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Abstract The development of the internet has allowed for the global distribution of content, redefining media communication and property structures through various streaming platforms. Previous studies successfully clarified the factors contributing to trends in each streaming service, yet the similarities and differences between platforms are commonly unexplored; moreover, the influence of social connections and cultural similarity is usually overlooked. We hereby examine the social aspects of three significant streaming services–Netflix, Spotify, and YouTube–with an emphasis on the dissemination of content across countries. Using two-year-long trending chart datasets, we find that streaming content can be divided into two types: video-oriented (Netflix) and audio-oriented (Spotify). This characteristic is differentiated by accounting for the significance of social connectedness and linguistic similarity: audio-oriented content travels via social links, but video-oriented content tends to spread throughout linguistically akin countries. Interestingly, user-generated contents, YouTube, exhibits a dual characteristic by integrating both visual and auditory characteristics, indicating the platform is evolving into unique medium rather than simply residing a midpoint between video and audio media.

Compared with the traditional frame structures, the novel composite frame with replaceable steel links can realize the rapid recovery of building occupancy after seismic actions to provide the capacity of reducing structural damage and ensure the reuse of a structure. In this system, plastic deformation and damage mainly concentrated in the steel links serving as the structural fuses and other structural members still remained elastic or minor plastic, and then the damaged steel links can be easy for replace. In order to study the seismic performance of the replaceable steel links, a total of four test specimens with different short length ratios were designed. A low-cycle reversed loading test was carried out in terms of failure characteristic, hysteretic response and shear strength. The results indicated that all tested specimens presented a stable and full hysteretic response while the steel links especially exhibited a large inelastic deformation capacity and fully developed shear strength as the structural fuses. Besides, failure modes of steel links included two types of shear failure and bending-shear failure, followed by two types of damage features, including web-to-stiffener weld tear, web buckling, flange-to-end plate weld tear and flange buckling, respectively. Finally, nonlinear finite element models (FEMs) of test specimens were implemented by the Abaqus software. The numerical results were in good agreement with the experimental results in terms of load-deformation curves, initial stiffness, the development of Von Mises stress and cumulative plastic equivalent strain (PEEQ) indexes to facilitate design practice. [ABSTRACT FROM AUTHOR]

Increased fracture risk in type 1 diabetes (T1D) patients is not fully captured by bone mineral density (BMD) by DXA. Advanced glycation end-products (AGEs) have been implicated in the increased fracture risk in T1D, yet recent publications question this. To test the hypothesis that enzymatic collagen cross-links rather than AGEs correlate with fracture incidence in T1D, we analyzed iliac crest biopsies from sex-matched, fracturing T1D patients (N = 5; T1DFx), 6 non-fracturing T1D patients (T1DNoFx), and 6 healthy subjects, by Raman microspectroscopy as a function of tissue age (based on double fluorescent labels), in intracortical and trabecular bone, to determine pyridinoline (Pyd), ε-N-Carboxymethyl-L-lysine, and pentosidine (PEN)). There were no differences in the clinical characteristics between the T1DFx and T1DNoFx groups. At trabecular forming surfaces, T1DFx patients had higher PEN and Pyd content compared to T1DNoFx ones. Previous studies have shown that elevated PEN does not necessarily correlate with fracture incidence in postmenopausal, long-term T1D patients. On the other hand, the elevated Pyd content in the T1DFx patients would be consistent with published studies showing a significant correlation between elevated trivalent enzymatic collagen cross-links and fracture occurrence independent of BMD. Collagen fibers with high Pyd content are more brittle. Thus, a plausible suggestion is that it is the enzymatic collagen cross-links that either by themselves or in combination with the adverse effects of increased AGE accumulation that result in fragility fracture in T1D. [ABSTRACT FROM AUTHOR]

We suggest a new random model for links based on meander diagrams and graphs. We then prove that trivial links appear with vanishing probability in this model, no link L is obtained with probability 1, and there is a lower bound for the number of non-isotopic knots obtained for a fixed number of crossings. A random meander diagram is obtained through matching pairs of parentheses, a well-studied problem in combinatorics. Hence tools from combinatorics can be used to investigate properties of random links in this model, and, moreover, of the respective 3-manifolds that are link complements in 3-sphere. We use this for exploring geometric properties of a link complement. Specifically, we give expected twist number of a link diagram and use it to bound expected hyperbolic and simplicial volume of random links. The tools from combinatorics that we use include Catalan and Narayana numbers, and Zeilberger's algorithm. [ABSTRACT FROM AUTHOR]

The highly blistering sulfur mustard analogue agent T (bis(2-chloroethylthioethyl) ether), also known as O-mustard or oxy-mustard, is a common impurity in military grade sulfur mustard (SM) and a component of mixtures such as "HT" that are still found in old munitions. Together with sesquimustard (Q), it is the most important SM analogue and tightly regulated as a Schedule 1 chemical under the Chemical Weapons Convention. We report the adducts of T with nucleophilic Cys34 and other residues in human serum albumin (HSA) formed in vitro. A micro liquid chromatography electrospray ionization high-resolution tandem-mass spectrometry method (µLC-ESI MS/HR MS) was developed for the detection and identification of biomarker peptides alkylated by a T-derived hydroxyethylthioethyloxyethylthioethyl (HETEOETE)-moiety (as indicated by an asterisk below). Following proteolysis of T-exposed human plasma with pronase, the dipeptide Cys34*Pro and the single amino acid residue His* were produced. The use of proteinase K yielded Cys34*ProPhe and the use of pepsin generated ValThrGlu48*Phe, AlaGlu230*ValSerLysLeu, and LeuGlyMet329*Phe. Corresponding peptide-adducts of SM and Q were detected in a common workflow that in principle allowed the estimation of the mustard or mustard composition encountered during exposure. Novel adducts of Q at the Glu230 and Met239 residues were detected and are reported accordingly. Based on molecular dynamics simulations, we identified regular interactions of the Cys34(-HETEOETE)-moiety with several glutamic acid residues in HSA including Glu86, which is not an obvious interaction partner by visual inspection of the HSA crystal structure. The existence of this and other intramolecular cross-links was experimentally proven for the first time. [ABSTRACT FROM AUTHOR]

This paper aimed to investigate the cyclic performance of short and very short links made of ASTM A992 steel in eccentrically braced frames. An extensive parametric study was conducted using ABAQUS software, considering the effects of local buckling, cumulative damage under repeated loads, and steel fracture on strength and stiffness degradation. The study analyzed 114 isolated I-shaped links with various link lengths, stiffener arrangements, and a wide range of web and flange widths and thicknesses. The results showed that the shear links developed overstrength factors ranging from 1.73 to 2.53, with an average value of 2, indicating that the overstrength factor of 1.5, which is proposed by current seismic provisions, results in unconservative design predictions compared to the test results. Moreover, the rotation capacity of shear links exceeded the AISC 341-22 requirement with a large margin, and the stiffener requirements could be relaxed for very short links. The results also revealed that the link-length-ratio parameter could not represent the actual behavior differences among the shear links, and thus an effective parameter was proposed to determine the overstrength factor of shear links. [ABSTRACT FROM AUTHOR]

Atherosclerotic lesions develop preferentially in arterial regions exposed to disturbed blood flow, where endothelial cells acquire an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. Here we show that histone H3.3 phosphorylation at serine 31 (H3.3S31) regulates disturbed-flow-induced endothelial inflammation by allowing rapid induction of FOS and FOSB, required for inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed-flow-induced H3.3S31 phosphorylation. Disturbed flow activates PKN1 in an integrin α5β1-dependent manner and induces its translocation into the nucleus, and PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific PKN1 loss or endothelial expression of S31 phosphorylation-deficient H.3.3 mutants show reduced endothelial inflammation and disturbed-flow-induced vascular remodeling in vitro and in vivo. Together, we identified a pathway whereby disturbed flow through PKN1-mediated histone phosphorylation and FOS/FOSB induction promotes inflammatory gene expression and vascular inflammation., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Competing Interests: Competing interests: The author declares no competing interests.

Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients with cardiovascular diseases, but the underlying mechanisms remain largely unknown. Using the human MESA cohort, here we show that plasma glutamine-glutamate ratio is an independent risk factor for carotid plaque progression. Mice deficient in glutaminase-2 (Gls2), the enzyme that mediates hepatic glutaminolysis, developed accelerated atherosclerosis and susceptibility to catastrophic cardiac events, while Gls2 overexpression partially protected from disease progression. High-throughput transcriptional profiling and high-resolution structural biology imaging of aortas showed that Gls2 deficiency perturbed extracellular matrix composition and increased vessel stiffness. This results from an imbalance of glutamine- and glutamate-dependent cross-linked proteins within atherosclerotic lesions and cellular remodeling of plaques. Thus, hepatic glutaminolysis functions as a potent regulator of glutamine homeostasis, which affects the aortic wall structure during atherosclerotic plaque progression., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Space division multiplexing (SDM) with Hermite Gaussian (HG) modes, for instance, can significantly boost the transmission link capacity. However, SDM is not suitable in existing single mode fiber networks, and in long-distance wireless, microwave, THz or optical links, the far-field beam distribution may present a problem. Recently it has been demonstrated, that time domain HG modes can be employed to enhance the link capacity. However, implementing this method in wireless or fiber-based transmission systems is impractical due to the need for highly complex setups involving specialized lasers, wave shapers and other advanced devices. We propose a simple and fully electrical time-domain mode-division-multiplexing (TD-MDM) method based on the recursive generation of Hermite–Gaussian (HG) modes. It utilizes Gaussian pulse sequences, sawtooth signals, RF multipliers, adders, amplifiers, and Mach–Zehnder modulators for efficient multiplexing and demultiplexing. We show the time and bandwidth performance of 4 multiplexed orthogonal modes in transmitting 8 Gbps communication data (4 × 2 Gbit/s), demonstrating the feasibility of the recursive generation and multiplexing technique for TD-MDM with HG modes. The data rates were restricted by our experimental capabilities. With state-of-the-art equipment the method can easily be scaled to the terabit per second range. [ABSTRACT FROM AUTHOR]

This sentence discusses a possible solution to overcome the disadvantages of traditional eccentrically braced frame systems (EBFs). The proposed solution involves separating the shear links from the frame beams and utilizing double-tube buckling restrained braces with contact rings. These modifications aim to improve the overall performance of the frame system. To investigate the mechanical characteristics of this structural system, an experimental study was conducted, involving the design of two K-type EBFs and testing four distinct replaceable shear links. The stress distribution, load–displacement curves, and hysteresis curves of this structural system were obtained by conducting cyclic lateral loading tests on these specimens. Subsequently, the hysteretic properties, load bearing capacity, and deformation capacity of the member underwent analysis. An exploration was conducted into the primary influences on the structural mechanical characteristics. The research indicates that the double-tube buckling restrained braces with contact ring enhance the structural strength and synergistically perform with shear links to dissipate energy, while ensuring improved performance. Comparison of the date of different parameters shear links shows that the placement of stiffening rib increased the energy dissipation performance by 41.2% and shear capacity by 14.6% for the same sectional dimension of shear links. In the shear links with two stiffening ribs, the larger sectional dimension improved the energy dissipation performance by 11.3% relative to the shear links with smaller sectional dimension. For the shear links with one stiffening rib, the increase in sectional dimension, on the contrary, reduced the energy dissipation performance by 18.4% [ABSTRACT FROM AUTHOR]

In spite of extensive research that links the absence of pain with happiness, it remains puzzling why possessing beliefs equating the absence of pain with happiness (negative hedonic beliefs) undermine experienced happiness and what underlying mechanisms can explain this paradox. We conducted five studies to address these questions. The participants who had more negative hedonic beliefs exhibited decreased well-being, including subjective well-being and psychological well-being, alongside heightened depression and physical symptoms (Study 1a), an effect that persisted after controlling for behavioral inhibition/activation systems (Study 1b). Hypersensitivity to negative experiences, which reflects a reduced inclination to engage in negative experiences, even when positives exist, mediated the links between negative hedonic beliefs and poor well-being both cross-sectionally (Study 2) and longitudinally (Study 3). Moreover, the propensity to avoid negative experiences was observed in behavioral intention, primarily due to heightened anticipated negative affect when an event was manipulated to include negative aspects (Study 4). Together, the effort to eliminate negative experiences, as adhered to by individuals with negative hedonic beliefs, tends to prevent them from recognizing the potential benefits of unpleasant experiences, inadvertently depriving themselves of opportunities for the enhancement of their well-being. [ABSTRACT FROM AUTHOR]

Many existing reinforced concrete buildings have been designed based on earlier codes of practice that underestimated seismic forces, making them vulnerable to damage during seismic action. Equipping existing buildings with shear links and eccentric braces is one of the available seismic retrofitting methods to dissipate seismic energy away from the main structural members. In this paper, a proposal for the seismic retrofitting of two existing reinforced concrete buildings using aluminium shear links and steel braces is presented. First, a capacity-based design approach is followed to determine the required sizes of the shear links and eccentric braces. Second, numerical analyses are used to compare how the original and retrofitted buildings responded. These tests include pushover analysis, nonlinear time-history analysis, damage analysis, incremental dynamic analysis, fragility and reliability analysis, and damage analysis. The results reveal that the proposed retrofitting method can sufficiently upgrade the performance level of the buildings and reduce their storey displacements and interstorey drifts, as shear links are found to absorb almost all seismic energy, therefore keeping other structural members responding elastically. Yet, using shear links alters the local behaviour of the surrounding structural members, which should be considered in the design process. Furthermore, compared to the original buildings, retrofitted buildings are expected to undergo less structural damage as they have lower damage indices. Meanwhile, the fragility of retrofitted buildings is significantly reduced compared to the original ones, which indicates the efficiency of the proposed retrofitting methods in upgrading the performance of seismically deficient reinforced concrete buildings. [ABSTRACT FROM AUTHOR]

Eccentrically Braced Frames (EBFs) equipped with steel shear links primarily sustain large deformation demands through inelastic actions in the links, including yielding, bucking, and fracture of the steel plates or weld parts. This failure mode becomes more complex and results in highly nonlinear behavior using Low-Yield-Point (LYP) steels for the construction of the links due to their high strain hardening capacities. The existing analytical models have been presented for links made of normal steel grades, and thus there is a substantial research need for developing an analytical model to capture the actual behavior of links made of LYP steels. To fill this gap, this paper developed both shear-hinge and shear-spring-based models for performance-based evaluation of EBFs equipped with LYP steel shear links, which are more practical models in general-purpose structural analysis programs. The accuracy of the proposed model was assessed by comparing it with existing experimental tests and analytical models. As a result, there is good agreement between the proposed model and test results in terms of initial stiffness, post-yielding stiffness, and strength, which shows significant improvement over existing analytical models. [ABSTRACT FROM AUTHOR]

This study investigates the impact of regional climate changes on the production, quality, chemical composition, and phenological patterns of Rioja wine in Spain from 1993 to 2017. Data from DOCa Rioja and the Marqués de Riscal winery were analyzed in conjunction with meteorological and remote sensing data to provide a comprehensive evaluation. The findings reveal an increase in alcohol content and pH, coupled with a decrease in acidity, correlative to phenological shifts such as earlier grape ripening and reduced leaf canopy. Additionally, a thorough examination of monthly climate anomalies highlights the significance of May in determining harvest outcomes, influenced by the Eastern Atlantic (EA) mode of low-frequency variability. The potential connection between springtime weather conditions and tropical climate variability is also explored. [ABSTRACT FROM AUTHOR]

Long-term changes in climate variability represent an important aspect of climate change, with various impacts on society and environment. In this study, we analyze outputs from 13 CMIP6 global climate models (GCMs) across the North Atlantic–European domain, focusing on their simulations of precipitation probability and short-term variability in both historical and future climates. Precipitation probability denotes the probability of a wet day (> 1 mm), and precipitation variability reflects the tendency to cluster wet days into sequences. By comparing against the ERA5 reanalysis, we found that the GCMs tend to overestimate precipitation probability across Europe in winter, whereas in summer, they have a tendency to underestimate it around 50°N. Precipitation variability is, on average, underestimated by the GCMs in summer, while overestimated in several regions in winter. Projections for the end of the twenty-first century indicate significant changes in both precipitation probability and variability which are more pronounced under the more pessimistic emission scenario compared to the moderate one. We found that the changes in probability and variability are mutually independent: the former being more latitudinal-dependent while the latter differs between the west and east. After identifying atmospheric circulation conducive and non-conducive to precipitation occurrence, we found that GCMs overestimating the frequency of conducive circulation tend to overestimate precipitation probability, and vice versa. Furthermore, increased precipitation variability is associated with higher circulation variability. Finally, our analysis reveals that projected changes in precipitation probability and variability are often linked to projected changes in atmospheric circulation, especially in winter. [ABSTRACT FROM AUTHOR]

A primary challenge of terahertz communications is the high free-space path loss experienced by THz signals, rendering omnidirectional antennas inadequate for communications needs in this spectral range. One possible solution lies in using types of antennas that emit radiation in specific directions, such as leaky-wave antennas (LWAs), in order to direct power in the exact direction of the receiver. However, for an arbitrary arrangement of receivers, designing an antenna that emits power in all of their directions while avoiding wasting power elsewhere is a significant challenge. In this paper, we propose an irregular, aperiodic design schema for LWAs that can generate emission maxima simultaneously at a variety of angles. We combine this novel antenna architecture with the power of neural networks in order to build a model that can accurately and quickly select a design from among the extremely large set of options, that will produce a desired far-field signal. Combined with the ability to perform experimental tests using rapid-prototyping methods, we propose an end-to-end solution for antenna design that allows researchers to both generate and fabricate a slot design for some chosen far-field signal within minutes, reducing the need for lengthy finite-element calculations or tedious trial-and-error experiments. [ABSTRACT FROM AUTHOR]

Numerous studies have sought to determine whether low self-esteem acts as a risk factor for depressive symptoms (i.e., a vulnerability model) or whether depressive symptoms lead to a decrease in self-esteem (i.e., a scar model). Although both models have received some support, very little research has: (a) addressed this question across critical life transitions likely to modify this pattern of associations, such as the transition to adulthood; (b) sought to identify the psychological mechanisms (i.e., mediators) underpinning these associations. The present study was designed to address these two limitations, focusing on the directionality of the associations between depressive symptoms and self-esteem from mid-adolescence to early adulthood while considering the role of motivational factors, namely mastery (intrinsic/extrinsic) and performance (approach/avoidance) goals as conceptualized in achievement goal theory. A sample of 707 Finnish adolescents aged 15–16 (52.1% boys) was surveyed six times up to the age of 25. Results from a cross-lagged panel model (CLPM) revealed that depressed individuals were more likely to have low self-esteem, although self-esteem protected against depressive symptoms between ages 16–17 to 20–21. Moreover, while self-esteem promoted mastery-extrinsic goals which in turn reinforced self-esteem, depressive symptoms promoted performance-avoidance goals which led to more depressive symptoms and lower self-esteem. Overall, these findings highlight (1) the long-lasting negative consequences of depressive symptoms on self-esteem and (2) the crucial role played by academic motivation in explaining the development of depressive symptoms and self-esteem over time. In turn, these results help refine the vulnerability and scar models, and suggest that motivational factors should be considered in prevention and intervention efforts among young populations. [ABSTRACT FROM AUTHOR]

The extracellular parasite Trypanosoma brucei evades the immune system of the mammalian host by periodically exchanging its variant surface glycoprotein (VSG) coat. Hereby, only one VSG gene is transcribed from one of 15 subtelomeric so-called bloodstream form expression sites (BES) at any given timepoint, while all other BESs are silenced. VSG gene expression is altered by homologous recombination using a large VSG gene repertoire or by a so-called in situ switch, which activates a previously silent BES. Transcriptional activation, VSG switching and VSG silencing during developmental differentiation from the bloodstream form to the procyclic form present in the tsetse fly vector are tightly regulated. Due to their subtelomeric position, telomere-associated proteins are involved in the regulation of VSG expression. Three functional homologs of mammalian telomere complex proteins have been characterized thus far, and novel telomere-interacting proteins, such as telomere-associated protein 1 (TelAP1), have recently been identified. Here, we used mass spectrometry-based proteomics and interactomics approaches, telomere pull-down assays with recombinant material and immunofluorescence analysis to elucidate the interactions of 21 other putative TelAPs. We investigated the influence on VSG expression and showed that depletion of TelAPs does not ultimately lead to changes in VSG expression. Additionally, we examined the interaction patterns of four TelAPs with the TbTRF/TbTIF2/TbRAP1 telomere complex by reciprocal affinity purification. We further propose that TelAP1 interacts with Tb927.6.4330, now called TelAP2, and that TelAP1 depends on this interaction to form a complex with the telomeric proteins TbTRF, TbTIF2 and TbRAP1. [ABSTRACT FROM AUTHOR]

This study investigated maternal oxytocin, caregiving sensitivity and mother-to-infant bonding at 3-months postpartum as predictors of child behavior and psychological outcomes in the preschool years, when controlling for concurrent maternal negative emotional symptoms and adult attachment state-of-mind. Forty-five mother–child dyads were assessed at 3-months and 3.5 years postpartum using mix of questionnaires, observational, interview and biological methods. Results showed that lower levels of maternal baseline oxytocin at 3-months postpartum significantly predicted emotional reactivity in the child at 3.5 years. When maternal adult attachment state-of-mind and negative emotional symptoms were included, lower levels of maternal baseline oxytocin at 3-months postpartum significantly predicted withdrawn child behavior. In addition, unresolved adult attachment and maternal negative emotional symptoms were significantly associated child behavioral disturbance in a range of areas. Findings highlight maternal postnatal oxytocin as a potential indicator of children who may be more likely to show emotional reactivity and withdrawn behavior in the preschool years. [ABSTRACT FROM AUTHOR]

Emotional reactivity has been linked to adolescent psychopathology and mental health problems. However, limited research has investigated the distinct associations between emotional reactivity in multiple interpersonal contexts and the development of adolescent psychopathology. The current study examined emotional reactivity to interparental conflict, parent-adolescent conflict, and school problems as predictors of adolescent internalizing problems, depressive symptoms, and anxiety symptoms six months later. The sample included 139 adolescents (54% girls; Mage = 13.30, SDage = 0.73) and their parents who completed 10-day daily reports and 6-month follow-up assessments in Taiwan. Results showed that negative emotional reactivity to interparental conflict was associated with increased internalizing problems, depressive symptoms, and anxiety symptoms, after controlling for emotional reactivity to parent-adolescent conflict and school problems, outcomes at baseline, mean negative emotions, and sex. Furthermore, the associations between both positive and negative emotional reactivity to interparental conflict and adolescent anxiety symptoms was stronger for girls than boys. Findings suggested that heightened emotional reactivity to interparental conflict is a risk factor for predicting adolescent psychopathology, especially for girls' anxiety symptoms. Results highlight the importance of emotional reactivity across multiple interpersonal contexts in adolescence. [ABSTRACT FROM AUTHOR]

Background: Gout, a prevalent form of inflammatory arthritis, has a complex etiology where the causal relationship between metabolites and the disease remains underexplored. This study aims to elucidate the impact of genetically determined blood metabolites on gout. Methods: Employing a two-sample bidirectional Mendelian randomization analysis, we examined the association between 1400 blood metabolites and gout. Causal associations were determined using the inverse variance weighted (IVW) method with false discovery rate (FDR) correction. Sensitivity analyses encompassed weighted models, MR-Egger, weighted median, and MR-PRESSO approaches. MR-pleiotropy and Cochran's Q statistic were utilized to evaluate potential heterogeneity and pleiotropy. Additionally, metabolic pathway analyses were conducted to pinpoint relevant pathways. Results: Of the initial 4 serum metabolites identified, 3 known metabolites—hexanoylglutamine levels, mannose content, and the phosphate to mannose ratio—were found to be causally associated with gout, along with 55 serum metabolites identified as potential predictors of gout (PIVW < 0.05). Furthermore, we discovered 3 metabolic pathways implicated in gouty attacks. Conclusion: Our findings, derived from Mendelian randomization, indicate that the identified metabolites and pathways may serve as biomarkers for clinical screening and prevention of gout. Additionally, they offer novel insights into the mechanisms of the disease and potential drug targets. Key points • Conducted a comprehensive Mendelian randomization study involving 1400 blood metabolites to explore their genetic impact on gout development and progression • Identified three key metabolites—hexanoylglutamine, mannose, and the phosphate-to-mannose ratio—with causal associations to gout, highlighting their potential use as biomarkers for early detection and risk stratification • Discovered 55 additional serum metabolites as potential predictors of gout, offering new insights into the pathophysiology of the disease and identifying high-risk individuals • Revealed three novel metabolic pathways involved in gout attacks, providing new therapeutic targets for precision medicine in gout treatment [ABSTRACT FROM AUTHOR]

Some aspects of the relationship between ascorbate (Asc) metabolism and the functioning of mitochondrial alternative oxidase (AOX) under moderately high light (MHL, 400 μmol m−2 s−1) using Arabidopsis thaliana mutant lines were studied. After 8 h of MHL in the AOX1a antisense line (AS-12), decreasing the relative reduced Asc pool due to increased ascorbate peroxidase activity was accompanied by the accumulation of a pool of the other highly effective antioxidant – glutathione. In the vitamin C-deficient line (vtc2), VTC2 expression and the Asc pool were expectedly low, and after 8 h of MHL, dehydroascorbate (DHA) content was increased, although slight activation of AOX and L-galacton-1,4-lactone dehydrogenase was detected. In the AOX-inhibited vtc2 line after 8 h of MHL, both the DHA levels and cytochrome pathway capacity increased. Interestingly, the suppression of AOX in the AS-12 line had a negative effect on the ATP content, whereas the activation of AOX in the vtc2 line improved the energy balance in MHL conditions. Possible mechanisms of interaction at the level of the ascorbate–glutathione hub and mitochondrial electron transport pathways, mediated through Asc synthesis, for the regulation of energy balance and Asc metabolism during plant adaptation to high light are discussed. [ABSTRACT FROM AUTHOR]

Local types of coinage testify to the emerging use of silver in the Balkan interior, possibly related to abundant ore deposits in the region. Here, we present Pb isotope data for silver coins minted by local tribes and settlements (anepigraphic coins attributed to the Derrones/Laeaei, Damastion, Pelagia, Kings of Paeonia) between the 5th and 3rd centuries BCE. For comparison, we analysed coinage of the potential Greek emporia Dyrrhachium and Apollonia for their main element and Pb-Ag isotope compositions. Statistical data evaluation demonstrates close material connections between coins from the Balkan interior and identify a predominantly local raw material provenance. The majority of Damastion’s issues defines a tight cluster fitting Strabo’s (VII.7.8) account that the settlement possessed nearby silver mines in the Balkan interior. Novobërdë/Novo Brdo (Kosovo) can be plausibly hypothesised among the available reference data to have been one of the main ore districts supplying the mint. Mixing is evident for coins from the Kings of Paeonia and coinage attributed to the Derrones/Laeaei. Virtually identical end-members suggest that Paeonian regal coinage recycled tribal issues with contribution of metal obtained from Damastion’s hypothesised mines. Contemporaneous coinage struck by Dyrrhachium as well as end-members calculated for Thasos and the Macedon kingdom (Albarede et al. in Bullion mixtures in silver coinage from ancient Greece and Egypt, J Archaeol Sci 162:105918, 2024a) signal metal sourced from the Balkans, presumably the Macedonian/Paeonian border area. Comparison of data from Greek city-states and coinage issued by Apollonia and Dyrrhachium for the Romans demonstrates a change in the type and origin of raw materials and bullion composition, indicating a shift in monetary customs and possibly metal production technology. [ABSTRACT FROM AUTHOR]

Abstract Complex networks are mathematical abstractions of real-world systems using sets of nodes and edges representing the entities and their interactions. Prediction of unknown interactions in such networks is a problem of interest in biology, sociology, physics, engineering, etc. Most complex networks exhibit the recurrence of subnetworks, called network motifs. Within the realm of social science, link prediction (LP) models are employed to model opinions, trust, privacy, rumor spreading in social media, academic and corporate collaborations, liaisons among lawbreakers, and human mobility resulting in contagion. We present an LP metric based on a motif in directed complex networks, called feed-forward loop (FFL). Unlike nearest neighbor-based metrics and machine learning-based techniques that gauge the likelihood of a link based on node similarity, the proposed approach leverages a known dichotomy in the motif distribution of directed networks. Complex networks are sparse, causing most nodes and their associated links to have low motif participation. Yet, due to intrinsic network motif-richness, few links participate in many distinct motif substructures. Thus, the FFL-based metric combines the presence and absence of motifs as a signature to outperform baseline metrics on ten directed social and biological network datasets. We conclude with the future of the FFL-based metric in dynamic network inference as well as its use in designing combined metrics using network motifs of varying orders as features.

Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20-1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including L-valine and uric acid, potentially mediating the haem iron-T2D relationship, highlighting their pivotal role in T2D pathogenesis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The trophic organization of estuarine fish communities is poorly known. We used Stable Isotopes (δ13C and δ15N) to classify the most abundant fishes of the Atrato River Delta (Colombia) into trophic guilds. We examined trophic niches and the relationships between the abundance of the trophic guilds (catch per unit effort) and environmental variables. The zoobenthivores were the dominant trophic guild. The isotopic niche width, based on Bayesian estimate of the standard ellipse areas, was more significant for carnivores (25.3‰2) and planktivores (24.4‰2) than for omnivores (7.8‰2) and phytobenthivores (3.1‰2). The overlap combinations showed a medium probability of isotopic overlap (≈50%) between carnivores and planktivores and between carnivores and omnivores. Isotopic niche size and overlap suggested diversity in food sources and considerable niche segregation of the fish community. Mangrove area was the main factor explaining the abundance of omnivores and zoobenthivores, supporting that the causal links between mangrove habitat and local fishery production may be explained through the trophic contribution of mangroves and mangrove-related sources. The results underscore the importance of mangrove areas in the trophic organization of fish communities and can inform strategies aimed at managing the ecosystem impacts of fishing and protecting extensive mangrove areas in the southern Caribbean. [ABSTRACT FROM AUTHOR]

Adolescent sleep and mental health are closely linked; however, less is known regarding how unique patterns of sleep influence youth mental health. This study aimed to identify subgroups of adolescent sleepers, demographic predictors of subgroup membership, and their prospective links with mental health outcomes. Youth from the National Longitudinal Study of Adolescent to Adult Health (N = 5411; 51.8% female) self-reported sleep (duration, sufficiency, problems, bedtime), depressive symptoms, alcohol use, cannabis use, and demographics at baseline (W1; 1994–1995; Mage = 15.06) and 1 year later (W2; 1996). Latent profile analysis revealed three sleep profiles: Optimal (highest quantity/quality, earliest bedtime), Low-Quantity/Later Bedtime (lowest duration/sufficiency, latest bedtime), and Low-Quality (highest problems). Several demographic covariates were associated with profiles. Less-optimal profiles were associated with greater W2 depressive symptoms and substance use, controlling for W1 levels. Youth with low-quantity/later bedtimes were especially at-risk for cannabis use. Results may inform interventions seeking to improve adolescent mental health by targeting multiple aspects of sleep. [ABSTRACT FROM AUTHOR]

This paper studies how to design a control scheme for a complex dynamical network (CDN) such that the state of nodes and links can track on any given reference signals respectively, under the view that the CDN is coupled by the nodes and links. Since the dynamic behavior of the links reflects the changes in network topology(NT), the weights of the links are regarded as state variables of the NT. In addition, since the state of the links is not always avaluable in practical engineering applications, in order to address this problem, this paper provides an asymptotical state observer that uses its observation values to estimate the links state. Based on this, this paper proposes a new control scheme which designs controllers in the nodes and links respectively, to realize the asymptotical tracking control of the nodes and links. In order to understand the NT tracking target, an illustrative example is that the star topology can be chosen as the NT tracking target of communication transmission network for the centralized management. Finally, the validity of the theoretical results is verified by a numerical experiment that applies the control scheme to a helicopter model. [ABSTRACT FROM AUTHOR]

We introduce the notion of a (strongly) inner non-degenerate mixed function f : C 2 → C. We show that inner non-degenerate mixed polynomials have weakly isolated singularities and strongly inner non-degenerate mixed polynomials have isolated singularities. Furthermore, under one additional assumption, which we call “ Γ -niceness”, the links of these singularities can be completely characterized in terms of the Newton boundary of f. In particular, adding terms above the Newton boundary does not affect the topology of the link. [ABSTRACT FROM AUTHOR]

In this paper, we improve networks' spectral efficiency (SE), extend networks' lifetime, and maximize networks' energy efficiency (EE) of two-way full-duplex (FD) relay networks. Firstly, to improve networks' SE and to extend networks' lifetime simultaneously, we design a two-way FD relay transmission strategy with simultaneous wireless information and power transfer and direct links (DLs). The designed transmission strategy can complete a bidirectional communication in only one time slot with the exists of DLs and the energy-constrained relay node. With the designed transmission strategy, we further give the characteristics of relay amplification factor, the analysis of the designed transmission strategy, and the EE analysis of traditional half-duplex two-way amplify-and-forward relaying. Secondly, to maximize networks' EE, we present both the EE maximization problems and analyses of the designed transmission strategy with equal power allocation and optimal power allocation. To solve the EE maximization problems, we further propose the alternating optimal algorithm and give complexity analysis of the algorithm. Simulations show that our designed transmission strategy can improve the SE and EE of the networks. [ABSTRACT FROM AUTHOR]

Call a polyhedron in a three-dimensional hyperbolic space generalized if finite, ideal, and truncated vertices are admitted. By Belletti's theorem of 2021 the exact upper bound for the volumes of generalized hyperbolic polyhedra with the same one-dimensional skeleton equals the volume of an ideal right-angled hyperbolic polyhedron whose one-dimensional skeleton is the medial graph for . We give the upper bounds for the volume of an arbitrary generalized hyperbolic polyhedron such that the bounds depend linearly on the number of edges. Moreover, we show that the bounds can be improved if the polyhedron has triangular faces and trivalent vertices. As application we obtain some new upper bounds for the volume of the complement of the hyperbolic link with more than eight twists in a diagram. [ABSTRACT FROM AUTHOR]

Traditionally, alternating links are studied with alternating diagrams on S 2 in S 3 . In this paper, we consider links which are alternating on higher genus surfaces F in thickened surface F × I . We define what it means for such a link to be right-angled generalized completely realizable (RGCR) and show that this property is equivalent to the link having two totally geodesic checkerboard surfaces, equivalent to each checkerboard surface consisting of one type of polygon, and equivalent to a set of restrictions on the link’s alternating projection diagram. We then use these diagram restrictions to classify RGCR links according to the polygons in their checkerboard surfaces, provide a bound on the number of RGCR links for a given surface of genus g, and find a right-angled knot in a thickened surface. Along the way, we answer a question posed by Champanerkar, Kofman, and Purcell about links with alternating projections on the torus. [ABSTRACT FROM AUTHOR]

Despite ongoing climate change and warming, extreme cold events still negatively affect human society. Since cold air incursions are related to specific circulation patterns, the main aims of this study are (1) to validate how well current EURO-CORDEX regional climate models (RCMs) reproduce these synoptic links and (2) to assess possible future changes in atmospheric circulation conducive to cold events. Using anomalies of daily minimum temperature, we define cold days (CDs) in central Europe and analyse their characteristics over the historical (1979−2020) and future (2070−2099) periods. We classify wintertime atmospheric circulation by applying a novel technique based on Sammon mapping to the state-of-the-art ERA5 reanalysis output. We discover that circulation types (CT) conducive to CDs are characterised by easterly advection and/or clear-sky anticyclonic conditions. While the RCM ensemble generally reproduces these synoptic links relatively well, we observe biases in the occurrence of CDs in individual simulations. These biases can be attributed to inadequately reproduced frequencies of CTs conducive to CDs (primarily propagating from driving data), as well as to deviations in the conduciveness within these CTs (primarily originating in the RCMs). Interestingly, two competing trends are identified for the end of the twenty-first century: (1) most RCMs project an increased frequency of CTs conducive to CDs, suggesting more frequent CDs, while (2) the same CTs are projected to warm faster compared to their counterparts, suggesting weaker CDs. The interplay between these opposing trends contributes to the overall uncertainty surrounding the recurrence and severity of future winter extremes in central Europe. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) and gut microbiota (GM) are epidemiologically correlated but the causal inter-relationships remain poorly understood. We aim to explore the causal relationships between GM and PBC. Using the MiBioGen consortium, GWAS data for GM at the species level and the largest publicly available PBC GWAS data to date, we performed a bidirectional two-sample Mendelian randomization by the inverse variance weighted, MR-Egger, weighted median, weighted model and MR-PRESSO to elucidate the potential causal role of GM in PBC. To measure the heterogeneity of instrumental variables (IV), Cochran's Q statistic and MR-Egger intercept test were used. Genetically instrumented order Coriobacteriales (odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.30–3.66, P = 0.004) significantly increased the risk for PBC, while genetically driven class Deltaproteobacteria (OR = 0.52, 95% CI 0.36–0.74, P = 0.002) causally decrease the NAFLD risk. Reverse MR analysis showed no significant association between PBC and the two specific GM. However, it indicated that PBC progression significantly increases the abundance of the class Bacteroidia, order Bacteroidales, and phylum Bacteroidetes (OR = 1.02, 95% CI 1.002–1.03, P = 0.026), while decreasing the abundance of the genus Lachnospiraceae UCG010 (OR = 0.98, 95% CI 0.96–0.995, P = 0.026). Our study demonstrated that genetically driven order Coriobacteriales and class Deltaproteobacteria were causally related to PBC risk. This causality provided a new perspective on ameliorating PBC by modulating GM. Our study demonstrated that genetically driven order Coriobacteriales and class Deltaproteobacteria were causally related to PBC risk. PBC was causally related to the abundance of four GM taxa(class Bacteroidia, order Bacteroidales, phylum Bacteroidetes and genus Lachnospiraceae UCG010). This causality provided a new perspective on ameliorating PBC by modulating GM. [ABSTRACT FROM AUTHOR]

Although primarily studied in relation to photorespiration, serine metabolism in chloroplasts may play a key role in plant CO2 fertilization responses by linking CO2 assimilation with growth. Here, we show that the phosphorylated serine pathway is part of a 'photosynthetic C1 pathway' and demonstrate its high activity in foliage of a C3 tree where it rapidly integrates photosynthesis and C1 metabolism contributing to new biomass via methyl transfer reactions, imparting a large natural 13C-depleted signature. Using 13CO2-labelling, we show that leaf serine, the S-methyl group of leaf methionine, pectin methyl esters, and the associated methanol released during cell wall expansion during growth, are directly produced from photosynthetically-linked C1 metabolism, within minutes of light exposure. We speculate that the photosynthetic C1 pathway is highly conserved across the photosynthetic tree of life, is responsible for synthesis of the greenhouse gas methane, and may have evolved with oxygenic photosynthesis by providing a mechanism of directly linking carbon and ammonia assimilation with growth. Although the rise in atmospheric CO2 inhibits major metabolic pathways like photorespiration, our results suggest that the photosynthetic C1 pathway may accelerate and represents a missing link between enhanced photosynthesis and plant growth rates during CO2 fertilization under a changing climate. A photosynthetic C1 pathway starting with CO2 and NH3 assimilation and ending with methionine synthesis is highly active in foliage of a C3 tree, where it rapidly integrates photosynthesis and C1 metabolism contributing to new biomass via methyl transfer reactions. [ABSTRACT FROM AUTHOR]

This study examined the presence of autistic traits in a sample of adult women diagnosed with different Eating Disorders (ED), and explored the concurrent role of autistic traits and sensory sensitivity in influencing both their eating disorder symptomatology and their autism-related eating behaviours. Seventy-five women with different ED (Anorexia Nervosa, Bulimia Nervosa, Binge-Eating Disorder, Other Specified Feeding or Eating Disorder) completed the Eating Attitude Test (EAT-26), the Autism Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), the Sensory Perception Quotient - Short Form 35 item (SPQ-SF35) and the Swedish Eating Assessment for Autism Spectrum Disorders (SWEAA). Twelve percent of participants scored above the cut-off on both the AQ and the RAADS-R, while 68% scored above the cut-off on the RAADS-R only. A mediation analysis revealed that the association between sensory sensitivity (SPQ-SFR35) and scores on both the EAT-26 and the SWEAA was significantly mediated by the presence of autistic traits (RAADS-R). These findings, first, confirm the presence of autistic traits in individuals with ED; second, they show that a lower sensory threshold (i.e., a higher sensory sensitivity) is associated with a higher presence of autistic traits which were, in turn, positively associated with dysfunctional eating behaviours typical of ED and ASD. This study ultimately highlights the importance of further research on autistic traits across all diagnostic categories of ED. [ABSTRACT FROM AUTHOR]

Introduction: Whereas (GCC)-repeats are overrepresented in genic regions, and mutation hotspots, they are largely unexplored with regard to their link with natural selection. Across numerous primate species and tissues, SMAD9 (SMAD Family Member 9) reaches highest level of expression in the human brain. This gene contains a (GCC)-repeat in the interval between + 1 and + 60 of the transcription start site, which is in the high-ranking (GCC)-repeats with respect to length. Methods: Here we sequenced this (GCC)-repeat in 396 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 181) and controls (N = 215). Results: We detected two predominantly abundant alleles of 7 and 9 repeats, forming 96.2% of the allele pool. The (GCC)7/(GCC)9 ratio was in the reverse order in the NCD group versus controls (p = 0.005), resulting from excess of (GCC)7 in the NCD group (p = 0.003) and (GCC)9 in the controls (p = 0.01). Five genotypes, predominantly consisting of (GCC)7 and lacking (GCC)9 were detected in the NCD group only (p = 0.008). The patients harboring those genotypes received the diagnoses of Alzheimer's disease (AD) and vascular dementia (VD). Five genotypes consisting of (GCC)9 and lacking (GCC)7 were detected in the control group only (p = 0.002). The group-specific genotypes formed approximately 4% of the genotype pool in the human samples studied. Conclusion: We propose natural selection and a novel locus for late-onset AD and VD at the SMAD9 (GCC)-repeat in humans. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic systemic disease, which results in endometrial-type tissue growing outside the uterus, and affects approximately 10% of reproductive-aged women worldwide. Its aetiology is poorly understood, and there is currently no long-term cure. Development and persistence of the disease depend on several coexisting factors including the vaginal microbiome. However, the role played by this important entity in endometriosis and its systemic involvement is not fully understood. Here, we investigated the vaginal microbiota, the serum and urine glycome, and antibody glycosylation in endometriosis patients. We reveal an endometriosis-specific vaginal microbiota in patients, being distinct from that present in a control group. Endometriosis patients were typified by a loss of the dominant Lactobacillus species, i.e. Lactobacillus iners, increased bacterial diversity and the presence of species such as Anaerococcus senegalensis, Prevotella jejuni, Porphyromonas bennonis and Anaerococcus octavius. The presence of trigalactosylated and triantennary serum glycans and urine core fucosylated mono-antennary glycans from IgG correlated with the vaginal presence of the bacterium A. senegalensis in endometriosis patients. Urine glycans did not differ in endometriosis, but urine IgG identified four novel sulfated glycans differing from serum IgG indicating functional relevance. Our findings contribute to understanding the relationships between the vaginal microbiota and the serum and urine glycome on the one hand, and endometriosis on the other. Further functional studies are warranted. [ABSTRACT FROM AUTHOR]

In all domains of life, the biosynthesis of the pterin-based Molybdenum cofactor (Moco) is crucial. Molybdenum (Mo) becomes biologically active by integrating into a unique pyranopterin scaffold, forming Moco. The final two steps of Moco biosynthesis are catalyzed by the two-domain enzyme Mo insertase, linked by gene fusion in higher organisms. Despite well-understood Moco biosynthesis, the evolutionary significance of Mo insertase fusion remains unclear. Here, we present findings from Neurospora crassa that shed light on the critical role of Mo insertase fusion in eukaryotes. Substituting the linkage region with sequences from other species resulted in Moco deficiency, and separate expression of domains, as seen in lower organisms, failed to rescue deficient strains. Stepwise truncation and structural modeling revealed a crucial 20-amino acid sequence within the linkage region essential for fungal growth. Our findings highlight the evolutionary importance of gene fusion and specific sequence composition in eukaryotic Mo insertases. Convergent evolution of Mo insertase fusion reveals species-specific sequences critical for Moco biosynthesis in N. crassa, providing new insights into the role of gene fusion in enzyme function and evolutionary adaptation. [ABSTRACT FROM AUTHOR]

Obesity is a global health issue that is intricately linked to the development and progression of chronic liver disease (CLD). This bidirectional connection, coupled with the obesity paradox (OP), presents a management dilemma. The established influence of obesity on the development and progression of chronic liver disease (CLD) is surpassed by the liver's impact on the onset and advancement of obesity. Patients with CLD always experience increased energy expenditure, reduced appetite, and low protein synthesis, all of which might lead to weight loss. However, metabolic disturbances, hormonal imbalances, inflammatory signaling, immobility, drugs, and alterations in nutrient metabolism can contribute to the development and exacerbation of obesity. Despite the propagation of the OP concept, none of the guidelines has changed, recommending being overweight. Research bias and confounders might be the lifebuoy explanation. Additionally, overlooking the lethal morbidities of obesity for survival benefits full of suffering seems to be an illogical idea. Therefore, rather than endorsing an overweight status, emphasis should be placed on improving cardiorespiratory fitness and preventing sarcopenia to achieve better outcomes in patients with CLD. Accordingly, the complex interplay between obesity, CLD, and the concept of OP requires a sophisticated individualized management approach. Maximizing cardiorespiratory fitness and mitigating sarcopenia should be considered essential strategies for attaining the most favourable outcomes in patients with chronic liver disease (CLD). [ABSTRACT FROM AUTHOR]

Visceral obesity (VO), characterized by excess fat around internal organs, is a recognized risk factor for gynecological tumors, including benign uterine leiomyoma (ULM) and malignant uterine leiomyosarcoma (ULS). Despite this association, the shared molecular mechanisms remain underexplored. This study utilizes an integrated bioinformatics approach to elucidate common molecular pathways and identify potential therapeutic targets linking VO, ULM, and ULS. We analyzed gene expression datasets from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) in each condition. We found 101, 145, and 18 DEGs in VO, ULM, and ULS, respectively, with 37 genes overlapping across all three conditions. Functional enrichment analysis revealed that these overlapping DEGs were significantly enriched in pathways related to cell proliferation, immune response, and transcriptional regulation, suggesting shared biological processes. Protein–protein interaction network analysis identified 14 hub genes, of which TOP2A, APOE, and TYMS showed significant differential expression across all three conditions. Drug-gene interaction analysis identified 26 FDA-approved drugs targeting these hub genes, highlighting potential therapeutic opportunities. In conclusion, this study uncovers shared molecular pathways and actionable drug targets across VO, ULM, and ULS. These findings deepen our understanding of disease etiology and offer promising avenues for drug repurposing. Experimental validation is needed to translate these insights into clinical applications and innovative treatments. [ABSTRACT FROM AUTHOR]

Elucidating the molecular dependencies behind the cancer-type specificity of driver mutations may reveal new therapeutic opportunities. We hypothesized that developmental programs would impact the transduction of oncogenic signaling activated by a driver mutation and shape its cancer-type specificity. Therefore, we designed a computational analysis framework by combining single-cell gene expression profiles during fetal organ development, latent factor discovery, and information theory-based differential network analysis to systematically identify transcription factors that selectively respond to driver mutations under the influence of organ-specific developmental programs. After applying this approach to VHL mutations, which are highly specific to clear cell renal cell carcinoma (ccRCC), we revealed important regulators downstream of VHL mutations in ccRCC and used their activities to cluster patients with ccRCC into three subtypes. This classification revealed a more significant difference in prognosis than the previous mRNA profile-based method and was validated in an independent cohort. Moreover, we found that EP300, a key epigenetic factor maintaining the regulatory network of the subtype with the worst prognosis, can be targeted by a small inhibitor, suggesting a potential treatment option for a subset of patients with ccRCC. This work demonstrated an intimate relationship between organ development and oncogenesis from the perspective of systems biology, and the method can be generalized to study the influence of other biological processes on cancer driver mutations. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the possible relationship between the recent global warming and the interdecadal changes in incoming surface solar radiation (SSR), known as global dimming and brightening (GDB). The analysis is done on a monthly and annual basis on a global scale for the 35-year period 1984–2018 using surface temperature data from the European Centre for Medium-Range Weather Forecasts (ECMWF) v5 (ERA5) reanalysis and SSR fluxes from the FORTH (Foundation for Research and Technology-Hellas) radiative transfer model (RTM). Our analysis shows that on a monthly basis, SSR is correlated with temperature more strongly over global land than ocean areas. According to the RTM calculations, the SSR increased (inducing brightening) over most land areas during 1984–1999, while this increase leveled-off (causing dimming) in the 2000s and strengthened again in the 2010s. These SSR fluctuations are found to affect the global warming rates. Specifically, during the dimming phase in the 2000s, the warming rates across land areas with intense anthropogenic pollution, like Europe and East Asia, slowed down, while during the brightening phases, in the 1980s, 1990s and 2010s, the warming rates were reinforced. Although the magnitude of GDB and the Earth’s surface warming trends are not proportional, indicating that GDB is not the primary driver of the recent global warming, it seems that GDB can affect the warming rates, partly counterbalancing the dominant greenhouse warming during the dimming or accelerating the greenhouse-induced warming during the brightening phases of GDB. [ABSTRACT FROM AUTHOR]

Young people are navigating an increasingly uncertain and unstable social and economic environment, further complicated by COVID-19. Individual resources and vulnerabilities, such as mental health and sensitivity to stress, play a significant role in how well youth adapt to the career paths and living conditions altered by the pandemic, a dynamic that is not yet well understood. This study examined the role of COVID-19 on the intertwined relation between perceived stress and depressiveness (negative and positive affect) in adolescents, focusing on gender differences. Longitudinal data from 673 German adolescents (Mage = 16.8 years, SDage = 0.91; female = 59%) were collected in three waves, before (T1) and during the pandemic (T2, T3). Using Latent Change Score models, the bidirectional relation between perceived stress and depressiveness was analyzed, considering gender as a moderator. The results showed that adolescents who found their situation stressful were at risk of developing depressiveness at the outbreak of the pandemic and throughout its progression. As the pandemic progressed, an increase in positive affect was linked to heightened perceived stress. Gender-specific differences were particularly evident in the levels of perceived stress and depressiveness, with women being more vulnerable. This study highlights how vulnerabilities in stress perception affect adolescents' mental health, with gender-specific differences underscoring the need for tailored mental health measures. [ABSTRACT FROM AUTHOR]

Language is supported by a distributed network of brain regions with a particular contribution from the left hemisphere. A multi-level understanding of this network requires studying its genetic architecture. We used resting-state imaging data from 29,681 participants (UK Biobank) to measure connectivity between 18 left-hemisphere regions involved in multimodal sentence-level processing, as well as their right-hemisphere homotopes, and interhemispheric connections. Multivariate genome-wide association analysis of this total network, based on genetic variants with population frequencies >1%, identified 14 genomic loci, of which three were also associated with asymmetry of intrahemispheric connectivity. Polygenic dispositions to lower language-related abilities, dyslexia and left-handedness were associated with generally reduced leftward asymmetry of functional connectivity. Exome-wide association analysis based on rare, protein-altering variants (frequencies <1%) suggested 7 additional genes. These findings shed new light on genetic contributions to language network organization and related behavioural traits. Common and rare genetic variants, as well as polygenic scores of dyslexia and handedness are associated with the functional brain language network and hemispheric differences within this network, shedding light on its developmental basis. [ABSTRACT FROM AUTHOR]

Some patients with polycystic ovarian syndrome (PCOS) suffered from metabolic syndrome (MetS) including dyslipidemia, hyperinsulinism, but the underlying mechanism is unclear. Although C-terminal Binding Protein 1 (CTBP1) is a transcriptional co-repressor frequently involved in hormone secretion disorders and MetS-associated diseases, the role of CTBP1 in PCOS is rarely reported. In the present study, we found that CTBP1 expression was significantly elevated in primary granulosa cells (pGCs) derived from the PCOS with MetS patients and was positively associated with serum triglyceride, but negatively correlated with serum estradiol (E2) or high-density lipoprotein. Mechanistic study suggested that CTBP1 physically bound to the promoter II of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) to inhibit the aromatase gene transcription and expression, resulting in the reduced E2 synthesis. Moreover, CTBP1 interacted with the phosphorylated SREBP1a at S396 in nuclei, leading to the FBXW7-dependent protein degradation, resulting in the reduced lipid droplets formation in pGCs. Therefore, we conclude that CTBP1 in GCs dysregulates the synthesis of steroid hormones and lipids through suppression of aromatase expression and promotion of SREBP1a protein degradation in PCOS patients, which may offer some fresh insights into the potential pathological mechanism for this tough disease.CTBP1 in granulosa cells of PCOS patients represses transcription of aromatase CYP19A1 and regulates stability of SREBP1a, which both contributes to dysregulation of hormone synthesis and lipid metabolism. [ABSTRACT FROM AUTHOR]