Browse Articles

A deep learning-based multiscale integration of spatial omics with tumor morphology

Fault diagnosis of permanent magnet synchronous motor based on MTF fusion image and NRBO-SCN method

Correction: Determinants of indiscriminate antimicrobial use in commercial chicken farms in Bangladesh and their impact on food safety and public health

Osilodrostat for Bilateral Adrenal Hypercortisolism in Primary Aldosteronism

Frequency multiplexing with dispersion-engineered elastic metasurfaces

In Türkiye, very few internal medicine research assistants consider becoming nephrologists in the future

Universal method to extract the average electron spin relaxation in organic semiconductors from muonium ALC resonances

Abstract Muon spin spectroscopy and in particular the avoid level crossing (ALC) technique is a sensitive probe of electron spin relaxation (eSR) in organic semiconductors. In complex ALC spectra, eSR can be challenging to extract, as it requires the modelling of overlapping ALCs, where covariance between parameters can result in significant uncertainties. Here we demonstrate a general method to extract eSR rate, which is independent on the number of ALCs resonances present, whether they overlap or not, and what the muonium hyperfine (isotropic and anisotropic) parameters are. This can then be used to extract an accurate value for eSR rate and as guidance for undertaking experiments efficiently.

Venture Capital Investments by U.S. Academic Medical Centers

Dynamic assembly of a large multidomain ribozyme visualized by cryo-electron microscopy

Abstract Many RNAs rely on their 3D structures for function. While acquiring functional 3D structures, certain RNAs form misfolded, non-functional states (‘kinetic traps’). Instead, other RNAs sequentially assemble into their functional conformations over pre-folded scaffolds. Elucidating the principles of RNA sequential assembly is thus important to understand how RNAs avoid the formation of misfolded, non-functional states. Integrating single-particle electron cryomicroscopy (cryo-EM), image processing, in solution small-angle X-ray scattering (SAXS), EM-driven molecular dynamics (MD) simulations, structure-based mutagenesis, and enzymatic assays, we have visualized the sequential multidomain assembly of a self-splicing ribozyme of biomedical and bioengineering significance. Our work reveals a distinct dynamic interplay of helical subdomains in the ribozyme’s 5’-terminal scaffold, which acts as a gate to control the docking of 3’-terminal domains. We identify specific conserved and functionally important secondary structure motifs as the key players for orchestrating the energetically inexpensive conformational changes that lead to the productive formation of the catalytic pocket. Our work provides a near-atomic resolution molecular movie of a large multidomain RNA assembling into its functionally active conformation and establishes a basis for understanding how RNA avoids the formation of non-functional ‘kinetic traps’.

Exercise attenuates hepatic ectopic lipid deposition in high fat-diet rats via PKA-mediated phosphorylation of Perilipin5

Pathological findings from surgical specimens and long-term outcome in cerebral amyloid angiopathy patients with intracerebral hemorrhage

Adrenal Aldosterone Synthase Expression Imaging in Primary Aldosteronism

Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma

Abstract Cutaneous squamous cell carcinomas (cSCCs) arise from keratinocytes in the skin, but the molecular changes driving this transformation remain unclear. To better understand this process, we perform multi-omic profiling of keratinocytes, actinic keratoses, and cSCCs. Single-cell mutational analyses reveal that most keratinocytes have remarkably low mutation burdens; however, keratinocytes with TP53 or NOTCH1 mutations exhibit substantially higher burdens. These findings suggest that keratinocytes can withstand high dosages of cumulative ultraviolet radiation, but certain pathogenic mutations break these adaptive mechanisms, inducing a mutator phenotype. Mutational profiling of cSCCs adjacent to actinic keratoses reveals TERT promoter and CDKN2A mutations emerge in actinic keratoses, whereas additional mutations that inactivate ARID2 and activate the mitogen-activated protein kinase pathway delineate the transition to cSCC. Surprisingly, actinic keratoses are often not related to their neighboring cSCC. Spatial analyses reveal gene expression heterogeneity, including checkpoint molecule enrichment at invasive fronts, highlighting tumor and immune cell interactions.

The perception of gender in two allegedly sex-specific body odor compounds MSH and HMHA

Abstract 3-methyl-3-sulfanylhexan-1-ol (MSH) and 3-hydroxy-3-methylhexanoic acid (HMHA) are two allegedly sexually dimorphic compounds present in human sweat. While MSH is more typically found in women, HMHA is more typically found in men. Here we investigated whether it was possible to identify these two compounds as explicitly masculine or feminine. We also investigated whether gender and age differences would suggest a possible role of these compounds in mate preferences. To this end, we analyzed the perceptual ratings of t-shirts impregnated with these odors by 2,716 individuals (62% female) aged between 6 and 90, collected during a one-year museum exhibition. Analyses revealed that only women rated MSH as more feminine than HMHA. However, this effect remained very small and masculinity/femininity ratings were extremely variable among the population. Women also rated both odors as more intense and less pleasant than men. Age-related differences reflected the effect of increasing experience with body odors (familiarity). The loss of olfactory function with age was also reflected by decreased perceived intensity and unpleasantness (for HMHA). Overall, the results are not in favor of a role of MSH and/or HMHA in mate preferences, however they do agree with the known gender and age differences in odor perception.

COGEniX: an industrial informatics framework for cognitive energy forecasting and carbon-aware scheduling in smart zones

Discontinuation of Aspirin in Acute Coronary Syndromes Treated with Coronary-Artery Stents

George Smoot obituary: Charismatic cosmologist who revealed ripples in the Big Bang’s afterglow

Edge polaritons at metal-insulator boundaries in a phase separated correlated oxide

Longitudinal trajectories of social isolation and loneliness across the lifespan during the COVID-19 pandemic in South Korea

Computational modelling reveals novel insights into GnRH receptor activation and binding dynamics

Abstract Gonadotrophin-releasing hormone (GnRH) regulates the mammalian reproductive system by binding to its receptor (GnRH1R) and is a target for treating reproductive hormone-dependent disorders and cancers. While the inactive structure of GnRH1R is known, the active conformation and GnRH binding mode that lead to receptor activation are not fully understood. The mechanism of GnRH-induced receptor activation remains poorly understood due to the absence of experimental structures of the active GnRH1R-GnRH complex. To address this gap, we employed computational docking simulations using Rosetta, coupled with a custom Python-based elimination protocol, to identify near-native binding poses. This approach yielded two top-ranked candidates, ROS-1 and ROS-2. Molecular dynamics simulations revealed that ROS-1 induced GnRH1R activation within 1.0 $$\mu$$ s, characterised by a $$\approx$$ 4 Å outward shift of the cytoplasmic end of TM6. Key interactions included $$\pi -\pi$$ stacking between GnRH and GnRH1R (notably Y5 with Y283 $$\phantom{0}^{6.51}$$ , Y290 $$\phantom{0}^{6.58}$$ , and F309 $$\phantom{0}^{7.38}$$ ) and hydrogen bonds with L286 $$\phantom{0}^{6.54}$$ . Intramolecular $$\pi -\pi$$ interactions within GnRH (Y5 and W3) also played a significant role. Two main communication pathways initiated by R8 of GnRH were identified. R8 formed cation- $$\pi$$ interactions with W280 $$\phantom{0}^{6.48}$$ and communicated with N87 $$\phantom{0}^{2.50}$$ and the DPxxY motif via water-mediated hydrogen bonds. Additional interactions involved M125 $$\phantom{0}^{3.36}$$ and the PAF and DRS motifs, which are critical for receptor activation. Key differences in $$\pi -\pi$$ interactions at they cytosolic end of TM7 between active and inactive states were identified due to the reorganisation of the DPxxY motif. Finally, GnRH1R communication with lipids through hydrogen bonds involving R240 $$\phantom{0}^{5.67}$$ , R75 $$\phantom{0}^{2.38}$$ , and S140 $$\phantom{0}^{3.51}$$  was observed. This study provides insights into the active conformation and binding dynamics of the GnRH-GnRH1R complex, advancing our current understanding by providing a coherent picture that consolidates previous interpretations, thereby paving the way to better therapeutic applications.