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Purpose: This study aimed to explore the abnormal changes in short- and long-range functional connectivity density (FCD) in patients with herpes zoster (HZ) and postherpetic neuralgia (PHN). Patients and Methods: Twenty HZ patients, 22 PHN patients, and 19 well-matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging scans. We used FCD mapping, a data-driven graph theory method, to investigate local and global functional connectivity patterns. Both short- and long-range FCD were calculated and compared among the PHN, HZ, and HC groups. Then, the abnormal regions were used to calculate seed-based functional connectivity. Finally, correlation analyses were performed between the altered FCD values and clinical datas. Results: Compared with HCs, HZ patients showed significantly increased long-range FCD of the bilateral cerebellum, thalamus, parahippocampal gyrus, superior temporal gyrus and lingual gyrus. HZ patients also displayed significantly decreased short-range FCD of the bilateral posterior cingulate gyrus, median cingulate/paracingulate gyri, and left precuneus. Compared with HCs, PHN patients displayed significantly decreased long-range FCD of the bilateral superior frontal gyrus and decreased short-range FCD in the bilateral posterior cingulate gyrus, median cingulate/paracingulate gyri, and precuneus. However, there was no significant difference in either long-range or short-range FCD between the PHN and HZ patients. Long-range FCD deficit areas and the right insula showed altered functional connectivity in PHN patients. Furthermore, pain duration in patients with PHN was correlated with abnormal long-range FCD. Conclusion: Herpes zoster pain widely affects intra- and inter-regional functional connectivity, leading to disrupted short-range FCD and increased long-range FCD during different stages of the disease. Long-term chronic pain in PHN patients may impair the pain emotion regulation pathway. These findings could improve our understanding of the pathophysiological mechanisms of HZ and PHN and offer neuroimaging markers for HZ and PHN.

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BACKGROUND: Shingles can cause long-term pain and negative emotions, along with changes in brain function. In this study, Granger Causality Analysis (GCA) was used to compare herpes zoster (HZ) and postherpetic neuralgia (PHN) differences in effective connections within the "pain matrix" between patients and healthy controls to further understand patterns of interaction between brain regions and explore the relationship between changes in effective connections and clinical features. METHODS: Resting-state functional magnetic resonance imaging (fMRI) scans were performed on 55 HZ; 55 PHN; and 50 age-, sex- matched healthy controls (HCs). The brain regions associated with the pain matrix are used as the seeds of effective connectivity. GCA was used to analyze effective connections in brain regions that differed significantly between groups. Then the correlation between GCA values and clinical indicators was studied. RESULTS: Compared with HC, GCA values between the thalamus and the amygdala, between the thalamus and the precentral gyrus, from the thalamus to the postcentral gyrus, and from the parahippocampal gyrus to the amygdala, anterior cingulate gyrus were significantly reduced in HZ patients. Compared with HC, GCA values between the insular and the postcentral gyrus, from the insular to the inferior parietal lobe, and from the postcentral gyrus to the amygdala were significantly reduced in PHN patients. Compared with HZ, GCA values between the inferior parietal lobe and the parahippocampal gyrus, between the inferior parietal lobe and the anterior cingulate gyrus, and from the anterior cingulate gyrus to the amygdala were significantly increased in PHN patients. The visual analogue scale (VAS) score of PHN patients was positively correlated with the GCA value from the central posterior lobe to the insula. CONCLUSIONS: PHN and HZ patients showed a broad reduction in effective connections, mainly reflected in abnormal pain pathway regulation, pain perception, negative emotion and memory production, providing new perspectives to understand the neuroimaging mechanisms of shingles.

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Objective: To review and analyze the functional connectivity (FC) abnormalities in the brain olfactory network (ON) of patients with chronic rhinosinusitis with olfactory dysfunction (CRSwOD) and explore the relationship between these FC abnormalities and olfactory dysfunction, providing clues to the neurophysiological mechanisms underlying CRSwOD. Methods: FC analysis on the ON of patients with CRSwOD and patients with chronic rhinosinusitis without olfactory dysfunction (CRSsOD) identified the regions of the ON with abnormal FC in CRSwOD patients, and the correlation between abnormal FC and clinical scales for chronic rhinosinusitis was analyzed. Results: (1) Compared with the CRSsOD group, CRSwOD patients showed decreased FC between the bilateral orbitofrontal cortex (OFC) and the right middle frontal gyrus, (2) Receiver operating characteristic (ROC) curve analysis revealed that the FC value between the right middle frontal gyrus and the left OFC (area under the curve (AUC) = 0.852, sensitivity: 0.821, specificity: 0.800, p < 0.001) was more capable of distinguishing whether CRS patients may have olfactory dysfunction than the FC value between the right middle frontal gyrus and the right OFC (AUC = 0.827, sensitivity: 0.893, specificity: 0.667, p < 0.001), and (3) Lund-Kennedy scores were positively correlated with the FC values between the right middle frontal gyrus and the left OFC (r = 0.443, p < 0.018). Lund-Mackay scores were also positively correlated with the FC values between the right middle frontal gyrus and the left OFC (r = 0.468, p < 0.012). Questionnaire of Olfactory Disorders-Negative Statements scores were negatively correlated with the FC values between the right middle frontal gyrus and the left OFC (r = -0.481, p < 0.001). Conclusion: Persistent nasal inflammation affects the FC between the middle frontal gyrus and the OFC, which may serve as a potential imaging marker for identifying CRSwOD. The severity of nasal inflammation and olfactory damage is closely related to the FC between the middle frontal gyrus and OFC, and the abnormal changes in this FC can be used to explain the neurophysiological mechanisms behind the occurrence of olfactory dysfunction in patients.

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The purpose of this study was to explore the resting-state functional connectivity (FC) changes among the pain matrix and other brain regions in herpes zoster (HZ) and postherpetic neuralgia (PHN) patients. Fifty-four PHN patients, 52 HZ patients, and 54 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. We used a seed-based FC approach to investigate whether HZ and PHN patients exhibited abnormal FC between the pain matrix and other brain regions compared to HCs. A random forest (RF) model was constructed to explore the feasibility of potential neuroimaging indicators to distinguish the two groups of patients. We found that PHN patients exhibited decreased FCs between the pain matrix and the putamen, superior temporal gyrus, middle frontal gyrus, middle cingulate gyrus, amygdala, precuneus, and supplementary motor area compared with HCs. Similar results were observed in HZ patients. The disease durations of PHN patients were negatively correlated with those aforementioned impaired FCs. The results of machine learning experiments showed that the RF model combined with FC features achieved a classification accuracy of 75%. Disrupted FC among the pain matrix and other regions in HZ and PHN patients may affect multiple dimensions of pain processing.

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Tamoxifen, a triphenylethylene-based selective estrogen-receptor modulator, is a landmark drug for the treatment of breast cancer and is also used for treating liver cancer and osteoporosis. Structural studies of tamoxifen have led to the synthesis of more than 20 novel tamoxifen analogs as receptor modulators, including 16 ERα modulators 2-17, an ERRß inverse agonist 19 and six ERRγ inverse agonists 20-25. This paper summarizes the research progress and structure-activity relationships of tamoxifen analogs modulating these three nuclear receptors reported in the literature, and introduces the relationship between these three nuclear receptor-mediated diseases and tamoxifen analogs to guide the research of novel tamoxifen analogs.

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OBJECTIVE: Resting-state functional magnetic resonance imaging (rs-fMRI) and Granger causality analysis (GCA) were used to observe the characteristics of amygdala and whole-brain effect connections in patients with herpes zoster (HZ) and post-herpetic neuralgia (PHN) and to determine their relationship with clinical features. METHODS: Rs-fMRI scans were performed on 50 HZ; 50 PHN; and 50 age-, sex- and education-year-matched healthy controls (HCs). Bilateral amygdala subregions were used as seeds for functional connectivity (FC). GCA was used to analyze the effective connection of brain regions that were significantly different among groups. Then, the correlation between FC, and GCA values and clinical indices was investigated. RESULTS: PHN had impaired FC between the amygdala subregion with the putamen, cortex, anterior cingulate cortex (ACC) to HCs and reduced FC of medial amygdala (MeA) with the parieto-occipital lobe and motor cortex to HZ; HZ had reduced FC of the lateral amygdala (LA) with the insula to HCs. GCA values from the bilateral LA to the bilateral ACC, left MeA to the bilateral ACC and left putamen, and right ACC to the bilateral MeA were reduced in PHN patients compared to HCs. Compared with HCs, the GCA values from the left MeA to the left ACC and right putamen were reduced in HZ. The GCA values from the amygdala subregion to the ACC were positively correlated with HAMA or HAMD scores in PHN. CONCLUSION: PHN showed reduced FC between the amygdala subregions and cortico-putamen and decreased effective connectivity from the amygdala subregion to the ACC and putamen. ADVANCES IN KNOWLEDGE: HZ and PHN patients had significant changes in effective connectivity in brain regions, including diverse functional areas emanating from and projecting to the amygdala. The current findings will provide a new perspective for understanding the neuropathophysiological mechanism HZ and PHN.

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Cyclin-dependent kinase 12 (CDK12) is a transcription-associated CDK that plays key roles in transcription, translation, mRNA splicing, the cell cycle, and DNA damage repair. Research has identified that high expression of CDK12 in organs such as the breast, stomach, and uterus can lead to HER2-positive breast cancer, gastric cancer and cervical cancer. Inhibiting high expression of CDK12 suppresses tumor growth and proliferation, suggesting that it is both a biomarker for cancer and a potential target for cancer therapy. CDK12 inhibitors can competitively bind the CDK12 hydrophobic pocket with ATP to avoid CDK12 phosphorylation, blocking subsequent signaling pathways. The development of CDK12 inhibitors is challenging due to the high homology of CDK12 with other CDKs. This review summarizes the research progress of CDK12 inhibitors, their mechanism of action and the structure-activity relationship, providing new insights into the design of CDK12 selective inhibitors.

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Objectives: The aim of this study was to assess the brain functional changes of patients with chronic rhinosinusitis with olfactory dysfunction (CRSwOD) using regional homogeneity (ReHo) of resting-state functional magnetic resonance imaging (MRI) scans, and to better explain the occurrence and development of olfactory decline in patients with chronic sinusitis provides a new idea for the study of more advanced olfactory therapy modalities. Methods: A total of 28 CRSwOD patients, 24 patients with CRS without olfactory dysfunction (CRSsOD), and 25 healthy controls (HCs) were recruited. All subjects underwent olfactory testing, clinical and brief psychological assessments, and MRI scans. A two-sided two-sample t test with AlphaSim correction (voxel-p < 0.001, cluster size >54 voxels) was used to detect differences between CRSwOD, CRSsOD, and HC groups. Results: Compared with HCs, the ReHo values in traditional olfactory regions (e.g., parahippocampal gyrus (PHG), hippocampal, olfactory cortex) were increased, and ReHo values in the frontal gyrus, middle temporal gyrus, precuneus, and posterior cingulate gyrus were decreased in CRSwOD patients. The ReHo values in the precuneus and posterior cingulate gyrus of CRSwOD patients were negatively correlated with Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) scores. Compared with CRSsOD patients, the ReHo values in cerebellar regions were increased and those in the inferior temporal gyrus, precuneus, postcentral, and paracentral gyrus were decreased in CRSwOD patients. The receiver operating characteristic (ROC) curve showed that the mean ReHo values significantly differed between the CRSwOD and CRSsOD groups. Conclusion: Synchronization of regional brain activity in the regions of the secondary olfactory cortex orbitofrontal cortex (OFC), temporal gyrus, precuneus, and cerebellum may be closely related to the development of olfactory dysfunction. Precuneus and posterior cingulate gyrus may be critical brain areas of action for emotional dysfunction in CRSwOD patients.

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Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple- negative Breast Cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structureactivity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.

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Estrogen-related receptor gamma (ERRγ), one of three members of the ERR family, is an inducible transcription factor. ERRγ has dual functions in different tissues. The decreased expression of ERRγ in the brain, stomach, prostate, and fat cells can cause neuropsychological dysfunction, gastric cancer, prostate cancer, and obesity. However, when ERRγ is present in the liver, pancreas, and thyroid follicular cells, ERRγ overexpression is related to liver cancer, type II diabetes, oxidative liver injury, and anaplastic thyroid carcinoma. Signaling pathway studies have confirmed that ERRγ agonists or inverse agonists can regulate ERRγ expression to treat related diseases. The collision between residue Phe435 and the modulator is a key factor determining the activation or inhibition of ERRγ. Although more than 20 agonists and inverse agonists of ERRγ have been reported, no clinical studies have been found in the literature. This review summarizes the important relationship between ERRγ-related signaling pathways and diseases, research progress, and the structure-activity relationship of modulators. These findings provide guidance for further study on new ERRγ modulators.

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Rhizoma Drynariae (RD) was used clinically to treat osteoporosis in China due to stimulating bone formation and inhibiting bone resorption, however, the bioactive constituents with the dual effect on bone are still unknown exactly. Disease-causing mutations in calcium sensing receptor (CaSR) can alter parathyroid hormone secretion and affect Ca2+ release from bone and Ca2+ reabsorption from kidney, which gives an indication that CaSR is a potential target for developing therapeutics to manage osteoporosis. Herein, a chromatographic approach was established, by immobilizing the mutant CaSR onto the surface of silica gels as stationary phase in a one-step procedure and then adding the different amino acids into mobile phase as competitors, for exploring the binding features of the known agonists and further screening ligands from RD. The mutant CaSR-coated column was prepared rapidly without the complicated purification and separation of the receptor, which had the large capacity of 13.1 mg CaSR /g silica gels and kept a good stability and specificity for at least 35 days. The CaSR mutation can weaken the binding affinities for three agonists, and the largest decreases occurred on the mutational site Thr151Met for neomycin, on the two sites of Asn118Lys and Glu191Lys for gentamicin-C, and on the site Phe612Ser for kanamycin, which gained new insights into their structure-function relationship. The potential bioactive compounds from RD were screened using the mutant CaSR-coated column and were recognized as coumaric acid 4-O-ß-D-glucopyranoside, caffeic acid, and naringin using UPLC-MS. Among them, naringin targeting CaSR gives a possible explanation that RD could manage osteoporosis. These results indicated that, such a rapid and simple method, utilizing disease-associated mutation in CaSR to alter the binding affinity for agonists, can be applied in capturing the potential bioactive compounds efficiently from complex matrices like herb medicines.

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OBJECTIVE: This study aimed to compare whole brain network between herpes zoster (HZ) patients and post-herpetic neuralgia (PHN) patients, as well as to investigate the associations between whole brain network changes and pain intensity and the accuracy of classifying between different types of pain. METHODS: PHN patients (n = 50) and HZ patients (n = 50) and healthy controls (HCs) (n = 50) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Functional connectivity and global and local graph theory metrics were calculated by using Dosenbach-160 atlas. The relationship between neuroimaging indicators and clinical scales was evaluated using correlation analysis, and receiver operating characteristic (ROC) curves evaluated the feasibility of classifying PHN and HZ patients using specific neuroimaging indicators. RESULTS: (1) 10 greater average connectivities were found in HZ group among the default mode, frontoparietal, cingulo-opercular, sensorimotor, occipital networks (ONs), and cerebellum (p < 0.001). (2) HZ patients exhibited higher global efficiency than those in the PHN and HCs (t = 2.178, p = 0.038). (3) Multiple linear regression analyses indicated that functional connectivity between the ventral frontal cortex in the cingulo-opercular network and the occipital gyrus in the ON influenced the visual analog score pain scores (ß = 4.273; p = 0.004). CONCLUSION: The variation of functional connectivity between ventral frontal cortex in the cingulo-opercular network and occipital gyrus in the ON may be a robust neuroimaging marker of the transition from HZ to PHN patients. ADVANCES IN KNOWLEDGE: Whole-brain network analysis may be effective in distinguishing HZ and PHN patients and predicting pain intensity.

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This study aimed to explore changes in the white matter microstructure in herpes zoster (HZ) and postherpetic neuralgia (PHN) patients and to estimate the correlation of these changes with clinical data. Diffusion tensor imaging (DTI) data were collected from 33 HZ patients, 32 PHN patients, and 35 well-matched healthy controls (HCs). Subsequently, these data were analyzed by automated fiber quantification (AFQ) to accurately locate alterations in the white matter microstructure. Compared with HCs, HZ and PHN patients both showed a wide range of changes in the diffusion properties of fiber tracts. HZ patients exhibited changes primarily in the left superior longitudinal fasciculus (SLF), whereas PHN patients predominantly exhibited changes in the left inferior fronto-occipital fasciculus. The bilateral SLF and the left corticospinal tract were altered in the PHN patients compared with HZ patients. In addition, PHN patients showed a trend toward more expansive white matter alterations compared with those observed in HZ patients; additionally, in PHN patients, changes in the left cingulum cingulate were significantly correlated with changes in emotion and the duration of disease. These findings may help to elucidate the transformation from HZ to PHN and provide new ideas regarding the reasons for intractable neuropathic pain in PHN.

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Fouling on the heat exchanger surface during food processing has been researched extensively due to its great importance in energy efficiency, product quality and food safety. The nature of heat exchanger surface has an effect on the initial deposition behavior and deposit removal behavior to some degree. Protein adsorption on surface is considered to be the initial stage in fouling. In the current study, protein 'pre-adsorption' at room temperature on stainless steel has been investigated as a means to influence the behavior of protein fouling at pasteurization temperatures. Pre-adsorption was carried out with whey protein concentrate (WPC) and ovalbumin (OVA), respectively, which reduced the fouling of OVA (∼20-30% energy saving in the processing time examined). However, the pre-adsorption had little effect on fouling of whey protein concentrate. Contact angles were measured to show the surface change due to protein pre-adsorption. Protein pre-adsorption made the surfaces more hydrophilic.

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