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Systemic PCSK9 elevation characterises autoimmune liver disease across sexes

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum cholesterol. Its expression is particularly abundant in hepatocytes, yet its role in autoimmune liver diseases remains unclear. Here we investigated serum PCSK9 levels in patients with autoimmune liver diseases and compared them to healthy controls, with attention to sex-specific differences. Serum PCSK9 levels were measured in 100 patients with autoimmune liver diseases — 57 with primary sclerosing cholangitis (PSC), 33 with primary biliary cholangitis (PBC), and 10 with autoimmune hepatitis (AIH)—and 88 healthy controls. Subgroup analyses were conducted based on sex and disease type. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curves. PCSK9 levels were significantly elevated in patients with autoimmune liver diseases compared to healthy controls ( p  < 0.001). In male patients, serum PCSK9 levels discriminated between patients with PSC and controls. In female patients, they discriminated between patients with PBC and controls. The area under the ROC curve (AUROC) for distinguishing between these groups was 0.765 ± 0.057 and 0.834 ± 0.047, respectively. Patients with almost normal aminotransferase and cholestasis marker levels ( n  = 47) had significantly higher PCSK9 levels than controls. The AUROC was 0.788 ± 0.039 and a serum PCSK9 level of 224 ng/ml had a sensitivity of 92% and a specificity of 60% for diagnosing autoimmune liver disease. Serum PCSK9 levels did mostly not correlate with serum cholesterol, markers of liver disease severity, the model for end stage liver disease score, or fibrosis stage. Patients who experienced decompensation or required a liver transplant during the course of their disease had PCSK9 levels similar to those who did not experience these adverse events. Serum PCSK9 levels are elevated in both male and female patients with autoimmune liver diseases, independent of cholesterol levels or fibrosis stage. PCSK9 may serve as a biomarker in the diagnosis of autoimmune liver disease, even in patients with almost normal liver function test results.

Neural network solution of non-Markovian quantum state diffusion and operator construction of quantum stochastic process

Non-Markovian quantum state diffusion provides a wavefunction-based framework for modeling open quantum systems. In this work, we introduce a novel machine learning approach based on an operator construction algorithm. This algorithm employs a neural network as a universal generator to reconstruct the stochastic time evolution operator from an ensemble of quantum trajectories. Unlike conventional machine learning methods that approximate time-dependent wavefunctions or expectation values, our operator-based approach offers broader applicability to stochastic processes. We benchmark the algorithm on the spin-boson model across diverse spectral densities, demonstrating its accuracy. Furthermore, we showcase the operator’s utility in calculating absorption spectra and reconstructing reduced density matrices at extended timescales. These results establish a new paradigm for the application of machine learning in quantum dynamics.

Molecular Basis for Catalysis and Regulation of the Strigolactone Catabolic Enzyme CXE15

Fermented rice polishings dietary supplementation sustainably enhanced growth performance, gut morphology, immune response and antioxidant status of Nile tilapia

Abstract Fermentation of plant-derived by-products, including rice polishings (RP), is suggested for the sustainability of the aquafeed industry. In this study, fermented rice polishings (FRP) were incorporated into Nile tilapia diets at various levels: 0, 100, 200, 300, and 400 g/kg. Nile tilapia with an average initial weight of 19.25 ± 0.25 g/fish were divided into five groups (triplicates) and fed five test diets (R0, R10, R20, R30, and R40) for 85 days. Dietary FRP substantially increased final body weight, weight gain, specific growth rate, and protein efficiency ratio, but decreased feed conversion ratio compared to the control group (R0). According to regression analysis, dietary FRP at 210 to 230 g/kg leads to optimal growth performance. Fish fed with higher levels of FRP (R20, R30, and R40) showed greater crude lipid content in the carcass compared to R0 and R10. Graded FRP levels considerably enhanced intestinal architexture, particularly at R20 and R30 levels. Fish fed FRP showed a dose-dependent increase in digestive enzyme activity up to 300 g/kg (R30), with the R20 having the greatest activity. Serum lysozyme levels increased significantly across all FRP levels. Serum immunoglobulin activity enhanced considerably in the R20 and R30 groups. R20 had the greatest lysozyme and immunoglobulin activity. Fish given graduated FRP levels had higher levels of total antioxidant capacity, SOD, and CAT compared to R0, with R20 exhibiting the greatest activity. Ultimately, dietary FRP can be added at 210–230 g/kg to enhance the growth performance, productivity, gut shape, digestive enzyme activity, blood health, immunity, and antioxidant response of Nile tilapia.

Exploring the intra- and intermolecular disulfide-centered non-covalent interactions in methyl allyl disulfide and its complex with water

The conformations of methyl allyl disulfide and its water adduct were studied experimentally by rotational spectroscopy supported by quantum chemical calculations. For the monomer, two conformers of methyl allyl disulfide, being stabilized by intramolecular S⋯π and CH⋯π interactions, are observed in a helium supersonic expansion. The measurement of the singly heavy atom substituted isotopologues (four 13C and two 34S isotopologues for the most stable monomer conformer and two 34S isotopologues for the second stable conformer) facilitates an accurate determination of the molecular structures. One isomer of the methyl allyl disulfide⋯water complex was identified. The observed conformation involves the most stable monomer conformer, wherein the water molecule forms one OH⋯S–S and one bifurcated CH⋯O hydrogen bond with the methyl allyl disulfide moiety. The OH⋯S–S interaction, with an energy of 29.5 kJ mol−1, is significantly stronger than the CH⋯O contact, which has energies of 3.3 and 3.6 kJ mol−1, respectively, and plays a major role in the formation of the complex. The nature of these intra- and intermolecular disulfide-centered non-covalent interactions was quantitatively revealed by the combination of accurate structural determination, natural bond orbital analysis, and energy decomposition analysis.

The tymbal of a cicada: nature’s sound-generating metastructure

Evaluating the impact of land use/cover changes on hydrological processes in the Lake Tana Basin

Abstract Land use/cover (LULC) changes has a fundamental effect on the hydrological components in the Lake Tana Basin. The Lake Tana Basin, the source origin of the Blue Nile, has experienced notable LULC transitions over the past two decades. The present study evaluates the effect of land use/cover (LULC) changes on hydrological components in the Lake Tana basin using the soil and water assessment tool (SWAT). Two LULC maps, one from the International Livestock Research Institute (ILRI) for 2004 and another developed from Landsat 8 images for 2021, were used. Both models were calibrated and validated by SUFI-2 using observed discharge data, results showed strong performance (NSE > 0.79, R 2 > 0.79 calibration; NSE > 0.90, R 2 > 0.94 validation). Between 2004 and 2021, agricultural land decreased by 10.2% and forest cover declined by 33.1%, while wetlands and rangelands increased by 81.4 and 299.2%, respectively. Moreover, urban land was presented as a new class. These changes affected the basin’s hydrology as surface runoff increased from 111.6 to 118 mm/year (+ 5.8%), lateral flow decreased from 106.3 to 100.7 mm/year, and shallow aquifer evaporation declined by 10.2%. Evapotranspiration remained nearly constant at 1066 mm/year dominated by the lake evaporation. The results confirm the significant influence of LULC changes on the hydrological components of the Lake Tana Basin which highlight the need for sustainable land and water management.

Modeling the dimerization of amyloid- <i>β</i> (1–40) and amyloid- <i>β</i> (1–42)

The early stages of aggregation of amyloidogenic proteins, such as amyloid-β (Aβ), are of great interest due to the possible pathogenic nature of small oligomeric aggregates. To shed light on the thermodynamics of this aggregation process, we perform a comparative study of the dimerization of Aβ(1–40) and Aβ(1–42) using an intermediate resolution protein model (PRIME20) and a flat-histogram Monte Carlo technique, stochastic approximation Monte Carlo. We show that aggregation drives secondary structure formation in both variants of Aβ. The dimers show a prevalence of β-sheet formation near the N-terminus of the chains and the beginning of β-sheet formation in the center of the chains, where the cross-beta structure will form for the mature amyloid fibril. Aβ(1–42) exhibits a stronger contribution of intermolecular hydrogen bonding compared to Aβ(1–40). It also shows a better defined intermolecular hydrogen-bonding pattern and less structural polymorphism of the dimer. Both findings constitute a molecular picture for the observed phenomenology of faster aggregation and growth of Aβ(1–42) amyloid fibrils compared to the Aβ(1–40) ones.

Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo

Abstract The continuous emergence of antibody-escape variants of SARS-CoV-2 demands the identification of alternative methods of protection against infection that do not directly target viral proteins. Here, we generated heavy-chain-only antibody (VHHs) from an alpaca immunized with the human angiotensin-converting enzyme 2 (hACE2), the major entry receptor for SARS-CoV-2. The VHHs bind hACE2 without affecting its enzymatic activity, and two of them (B07 and B09) inhibit all SARS-CoV-2 isolates tested (Delta, BA.1, BQ1.1, XBB.1.5, XBB.1.16.1, EG.5.1.3, BA.2.86.1). Their X-ray structure in complex with hACE2 show that their epitope overlaps with the footprint of the receptor binding domain (RBD) of the SARS-CoV-2 spike on hACE2. A dimeric B07-Fc fusion construct avidly binds hACE2 with an apparent dissociation constant of 0.1 nM and inhibits in vitro infection of previously tested variants and, of JN.1.1 and KP.3.3 variants, with an IC50 ~ 1 nM. In vivo experiments using K18-hACE2 mice show that intranasal prophylactic administration of B07-Fc confer a dose-dependent protection against SARS-CoV-2 D614G and Omicron variants. These VHHs targeting hACE2 represent potential broad-spectrum therapeutic candidates against potential new emerging coronaviruses using hACE2 as a receptor.

MiRNome alterations drive the malignant transformation of endometriosis into endometriosis-correlated ovarian cancer

Transport energy concept as a unifying framework for hopping conductivity in disordered organic semiconductors

Charge transport in disordered organic semiconductors has been studied using a variety of theoretical and computational approaches. Among these, the concept of a transport energy (TE) level provides a particularly useful framework: it acts as an analog of a mobility edge, reducing the complex problem of hopping transport to the simpler picture of the multiple-trapping model. In this work, we demonstrate that for a given system, the existence and position of the TE are universal: for any transition rate that satisfies detailed balance, regardless of its specific form, the TE is uniquely determined and governs charge-carrier dynamics. This universality establishes a coherent framework that unifies diverse hopping models and simplifies the description of transport in spatially and energetically disordered systems. To support this result, we introduce an optimized kinetic Monte Carlo approach and employ it to show that model-specific rate parameters do not affect the TE. The framework is validated across a wide range of hopping models, energetic disorders, and localization lengths, and its practical utility is demonstrated through the interpretation of experimental mobility data.

Interpretable molecular decision-making with DNA-based scalable and memory-efficient tree computation

Repurposing cephalosporins as excellent anticancer agents and chemosensitizers for inflammation-driven cancer therapy

Abstract Could cephalosporin antibiotics, extending beyond their established antimicrobial role, be repurposed as precision anticancer agents and chemosensitizers, particularly against inflammation-driven carcinogenesis? To address this question, this study systematically evaluated the anti-colorectal cancer efficacy of cephalosporins both as monotherapies and in synergistic combinations, elucidating their underlying molecular mechanisms. Employing combinatorial phenotypic screening (viability, cell cycle, apoptosis, colony formation), BALB/c nude mouse xenografts, and omics profiling (RNA-seq, RT-qPCR), we identified conserved anticancer pathways and core regulatory axes. Among 18 evaluated cephalosporins, therapeutic specificity was largely associated exclusively variable side-chain moieties, not the conserved β-lactam core. Cefamandole nafate (CAN) and cefuroxime sodium (CUS) demonstrated potent dual efficacy against colorectal cancer model while enhancing cisplatin chemosensitivity. Building on links to inflammation-driven chemosensitization, CUS synergistically potentiated cisplatin and levofloxacin cytotoxicity in colorectal cancer. This synergy was mechanistically driven by apoptosis induction, cell cycle arrest, significant up-regulation of HMOX1 (80-fold peak in combinations; 40-fold as monotherapy) and DDIT3, coupled with down-regulation of MUC1, CASC19, KRT23, SPNS3, LFNG, HS3ST1, NCOA5, and GJB4. Crucially, we reveal for the first time that CUS significantly up-regulates HMOX1 expression in HCT116 cells in a dose-dependent manner, establishing this ferroptosis regulator as the central effector governing both intrinsic anticancer activity and chemosensitization. This study unveils the translational potential of repurposing cephalosporins for combinatorial precision oncology strategies targeting inflammation-driven cancers.

Carrier mobility in Holstein–Peierls models of organic materials: A tensor-train HEOM approach

We present a comprehensive theoretical study of charge transport in organic materials on the basis of the one-dimensional dispersive Holstein–Peierls model. The hierarchical equations of motion in tensor-train format (HEOM-TT) method is employed to accurately describe both local Holstein-type and nonlocal Peierls-type electron–phonon couplings in the presence of low-frequency dispersive phonons. Linear response formulation of carrier mobility is obtained by employing the generating functional method. We demonstrate the capability of the method by calculating current correlation functions, diffusivities, and mobilities for various transport regimes. Our results provide new insights into the mechanisms underlying charge transport in organic semiconductors and establish HEOM-TT as a powerful tool for studying complex vibronic quantum dynamics and transport properties in condensed matter systems.

Presence of SARS-CoV-2 in fetal organs via intraamniotic infection

Cross-country life cycle assessment of construction and demolition waste recycling with evaluation of energy use, carbon emissions, and regional trade-offs

Giant second-harmonic generation in two-dimensional flexible materials CuBiP2X6 (X = S, Se) for azimuthal-angle-dependent tunable nonlinear photonic devices

Two-dimensional nonlinear optical materials with mechanical flexibility and strong second-harmonic generation capability have been increasingly recognized as a research focus in the field of nano-integration, owing to the rapid development of flexible optoelectronics and devices. Herein, the mechanical, electronic, and optical properties of CuBiP2X6 (X = S, Se) are studied systematically. The low elastic modulus indicates that CuBiP2X6 exhibits high structural flexibility, making it a promising candidate for flexible electronic devices. Meanwhile, an absorption coefficient as high as 4.2 × 105 cm−1 is observed in the near-ultraviolet region. CuBiP2X6 exhibits excellent absorption performance in the visible to near-ultraviolet range, characterized by multiple distinct absorption peaks. These characteristics are beneficial for efficient light harvesting and suitable for use in ultrathin optoelectronic devices. In addition, the material exhibits a strong second-harmonic response in the visible range, and this response exhibits a pronounced dependence on the azimuthal angle. This study not only enhances the understanding of the optoelectronic properties of CuBiP2X6 (X = S, Se) but also provides a theoretical basis and direction for the design and application of devices based on this material.

Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change

Abstract Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer’s Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reaching moderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

Evaluation of bioaccessibility of bioactive compounds in ready-to-eat refrigerated and frozen broccoli using in vitro digestion models

Abstract Refrigerated and frozen ready-to-eat cooked vegetables are becoming increasingly popular with consumers and catering services. Simulating digestion is essential for accurately assessing the nutritional value of ready-to-eat vegetables, as raw composition data alone may overestimate their health benefits. Therefore, this study evaluated the bioaccessibility of bioactive compounds in broccoli after heat treatment, storage, and in vitro gastrointestinal digestion. Fresh broccoli (FB) and heat-treated (boiled or steamed) broccoli were subjected to refrigerated (RBB, RSB) or frozen (FBB, FSB) storage. FB exhibited high phenol (610 mg GAE/100 g) and flavonoid (295 mg QE/100 g) contents. Thermal treatment significantly decreased the phenolic content to 503, 515, 368, and 393 mg GAE/100 g in RBB, RSB, FBB, and FSB, respectively. Total phenols, flavonoids, vitamin C, antioxidant capacity, dietary fibers, and phenolic profiles were analyzed before and after in vitro gastrointestinal digestion. After in vitro gastrointestinal digestion, phenol, flavonoid, and vitamin C contents decreased significantly compared to those after digestion with FB (DFB). No significant changes in total, soluble (SDF), or insoluble (IDF) dietary fiber were observed between heat-treated broccoli and FBs. However, in vitro , gastrointestinal digestion of FB decreased SDF from 1.84 to 1.59% and increased IDF from 1.02 to 1.3%. HPLC analysis revealed substantial phenolic compound losses after in vitro gastrointestinal digestion, ranging from 64.9% in DFB to 88% in DFBB. After digestion, the recovery of bioactive compounds decreased, particularly for vitamin C and phenolics. These findings emphasize the importance of simulating digestion when evaluating the nutritional value of processed vegetables, as relying solely on raw composition data may overestimate health-promoting compound intake. Therefore, dietary recommendations should consider cooking methods and the loss of bioactive substances during digestion. Further research is needed to gain deeper insights into the bioaccessibility of antioxidant compounds after the digestion of cooked and preserved vegetables.

On the entropic driving force of the contact-minimum configuration of two large Lennard-Jones particles in TIP4P/2005 water

In a recent work by Naito, Sumi, and Koga (NSK) [Naito et al., J. Chem. Phys. 161, 214501 (2024)], the analysis of long molecular dynamics (MD) trajectories showed that the formation of the contact-minimum (cm) configuration of two Lennard-Jones (LJ) particles in the TIP4P/2005 water model is driven by entropy, regardless of the particle diameter. This result is striking as it contrasts with the claim that the driving force should be enthalpic for large spherical particles. The observed entropy gain must arise from water, and its molecular origin needs to be clarified. In the past, one of us [Graziano, Chem. Phys. Lett., 499, 79 (2010)] devised a theoretical approach based on the geometric features of the cm configuration. The latter has a smaller solvent-excluded volume than the two particles when they are separated by a large distance. The decrease in solvent-excluded volume, which can be measured by the decrease in water accessible surface area, produces an increase in the volume available to water molecules, which translates into an increase in their translational entropy. This entropy gain drives the formation of the cm configuration. Applying this geometric approach to the largest LJ particles investigated by NSK yields values for the water-mediated thermodynamic functions consistent with those obtained through MD simulations.