non-cooperation is higher, then human groups will tend to be non-cooperative even if a cooperative subgroup pushes them to cooperate.Our results demonstrate that the degree of cooperation significantly impacts survival during periods of extreme climatic deterioration. This finding provides valuable insight into the settlement patterns of ancient civilizations, potentially shedding light on why Central Asia might have been settled later than some other regions in Asia.
Behavioral Influence of Social Self Perception in a Sociophysical Simulation
2023-11-24

Humans make decisions about their actions based on a combination of their objectives and their knowledge about the state of the world surrounding them. In social interactions, one prevalent goal is the ambition to be perceived to be an honest, trustworthy person in terms of having a reputation of frequently making true statements. Aiming for this goal requires the decision whether to communicate information truthfully or if deceptive lies might improve the reputation even more. The basis of this decision involves not only an individual's belief about others, but also their understanding of others' beliefs, described by the concept of Theory of Mind, and the mental processes from which these beliefs emerge. In the present work, we used the Reputation Game Simulation as an approach for modeling the evolution of reputation in agent-based social communication networks, in which agents treat information approximately according to Bayesian logic. We implemented a second-order Theory of Mind based message decision strategy that allows the agents to mentally simulate the impact of different communication options on the knowledge of their counterparts' minds in order to identify the message that is expected to maximize their reputation. Analysis of the communication patterns obtained showed that deception was chosen more frequently than the truthful communication option. However, the efficacy of such deceptive behavior turned out to have a strong correlation with the accuracy of the agents' Theory of Mind representation.
Development of selective pyrido[2,3-d]pyrimidin-7(8H)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors
2023-11-25

ABSTRACT Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part due to the lack of potent and selective MST3/4 inhibitors. Here, we re-evaluated literature compounds, and used structure-guided design to optimize the p21-activated kinase (PAK) inhibitor G-5555 ( 8 ) to selectively target MST3/4. These efforts resulted in the development of MR24 ( 24 ) and MR30 ( 27 ) with good kinome-wide selectivity, high potency for MST3/4, and selectivity towards the closely related MST1/2. In combination with the MST1/2 inhibitor PF-06447475 ( 2 ) the two MST3/4 inhibitors can be used to elucidate the multiple roles of MST kinases in cells. We found that MST3/4-selective inhibition caused a cell cycle arrest in the G1 phase, while MST1/2 inhibition resulted in accumulation of cells in the G2/M phase. These data point to distinct functions of these closely related kinases, which can now be addressed with subfamily-selective chemical tool compounds.
Long-term efficacy of the peptide-based COVID-19 T cell activator CoVac-1 in healthy adults
2023-11-26

Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects.