Synthesis of 64Cu-, 55Co-, and 68Ga-Labeled Radiopharmaceuticals Targeting Neurotensin Receptor-1 for Theranostics: Adjusting In Vivo Distribution Using Multiamine Macrocycles.

The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors. Methods: We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [64Cu]Cu-DOTA-SR-3MA, [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, [64Cu]Cu-NT-CB-DOTA, and [64Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [55Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [55Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. Results: In vivo PET imaging with [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, and [55Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1-positive tumors. Tumor uptake of [64Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [55Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [64Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection Conclusion: Tumor uptake and pharmacokinetic properties of NTSR-1-targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either 64Cu/67Cu, 55Co/58mCo, or 68Ga (effect of 177Lu in tumor to be determined in future studies) and NT-Sarcage labeled with 64Cu/67Cu or 55Co/58mCo may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1-positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach.

Branch-Chain-Rich Diisopropyl Ether with Steric Hindrance Facilitates Stable Cycling of Lithium Batteries at - 20 °C.

Li metal batteries (LMBs) offer significant potential as high energy density alternatives; nevertheless, their performance is hindered by the slow desolvation process of electrolytes, particularly at low temperatures (LT), leading to low coulombic efficiency and limited cycle stability. Thus, it is essential to optimize the solvation structure thereby achieving a rapid desolvation process in LMBs at LT. Herein, we introduce branch chain-rich diisopropyl ether (DIPE) into a 2.5 M Li bis(fluorosulfonyl)imide dipropyl ether (DPE) electrolyte as a co-solvent for high-performance LMBs at - 20 °C. The incorporation of DIPE not only enhances the disorder within the electrolyte, but also induces a steric hindrance effect form DIPE's branch chain, excluding other solvent molecules from Li+ solvation sheath. Both of these factors contribute to the weak interactions between Li+ and solvent molecules, effectively reducing the desolvation energy of the electrolyte. Consequently, Li (50 µm)||LFP (mass loading ~ 10 mg cm-2) cells in DPE/DIPE based electrolyte demonstrate stable performance over 650 cycles at - 20 °C, delivering 87.2 mAh g-1, and over 255 cycles at 25 °C with 124.8 mAh g-1. DIPE broadens the electrolyte design from molecular structure considerations, offering a promising avenue for highly stable LMBs at LT.

Chelator boosted tumor-retention and pharmacokinetic properties: development of 64Cu labeled radiopharmaceuticals targeting neurotensin receptor.

PURPOSE: Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in lung cancer progression by triggering multiple oncogenic signaling pathways. This study aims to develop Cu-labeled neurotensin receptor 1 (NTSR1)-targeting agents with the potential for both imaging and therapeutic applications. METHOD: A series of neurotensin receptor antagonists (NRAs) with variable propylamine (PA) linker length and different chelators were synthesized, including [64Cu]Cu-CB-TE2A-iPA-NRA ([64Cu]Cu-4a-c, i = 1, 2, 3), [64Cu]Cu-NOTA-2PA-NRA ([64Cu]Cu-4d), [64Cu]Cu-DOTA-2PA-NRA ([64Cu]Cu-4e, also known as [64Cu]Cu-3BP-227), and [64Cu]Cu-DOTA-VS-2PA-NRA ([64Cu]Cu-4f). The series of small animal PET/CT were conducted in H1299 lung cancer model. The expression profile of NTSR1 was also confirmed by IHC using patient tissue samples. RESULTS: For most of the compounds studied, PET/CT showed prominent tumor uptake and high tumor-to-background contrast, but the tumor retention was strongly influenced by the chelators used. For previously reported 4e, [64Cu]Cu-labeled derivative showed initial high tumor uptake accompanied by rapid tumor washout at 24 h. The newly developed [64Cu]Cu-4d and [64Cu]Cu-4f demonstrated good tumor uptake and tumor-to-background contrast at early time points, but were less promising in tumor retention. In contrast, our lead compound [64Cu]Cu-4b demonstrated 9.57 ± 1.35, 9.44 ± 2.38 and 9.72 ± 4.89%ID/g tumor uptake at 4, 24, and 48 h p.i., respectively. Moderate liver uptake (11.97 ± 3.85, 9.80 ± 3.63, and 7.72 ± 4.68%ID/g at 4, 24, and 48 h p.i.) was observed with low uptake in most other organs. The PA linker was found to have a significant effect on drug distribution. Compared to [64Cu]Cu-4b, [64Cu]Cu-4a had a lower background, including a greatly reduced liver uptake, while the tumor uptake was only moderately reduced. Meanwhile, [64Cu]Cu-4c showed increased uptake in both the tumor and the liver. The clinical relevance of NTSR1 was also demonstrated by the elevated tumor expression in patient tissue samples. CONCLUSIONS: Through the side-by-side comparison, [64Cu]Cu-4b was identified as the lead agent for further evaluation based on its high and sustained tumor uptake and moderate liver uptake. It can not only be used to efficiently detect NTSR1 expression in lung cancer (for diagnosis, patient screening, and treatment monitoring), but also has the great potential to treat NTSR-positive lesions once chelating to the beta emitter 67Cu.

Synergistic effect of mesenchymal stem cell-derived extracellular vesicle and miR-137 alleviates autism-like behaviors by modulating the NF-κB pathway.

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption.

[Clinical features and genetic analysis of 17 Chinese pedigrees affected with X-linked intellectual disability].

OBJECTIVE: To analyze the clinical features and genetic etiology of 17 Chinese pedigrees affected with X-linked intellectual disability (XLID). METHODS: Seventeen pedigrees affected with unexplained intellectual disability which had presented at Henan Provincial People's Hospital from May 2021 to May 2023 were selected as the study subjects. Clinical data of the probands and their pedigree members were collected. Trio-whole exome sequencing (Trio-WES), Sanger sequencing and X chromosome inactivation (XCI) analysis were carried out. Pathogenicity of candidate variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics and co-segregation analysis. RESULTS: The 17 probands, including 9 males and 8 females with an age ranging from 0.6 to 8 years old, had all shown mental retardation and developmental delay. Fourteen variants were detected by genetic testing, which included 4 pathogenic variants (MECP2: c.502C>T, MECP2: c.916C>T/c.806delG, IQSEC2: c.1417G>T), 4 likely pathogenic variants (MECP2: c.1157_1197del/c.925C>T, KDM5C: c.2128A>T, SLC6A8: c.1631C>T) and 6 variants of uncertain significance (KLHL15: c.26G>C, PAK3: c.970A>G/c.1520G>A, GRIA3: c.2153C>G, TAF1: c.2233T>G, HUWE1: c.10301T>A). The PAK3: c.970A>G, GRIA3: c.2153C>G and TAF1: c.2233T>G variants were considered as the genetic etiology for pedigrees 12, 14 and 15 by co-segregation analysis, respectively. The proband of pedigree 13 was found to have non-random XCI (81:19). Therefore, the PAK3: c.1520G>A variant may underlie its pathogenesis. CONCLUSION: Trio-WES has attained genetic diagnosis for the 17 XLID pedigrees. Sanger sequencing and XCI assay can provide auxiliary tests for the diagnosis of XLID.

Development and application of haploid embryonic stem cells.

Haploid cells are a kind of cells with only one set of chromosomes. Compared with traditional diploid cells, haploid cells have unique advantages in gene screening and drug-targeted therapy, due to their phenotype being equal to the genotype. Embryonic stem cells are a kind of cells with strong differentiation potential that can differentiate into various types of cells under specific conditions in vitro. Therefore, haploid embryonic stem cells have the characteristics of both haploid cells and embryonic stem cells, which makes them have significant advantages in many aspects, such as reproductive developmental mechanism research, genetic screening, and drug-targeted therapy. Consequently, establishing haploid embryonic stem cell lines is of great significance. This paper reviews the progress of haploid embryonic stem cell research and briefly discusses the applications of haploid embryonic stem cells.

Development of 18F-Labeled hydrophilic trans-cyclooctene as a bioorthogonal tool for PET probe construction.

We report the development of a hydrophilic 18F-labeled a-TCO derivative [18F]3 (log P = 0.28) through a readily available precursor and a single-step radiofluorination reaction (RCY up to 52%). We demonstrated that [18F]3 can be used to construct not only multiple small molecule/peptide-based PET agents, but protein/diabody-based imaging probes in parallel.

Generation of a human haploid neural stem cell line for genome-wide genetic screening.

BACKGROUND: Haploid embryonic stem cells (haESCs) have been established in many species. Differentiated haploid cell line types in mammals are lacking due to spontaneous diploidization during differentiation that compromises lineage-specific screens. AIM: To derive human haploid neural stem cells (haNSCs) to carry out lineage-specific screens. METHODS: Human haNSCs were differentiated from human extended haESCs with the help of Y27632 (ROCK signaling pathway inhibitor) and a series of cytokines to reduce diploidization. Neuronal differentiation of haNSCs was performed to examine their neural differentiation potency. Global gene expression analysis was con-ducted to compare haNSCs with diploid NSCs and haESCs. Fluorescence activated cell sorting was performed to assess the diploidization rate of extended haESCs and haNSCs. Genetic manipulation and screening were utilized to evaluate the significance of human haNSCs as genetic screening tools. RESULTS: Human haESCs in extended pluripotent culture medium showed more compact and smaller colonies, a higher efficiency in neural differentiation, a higher cell survival ratio and higher stability in haploidy maintenance. These characteristics effectively facilitated the derivation of human haNSCs. These human haNSCs can be generated by differentiation and maintain haploidy and multipotency to neurons and glia in the long term in vitro. After PiggyBac transfection, there were multiple insertion sites in the human haNSCs' genome, and the insertion sites were evenly spread across all chromosomes. In addition, after the cells were treated with manganese, we were able to generate a list of manganese-induced toxicity genes, demonstrating their utility as genetic screening tools. CONCLUSION: This is the first report of a generated human haploid somatic cell line with a complete genome, proliferative ability and neural differentiation potential that provides cell resources for recessive inheritance and drug targeted screening.

Motor neuron-specific RhoA knockout delays degeneration and promotes regeneration of dendrites in spinal ventral horn after brachial plexus injury.

Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults. Peripheral axotomy of motor neurons results in the retraction of dendritic arbors, and the dendritic arbor can be re-expanded when reinnervation is allowed. RhoA is a target that regulates the cytoskeleton and promotes neuronal survival and axon regeneration. However, the role of RhoA in dendrite degeneration and regeneration is unknown. In this study, we explored the potential role of RhoA in dendrites. A line of motor neuronal RhoA conditional knockout mice was developed by crossbreeding HB9Cre+ mice with RhoAflox/flox mice. We established two models for assaying dendrite degeneration and regeneration, in which the brachial plexus was transection or crush injured, respectively. We found that at 28 days after brachial plexus transection, the density, complexity, and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice were slightly decreased compared with that in Cre mice. Dendrites underwent degeneration at 7 and 14 days after brachial plexus transection and recovered at 28-56 days. The density, complexity, and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice recovered compared with results in Cre mice. These findings suggest that RhoA knockout in motor neurons attenuates dendrite degeneration and promotes dendrite regeneration after peripheral nerve injury.

Schwann cell-specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation.

Our previous studies indicated that RhoA knockdown or inhibition could alleviate the proliferation, migration, and differentiation of Schwann cells. However, the role of RhoA in Schwann cells during nerve injury and repair is still unknown. Herein, we developed two lines of Schwann cells conditional RhoA knockout (cKO) mice by breeding RhoAflox / flox mice with PlpCre -ERT2 or DhhCre mice. Our results indicate that RhoA cKO in Schwann cells accelerates axonal regrowth and remyelination after sciatic nerve injury, which enhances the recovery of nerve conduction and hindlimb gait, and alleviates the amyotrophy in gastrocnemius muscle. Mechanistic studies in both in vivo and in vitro models revealed that RhoA cKO could facilitate Schwann cell dedifferentiation via JNK pathway. Schwann cell dedifferentiation subsequently promotes Wallerian degeneration by enhancing phagocytosis and myelinophagy, as well as stimulating the production of neurotrophins (NT-3, NGF, BDNF, and GDNF). These findings shed light on the role of RhoA in Schwann cells during nerve injury and repair, indicating that cell type-specific RhoA targeting could serve as a promising molecular therapeutic strategy for peripheral nerve injury.

Predictive Value of Cardiovascular Health Score for Health Outcomes in Patients with PCI: Comparison between Life's Simple 7 and Life's Essential 8.

The American Heart Association recently published an updated algorithm for quantitative assessments of cardiovascular health (CVH) metrics, namely Life's Essential 8 (LE8). This study aimed to compare the predictive value between Life's Simple 7 (LS7) and LE8 and predict the likelihood of major adverse cardiac events (MACEs) in patients undergoing percutaneous coronary intervention (PCI) to determine the utility of the LE8 in predicting CVH outcomes. A total of 339 patients with acute coronary syndrome (ACS) who had undergone PCI were enrolled to assess the CVH scores using the LS7 and LE8. Multivariable Cox regression analysis was employed to evaluate the predictive value of the two different CVH scoring systems at 2 years for MACEs. Multivariable Cox regression analysis revealed that both the LS7 and LE8 scores were protective factors for MACEs (HR = 0.857, [95%CI: 0.78-0.94], HR = 0.964, [95%CI: 0.95-0.98]; p < 0.05, respectively). Receiver operator characteristic analysis indicated that the area under the curve (AUC) of LE8 was higher than that of LS7 (AUC: 0.662 vs. 0.615, p < 0.05). Lastly, in the LE8 score, diet, sleep health, serum glucose levels, nicotine exposure, and physical activity were found to be correlated with MACEs (HR = 0.985, 0.988, 0.993, 0.994, 0.994, respectively). Our study established that LE8 is a more reliable assessment system for CVH. This population-based prospective study reports that an unfavorable cardiovascular health profile is associated with MACEs. Future research is warranted to evaluate the effectiveness of optimizing diet, sleep health, serum glucose levels, nicotine exposure, and physical activity in reducing the risk of MACEs. In conclusion, our findings corroborated the predictive value of Life's Essential 8 and provided further evidence for the association between CVH and the risk of MACEs.

11C, 12C and 13C-Cyanation of Electron-Rich Arenes via Organic Photoredox Catalysis.

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C and 13C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [11C]nitriles into arenes. The aryl [11C]nitriles can be further derivatized to [11C]carboxylic acids, [11C]amides, and [11C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.

Development of [18F]F-5-OMe-Tryptophans through Photoredox Radiofluorination: A New Method to Access Tryptophan-Based PET Agents.

Although various radiolabeled tryptophan analogs have been developed to monitor tryptophan metabolism using positron emission tomography (PET) for various human diseases including melanoma and other cancers, their application can be limited due to the complicated synthesis process. In this study, we demonstrated that photoredox radiofluorination represents a simple method to access novel tryptophan-based PET agents. In brief, 4-F-5-OMe-tryptophans (l/d-T13) and 6-F-5-OMe-tryptophans (l/d-T18) were easily synthesized. The 18F-labeled analogs were produced by photoredox radiofluorination with radiochemical yields ranging from 2.6 ± 0.5% to 32.4 ± 4.1% (3 ≤ n ≤ 5, enantiomeric excess ≥ 99.0%) and over 98.0% radiochemical purity. Small animal imaging showed that l-[18F]T13 achieved 9.58 ± 0.26%ID/g tumor uptake and good contrast in B16F10 tumor-bearing mice (n = 3). Clearly, l-[18F]T13 exhibited prominent tumor uptake, warranting future evaluations of its potential usage in precise immunotherapy monitoring.

A computer model of the effect of venous-arterial-venous extracorporeal membrane oxygenation venous return of oxygenated blood on right atrial recirculation and tricuspid valve blood oxygen saturation.

OBJECTIVE: Venous-arterial venous extracorporeal membrane oxygenation (V-AV ECMO), as a new clinical application of ECMO, showed great clinical application potential in the treatment of patients with combined cardiopulmonary failure. Given the complicated cannulation strategy of V-AV ECMO, its influence on the hemodynamics of the human circulatory system remained unclear. METHODS: In this paper, a fluid-structure interaction was used to study the effect of V-AV ECMO oxygenated blood shunt ratio on right atrial recirculation and tricuspid valve (TV) blood oxygen saturation. In this study, the right atrium, superior vena cava supplying cannulae and inferior vena cava draining cannulae model of a specific patient was constructed. Seven cases with shunt ratio of 12.50%, 18.75%, 25.00%, 31.25%, 37.50%, 43.75% and 50.00% were designed. RESULTS: The streamline diagram and velocity contour of oxygenated blood, recirculation fraction (RF), correlation of three variables (shunt ratio, RF, and oxygen saturation), and the oxygen saturation of blood at the TV were extracted for the study. Study results showed that, first, as the shunt ratio increased, the RF of the seven cases was 14.64%, 29.87%, 33.85%, 40.12%, 40.40%, 40.02%, and 38.09%. Second, with the increase of the shunt ratio, oxygen saturation of blood at the TV in seven cases was 82.1%, 82.5%, 83.3%, 83.3%, 84.0%, 84.6%, and 85.3%. CONCLUSIONS: In this study, the shunt ratio had a strong correlation with the RF and oxygen saturation of blood at the TV. As the shunt ratio increased, the RF initially increased and then stabilized. However, oxygen saturation of blood at the TV would increase with the increase of the shunt ratio, but the degree of increase was small. This research provided useful information for surgeons and operators using V-AV ECMO.

Mental Health of Emergency Department Healthcare Workers During COVID-19 in Brooklyn, New York.

Background: Maintaining good mental health among Emergency Department healthcare workers (ED HCW) is paramount to well-functioning healthcare. We measured mental health and COVID-19 symptoms in ED HCW at a COVID-19 epicenter. Methods: A cross-sectional, convenience sample of adult (≥18 years) ED HCW in Brooklyn, New York, USA, who were employed at ≥50% of a full-time effort, was surveyed September-December, 2020 with reference period March-May 2020. An anonymous email-distributed survey assessed gender, age, race, healthcare worker status (clinical versus non-clinical), SARS-CoV-2 testing, number of people to talk to, COVID-19-related home problems, mental health care interruption during COVID-19, loneliness, and survey date. Outcomes included symptoms of depression, psychological distress, perceived stress, post-traumatic stress disorder (PTSD), anxiety, and resilience measured using validated scales. Results: Of 774 HCW, 247 (31.9%) responded (mean age 38.2±10.8 years; 59.4% White; 52.5% men; 80.1% clinical; 61.6% SARS-CoV-2 tested). Average mental health scores were significantly higher among clinical vs non-clinical HCW (P's<0.0001-0.019). The proportion reporting a clinically-relevant psychological distress symptom burden was higher among clinical vs non-clinical HCW (35.8% vs 13.8%, p=0.019); and suggested for depression (53.9% clinical vs 35.7% non-clinical, p=0.072); perceived stress (63.6% clinical vs 44.8% non-clinical, p=0.053); and PTSD (18.2% clinical vs 3.6% non-clinical, p=0.064). Compared to non-clinical staff, Medical Doctors and Doctors of Osteopathy reported 4.8-fold higher multivariable-adjusted odds of clinically-relevant perceived stress (95%CI 1.8-12.9, p=0.002); Emergency Medical Technicians reported 15.5-fold higher multivariable-adjusted odds of clinically-relevant PTSD (95%CI 1.6-150.4, p=0.018). Increasing age, number of COVID-19-related home problems and people to talk to, loneliness and mental health care interruption were adversely associated with mental health; being male and SARS-CoV-2 testing were beneficial. Conclusions: COVID-19-related mental health burden was high among ED HCW in Brooklyn. Mental health support services are essential for ED HCW.

miR-301a Deficiency Attenuates the Macrophage Migration and Phagocytosis through YY1/CXCR4 Pathway.

(1) Background: the miR-301a is well known involving the proliferation and migration of tumor cells. However, the role of miR-301a in the migration and phagocytosis of macrophages is still unclear. (2) Methods: sciatic nerve injury, liver injury models, as well as primary macrophage cultures were prepared from the miR-301a knockout (KO) and wild type (WT) mice to assess the macrophage's migration and phagocytosis capabilities. Targetscan database analysis, Western blotting, siRNA transfection, and CXCR4 inhibition or activation were performed to reveal miR301a's potential mechanism. (3) Results: the macrophage's migration and phagocytosis were significantly attenuated by the miR-301a KO both in vivo and in vitro. MiR-301a can target Yin-Yang 1 (YY1), and miR-301a KO resulted in YY1 up-regulation and CXCR4 (YY1's down-stream molecule) down-regulation. siYY1 increased the expression of CXCR4 and enhanced migration and phagocytosis in KO macrophages. Meanwhile, a CXCR4 inhibitor or agonist could attenuate or accelerate, respectively, the macrophage migration and phagocytosis. (4) Conclusions: current findings indicated that miR-301a plays important roles in a macrophage's capabilities of migration and phagocytosis through the YY1/CXCR4 pathway. Hence, miR-301a might be a promising therapeutic candidate for inflammatory diseases by adjusting macrophage bio-functions.

Modular PET Agent Construction Strategy through Strain-Promoted Double-Click Reagent with Efficient Photoclick Step.

An efficient modular strategy for rapid assembly of positron emission tomography (PET) agents has been developed. The use of a sequential, rapid, and selective double-click reaction allows for a combinatorial approach to the cross-linking of positron emitter-bearing prosthetic groups with various ligands. The strain-promoted azide alkyne cyclization (SPAAC) coupling of 18F-labeled azide synthon with MC-DIBOD, a cyclooctadiyne with one of the triple bonds caged as a cyclopropenone moiety, produces a stable intermediate. A brief exposure of the latter to 350-420 nm light removes protection of the second triple bond allowing for the addition of an azide-tagged biomolecule. The utility of this strategy has been demonstrated by the construction of several PET agents. The value of modularity was demonstrated in the preparation of PSMA PET agents, where the hydrophilicity was easily modified to improve tumor to background contrast.

Hemodynamic study of the effect of the geometric height of leaflets on the performance of the aortic valve under aortic valve reconstruction.

Background: Although aortic valve reconstruction has become an alternative treatment for aortic valve disease, the design of the geometric parameters of the reconstructed leaflet still mainly depends on the experience of doctors. The present study investigates the effects of the height of the leaflets on the performance and biomechanical states of the reconstructed aortic valve. Methods: This numerical study was carried out using the finite element approach and the lattice Boltzmann method. The dynamic and biomechanical characteristics of the leaflets were evaluated by using the finite element approach, while the blood flow in the aortic sinus was evaluated by applying the lattice Boltzmann method. Three types of leaflets with different heights were designed. Then the dynamic characteristics, stress distribution, and effective orifice area (EOA) of the aortic valve and flow pattern were calculated as the indicators. Results: The results demonstrated that the height of the leaflets could indeed regulate the performance and the biomechanical states of the aortic valve. The rapid valve opening times of the 3 types of leaflets gradually reduced along with the decrease of the height ratio (HR_0.8: 120 ms vs. HR_1.0: 68 ms vs. HR_1.2: 31 ms), while the rapid valve closing times (RVCTs) of the 3 types of leaflets were similar to each other (approximately 75 ms). Moreover, the radial displacement of the leaflet at the fully open time increased along with the decrease of the HR of the leaflets (HR_0.8: 8 mm vs. HR_1.0: 6 mm vs. HR_1.2: 4 mm). In addition, the stress level of the leaflets also increased with the increase of the height of the leaflets (max stress, HR_0.8: 0.5 MPa, vs. HR_1.0: 1.1 MPa, vs. HR_1.2: 1.8 MPa). Similarly, the low velocity region near the ascending aortic wall and the wall shear stress (WSS) level on the ventricular side of the leaflets also increased along with the increase of the HR of the leaflets. Conclusions: In short, the height of the leaflets mainly affects the opening performance of the reconstructed aortic leaflets. The HR of the reconstructed leaflets for adults should be less than 1.0 to balance the opening and closing performance of aortic leaflets.

The piRNAs present in the developing testes of Chinese indigenous Xiang pigs.

The piRNA pathway plays an essential role in defense against transposable elements in the germline tissues of animals and contributes to post-transcriptional regulation of genes. Xiang pigs present an earlier sexual maturation compared with most European pig breeds, but the role that the piRNA pathway plays in the development of Xiang pigs is currently not understood. In this study, we sequenced and analyzed piRNAs expressed in the testes of Xiang pigs at four different ages, and identified endogenous piRNAs which were highly abundant at each time point. The lengths of the identified piRNAs ranged from 24 to 34 nucleotides (nt), with the most abundant length being 29 nt. Additionally, there was a strong bias for uracil at the first position, a slight bias for adenine at position 10 and frequent 5'-10 nt complementary sequences, suggesting that ping-pong-mediated silencing is present in the Xiang pig germline. We observed that the piRNA composition changed from TE-associated piRNAs in two- and three-month-old testes to predominantly gene-derived and intergenic piRNAs in six- and twelve-month-old testes, with a gradual increase in the expression level of piRNAs over the course of testis development. And more than half of piRNA reads mapped to just a few of 473 predicted piRNA clusters. Additionally, we found that several genes were highly enriched by piRNA reads, including CYP19A1, PRMT8, SUZ12, WWOX, SGSM1 and MIF. The functions of these genes are primarily associated with steroidogenesis and histone modification. Changes in piRNA composition and widespread expression patterns during spermatid development indicate that these small ncRNAs may be responsible not only for transposon suppression but also for post-transcriptional regulation of several protein-coding genes essential for normal spermatogenesis.

The Synthesis and Initial Evaluation of MerTK Targeted PET Agents.

MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to MerTK suppression may not be uniform due to the heterogeneity of solid tumors and different tumor stages. In this report, we develop a series of radiolabeled agents as potential MerTK PET (positron emission tomography) agents. In our initial in vivo evaluation, [18F]-MerTK-6 showed prominent uptake rate (4.79 ± 0.24%ID/g) in B16F10 tumor-bearing mice. The tumor to muscle ratio reached 1.86 and 3.09 at 0.5 and 2 h post-injection, respectively. In summary, [18F]-MerTK-6 is a promising PET agent for MerTK imaging and is worth further evaluation in future studies.