Whole genome resequencing reveals candidate genes for postaxial polydactyly in Large White pigs.

Polydactyly is a genetic abnormality that affects both pig welfare and industry profits. Despite efforts to explore the genetic basis of pig polydactyly, progress remains limited. In this study, we analyzed a group of Large White pigs with postaxial polydactyly, including 29 cases and 79 controls from 24 families. High-depth sequencing was performed on 20 pigs, while low-depth sequencing was improved through imputation for the remaining pigs. A genome-wide association study (GWAS) and genetic differentiation were conducted using the resequencing dataset, resulting in the identification of 48 significantly associated SNPs and 27 candidate regions. The genetic differentiation regions on chromosomes 5 and 18, which harbored GWAS-identified SNPs, were delineated as confidence regions. The confidence region at Chr18: 1.850-1.925 Mb covers the fifth intron of LMBR1, a gene that contains an important regulatory element for SHH, known as ZRS. Mutations in this ZRS have been found to cause polydactyly in animals and humans. Therefore, we propose LMBR1 as a prospective candidate gene for postaxial polydactyly. These findings emphasize the importance of exploring the role of ZRS within LMBR1 in the pathogenesis of polydactyly in pigs.

Musculoskeletal imaging of senescence.

Senescent cells play a vital role in the pathogenesis of musculoskeletal (MSK) diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities in afflicted patients. It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, preventing further disease progression and supporting healing processes. To identify patients who might benefit from these new senolytic therapies and monitor therapy response, there is an unmet need to identify and map senescent cells in articular joints and related musculoskeletal tissues. To fill this gap, new imaging biomarkers are being developed to detect and characterize senescent cells in human joints and musculoskeletal tissues. This review article will provide an overview of these efforts. New imaging biomarkers for senescence cells are expected to significantly improve the specificity of state-of-the-art imaging technologies for diagnosing musculoskeletal disorders.

Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review.

Sinomenine, an isoquinoline alkaloid extracted from the roots and stems of Sinomenium acutum, has been extensively studied for its derivatives as bioactive agents. This review concentrates on the research advancements in the biological activities and action mechanisms of sinomenine-related compounds until November 2023. The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. These compounds are notably effective against breast, lung, liver, and prostate cancers, exhibiting IC50 values of approximately 121.4 nM against PC-3 and DU-145 cells, primarily through the PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT signaling pathways. Additionally, they manifest anti-inflammatory and analgesic effects predominantly via the NF-κB, MAPK, and Nrf2 signaling pathways. Utilized in treating rheumatic arthritis, these alkaloids also play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection through the NF-κB, Nrf2, MAPK, and PI3K/Akt/mTOR signaling pathways. This review concludes with perspectives and insights on this topic, highlighting the potential of sinomenine-related compounds in clinical applications and the development of medications derived from natural products.

Molecular Engineering of Self-Immolative Bioresponsive MR Probes.

Real-time detection of bio-event in whole animals provides essential information for understanding biological and therapeutic processes. Magnetic resonance (MR) imaging represents a non-invasive approach to generating three-dimensional anatomic images with high spatial-temporal resolution and unlimited depth penetration. We have developed several self-immolative enzyme-activatable agents that provide excellent in vivo contrast and function as gene expression reporters. Here, we describe a vast improvement in image contrast over our previous generations of these bioresponsive agents based on a new pyridyl-carbamate Gd(III) complex. The pyridyl-carbamate-based agent has a very low MR relaxivity in the "off-state" (r1 = 1.8 mM-1 s-1 at 1.41 T). However, upon enzymatic processing, it generates a significantly higher relaxivity with a Δr1 = 106% versus Δr1 ∼ 20% reported previously. Single X-ray crystal and nuclear magnetic relaxation dispersion analyses offer mechanistic insights regarding MR signal enhancement at the molecular scale. This work demonstrates a pyridyl-carbamate-based self-immolative molecular platform for the construction of enzymatic bio-responsive MR agents, which can be adapted to a wide range of other targets for exploring stimuli-responsive materials and biomedical applications.

Aloe-emodin targets multiple signaling pathways by blocking ubiquitin-mediated degradation of DUSP1 in nasopharyngeal carcinoma cells.

Aloe-emodin (AE) has been shown to inhibit the proliferation of several cancer cell lines, including human nasopharyngeal carcinoma (NPC) cell lines. In this study, we confirmed that AE inhibited malignant biological behaviors, including cell viability, abnormal proliferation, apoptosis, and migration of NPC cells. Western blotting analysis revealed that AE upregulated the expression of DUSP1, an endogenous inhibitor of multiple cancer-associated signaling pathways, resulting in blockage of the extracellular signal-regulated kinase (ERK)-1/2, protein kinase B (AKT), and p38-mitogen activated protein kinase（p38-MAPK） signaling pathways in NPC cell lines. Moreover, the selective inhibitor of DUSP1, BCI-hydrochloride, partially reversed the AE-induced cytotoxicity and blocked the aforementioned signaling pathways in NPC cells. In addition, the binding between AE and DUSP1 was predicted via molecular docking analysis using AutoDock-Vina software and further verified via a microscale thermophoresis assay. The binding amino acid residues were adjacent to the predicted ubiquitination site (Lys192) of DUSP1. Immunoprecipitation with the ubiquitin antibody, ubiquitinated DUSP1 was shown to be upregulated by AE. Our findings revealed that AE can stabilize DUSP1 by blocking its ubiquitin-proteasome-mediated degradation and proposed an underlying mechanism by which AE-upregulated DUSP1 may potentially target multiple pathways in NPC cells.

CCR5 as a prognostic biomarker correlated with immune infiltrates in head and neck squamous cell carcinoma by bioinformatic study.

BACKGROUND: C-C chemokine receptor 5 (CCR5) has recently been recognized as an underlying therapeutic target for various malignancies. However, the association of CCR5 with prognosis in the head and neck squamous cell carcinoma (HNSC) patients and tumor-infiltrating lymphocytes (TILs) is unclear. METHODS: In the current experiment, methods such as the Tumor Immune Estimation Resource Analysis (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier plotter Analysis were used to comprehensively evaluate the expression of CCR5 in human various malignancies and the clinical prognosis in HNSC patients. Subsequently, we used the TIMER database and the TISIDB platform to investigate the correlation between CCR5 expression levels and immune cell infiltration in the HNSC tumor microenvironment. Furthermore, immunomodulatory and chemokine profiling were performed using the TISIDB platform to analyse the correlation between CCR5 expression levels and immunomodulation in HNSC patients. RESULTS: We found that CCR5 expression in HNSC tumor tissues was significantly upregulated than in normal tissues. In HNSC, patients with high CCR5 expression levels had worse overall survival (OS, HR = 0.59, p = 0.00015) and worse recurrence-free survival (RFS, HR = 3.27, p = 0.00098). Upregulation of CCR5 expression is closely associated with immunomodulators, chemokines, and infiltrating levels of CD4+ T cells, neutrophils, macrophages, and myeloid dendritic cells. Furthermore, upregulated CCR5 was significantly associated with different immune markers in the immune cell subsets of HNSC. CONCLUSIONS: High expression of CCR5 plays an important prognostic role in HNSC patients and may serve as a prognostic biomarker correlated with immune infiltration, and further studies are still needed to investigate therapeutic targeting HNSC patients in the future.

Anthracene-Triphenylamine-Based Platinum(II) Metallacages as Synthetic Light-Harvesting Assembly.

Two trigonal prismatic metallacages 1 and 2 bearing triphenylamine and anthracene moieties are designed and synthesized to fabricate artificial light-harvesting systems (LHSs). These two cages are prepared via the coordination-driven self-assembly of two anthracene-triphenylamine-based tripyridyl ligand 3, three dicarboxylates, and six 90° Pt(II) acceptors. The design of the anthracene-triphenylamine chromophore makes possible the tunable excited-state property (like the emissive transition energy and lifetime) as a function of the solvent polarity, temperature, and concentration. The synergistic photophysical footprint of these metallacages, defined by their high absorptivity and emission quantum yield (QY) relative to the free ligand 3, signifies them as a superior light sensitizer component in an LHS. In the presence of the fluorescent dye Nile Red (NR) as an energy acceptor, the metallacages display efficient (>93%) excited energy transfer to NR through an apparent static quenching mechanism in viscous dimethyl sulfoxide solvent.

Dual-Emissive Tris-Heteroleptic Ruthenium Complexes: Tuning the DNA-Triggered Ratiometric Emission Response by Ancillary Ligands.

Three tris-heteroleptic mononuclear Ru(II) complexes with dual fluorescence and phosphorescence-[Ru(dpma)(bpy)(phen)]2+ (12+), [Ru(dpma)(bpy)(dppz)]2+ (22+), and [Ru(dpma)(phen)(dppz)]2+ (32+)-have been designed and used as ratiometric light-response probes for DNA, where dpma is di(pyrid-2-yl)(methyl)-amine, bpy is 2,2'-bipyridine, phen is 1,10-phenanthroline, and dppz is dipyridophenazine, respectively. Single crystals of complex 2(PF6)2 have been obtained and studied by X-ray analysis. The interactions of these complexes with different DNAs are investigated by means of spectroscopic methods, viscosity measurements, and molecular modeling. In the presence of calf thymus DNA, complexes 2(PF6)2 and 3(PF6)2 show the emergence of a new lower-energy phosphorescence emission band; meanwhile, the higher-energy fluorescence emission band is essentially unchanged, functioning as an intrinsic internal reference. These two complexes exhibit stronger preference for calf thymus DNA over single-strand DNA (d(A)16 and d(C)16). In contrast, no binding interaction between 1(PF6)2 and calf thymus DNA is observed. The intrinsic binding constants (Kb) of 2(PF6)2 and 3(PF6)2 with calf thymus DNA are determined to be (1.4 ± 0.4) × 105 and (9.5 ± 0.15) × 104 M-1, respectively. In addition, these spectroscopic results are compared with those of the prototype complex [Ru(bpy)2(dppz)]2+ (42+), and density functional theory and time-dependent density functional theory calculations are employed to elucidate these experimental findings.

Capture and Release of Singlet Oxygen in Coordination-Driven Self-Assembled Organoplatinum(II) Metallacycles.

Singlet oxygen (1O2), as an important active reagent, has found wide applications in photodynamic therapy (PDT), synthetic chemistry, and materials science. Organic conjugated aromatics serving as hosts to capture and release singlet oxygen have been systematically investigated over the last decades. Herein, we present a [6 + 6] organoplatinum(II) metallacycle by using ∼180° dipyridylanthracene donor and ∼120° Pt(II) acceptor as the building blocks, which enables the capture and release of singlet oxygen with relatively high photooxygenation and thermolysis rate constants. The photooxygenation of the metallacycle to the corresponding endoperoxide was performed by sensitized irradiation, and the resulting endoperoxide is stable at room temperature and can be stored under ambient condition over months. Upon simple heating of the neat endoperoxide under inert atmosphere at 120 °C for 4 h, the resulting endoperoxide can be reconverted to the corresponding parent form and singlet oxygen. The photooxygenation and thermolysis products were characterized by NMR spectroscopy and electrospray ionization time-of-flight mass spectrometric analysis. Density functional theory calculations were conducted in order to reveal the frontier molecular orbital interactions and reactivity. This work provides a new material platform for singlet oxygen related promising applications.

Spontaneous Supramolecular Polymerization Driven by Discrete Platinum Metallacycle-Based Host-Guest Complexation.

Considerable progress in platinum metallacycle-based supramolecular polymerization has promoted the fabrication and application of supramolecular materials. However, despite recent advances, supramolecular polymers constructed through platinum metallacycle-based host-guest complexation remain rare because of the dynamics of platinum metallacycles. Here, we achieve linear supramolecular polymerization via platinum metallacycle-based host-guest complexation by following the design rule of suppressing the dynamics of the metallacycles. The establishment of the platinum metallacycle-based host-guest system and the realization of this type of supramolecular polymerization are expected to open opportunities for platinum metallacycle-based functional materials.

Spontaneous Formation of a Cross-Linked Supramolecular Polymer Both in the Solid State and in Solution, Driven by Platinum(II) Metallacycle-Based Host-Guest Interactions.

The recent progress in platinum(II) coordination-driven supramolecular polymers has had a substantial effect on the design of functional soft materials. However, the prospect of realizing polymerization induced by platinum(II) metallacycle-based host-guest interactions has received little attention until recently. Here we report the realization of supramolecular polymerization driven by platinum(II) metallacycle-based host-guest interactions both in the solid state and in solution. On the basis of the disclosed polymerization mechanism, we present a new strategy for the preparation of platinum(II) metallacycle-based supramolecular polymers.

Metal-Organic Pt(II) Hexagonal-Prism Macrocycles and Their Photophysical Properties.

In this work, we present the formation of two open-ended hexagonal-prism tubular macrocycles by the [6 + 12] self-assembly of the symmetric ∼120° organic ligand donor with ∼90° Pt(II) acceptor in a 1:2 ratio. The assembled structures were characterized by multinuclear NMR (1H NMR, 31P{1H} NMR, and 1H-1H COSY NMR), electrospray ionization mass spectrometry (ESI-TOF-MS), traveling wave ion mobility-mass spectrometry (TWIM-MS), and transmission electron microscopy. Molecular modeling was further conducted to get insight into their structured characteristics. We also examined their photophysical properties.

Unravelling the genetic loci for growth and carcass traits in Chinese Bamaxiang pigs based on a 1.4 million SNP array.

Bamaxiang pig is from Guangxi province in China, characterized by its small body size and two-end black coat colour. It is an important indigenous breed for local pork market and excellent animal model for biomedical research. In this study, we performed genomewide association studies (GWAS) on 43 growth and carcass traits in 315 purebred Bamaxiang pigs based on a 1.4 million SNP array. We observed considerable phenotypic variability in the growth and carcass traits in the Bamaxiang pigs. The corresponding SNP based heritability varied greatly across the 43 traits and ranged from 9.0% to 88%. Through a conditional GWAS, we identified 53 significant associations for 35 traits at p value threshold of 10-6 . Among which, 26 associations on chromosome 3, 7, 14 and X passed a genomewide significance threshold of 5 × 10-8 . The most remarkable loci were at around 30.6 Mb on chromosome 7, which had growth stage-dependent effects on body lengths and cannon circumferences and showed large effects on multiple carcass traits. We discussed HMGA1 NUDT3, EIF2AK1, TMEM132C and AFF2 that near the lead SNP of significant loci as plausible candidate genes for corresponding traits. We also showed that including phenotypic covariate in GWAS can help to reveal additional significant loci for the target traits. The results provide insight into the genetic architecture of growth and carcass traits in Bamaxiang pigs.

Molecular Quadripod as a Noncovalent Interfacial Coupling Reagent for Forming Immobilized Coordination Assemblies.

A pyrene-cored molecular quadripod 1,3,6,8-tetra(di( p-pyrid-4-ylphenyl)amino)pyrene (TAPyr) is presented as a noncovalent interfacial coupling reagent for the immobilization of coordination assemblies. This bench-stable molecule is readily available and has a quadripod shape with four pyridine legs and four pyridine handles on the top exterior. By a simple and short dipping procedure under ambient conditions, TAPyr is firmly immobilized on electrode surfaces in an upright fashion as probed by electrochemical, absorption spectral, atomic force microscopy, and scanning tunneling microscopy analysis. Using Pd(PhCN)2Cl2 as a metallolinker, 4-ferrocenylpyridine, a pyridine-terminated monoruthenium complex 1, and a diruthenium complex 2 with two pyridine ends have been grafted onto the ITO/TAPyr surface. The obtained thin films exhibit good electrochemical stability that is comparable or superior to those prepared by the state-of-the-art Si-O-Sn covalent functionalization. Appealing electrochromism is demonstrated with the thin films of ruthenium complexes on ITO.

Temperature-Responsive Fluorescent Organoplatinum(II) Metallacycles.

The synthesis, characterization, and temperature-responsive properties of two fluorescent organoplatinum(II) metallacycles are reported. Metallacycles M1 and M2 were prepared via the coordination-driven self-assembly of a 120° triarylamine ligand L1 and a 120° diplatinum(II) acceptor Pt-1 or 180° diplatinum(II) acceptor Pt-2, respectively. M1 and M2 are hexagonal metallacycles, comprising of three or six freely rotating anthracene pendants on their periphery, respectively. In response to the temperature variation between -20 and 60 °C, the ligand displays irregular emission changes, whereas both metallacycles show reversible absorption and emission spectral changes in THF. The changes in their green emission intensity also exhibit a linear correlation with the temperature variation, with an average sensitivity of -0.67% and -0.77% per °C for M1 and M2, respectively. Furthermore, in coordinating solvents, such as DMF and CH3CN, M1 and M2 show different behaviors: in the lower temperature range, i.e., below 30 °C, their spectral changes are similar to those observed in THF; however, at a higher temperature the metallacycles were presumably destroyed by the solvents and displayed ratiometric fluorescent responses, including a cyan emission of the ligand L1.

Identification of loci affecting teat number by genome-wide association studies on three pig populations.

OBJECTIVE: Three genome-wide association studies (GWAS) and a meta-analysis of GWAS were conducted to explore the genetic mechanisms underlying variation in pig teat number. METHODS: We performed three GWAS and a meta-analysis for teat number on three pig populations, including a White Duroc×Erhualian F2 resource population (n = 1,743), a Chinese Erhualian pig population (n = 320) and a Chinese Sutai pig population (n = 383). RESULTS: We detected 24 single nucleotide polymorphisms (SNPs) that surpassed the genome-wide significant level on Sus Scrofa chromosomes (SSC) 1, 7, and 12 in the F2 resource population, corresponding to four loci for pig teat number. We highlighted vertnin (VRTN) and lysine demethylase 6B (KDM6B) as two interesting candidate genes at the loci on SSC7 and SSC12. No significant associated SNPs were identified in the meta-analysis of GWAS. CONCLUSION: The results verified the complex genetic architecture of pig teat number. The causative variants for teat number may be different in the three populations.

Transition from a Metal-Localized Mixed-Valence Compound to a Fully Delocalized and Bridge-Biased Electrophore in a Ruthenium-Amine-Ruthenium Tricenter System.

A series of cyclometalated diruthenium complexes with a redox-active amine bridge were synthesized. Depending on the terminal ligands of the ruthenium components and the substituent on the amine unit, the one-electron-oxidized state can be either in the form of a weakly or strongly coupled mixed-valence diruthenium complex, a fully charge-delocalized three-center system, or a bridge-biased electrophore. This transition among different electronic forms was supported by electrochemistry, near-infrared absorption, electron paramagnetic resonance, and density functional theory analysis.

Ruthenium-Amine Conjugated Organometallic Materials for Multistate Near-IR Electrochromism and Information Storage.

Monometallic and dimetallic complexes with the ruthenium-amine conjugated structural unit have been prepared. These complexes display consecutive redox waves with low potentials and rich and intense absorptions in the near-infrared region. The electrochemical and spectroscopic properties can be modulated using substituents or auxiliary ligands with different electronic natures. Through simple functionalization, electropolymerized or monolayer thin films of these complexes have been prepared. These films display multistate near-infrared electrochromism with good contrast ratios and long optical retention times. In addition, flip-flop and flip-flap-flop memories have been demonstrated on the basis of these thin films.

Observation of the excretion pattern of a precocious line of Eimeria necatrix and the strengthening of immune homogeneity.

The excretion frequencies of cecal and intestinal droppings of Chinese Lingnan yellow chickens were observed for 10 consecutive days. The chickens were then orally inoculated with a precocious line of Eimeria necatrix, and the oocysts present in the cecal and intestinal droppings were separately collected and monitored using the McMaster method. The results showed that the excretion frequency of cecal droppings was significantly lower than that of intestinal droppings, and the oocysts of E. necatrix were distributed primarily in the cecal droppings. This distribution affects the homogeneity of the second and third generation of oocysts ingested by the chickens and therefore affects the immune effect observed during E. necatrix immunization. To artificially strengthen the immunologic homogeneity against E. necatrix, a method of artificially strengthening the second immunization was applied, and the immune effect was evaluated based on oocyst excretion, body weight gain, fecal scores, intestinal lesion scores and survival percentages. The results showed that no significant intestinal damage was caused by immunization reactions in the chickens. In addition, the number of excreted oocysts in the immunized chicken groups could be significantly increased, and the immunologic homogeneity of the immunized chickens could be improved by artificially strengthening the second immunization, which could in turn improve the immune protective effect.

A Molecular Platform for Multistate Near-Infrared Electrochromism and Flip-Flop, Flip-Flap-Flop, and Ternary Memory.

A diruthenium complex with a redox-active amine bridge has been designed, synthesized, and studied by single-crystal X-ray analysis and DFT and TDDFT calculations. It shows three well-separated redox processes with exclusive near-infrared (NIR) absorbance at each redox state. The electropolymerized film of a related vinyl-functionalized complex displays multistate NIR electrochromism with low operational potential, good contrast ratio, and long retention time. Flip-flop, flip-flap-flop, and ternary memories have been realized by using the obtained film (ca. 15-20 nm thick) with three electrochemical inputs and three NIR optical outputs that each displays three levels of signal intensity.