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Objectives

To calculate a polygenic risk score (PRS) based on single nucleotide variants (SNVs) previously associated with primary Sjögren’s disease (SjD) with genome-wide significance and determine the genetic risk for SjD stratified by antibodies, sex and age at diagnosis.

Methods

Patients with SjD (n = 1065) were genotyped using Illumina OmniExpressExome chip. Control genotype data were available (n = 7742). Two PRSs were constructed, one including HLA gene variants (n = 21 SNVs), and one without HLA (n = 18 SNVs). High PRS quartile (Q4) individuals were compared with low PRS (Q1–3).

Results

A high PRS was associated with SSA antibody-positive SjD (OR 9.16, 95% CI 7.75–10.85, P = 3.7 × 10⁻¹⁴⁶), and strengthened in SjD positive for both SSA/SSB antibodies (OR 13.67, 95% CI 10.88–17.32, P = 4.6 × 10⁻¹⁰⁸). High PRS classified SSA/SSB antibody-positive SjD with very good accuracy (AUC 0.86). PRS without HLA showed a weaker association with SSA/SSB positive SjD (OR 2.09, 95% CI 1.71–2.55, P = 6.4 × 10⁻¹³). Antibody negative SjD displayed a PRS similar to controls. Patients in the high PRS quartile were significantly younger at diagnosis, 48.9 ± 14.9 vs 53.4 ± 13.4 years in the low PRS quartiles (Q1–3), P = 2.2 × 10⁻⁶, and presented higher frequencies of ANA, SSA and SSA/SSB antibodies, P < 1 × 10⁻⁵.

Conclusion

A high PRS is associated with SSA/SSB antibody positivity and early disease onset, both largely attributed to the weight of the HLA alleles. Integration of PRS with other biomarkers applied to clinical phenotypes could be a useful tool for disease risk stratification and treatment decisions.

Chiral superconductors are topological as characterized by a finite Chern number and chiral edge modes. Direct fingerprints of chiral superconductivity are thus often taken to be spontaneous edge currents with associated magnetic signatures. However, a number of recent theoretical studies have shown that the total edge current along semi-infinite edges is greatly reduced or even vanishes in many scenarios for all pairing symmetries except chiral p wave, thus impeding experimental detection. We demonstrate how mesoscopic finite-sized samples can be designed to give rise to a shape-and size-dependent strong enhancement of the chiral edge currents and their generated orbital magnetic moment and magnetic fields. In particular, we find that low rotational symmetry systems, such as pentagons and hexagons, give rise to the largest currents, while circular disks also generate large currents but in the opposite direction. We estimate the resulting magnetic fields to be as large as 0.01-0.5 mT, with a magnetic moment approaching mu B/2 per Cooper pair, where mu B is the Bohr magneton. The current and magnetic signatures diverge with shrinking system sizes, eventually cut off by finite-size suppression of chiral superconductivity. We thus also extract the full phase diagram as a function of temperature and system size for different geometries, including competing superconducting orders. In geometries strongly suppressing only one of the d-wave components, we find an additional heat capacity jump, as large as 10% of the bulk normal-superconducting transition, marking the transition between a chiral and a nodal d-wave state. This further acts as an indirect signature of chiral superconductivity, measurable with nanocalorimetry. Our results are relevant for system sizes on the order of tens to hundreds of coherence lengths, and highlight mesoscopic patterning as a viable route to experimentally identify chiral d-wave superconductivity.

Eye-movement metrics like fixation location and duration are increasingly being used in infancy research. We tested whether fixation durations during meaningful social stimulus viewing involve common or different familial influences than fixation durations during viewing of abstract stimulus. We analysed the duration of fixations, and the allocation of fixations to face and motion, from 536 dizygotic and monozygotic 5-month-old twins in: naturalistic scenes including low- and high-level social features, and abstract scenes only having low-level features. We observed significant genetic influences in both conditions (h²_naturalistic = 0.30, 95% confidence interval (CI) 0.14 to 0.44; h²_abstract = 0.25, 95% CI 0.09 to 0.39), while shared environmental influences were negligible. Although some genetic influences were shared between the two conditions, unique genetic factors were linked to naturalistic scene viewing, indicating that fixation durations index different phenomena dependent on the context. Heritability for face looking was moderate (h² = 0.19, 95% CI 0.03 to 0.34), and no familial influences were found for motion looking. Exploratory polygenic score analyses revealed no significant associations with fixation measures. This study underscores the dissociable genetic influences on infants’ visual exploration of abstract versus naturalistic stimuli and the importance of considering context when interpreting eye-tracking data.

Multiple myeloma (MM) is a hematological disease of the plasma cell that remains clinically challenging despite the development of novel therapies. Epigenetic alterations have been demonstrated to contribute to MM pathogenesis, yet comprehensive studies into the links between different epigenetic regulatory systems in myeloma progression and drug resistance, though clinically relevant, are largely lacking. G9a and the DNA methyltransferases (DNMTs) are epigenetic modifiers that exhibit increased activity in MM, correlating with poor prognosis. To investigate the partnership between G9a and DNMTs, we used a combinatorial treatment approach involving small-molecule inhibitors. In-depth molecular analysis of the histone H3 lysine dimethylation distribution, the DNA methylome and the transcriptome of MM revealed a silencing mechanism involving G9a and DNMTs that represses key tumor suppressor genes. Moreover, dual inhibition of G9a and DNMTs reduced cell viability in primary MM cells and induced apoptosis in MM cell lines. This was accompanied by increased expression of apoptosis-related genes and decreased protein levels of the MM-associated oncoproteins IRF4, XBP1, and MYC. To assess the translational relevance of our in vitro findings, we evaluated the combination therapy in an in vivo preclinical xenograft MM model. Specifically, we demonstrate that the G9a inhibitor A366 synergizes with the DNMTs inhibitor decitabine to promote a robust tumor regression in vivo. Together, these data provide new insights into the cooperative role of G9a and the DNMTs in regulating gene silencing in MM, and support dual epigenetic inhibition as a promising therapeutic strategy.

Context. Mass loss through stellar winds governs the evolution of stars on the asymptotic giant branch (AGB). In the case of carbonrich AGB stars, the wind is believed to be driven by radiation pressure on amorphous carbon (amC) dust forming in the atmosphere. The structural complexity of amC is evident from the diversity of laboratory optical data that are available in the literature. Consequently, the choice of dust optical data will have a significant impact on atmosphere and wind models of AGB stars.

Aims.We compare two commonly used optical data sets of amC and investigate how the wind characteristics and photometric properties resulting from dynamical models of carbon-rich AGB stars are influenced by the micro-physical properties of dust grains.

Methods. We computed two extensive grids of carbon star atmosphere and wind models with the DARWIN 1D radiation-hydrodynamical code. A defining feature of these models is a self-regulating feedback between the time-dependent dynamics, grain growth, and dust optical properties. Thus, they are able to predict combinations of mass-loss rates, wind velocities, and grain sizes for given stellar parameters and micro-physical data. Each of the two grids uses a different amC optical data set. The stellar parameters of the models were varied in terms of the effective temperature, luminosity, stellar mass, carbon excess, and pulsation amplitude to cover a wide range of possible combinations. A posteriori radiative transfer calculations were performed for a sub-set of the models, resulting in photometric fluxes and colours.

Results. We find small, but systematic differences in the predicted mass-loss rates for the two grids. The grain sizes and photometric properties are affected by the different dust optical data sets. Higher absorption efficiency leads to the formation of a greater number of grains, which are smaller. Models that are obscured by dust exhibit differences in terms of the covered colour range compared to observations, depending on the dust optical data used.

Conclusions. An important motivation for this study was to investigate how strongly the predicted mass-loss rates depend on the choice of dust optical data, as these mass-loss values are more frequently used in stellar evolution models. Based on the current results, we conclude that mass-loss rates may typically differ by about a factor of two for DARWIN models of C-type AGB stars for commonly used dust optical data sets.

The bacterial chaperone Trigger factor (TF) binds to ribosome-nascent chain complexes (RNCs) and cotranslationally aids the folding of proteins in bacteria. Decades of studies have given a broad, but often conflicting, description of the substrate specificity of TF, its RNC-binding dynamics, and competition with other RNC-binding factors, such as the Signal Recognition Particle (SRP). Previous RNC-binding kinetics experiments were commonly conducted on stalled RNCs in reconstituted systems, and consequently, may not be representative of the interaction of TF with ribosomes translating mRNA in the cytoplasm of the cell. Here, we used single-particle tracking (SPT) to measure TF binding to actively translating ribosomes inside living Escherichia coli. In cells, TF displays distinct binding modes—longer (ca 1 s) and shorter (ca 50 ms) RNC bindings. Consequently, we conclude that TF, on average, stays bound to the RNC for only a fraction of the translation cycle. Further, binding events are interrupted only by transient excursions to a freely diffusing state (ca 40 ms), suggesting a highly dynamic binding and unbinding cycle of TF in vivo. We also show that TF competes with SRP for RNC binding, and in doing so, tunes the binding selectivity of SRP.

We study future changes in extreme precipitation and warm days over selected megacities of India and the semi-arid Tirupati district. This work synthesises projected changes in climate extremes using indices from the Expert Team on Climate Change Detection and Indices (ETCCDI). It utilises gridded rainfall and temperature data from IMD for the historical period and future projections from the NEX-GDDP-CMIP6 dataset under moderate (SSP2-4.5) and high (SSP5-8.5) warming scenarios for 2026-2100. Projections indicate a consistent increase in both mean annual precipitation and the number of heavy rainfall days across the analysed cities, with larger increases under the high emissions scenario. Changes in consecutive wet days exhibit spatial heterogeneity, displaying complex patterns without a uniform trend across all cities. A consistent and accelerating warming trend is projected across all cities, leading to a significant increase in warm-day frequency throughout the century, particularly under the SSP5-8.5 scenario. For the Tirupati district, annual precipitation is projected to increase under both scenarios, with the southwest monsoon season showing particularly notable enhancement. Substantial warming is also projected across all seasons for Tirupati, with the pre-monsoon season expected to experience the most severe warming. These findings emphasise the critical need for tailored, region-specific adaptation strategies and highlight how future emissions pathways will significantly influence the severity of climate impacts.

The Norwegian lemming (Lemmus lemmus) is a small rodent distributed across the Fennoscandian mountain tundra and the Kola Peninsula. The Norwegian lemming likely evolved during the Late Pleistocene and inhabited Fennoscandia shortly prior to the Last Glacial Maximum. However, the exact timing and origins of the species, and its phylogenetic position relative to the closely related Siberian lemming (Lemmus sibiricus) remain disputed. Moreover, the presence of ancient or contemporary gene flow between both species is largely untested. The Norwegian lemming displays characteristic phenotypic and behavioral adaptations (e.g., coat color, aggression) that are not present in other Lemmus species. We generated a de novo genome assembly for the Norwegian lemming and resequenced nine modern and two ancient Lemmus spp. genomes. We show that all Lemmus species form distinct monophyletic clades, with concordant topology between the mitochondrial and nuclear genome phylogenies. The Siberian lemming is divided into two distinct but paraphyletic clades, one in the east and one in the west, where the western clade represents a sister taxon to the Norwegian lemming. We estimate that the Norwegian and western Siberian lemming diverged shortly before the Last Glacial Maximum, making the Norwegian lemming one of the youngest known mammalian species. We did not find any indication of gene flow between L. lemmus and L. sibiricus, suggesting postglacial isolation of L. lemmus. Furthermore, we identify species-specific genomic differences in genes related to coat color and fat transport, which are likely associated with the distinctive coloration and overwintering behavior observed in the Norwegian lemming.

The painted lady butterfly Vanessa cardui is renowned for its virtually cosmopolitan distribution and the remarkable long-distance migrations as part of its annual, multigenerational migratory cycle. In winter, V. cardui individuals inhabit breeding grounds north and south of the Sahara, suggesting distinct migratory behaviors within the species as individuals migrate southward from Europe in the autumn. However, the evolutionary and ecological factors shaping these differences in migratory behavior remain largely unexplored. Here, we performed whole-genome resequencing and analyzed the hydrogen and strontium isotopes of 40 V. cardui individuals simultaneously collected in the autumn from regions both north and south of the Sahara. Our investigation revealed two main migratory groups: (i) short-distance migrants, journeying from temperate Europe to the circum-Mediterranean region and (ii) long-distance migrants, originating from Europe, crossing the Mediterranean Sea and Sahara, and reaching West Africa, covering up to over 4,000 km. Despite these stark differences in migration distance, a genome-wide analysis revealed that short- and long-distance migrants belong to a single intercontinental panmictic population extending from northern Europe to sub-Saharan Africa. Contrary to common biogeographic patterns, the Sahara is not a catalyst for population structuring in this species. No significant genetic differentiation or signs of adaptation and selection were observed between the two migratory phenotypes. Nonetheless, two individuals, who were early arrivals to West Africa covering longer migration distances, exhibited some genetic differentiation. The lack of genetic structure between short- and long-distance migrants suggests that migration distance in V. cardui is a plastic response to environmental conditions.

Understanding the electronic, lattice, and magnetic contributions to the magnetocaloric effect in magnetic materials can help to elucidate and optimize their performance. In this work, the structural and magnetocaloric properties of Al–Mn–Ni alloy are experimentally determined and theoretically analyzed based on ab initio calculations. The dominating B2 phase associated with the Mn-rich sublattice is found to be responsible for the observed magnetocaloric properties. The magnetic entropy change, refrigerant capacity, and adiabatic temperature change are evaluated. Through the analysis of the data, we find that for the B2 phase, changing from ferromagnetic to paramagnetic configurations results in a pronounced elastic hardening despite the volume expansion. The decrease in lattice entropy is significant and contributes negatively to the magnetic and electronic entropy changes. Our work emphasizes the critical role of the lattice sector in the magnetocaloric effect, and provides an in-depth understanding of the individual entropy terms in magnetic solid solutions.