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Abstract Targeting receptor‐interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY‐10 is reported, which may enable brain RIPK1 imaging. [11C]CNY‐10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY‐10 is characterized by PET imaging in rodents and a non‐human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY‐10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY‐10‐based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY‐10 for AD and potentially other RIPK1‐related human studies.

Summary: Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

Abstract Background Prostate cancer (PCa) is the most common malignancy diagnosed in men. Immune checkpoint blockade (ICB) alone showed disappointing results in PCa. It is partly due to the formation of immunosuppressive tumor microenvironment (TME) could not be reversed effectively by ICB alone. Methods We used PCa cell lines to evaluate the combined effects of CN133 and anti-PD-1 in the subcutaneous and osseous PCa mice models, as well as the underlying mechanisms. Results We found that CN133 could reduce the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and CN133 combination with anti-PD-1 could augment antitumor effects in the subcutaneous PCa of allograft models. However, anti-PD-1 combination with CN133 failed to elicit an anti-tumor response to the bone metastatic PCa mice. Mechanistically, CN133 could inhibit the infiltration of PMN-MDSCs in the TME of soft tissues by downregulation gene expression of PMN-MDSC recruitment but not change the gene expression involved in PMN-MDSC activation in the CN133 and anti-PD-1 co-treatment group relative to the anti-PD-1 alone in the bone metastatic mice model. Conclusions Taken together, our work firstly demonstrated that combination of CN133 with anti-PD-1 therapy may increase the therapeutic efficacy to PCa by reactivation of the positive immune microenvironment in the TME of soft tissue PCa.

Abstract Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic sleep disruption (CSD) leads to heightened pain sensitivity, referred to as CSD-induced hyperalgesia. However, the underlying mechanisms are unclear. The thalamic reticular nucleus (TRN) has unique integrative functions in sensory processing, attention/arousal and sleep spindle generation. We report that the TRN played an important role in CSD-induced hyperalgesia in mice, through its projections to the ventroposterior region of the thalamus. Metabolomics revealed that the level of N-arachidonoyl dopamine (NADA), an endocannabinoid, was decreased in the TRN after CSD. Using a recently developed CB1 receptor (cannabinoid receptor 1) activity sensor with spatiotemporal resolution, CB1 receptor activity in the TRN was found to be decreased after CSD. Moreover, CSD-induced hyperalgesia was attenuated by local NADA administration to the TRN. Taken together, these results suggest that TRN NADA signaling is critical for CSD-induced hyperalgesia.

Abstract Background Citrus tristeza virus (CTV) is one of the most serious threats to the citrus industry, and is present in both wild and cultivated citrus. The origin and dispersal patterns of CTV is still poorly understood in China. Methods In this study, 524 CTV suspected citrus samples from China were collected, including 354 cultivated citrus samples and 174 wild citrus samples. Finally, 126 CTV coat protein sequences were obtained with time-stamped from 10 citrus origins in China. Bayesian phylodynamic inference were performed for CTV origin and dispersal patterns study in China. Result We found that CTV was mainly distributed in southern and coastal areas of China. The substitution rate of CTV was 4.70 × 10− 4 subs/site/year (95% credibility interval: 1.10 × 10− 4 subs/site/year ~ 9.10 × 10− 4 subs/site/year), with a slight increasing trend in CTV populations between 1990 and 2006. The CTV isolates in China shared a most common recent ancestor around 1875 (95% credibility interval: 1676.57 ~ 1961.02). The CTV in China was originated from wild citrus in Hunan and Jiangxi, and then spread from the wild citrus to cultivated citrus in the growing regions of Sichuan, Chongqing, Hubei, Fujian, Zhejiang, Guangxi and Guangdong provinces. Conclusions This study has proved that CTV in China was originated from wild citrus in Hunan and Jiangxi. The spatial-temporal distribution and dispersal patterns has uncovered the population and pandemic history of CTV, providing hints toward a better understanding of the spread and origin of CTV in China.

Abstract Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity ‐ with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D‐AD human neural culture model. Results suggest that the structure‐based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α‐tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho‐tau (p‐tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology‐based drug discovery in AD.

Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aβ1-42 aggregation, and potent neuroprotective effect on Aβ1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood–brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [11C]5f demonstrated that [11C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [18F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [18F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.

The link between amyloid and tau proteins with Alzheimer’s disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression.

Trigeminal neuralgia (TN) is a classic neuralgic pain condition with distinct clinical characteristics. Modeling TN in rodents is challenging. Recently, we found that a foramen in the rodent skull base, the foramen lacerum, provides direct access to the trigeminal nerve root. Using this access, we developed a foramen lacerum impingement of trigeminal nerve root (FLIT) model and observed distinct pain-like behaviors in rodents, including paroxysmal asymmetric facial grimaces, head tilt when eating, avoidance of solid chow, and lack of wood chewing. The FLIT model recapitulated key clinical features of TN, including lancinating pain–like behavior and dental pain–like behavior. Importantly, when compared with a trigeminal neuropathic pain model (infraorbital nerve chronic constriction injury [IoN-CCI]), the FLIT model was associated with significantly higher numbers of c-Fos–positive cells in the primary somatosensory cortex (S1), unraveling robust cortical activation in the FLIT model. On intravital 2-photon calcium imaging, synchronized S1 neural dynamics were present in the FLIT but not the IoN-CCI model, revealing differential implication of cortical activation in different pain models. Taken together, our results indicate that FLIT is a clinically relevant rodent model of TN that could facilitate pain research and therapeutics development.

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a “normal” operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain–like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos–expressing neurons and selective activation of GABAergic interneurons significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More important, restoring a “normal” range of neural dynamics through attenuation of pain-induced S1 synchronization alleviated pain-like behavior. These results suggest that spontaneous pain pushed the S1 regional network into a synchronized state, whereas reversal of this synchronization alleviated pain.

The sigma-1 receptor (σ1R) is a unique intracellular protein. σ1R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ1R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, σ1R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, in vivo PET/CT imaging of novel σ1R 11C-labeled radioligands based on 6-hydroxypyridazinone, [11C]HCC0923 and [11C]HCC0929. Two radioligands have high affinities to σ1R, with good selectivity. In mice PET/CT imaging, both radioligands showed appropriate kinetics and distributions. Additionally, the specific interactions of two radioligands were reduced by compounds 13 and 15 (self-blocking). Of the two, [11C]HCC0929 was further investigated in positive ligands blocking studies, using classic σ1R agonist SA 4503 and σ1R antagonist PD 144418. Both σ1R ligands could extensively decreased the uptake of [11C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined in vivo. These studies demonstrated that two radioligands, especially [11C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of σ1R in brain. KEY WORDS: σ1R, PET, Brain imaging, 6-Hydroxypyridazinone, 11C-labeled radioligand

Gene transcription is known to vary with age and sex, although the underlying mechanisms are unresolved. Here, the authors show that epigenetic enzymes known as HDACs, which regulate gene transcription, are increasingly expressed with age in the living human brain, with sex differences also observed.

α1-Adrenoceptor is implicated in numerous neuronal diseases. The development of new modulators targeting this receptor as well as the investigation of the role of α1-adrenoceptor in healthy and disease conditions, however, is hindered by the lack of specific positron emission tomography (PET) radiotracers. Iloperidone shows a high binding affinity to α1-adrenoceptor and moderate selectivity over other brain receptors. We report herein the synthesis and characterization of carbon-11 labeled iloperidone for imaging of α1-adrenoceptor in brain. The radiolabeling of [11C]iloperidone was carried out conveniently in one step by treating precursor with [11C]CH3I in DMF in the presence of K2CO3. Then, [11C]iloperidone was purified by semi-preparative HPLC, and characterized in C57BL/6 mice using PET/CT scanning. The desired product [11C]iloperidone was obtained in an average decay corrected radiochemical of 12% (n = 3) and over 99% radiochemical purity. The average molar radioactivity was 357 GBq/μmol with total synthetic time of 35–40 min. PET/CT scanning in C57BL/6 mice showed favorable pharmacokinetic properties and high brain exposure of [11C]iloperidone. Blocking experiments by pretreatment with the unlabeled iloperidone showed the significant blocking effects with about 25% reduction in brain uptake. These results suggested that [11C]iloperidone can serve as a lead compound for the further development of specific radiotracers for PET imaging of α1-adrenoceptor in brain clinically.

Bromodomain and extra-terminal domain (BET) family proteins have become a hot research area because of their close relationship with a variety of human diseases. The non-invasive imaging technique, such as positron emission tomography (PET), provides a powerful tool to visualize and quantify the BET family proteins that accelerating the investigation of this domain. Herein, we describe the development of a promising PET probe, [11C]1, specifically targeting BET family proteins based on the potent BET inhibitor CF53. [11C]1 was successfully radio-synthesized with good yield and high purity after the optimization of radiolabeling conditions. The in vivo bio-activities evaluation of [11C]1 was performed using PET imaging in rodents. The results demonstrated that [11C]1 has favorable uptake in peripheral organs and moderate uptake in the brain. Further blocking studies indicated the high binding specificity and selectivity for BET proteins of this probe. Our findings suggest that [11C]1 is a promising BET PET probe for BET proteins as well as epigenetic imaging.

Abstract Background Ribosomal RNA (rRNA) consists of four non‐coding RNAs, the 28S, 5.8S, 18S, and 5S rRNA. Abnormal expression of rRNA has been found in multiple tumors, and the methylation of rDNA promoter may affect rRNA expression as an epigenetic regulatory mechanism. Oral squamous cell carcinoma (OSCC) is a kind of aggressive tumors which occurs in multiple sites in oral cavity. rRNA expression and the methylation of rDNA promoter in modulating rRNA expression in OSCC maintain unclear. This study aims to investigate the rRNA expression, the methylation status within rDNA promoter, and the underlying mechanism of methylation in regulating rRNA expression in OSCC. Methods Twelve primary OSCC and matched normal tissue samples were collected from patients with OSCC. Quantitative real‐time PCR was used to evaluate the rRNA level. HpaII/MspI digestion and bisulfite sequencing were used to investigate the methylation status of rDNA promoter. Results Ribosomal RNA levels were suppressed in OSCC as compared with matched normal tissues. HpaII/MspI digestion and bisulfite sequencing showed no significant differences for the methylation of rDNA promoter between the tumor and matched normal tissues. Conclusion The methylation in rDNA promoter could not explain for the suppressed rRNA expression in OSCC tissues.

Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson’s disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5’ untranslated region (5’UTR) of α-Syn mRNA, and we have used the α-Syn 5’UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.

The orexin receptor (OX) is critically involved in motivation and sleep−wake regulation and holds promising therapeutic potential in various mood disorders. To further investigate the role of orexin receptors (OXRs) in the living human brain and to evaluate the treatment potential of orexin-targeting therapeutics, we herein report a novel PET probe ([11C]CW24) for OXRs in the brain. CW24 has moderate binding affinity for OXRs (IC50 = 0.253 μM and 1.406 μM for OX1R and OX2R, respectively) and shows good selectivity to OXRs over 40 other central nervous system (CNS) targets. [11C]CW24 has high brain uptake in rodents and nonhuman primates, suitable metabolic stability, and appropriate distribution and pharmacokinetics for brain positron emission tomography (PET) imaging. [11C]CW24 warrants further evaluation as a PET imaging probe of OXRs in the brain.

Amelogenesis imperfecta is a group of disorders causing abnormalities in enamel formation in various phenotypes. Many mutations in the FAM83H gene have been identified to result in autosomal dominant hypocalcified amelogenesis imperfecta in different populations. However, the structure and function of FAM83H and its pathological mechanism have yet to be further explored. Evolutionary analysis is an alternative for revealing residues or motifs that are important for protein function. In the present study, we chose 50 vertebrate species in public databases representative of approximately 230 million years of evolution, including 1 amphibian, 2 fishes, 7 sauropsidas and 40 mammals, and we performed evolutionary analysis on the FAM83H protein. By sequence alignment, conserved residues and motifs were indicated, and the loss of important residues and motifs of five special species (Malayan pangolin, platypus, minke whale, nine-banded armadillo and aardvark) was discovered. A phylogenetic time tree showed the FAM83H divergent process. Positive selection sites in the C-terminus suggested that the C-terminus of FAM83H played certain adaptive roles during evolution. The results confirmed some important motifs reported in previous findings and identified some new highly conserved residues and motifs that need further investigation. The results suggest that the C-terminus of FAM83H contain key conserved regions critical to enamel formation and calcification.

Art and science represent human creativity and rational thinking, respectively. When the two seemingly opposite fields are intertwined, there is always a life-changing spark. In particular, the integration of ancient traditional Chinese art into the latest electronic devices is always been an unexcavated topic. Fabricating two-dimensional material with a tensile strain less than 3% with an ultimate global stretch has been an important problem that plagues the current flexible electronics field. The current research is limited to material in small scale, and it is always necessary to develop and extend large-sized flexible electronic systems. Here, inspired by the traditional Chinese paper-cut structure, we present a highly deformable multifunctional electronic system based on the MoS2 nanosheet. In this work, we first demonstrate how the traditional paper-cut structure can open the view of flexible electronics. In order to obtain a large area of MoS2 with excellent performance, we use a metal-assisted exfoliation method to transfer MoS2, followed by fabricating a field effect transistor to characterize its excellent electrical properties. Two photodetectors and a temperature sensor are produced with good performance. The mechanical simulation proves that the structure has more advantages in stretchability than other typical paper-cut structures. From the experimental and mechanical point of view, it is proved that the device can work stably under high deformation. We finally show that the device has broad application prospects in highly deformed organs, tissues, and joints. These findings set a good example of traditional Chinese culture to guide innovation in the field of electronic devices.

Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [ 11 C]CO 2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [ 11 C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [ 11 C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system.

Periodontal tissue regeneration is the ultimate goal of the treatment for periodontitis-affected teeth. The success of regenerative modalities relies heavily on the utilization of appropriate biomaterials with specific properties. Poly (lactic-co-glycolic acid) (PLGA), a synthetic aliphatic polyester, has been actively investigated for periodontal therapy due to its favorable mechanical properties, tunable degradation rates, and high biocompatibility. Despite the attractive characteristics, certain constraints associated with PLGA, in terms of its hydrophobicity and limited bioactivity, have led to the introduction of modification strategies that aimed to improve the biological performance of the polymer. Here, we summarize the features of the polymer and update views on progress of its applications as barrier membranes, bone grafts, and drug delivery carriers, which indicate that PLGA can be a good candidate material in the field of periodontal regenerative medicine.

Optical three-dimensional (3D) molecular imaging is highly desirable for providing precise distribution of the target-of-interest in disease models. However, such 3D imaging is still far from wide applications in biomedical research; 3D brain optical molecular imaging, in particular, has rarely been reported. In this report, we designed chemiluminescence probes with high quantum yields, relatively long emission wavelengths, and high signal-to-noise ratios to fulfill the requirements for 3D brain imaging in vivo. With assistance from density-function theory (DFT) computation, we designed ADLumin-Xs by locking up the rotation of the double bond via fusing the furan ring to the phenyl ring. Our results showed that ADLumin-5 had a high quantum yield of chemiluminescence and could bind to amyloid beta (Aß). Remarkably, ADLumin-5' s radiance intensity in brain areas could reach 4 × 107 photon/s/cm2/sr, which is probably 100-fold higher than most chemiluminescence probes for in vivo imaging. Because of its strong emission, we demonstrated that ADLumin-5 could be used for in vivo 3D brain imaging in transgenic mouse models of Alzheimer's disease. [ABSTRACT FROM AUTHOR]