In the era of rapidly expanding human genomics in research and healthcare, efficient data reuse is essential to maximise benefits for society. In response, Federated EGA was launched in 2022, and as of 2024, the FEGA Network is composed of seven national nodes. Here we describe the complexities, challenges, and achievements of FEGA, unravelling the dynamic interplay between regulatory frameworks, technical challenges, and the shared vision of advancing genomic research.

Abstract Background Preeclampsia (PE) is currently one of the major causes threatening the health and leading to death of pregnant women and fetuses. The onset of PE is attributed to cellular biological dysfunction resulting from the disruption of the molecular regulatory network in the trophoblast cells. We discovered that FOXO1 was downregulated in the placenta of preeclampsia. Methods In order to delve deeper into the involvement of FOXO1 in the development of preeclampsia, trophoblast cell lines were generated with manipulated levels of FOXO1, either through overexpression or knockdown, to elucidate its biological function and underlying mechanisms. Results The expression level of FOXO1 is positively correlated with the invasive, migratory, and proliferative abilities of trophoblast cells. Transcriptome sequencing analysis revealed DUSP9 as a potential target gene of FOXO1. The suppression of DUSP9 expression has been shown to markedly diminish the invasive, migratory, and proliferative abilities of trophoblast cells. Silencing DUSP9 in trophoblast cells that exhibit elevated levels of FOXO1 can attenuate their physiological functions. We found that overexpression/inhibition of FOXO1 can correspondingly suppress/activate the p38/JNK signaling pathway. Notably, the inhibition of DUSP9 in the context of FOXO1 overexpression can activate the p38/JNK signaling pathway. Conclusions FOXO1 modulates the biofunctions of trophoblast cells in preeclampsia via the DUSP9/p38/JNK signaling pathway.

We present a method to significantly reduce the computational scaling of the post-Hartree- Fock (post-HF) component in Density Matrix Embedding Theory (DMET) calculations by exploiting the exponential decay properties of both the mean-field density matrix and the or- bital transformation matrix. Additionally, we extend this reduced-scaling approach to calculate the coupled-cluster CCSD(T) density matrix, facilitating DMET-CCSD(T) energy evaluations through a back-transformed energy formula. The accuracy of relative electronic energies is benchmarked using the all-electron solver, Lowdin-partitioned fragments, and fragments de- rived from Intrinsic Atomic Orbital and Projected Atomic Orbital (IAO+PAO) partitioning schemes. Our results demonstrate that, with appropriate utilization of the decay of one particle density matrix (1-PDM), the evaluation of the post-HF energy can achieve asymptotically linear scaling. Furthermore, for relative electronic energies calculations, Lowdin partitioning 1 performs well in weakly interacting systems, such as water clusters. This study underscores the potential of reduced-scaling techniques to improve computational efficiency and the efficacy of CCSD(T) solvers in delivering accurate thermochemical predictions in weakly interacting systems.

Abstract BACKGROUND Schizophrenia (SZ), a chronic and widespread brain disorder, presents with complex etiology and pathogenesis that remain inadequately understood. Despite the absence of a universally recognized endophenotype, peripheral blood mononuclear cells (PBMCs) serve as a robust model for investigating intracellular alterations linked to SZ. AIM To preliminarily investigate potential pathogenic mechanisms and identify novel biomarkers for SZ. METHODS PBMCs from SZ patients were subjected to integrative transcriptomic and proteomic analyses to uncover differentially expressed genes (DEGs) and differentially expressed proteins while mapping putative disease-associated signaling pathways. Key findings were validated using western blot (WB) and real-time fluorescence quantitative PCR (RT-qPCR). RNAi-lentivirus was employed to transfect rat hippocampal CA1 neurons in vitro, with subsequent verification of target gene expression via RT-qPCR. The levels of neuronal conduction proteins, including caMKII, CREB, and BDNF, were assessed through WB. Apoptosis was quantified by flow cytometry, while cell proliferation and viability were evaluated using the Cell Counting Kit-8 assay. RESULTS The integration of transcriptomic and proteomic analyses identified 6079 co-expressed genes, among which 25 DEGs were significantly altered between the SZ group and healthy controls. Notably, HP, LTF, and SERPING1 exhibited marked upregulation. KEGG pathway enrichment analysis implicated neuroactive ligand-receptor interaction pathways in disease pathogenesis. Clinical sample validation demonstrated elevated protein and mRNA levels of HP, LTF, and SERPING1 in the SZ group compared to controls. WB analysis of all clinical samples further corroborated the significant upregulation of SERPING1. In hippocampal CA1 neurons transfected with lentivirus, reduced SERPING1 expression was accompanied by increased levels of CaMKII, CREB, and BDNF, enhanced cell viability, and reduced apoptosis. CONCLUSION SERPING1 may suppress neural cell proliferation in SZ patients via modulation of the CaMKII-CREB-BDNF signaling pathway.

Voltammetry is widely used to detect and quantify oxidizable or reducible species in complex environments. The neurotransmitter serotonin epitomizes an analyte that is challenging to detect in situ due to low concentrations and co-existing similarly structured analytes and interferents. We developed rapid-pulse voltammetry for brain neurotransmitter monitoring due to the high information content elicited from voltage pulses. Generally, the design of voltammetry waveforms remains challenging due to prohibitively large combinatorial search spaces and a lack of design principles. Here, we illustrate how Bayesian optimization can be used to hone searches for optimized rapid pulse waveforms. Our machine-learning-guided workflow (SeroOpt) outperformed random and human-guided waveform designs and is tunable a priori to enable selective analyte detection. We interpreted the black box optimizer and found that the logic of machine-learning-guided waveform design reflected domain knowledge. Our approach is straightforward and generalizable for all single and multi-analyte problems requiring optimized electrochemical waveform solutions. Overall, SeroOpt enables data-driven exploration of the waveform design space and a new paradigm in electroanalytical method development.

Tyrosine phosphorylation is an important post-translational modification that regulates many biochemical signaling networks in multicellular organisms. To date, 46,000 tyrosines have been observed in human proteins, but relatively little is known about the function and regulation of most of these sites. A major challenge has been producing recombinant phosphoproteins in order to test the effects of phosphorylation. Mutagenesis to acidic amino acids often fails to replicate the size and charge of a phosphorylated tyrosine residue and synthetic amino acid incorporation has high cost with relatively low yield. Here, we demonstrate an approach, inspired by how native tyrosine kinases find targets in cells - through a secondary targeting interaction, augmenting innate catalytic specificity of a tyrosine kinase, without overriding it. We engineered complementary vector systems for multiple approaches to producing high yields of phosphoprotein products in E. coli. Here, we test phosphorylation as a function of the targeting interaction (an SH3-polyproline sequence) affinity, different reaction methods across kinases of different specificity. This system presents an inexpensive and tractable system to producing phosphoproteins and phosphopeptides and we demonstrate how it can be used for testing antibody specificity on targets of EGFR and PD-1. This methodology is a generalizable approach for enhancing the enzymatic action on a recombinant protein via the flexibility of in vitro reactions and co-expression approaches. We refer to this as SISA-KiT, for Signaling Inspired Synthetically Augmented Kinase Toolkit.

HIV-1 assembly is initiated by the binding of Gag polyproteins to the inner leaflet of the plasma membrane, mediated by the myristylated matrix (MA) domain of Gag. Subsequent to membrane binding, Gag oligomerizes and buds as an immature, non-infectious virus particle, which, upon cleavage of the Gag precursor by the viral protease, transforms into a mature, infectious virion. During maturation, the MA lattice underlying the viral membrane undergoes a structural rearrangement and the newly released capsid (CA) protein forms a mature capsid that encloses the viral genome. While it is well established that formation of the mature capsid is essential to particle infectivity, the functional role of MA structural maturation remains unclear. Here, we examine MA maturation of an MA triple mutant, L20K/E73K/A82T, which exhibits distinct biochemical behaviours. The L20K/E73K/A82T mutant is a revertant derived by propagating the L20K mutant, which exhibits reduced infectivity and increased association of the Gag polyprotein with membranes. L20K/E73K/A82T replicates similarly to wild type but retains the increased Gag membrane binding properties of L20K. L20K/E73K/A82T MA also sediments to high-density fractions in sucrose gradients after detergent treatment under conditions that fully solubilize WT MA, suggesting enhanced MA-MA interactions. Cryo-electron tomography with subtomogram averaging reveals that the immature MA lattice of L20K/E73K/A82T closely resembles the wild type. However, mature virions of the triple mutant lack a detectable MA lattice, in stark contrast to both the wild type and L20K mutant. All-atom molecular dynamics simulations suggest that this absence results from destabilized inter-trimer interactions in the mature L20K/E73K/A82T MA. Furthermore, introducing additional mutations designed to disrupt the mature MA lattice does not impair particle infectivity. These findings suggest that an ordered, membrane-associated mature MA lattice is not essential for HIV-1 infectivity, providing new insights into the structural plasticity of the matrix during maturation and its functional role in the viral lifecycle.

We present a detailed characterization of a hybrid photonic platform for robust and broadly tunable ultraviolet (UV) laser generation using Čerenkov nonlinear frequency conversion (CNFC). By integrating silicon nitride waveguides with barium borate (BBO) cladding, the platform achieves UV emission across an unprecedented wavelength range of 222–319 nm. Compared to state-of-the-art UV photonic devices, our approach addresses longstanding challenges in spectral range, tunability, and integration. Theoretical modeling and experimental validation demonstrate remarkable fabrication tolerance, maintaining phase matching over a 1500 nm waveguide width variation. These findings offer a compact, scalable solution addressing critical needs in disinfection, quantum technologies, and free-space optical communication.