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Pharmacological Reviews Jul 2024The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the...
The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched (PTCH). The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to a rapid development of our knowledge about structure-function relationships providing a great starting point for drug development. Despite the progress questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.
PubMed: 38955509
DOI: 10.1124/pharmrev.124.001062 -
RSC Advances Jun 2024The search for novel intrinsic two-dimensional (2D) magnetic materials is crucial to understand the fundamentals of 2D magnetism and realize next-generation...
The search for novel intrinsic two-dimensional (2D) magnetic materials is crucial to understand the fundamentals of 2D magnetism and realize next-generation magneto-electric and magneto-optical systems. Using the rigorous framework of spin-polarized density functional theory (SPDFT)-based calculations, this investigation systematically investigates the effects of a stepwise change in the Fe composition () on the structural, electro-magnetic and optical properties of the ordered SrS based single-layer alloys, with encompassing values from 0 to 1. Our comprehensive analysis revealed that the calculated formation energies, cohesive energies, phonon dispersions, molecular dynamics, and elastic constants of both bare SrS and FeS monolayers indicate their thermodynamic, dynamic, thermal, and mechanical stability in hexagonal and square structures, respectively. Significantly, the introduction of magnetic Fe dopants into the non-magnetic SrS semiconductor enabled the creation of an intrinsic magnetic (FM) state characterized by spin-polarized charge carriers at the Fermi level ( ). As doping increases, the electronic structure shows a noticeable dependence on the chemical composition. It is noteworthy that the systems doped with 0.750 and 1 Fe exhibit metallic-magnetic and metallic non-magnetic properties, respectively, and the rest are half-semiconductors (HSC) according to the GGA approximation. Conversely, the HSE approach shows a transition to HSC for a doping level of 0.750, while others maintain the same behavior. The study of the optical properties shows improvements compared to the bare SrS monolayer through the incorporation of Fe dopants. The bare SrS has light absorption in the ultraviolet region, while the absorption band edges for HSC compounds change from the infrared to visible regions. This study proposes a practical method to tune the properties of the SrS single-layer by selectively adjusting the dopant concentration. Such control is promising for applications in spintronics and optical based nanodevices.
PubMed: 38952946
DOI: 10.1039/d4ra04352a -
Frontiers in Neurology 2024Sleep is disturbed in Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting female patients (prevalence 7.1/100,000 female...
24-h continuous non-invasive multiparameter home monitoring of vitals in patients with Rett syndrome by an innovative wearable technology: evidence of an overlooked chronic fatigue status.
BACKGROUND
Sleep is disturbed in Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting female patients (prevalence 7.1/100,000 female patients) linked to pathogenic variations in the X-linked methyl-CpG-binding protein 2 () gene. Autonomic nervous system dysfunction with a predominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PSNS) is reported in RTT, along with exercise fatigue and increased sudden death risk. The aim of the present study was to test the feasibility of a continuous 24 h non-invasive home monitoring of the biological vitals (biovitals) by an innovative wearable sensor device in pediatric and adolescent/adult RTT patients.
METHODS
A total of 10 female patients (mean age 18.3 ± 9.4 years, range 4.7-35.5 years) with typical RTT and pathogenic variations were enrolled. Clinical severity was assessed by validated scales. Heart rate (HR), respiratory rate (RR), and skin temperature (SkT) were monitored by the YouCare Wearable Medical Device (Accyourate Group SpA, L'Aquila, Italy). The average percentage of maximum HR (HRmax%) was calculated. Heart rate variability (HRV) was expressed by consolidated time-domain and frequency-domain parameters. The HR/LF (low frequency) ratio, indicating SNS activation under dynamic exercise, was calculated. Simultaneous continuous measurement of indoor air quality variables was performed and the patients' contributions to the surrounding water vapor partial pressure [P (pt)] and carbon dioxide [P (pt)] were indirectly estimated.
RESULTS
Of the 6,559.79 h of biovital recordings, 5051.03 h (77%) were valid for data interpretation. Sleep and wake hours were 9.0 ± 1.1 h and 14.9 ± 1.1 h, respectively. HRmax % [median: 71.86% (interquartile range 61.03-82%)] and HR/LF [median: 3.75 (interquartile range 3.19-5.05)] were elevated, independent from the wake-sleep cycle. The majority of HRV time- and frequency-domain parameters were significantly higher in the pediatric patients ( ≤ 0.031). The HRV HR/LF ratio was associated with phenotype severity, disease progression, clinical sleep disorder, subclinical hypoxia, and electroencephalographic observations of multifocal epileptic activity and general background slowing.
CONCLUSION
Our findings indicate the feasibility of a continuous 24-h non-invasive home monitoring of biovital parameters in RTT. Moreover, for the first time, HRmax% and the HR/LF ratio were identified as potential objective markers of fatigue, illness severity, and disease progression.
PubMed: 38952469
DOI: 10.3389/fneur.2024.1388506 -
Scientific Reports Jun 2024In the field of hydrate formation cementing, the method of developing the low hydration exothermic cement systems cannot effectively solve the problem of hydrate...
In the field of hydrate formation cementing, the method of developing the low hydration exothermic cement systems cannot effectively solve the problem of hydrate dissociation caused by the hydration heat release of cement. Therefore, we proposed a new approach to address this issue by employing cement additives that can effectively delay the dissociation of hydrate. In our previous work, we designed a novel hydrate dissociation inhibitor, PVCap/dmapma, however, its applicability with cement slurry remains unverified. In this study, we established a more realistic model of oilwell cement gel based on experimental data. Additionally, we investigated the potential effects of PVCap/dmapma on the microstructure and mechanical properties of cement gel through molecular simulations. The results suggest that PVCap/dmapma has no negative effect on the performance of cement slurry compared to Lecithin. By adding PVCap/dmapma to cement slurry, the problem of cementing in hydrate formations is expected to be solved.
PubMed: 38951632
DOI: 10.1038/s41598-024-65935-z -
Scientific Reports Jul 2024The cotton whitefly, Bemisia tabaci, is considered as a species complex with 46 cryptic species, with Asia II-1 being predominant in Asia. This study addresses a...
The cotton whitefly, Bemisia tabaci, is considered as a species complex with 46 cryptic species, with Asia II-1 being predominant in Asia. This study addresses a significant knowledge gap in the characterization of odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) in Asia II-1. We explored the expression patterns of OBPs and CSPs throughout their developmental stages and compared the motif patterns of these proteins. Significant differences in expression patterns were observed for the 14 OBPs and 14 CSPs of B. tabaci Asia II-1, with OBP8 and CSP4 showing higher expression across the developmental stages. Phylogenetic analysis reveals that OBP8 and CSP4 form distinct clades, with OBP8 appearing to be an ancestral gene, giving rise to the evolution of other odorant-binding proteins in B. tabaci. The genomic distribution of OBPs and CSPs highlights gene clustering on the chromosomes, suggesting functional conservation and evolutionary events following the birth-and-death model. Molecular docking studies indicate strong binding affinities of OBP8 and CSP4 with various odour compounds like β-caryophyllene, α-pinene, β-pinene and limonene, reinforcing their roles in host recognition and reproductive functions. This study elaborates on our understanding of the putative roles of different OBPs and CSPs in B. tabaci Asia II-1, hitherto unexplored. The dynamics of the expression of OBPs and CSPs and their interactions with odour compounds offer scope for developing innovative methods for controlling this global invasive pest.
Topics: Animals; Hemiptera; Receptors, Odorant; Phylogeny; Insect Proteins; Gene Expression Regulation, Developmental; Molecular Docking Simulation; Polycyclic Sesquiterpenes; Limonene; Sesquiterpenes
PubMed: 38951601
DOI: 10.1038/s41598-024-65785-9 -
Scientific Reports Jul 2024The present study explores the effect of a magnetic field on the thermal conductivity of two-dimensional (2D) Yukawa systems in a wide range of system parameters using...
The present study explores the effect of a magnetic field on the thermal conductivity of two-dimensional (2D) Yukawa systems in a wide range of system parameters using the non-equilibrium molecular dynamic method (NEMD). We consider an external magnetic field with (with being the ratio of the cyclotron frequency to plasma frequency) and the coupling parameter values in the range (with being the ratio of the Coulomb interaction energy at mean inter-particle distance to the thermal energy of particles). The results show that an external uniform magnetic field results in the reduction of the thermal conductivity at the considered values of the coupling parameter . Additionally, we found that the effect of the magnetic field on thermal conduction is weaker at larger values of the system coupling parameter. To ensure that calculated results for the thermal conductivity are accurate and reliable, we performed a detailed investigation of the convergence of the results with respect to simulation parameters in NEMD with a strong external magnetic field. We believe that the presented results will serve as useful benchmark data for the theoretical models of (2D) Yukawa systems.
PubMed: 38951572
DOI: 10.1038/s41598-024-64866-z -
Communications Biology Jun 2024Adipose tissue development begins in the fetal period, and continues to expand after birth. Dysregulation of adipose tissue during weaning may predispose individuals to...
Adipose tissue development begins in the fetal period, and continues to expand after birth. Dysregulation of adipose tissue during weaning may predispose individuals to lifelong metabolic disorders. However, the developmental remodeling of adipose tissue during weaning remains largely unexplored. Here we comprehensively compare the changes in mouse subcutaneous white adipose tissue from 7 days after birth to 7 days after weaning using single-cell RNA sequencing along with other molecular and histologic assays. We characterize the developmental trajectory of preadipocytes and indicate the commitment of preadipocytes with beige potential during weaning. Meanwhile, we find immune cells unique to weaning period, whose expression of extracellular matrix proteins implies potential regulation on preadipocyte. Finally, the strongest cell-cell interaction during weaning determined by the TGFβ ligand-receptor pairs is between preadipocytes and endotheliocytes. Our results provide a detailed and unbiased cellular landscape and offer insights into the potential regulation of adipose tissue remodeling during weaning.
Topics: Animals; Weaning; Mice; Single-Cell Analysis; Adipose Tissue, White; Subcutaneous Fat; Mice, Inbred C57BL; Adipocytes; Male; Female
PubMed: 38951550
DOI: 10.1038/s42003-024-06448-3 -
Nature Communications Jul 2024Donor-acceptor Stenhouse adducts (DASAs) are molecular photoswitches spurring wide interest because of their dynamic photophysical properties, complex photoswitching...
Donor-acceptor Stenhouse adducts (DASAs) are molecular photoswitches spurring wide interest because of their dynamic photophysical properties, complex photoswitching mechanism, and diverse applications. Despite breakthroughs in modularity for the donor, acceptor, and triene compartments, the backbone heteroatom remains static due to synthetic challenges. We provide a predictive tool and sought-after strategy to vary the heteroatom, introduce amino DASA photoswitches, and analyze backbone heteroatom effects on photophysical properties. Amino DASA synthesis is enabled by aza-Piancatelli rearrangements on pyrrole substrates, imparting an aromaticity-breaking rearrangement that capitalizes on nitrogen's additional bonding orbital and the inductive properties of sulfonyl groups. Amino DASA structure is confirmed by single crystal X-ray diffraction, the photochromic properties are characterized, and the photoswitch isomerization is investigated. Overall, the discovered pyrrole rearrangement enables the study of the DASA backbone heteroatom compartment and furthers our insight into the structure-property relationship of this complex photoswitch.
PubMed: 38951197
DOI: 10.1038/s41467-024-49808-7 -
Genome Research Jul 2024Knowledge of locations and activities of -regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic...
Knowledge of locations and activities of -regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.
PubMed: 38951027
DOI: 10.1101/gr.277950.123 -
The Journal of Biological Chemistry Jun 2024Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment... (Review)
Review
Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment and biological processes. The low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed endocytic receptor that regulates cellular events by modulating the levels of numerous extracellular molecules via rapid endocytic removal. LRP1 also participates in signalling pathways through this modulation as well as in the interaction with membrane receptors and cytoplasmic adaptor proteins. LRP1 single nucleotide polymorphisms are associated with several diseases and conditions such as migraines, aortic aneurysms, cardiopulmonary dysfunction, corneal clouding, and bone dysmorphology and mineral density. Studies using Lrp1 knockout mice revealed a critical, non-redundant and tissue-specific role of LRP1 in regulating various physiological events. However, exactly how LRP1 functions to regulate so many distinct and specific processes is still not fully clear. Our recent proteomics studies have identified more than 300 secreted proteins that either directly interact with LRP1 or are modulated by LRP1 in various tissues. This review will highlight the remarkable ability of this receptor to regulate secreted molecules in a tissue-specific manner and discuss potential mechanisms underpinning such specificity. Uncovering the depth of these "hidden" specific interactions modulated by LRP1 will provide novel insights into a dynamic and complex extracellular environment that is involved in diverse biological and pathological processes.
PubMed: 38950861
DOI: 10.1016/j.jbc.2024.107521