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Despite both fluoroalkylsulfonyl groups and benzofurans are important bioactive moieties, the construction of fluoroalkanesulfonylated benzofurans that incorporate these two fragments remains underdeveloped. Here, we report a tandem cyclization protocol to construct a wide range of 3-fluoroalkylsulfonyl benzofurans using readily accessible o -hydroxyphenyl propargyl alcohols and sodium fluoroalkanesulfinates. Furthermore, this synthetic strategy can also be adapted to prepare 3-thio benzofurans by changing the S-nucleophiles to thiols or thiophenols.

Purpose: The aim of this study was to evaluate the utility of T1-mapping, high-spatial-resolution T2-weighted imaging (HR-T2WI), and their combined model in distinguishing between adenocarcinoma not otherwise specified (AC) and mucinous adenocarcinoma (MC) in rectal cancer., Methods: A total of 55 patients with pathologically confirmed AC and 37 patients with MC were included in the study. Two radiologists independently reviewed the HR-T2WI and provided assessments of histopathological type. Additionally, T1 relaxation times were quantified using whole-tumor volume methods both pre-contrast (T1p) and post-contrast administration (T1e). The absolute reduction in T1 value (T1d) and the percentage reduction (T1d%) were calculated. Receiver operating characteristic curve analysis was performed to evaluate diagnostic efficacy., Results: HR-T2WI demonstrated a sensitivity, specificity, and accuracy of 81.08%, 94.55%, and 89.13%, respectively, in distinguishing rectal MC. T1p, T1e, and T1d values were significantly higher in the MC group compared to the AC group (P < 0.001, = 0.019, and < 0.001, respectively), while there was no statistically significant difference in T1d% between the two groups. Among these quantitative parameters, T1p showed the highest diagnostic efficiency for identifying MC, with a sensitivity of 59.46%, specificity of 92.73%, and moderate diagnostic accuracy (AUC = 0.819). Combining HR-T2WI with T1p (sensitivity = 86.49%, specificity = 92.73, AUC = 0.927) yielded superior performance over single parameters in distinguishing histopathological subtypes., Conclusion: T1p is effective in discriminating between AC and MC in rectal cancer. Importantly, the combined model incorporating HR-T2WI and T1p demonstrated enhanced capability in distinguishing histopathological subtypes of rectal cancer, which benefits individualized treatment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To assess the value of orthogonal axial images (OAI) of MRI in gastric cancer T staging., Methods: This retrospective study enrolled 133 patients (median age, 63 [range, 24-85] years) with gastric adenocarcinoma who underwent both CT and MRI followed by surgery. MRI lacking or incorporating OAI and CT images were evaluated, respectively. Diagnostic performance (accuracy, sensitivity, and specificity) for each T stage, overall diagnostic accuracy and rates of over- and understaging were quantified employing pathological T stage as a reference standard. The McNemar's test was performed to compare the overall accuracy., Results: Among patients with pT1-pT4 disease, MRI with OAI (accuracy: 88.7-94.7%, sensitivity: 66.7-93.0%, specificity: 91.5-100.0%) exhibited superior diagnostic performance compared to MRI without OAI (accuracy: 81.2-88.7%, sensitivity: 46.2-83.1%, specificity: 85.5-99.1%) and CT (accuracy: 88.0-92.5%, sensitivity: 53.3-90.1%, specificity: 88.7-98.1%). The overall accuracy of MRI with OAI was significantly higher (83.5%) than that of MRI without OAI (67.7%) (p < .001). However, there was no significant difference in the overall accuracy of MRI with OAI and CT (78.9%) (p = .35). The over- and understaging rates of MRI with OAI (12.0, 4.5%) were lower than those of MRI without OAI (21.8, 10.5%) and CT (12.8, 8.3%)., Conclusion: OAI play a pivotal role in the T staging of gastric cancer. MRI incorporating OAI demonstrated commendable performance for gastric cancer T-staging, with a slight tendency toward its superiority over CT., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3' untranslated regions (3' UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear. In this study, we uncover PQBP1 as an emerging APA regulator that actively maintains cell-specific APA profiles in neural progenitor cells (NPCs) and delicately manages the equilibrium between NPC proliferation and differentiation. Multi-omics analysis shows that PQBP1 directly interacts with the upstream UGUA elements, impeding the recruitment of the CFIm complex and influencing polyadenylation site selection within genes associated with the cell cycle. Our findings elucidate the molecular mechanism by which PQBP1 orchestrates dynamic APA changes during neurogenesis, providing valuable insights into the precise regulation of cell-type-specific APA and the underlying pathogenic mechanisms in neurodevelopmental disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Herein, we present a new and general protocol for the assembly of 2,2'-bipyridyls from nonpyridine substrates without using any metal catalysts or organometallic reagents. The process starts from the coupling of two 1,3-dienyl isocyanides followed by a 6π-electrocyclization/aromatization cascade featuring the simultaneous formation of two pyridine rings in a single operation. Notably, this strategy is also applicable to the construction of nonsymmetrical 2-(2-pyridyl)-quinolines/-quinoxalines. Furthermore, the aggregation-induced emission (AIE) characteristics endow our approach with great potential in biorelevant fields.

Background: Diffusion-derived vessel density (DDVD) is a physiological surrogate of the area of micro-vessels per unit tissue area. DDVD is calculated according to: DDVD(b0b5) = Sb0/ROIarea0 - Sb5/ROIarea5, where Sb0 and Sb5 refer to the tissue signal when b is 0 or 5 s/mm 2 . This study applied DDVD to assess the perfusion of rectal carcinoma (RC)., Methods: MRI was performed with a 3.0-T magnet. Diffusion weighted image with b -values of 0, 5 s/mm 2 were acquired in 113 patients with non-mucinous RC and 15 patients with mucinous RC. Diffusion-derived vessel density ratio [DDVDr(b0b5)] was DDVD(b0b5) of RC divided by DDVD(b0b5) of tumor-free rectal wall., Results: The median value of the DDVDr(b0b5) for non-mucinous RCs was 1.430, with the majority of RCs showing a higher DDVD than the adjacent tumor-free wall [i.e., with DDVDr(b0b5) >1]. 90.3% (102/113) of non-mucinous RCs were hypervascular, 1.77% (2/113) were iso-vascular, and 7.96% (9/113) were hypovascular. The median value of the DDVDr(b0b5) for mucinous RCs was 1.660. 73.3% (11/15) of mucinous RCs were hypervascular, and 26.7% (4/15) were hypovascular. A trend (P=0.09) was noted that earlier clinical grades non-mucinous RCs had a higher DDVDr(b0b5) than those of the advanced clinical grades (2.245 for grade 0&I, 1.460 for grade II, 1.430 for grade III, 1.130 for grade IV). A non-significant trend was noted with well and moderately differentiated non-mucinous RCs had a higher DDVDr(b0b5)than that of poorly differentiated non-mucinous RCs (median: 1.460 vs. 1.320). A non-significant trend was noted with MRI-detected extramural vascular invasion (mrEMVI) positive non-mucinous RCs had a higher DDVDr(b0b5) than that of mrEMVI negative non-mucinous RCs (1.630 vs. 1.370)., Conclusions: DDVD results in this study approximately agree with contrast agent dynamically enhanced CT literature data., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-406/coif).Y.X.J.W. serves as the Editor-in-Chief of Quantitative Imaging in Medicine and Surgery. He is the founder of Yingran Medicals Ltd., which develops medical image-based diagnostics software. The other authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Objectives: To evaluate the identification of tumor deposits (TDs) and the prognostic significance of an MRI tumor regression grade for TDs in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (nCRT)., Methods: Ninety-one patients with cT3 or cT4 rectal cancer who underwent surgery following nCRT between August 2014 and June 2020 were retrospectively analyzed. Changes in pre-nCRT MRI-detected TDs (mrTDs) were described as mrTD regression grade. The diagnostic performance of post-nCRT MRI-detected TDs (ymrTDs) was compared with histopathological reference standard. The correlation between ymrTDs, mrTD regression grade, and disease-free survival (DFS) was assessed., Results: The sensitivity and specificity of ymrTDs were 88.00% and 89.39%, respectively. The area under the receiver operating characteristic curve was 0.887 (95% confidence interval [CI]: 0.803-0.944). The 3-year DFS of patients with positive ymrTDs was significantly lower than of the negative group (44.83% vs 82.73%, p < 0.001). The 3-year DFS was 33.33% for patients with poor regression of mrTDs following nCRT and 55.56% for those with moderate regression, compared to 69.23% in good responders and 83.97% in patients without mrTDs (p < 0.001). On multivariable Cox regression, mrTD regression grade was the only independent MRI factor associated with DFS (p = 0.042)., Conclusions: Diagnostic performance of ymrTDs was moderate. The mrTD regression grade was independently correlated with DFS, which may have a prognostic implication for treatment and follow-up., Clinical Relevance Statement: Patients with poor regression of MRI-detected tumor deposits may benefit from more aggressive treatments, such as chemoradiation therapy plus induction or consolidation chemotherapy., Key Points: • MRI provides a preoperative and noninvasive way to visualize tumor deposits (TDs) after neoadjuvant chemoradiotherapy (nCRT). • Post-nCRT MRI-detected TDs are a poor prognostic marker in cT3 and cT4 rectal cancer patients. • The regression of MRI-detected TDs after nCRT is associated with an improved disease-free survival., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The growing demands in integrating digital pedagogies in learning (e.g., social media) contribute to disrupting many fields, including the medical humanities education. However, the strengths and barriers behind social media and medical humanities context are blurred and contradictive. We examined the perceptions of integrating social media - Facebook - into a narrative medicine (NM) programme for 5th -year clerkship in Taiwan., Methods: We used purposive sampling to recruit participants. Sixteen medical students (Female/Male: 7/9) participated in four group interviews. Semi-structured focus group interviews were conducted to explore students' perceptions and experiences of the social media integrated into the NM programme. We analysed the data using a descriptive thematic analysis with a team-based approach. Data were managed and coded using ATLAS.ti version 9.0., Results: We identified six main themes: (1) Positive experiences of social media integration; (2) Negative experiences of social media integration; (3) Barriers on writing and sharing NM stories in social media; (4) Barriers on reading NM stories in social media; (5) Barriers on reacting contents in social media; (6) Suggestions for future improvement., Conclusions: The study revealed the strengths and barriers from medical students' perceptions, when integrating social media into a NM programme. It is important to match students' experiences, barriers, and perceptions towards learning. Understanding participants' suggestions for future improvement are also crucial. With this knowledge, we might better develop the social media integration systems that achieve our desired outcomes based on the medical humanities education curricula., (© 2024. The Author(s).)

Objectives: To explore the potential of dynamic contrast-enhanced MRI (DCE-MRI) quantitative parameters in predicting severe acute radiation-induced rectal injury (RRI) in rectal cancer., Methods: This retrospective study enrolled 49 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and rectal MRI including a DCE-MRI sequence from November 2014 to March 2021. Two radiologists independently measured DCE-MRI quantitative parameters, including the forward volume transfer constant (K trans ), rate constant (k ep ), fractional extravascular extracellular space volume (v e ), and the thickness of the rectal wall farthest away from the tumor. These parameters were compared between mild and severe acute RRI groups based on histopathological assessment. Receiver operating characteristic curve analysis was performed to analyze statistically significant parameters., Results: Forty-nine patients (mean age, 54 years ± 12 [standard deviation]; 37 men) were enrolled, including 25 patients with severe acute RRI. K trans was lower in severe acute RRI group than mild acute RRI group (0.032 min -1 vs 0.054 min -1 ; p = 0.008), but difference of other parameters (k ep , v e and rectal wall thickness) was not significant between these two groups (all p > 0.05). The area under the receiver operating characteristic curve of K trans was 0.72 (95% confidence interval: 0.57, 0.84). With a K trans cutoff value of 0.047 min -1 , the sensitivity and specificity for severe acute RRI prediction were 80% and 54%, respectively., Conclusion: K trans demonstrated moderate diagnostic performance in predicting severe acute RRI., Clinical Relevance Statement: Dynamic contrast-enhanced MRI can provide non-invasive and objective evidence for perioperative management and treatment strategies in rectal cancer patients with acute radiation-induced rectal injury., Key Points: • To our knowledge, this study is the first to evaluate the predictive value of contrast-enhanced MRI (DCE-MRI) quantitative parameters for severe acute radiation-induced rectal injury (RRI) in patients with rectal cancer. • Forward volume transfer constant (K trans ), derived from DCE-MRI, exhibited moderate diagnostic performance (AUC = 0.72) in predicting severe acute RRI of rectal cancer, with a sensitivity of 80% and specificity of 54%. • DCE-MRI is a promising imaging marker for distinguishing the severity of acute RRI in patients with rectal cancer., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Microtubules are hollow α/β-tubulin heterodimeric polymers that play critical roles in cells. In vertebrates, both α- and β-tubulins have multiple isotypes encoded by different genes, which are intrinsic factors in regulating microtubule functions. However, the structures of microtubules composed of different tubulin isotypes, especially α-tubulin isotypes, remain largely unknown. Here, we purify recombinant tubulin heterodimers composed of different mouse α-tubulin isotypes, including α1A, α1C and α4A, with the β-tubulin isotype β2A. We further assemble and determine the cryo-electron microscopy (cryo-EM) structures of α1A/β2A, α1C/β2A, and α4A/β2A microtubules. Our structural analysis demonstrates that α4A/β2A microtubules exhibit longitudinal contraction between tubulin interdimers compared with α1A/β2A and α1C/β2A microtubules. Collectively, our findings reveal that α-tubulin isotype composition can tune microtubule structures, and also provide evidence for the "tubulin code" hypothesis.

Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons in sensorimotor cortex are reported to receive the output of neurons in superficial layers; and their descending axons innervate the spinal cord to regulate basic sensorimotor functions. Here, we show that a subset of layer 5 neurons receives spinal inputs through a direct spino-cortical circuit bypassing the thalamus, and thus define these neurons as spino-cortical recipient neurons (SCRNs). Morphological studies revealed that the branches from spinal ascending axons formed a kind of disciform structure with the descending axons from SCRNs in the basilar pontine nucleus (BPN). Electron microscopy and calcium imaging further confirmed that the axon terminals from spinal ascending neurons and SCRNs made functional synaptic contacts in the BPN, linking the ascending sensory pathway to the descending motor control pathway. Furthermore, behavioral tests indicated that the spino-cortical connection in the BPN was involved in nociceptive responses. In vivo calcium imaging showed that SCRNs responded to peripheral noxious stimuli faster than neighboring layer 4 cortical neurons in awake mice. Manipulating activities of SCRNs could modulate nociceptive behaviors. Therefore, this direct spino-cortical circuit represents a noncanonical pathway, allowing a fast sensory-motor transition of the brain in response to noxious stimuli., (© 2023. The Author(s).)

Mammalian brain tubulins undergo a reversible posttranslational modification-polyglutamylation-which attaches a secondary polyglutamate chain to the primary sequence of proteins. Loss of its erasers can disrupt polyglutamylation homeostasis and cause neurodegeneration. Tubulin tyrosine ligase like 4 (TTLL4) and TTLL7 were known to modify tubulins, both with preference for the β-isoform, but differently contribute to neurodegeneration. However, differences in their biochemical properties and functions remain largely unknown. Here, using an antibody-based method, we characterized the properties of a purified recombinant TTLL4 and confirmed its sole role as an initiator, unlike TTLL7, which both initiates and elongates the side chains. Unexpectedly, TTLL4 produced stronger glutamylation immunosignals for α-isoform than β-isoform in brain tubulins. Contrarily, the recombinant TTLL7 raised comparable glutamylation immunoreactivity for two isoforms. Given the site selectivity of the glutamylation antibody, we analyzed modification sites of two enzymes. Tandem mass spectrometry analysis revealed their incompatible site selectivity on synthetic peptides mimicking carboxyl termini of α1- and β2-tubulins and a recombinant tubulin. Particularly, in the recombinant α1A-tubulin, a novel region was found glutamylated by TTLL4 and TTLL7, that again at distinct sites. These results pinpoint different site specificities between two enzymes. Moreover, TTLL7 exhibits less efficiency to elongate microtubules premodified by TTLL4, suggesting possible regulation of TTLL7 elongation activity by TTLL4-initiated sites. Finally, we showed that kinesin behaves differentially on microtubules modified by two enzymes. This study underpins the different reactivity, site selectivity, and function of TTLL4 and TTLL7 on brain tubulins and sheds light on their distinct role in vivo., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The eukaryotic chaperonin TRiC/CCT assists the folding of about 10% of cytosolic proteins through an ATP-driven conformational cycle, and the essential cytoskeleton protein tubulin is the obligate substrate of TRiC. Here, we present an ensemble of cryo-EM structures of endogenous human TRiC throughout its ATPase cycle, with three of them revealing endogenously engaged tubulin in different folding stages. The open-state TRiC-tubulin-S1 and -S2 maps show extra density corresponding to tubulin in the cis-ring chamber of TRiC. Our structural and XL-MS analyses suggest a gradual upward translocation and stabilization of tubulin within the TRiC chamber accompanying TRiC ring closure. In the closed TRiC-tubulin-S3 map, we capture a near-natively folded tubulin-with the tubulin engaging through its N and C domains mainly with the A and I domains of the CCT3/6/8 subunits through electrostatic and hydrophilic interactions. Moreover, we also show the potential role of TRiC C-terminal tails in substrate stabilization and folding. Our study delineates the pathway and molecular mechanism of TRiC-mediated folding of tubulin along the ATPase cycle of TRiC, and may also inform the design of therapeutic agents targeting TRiC-tubulin interactions., (© 2023. The Author(s).)

Known isocyanide-based multicomponent reactions (IMCRs) are usually triggered by addition of the isocyano group to the strong electrophilic component. We herein report a new isocyanide-based three-component reaction, in which an unprecedented quinoxaline-based zwitterionic intermediate is generated from the chemoselective heterodimerization of weak electrophilic ortho -diisocyanoarenes and common isocyanides. This reactive zwitterion could react in situ with various trapping agents to furnish a range of structurally diverse quinoxalines.

Somatosensory neurons are highly heterogeneous with distinct types of neural cells responding to specific stimuli. However, the distribution and roles of cell-type-specific long intergenic noncoding RNAs (lincRNAs) in somatosensory neurons remain largely unexplored. Here, by utilizing droplet-based single-cell RNA-seq (scRNA-seq) and full-length Smart-seq2, we show that lincRNAs, but not coding mRNAs, are enriched in specific types of mouse somatosensory neurons. Profiling of lincRNAs from single neurons located in dorsal root ganglia (DRG) identifies 200 lincRNAs localized in specific types or subtypes of somatosensory neurons. Among them, the conserved cell-type-specific lincRNA CLAP associates with pruritus and is abundantly expressed in somatostatin (SST)-positive neurons. CLAP knockdown reduces histamine-induced Ca 2+ influx in cultured SST-positive neurons and in vivo reduces histamine-induced scratching in mice. In vivo knockdown of CLAP also decreases the expression of neuron-type-specific and itch-related genes in somatosensory neurons, and this partially depends on the RNA binding protein MSI2. Our data reveal a cell-type-specific landscape of lincRNAs and a function for CLAP in somatosensory neurons in sensory transmission., (© 2022 The Authors.)

Background: The mesorectum surrounding the rectum provides an ideal substrate for tumour spread. However, preoperative risk assessment is still an issue. This study aimed to investigate the microstructural features of mesorectum with different prognostic statuses by intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI)., Methods: Patients with pathologically proven rectal adenocarcinoma underwent routine high-resolution rectal magnetic resonance imaging (MRI) and IVIM DWI sequences were acquired. The MRI-detected circumferential resection margin (mrCRM) and extramural vascular invasion (mrEMVI) were evaluated. IVIM parameters of the mesorectum adjacent to (MAT) and distant from (MDT) the tumour were measured and compared between and within the prognostic factor groups., Results: The positive mrCRM (p MAT  < 0.001; p MDT  = 0.013) and mrEMVI (p MAT  = 0.001; p MDT  < 0.001) groups demonstrated higher D values in the MAT and MDT than the corresponding negative groups. Conversely, the positive mrCRM (p = 0.001) and mrEMVI (p < 0.001) groups both demonstrated lower f values in the MAT. Similarly, in the self-comparison between the MAT and MDT in the above subgroups, D showed a significant difference in all subgroups (p < 0.001 for all), and f showed a significant difference in the positive mrCRM (p = 0.001) and mrEMVI (p = 0.002) groups. Moreover, the MAT displayed a higher D* in the positive mrCRM (p = 0.014), negative mrCRM (p = 0.009) and negative mrEMVI groups (p < 0.001)., Conclusion: The microstructure of the mesorectum in patients with rectal cancer with poor prognostic status shows changes based on IVIM parameters. IVIM parameters might be promising imaging biomarkers for risk assessment of tumour spread in mesorectum preoperatively., (© 2022. The Author(s).)

The establishment of a functional vasculature requires endothelial cells to enter quiescence during the completion of development, otherwise pathological overgrowth occurs. How such a transition is regulated remains unclear. Here, we uncover a role of Zeb1 in defining vascular quiescence entry. During quiescence acquisition, Zeb1 increases along with the progressive decline of endothelial progenitors' activities, with Zeb1 loss resulting in endothelial overgrowth and vascular deformities. RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq) analyses reveal that Zeb1 represses Wif1, thereby activating Wnt/β-catenin signaling. Knockdown of Wif1 rescues the overgrowth induced by Zeb1 deletion. Importantly, local administration of surrogate Wnt molecules in the retina ameliorates the overgrowth defects of Zeb1 mutants. These findings show a mechanism by which Zeb1 induces quiescence of endothelial progenitors during the establishing of vascular homeostasis, providing molecular insight into the inherited neovascular pathologies associated with human ZEB1 mutations, suggesting pharmacological activation of Wnt/β-catenin signaling as a potential therapeutical approach., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Long intergenic noncoding RNAs (lincRNAs) are crucial regulators in numerous biological processes. However, the functions and mechanisms of m 6 A-modified lincRNAs in neuronal development remain unclear. Here, we report an m 6 A-modified lincRNA, Dppa2 upstream binding RNA (Dubr), abundantly expressed at the early developmental stage of dorsal root ganglion (DRG) and cerebral cortex. Silencing Dubr impairs axon elongation of DRG neurons and axon projection and migration of cortical neurons, whereas lacking m 6 A modification of Dubr fully loses its functions. Mechanically, Dubr interacts with m 6 A-binding proteins, the YTHDF1/3 complex, through its m 6 A motifs to protect YTHDF1/3 from degradation via the proteasome pathway. Furthermore, Tau and Calmodulin are regulated by YTHDF1/3 and m 6 A-modified Dubr. Overexpression of YTHDF1/3 not only rescues the reduced Tau and Calmodulin but also restores axon elongation of DRG neurons by Dubr knockdown. This study uncovers a critical role of m 6 A-modified lincRNA in neuronal development by regulating the degradation of RNA-binding protein., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

In Qinghai-Tibet Plateau, crops are commonly subjected to freeze-thaw and salt stress factors simultaneously, and allelopathy is common, which affects the growth of highland barley (Hordeum vulgare L.), the largest food crop in Tibet. In order to explore the effects of artemisinin, salt and freeze-thaw (FAS) stress on physiological characteristics of highland barley seedlings, hydroponic experiment was carried out with the addition of 20mg/L artemisinin and 150mMNaCl as well as the simulation of freeze-thaw environment. The results suggested that under combined stress, the soluble protein content in combined stresses of artemisinin, FAS increased by 97.8%, the variation of relative conductivity in FAS group was lower than that in combined salt and freeze-thaw stress (FS), the relative water content decreased significantly (P <0.05), the malondialdehyde (MDA), H2 O2 and soluble sugar content in FAS group accumulated but less than those in FS group, and the superoxide dismutase (SOD) activity in combined artemisinin and freeze-thaw stress (FA) and FAS groups decreased. In addition, after freeze-thaw treatment, photosynthesis was weakened, and internal CO2 conentration (C i ) in FAS group significantly decreased (P <0.05). This study proved that appropriate amount of artemisinin can alleviate the damage of salt and freeze-thaw stress on barley seedlings.

Highland barley (Hordeum vulgare L.), as the dominant crop on the Qinghai-Tibetan Plateau, is a typical representative of plants adapted to extreme environmental conditions. However, the harsh environment, severe salinisation and frequent freezing and thawing in the Qinghai-Tibetan Plateau are main limiting factor for crop growth in this region. The physiological response of highland barley to salinisation and freeze-thaw stresses was studied in this paper. Under the combined stresses of 60mmol/LNaCl·60mmol/LNaHCO3 and freeze-thaw cycles (10, -5, and 10°C), the changes in the relative moisture content, relative electrical conductivity, soluble protein, malondialdehyde (MDA) and photosynthetic indices Pn and E in seedling leaves of eight groups of treatments (CK, S, A, S-A, CK (FT), S (FT), A (FT), and S-A (FT)) were analysed. Results showed that a single stress did not cause a change in the MDA content. All of the combined stresses in S-A, CK (FT), S (FT), A (FT), and S-A (FT) treatments increased the MDA content of barley seedlings, and the MDA content of S-A (FT) reached 28.438 at T2 (-5°C) μmol/g. During the freeze-thaw cycle, the cell membrane of seedlings was damaged more seriously by alkali stress, which showed a significant increase in relative conductivity. The relative moisture content value of seedlings was more than 100% because the seedlings could absorb more moisture due to mechanical injury. The protein content of osmoregulatory substances in highland barley seedlings increased with increasing stress, indicating resistance to stress. Moreover, the effect of freeze-thaw stress on photosynthesis was more significant. The changes in indices proved that an appropriate amount of salt stress could improve the resistance of the plant cell membrane. Alkali stress had a significant effect on the growth of highland barley seedlings. Freezing and thawing can aggravate the damage of saline-alkali stress to highland barley seedlings, resulting in changes in the biological membrane permeability and photosynthesis of seedlings. The fluctuation of osmoregulation substance content confirmed that highland barley seedlings had a certain degree of stress resistance. Freeze-thaw cycles will aggravate the damage of land salinisation to highland barley seedlings. To better reduce the impact and loss of land salinisation and freeze-thaw disasters on agriculture in the Qinghai-Tibetan Plateau, priority should be given to solving freeze-thaw stress in the process of grain production.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin ( Gal ) and one type of pruriceptors expressing neurotensin ( Nts ). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts -expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal -containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts -expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.

Psoriasis is a chronic immune-mediated skin disorder with the nervous system contributing to its pathology. The neurogenic mediators of psoriasis are elusive, and whether the intervention of the cutaneous nervous system can treat psoriasis remains to be determined. In this study, we conducted a pilot study using an epidural injection of lidocaine to treat patients with psoriasis. Lidocaine treatment markedly reduced patients' clinical scores and improved an imiquimod-induced rat model of psoriasis as competent as systemic delivery of a TNF-α antibody. Imiquimod application elicited aberrant cutaneous nerve outgrowth and excessive generation of neuropeptide calcitonin gene-related peptide from dorsal root ganglion neurons, both of which were inhibited by epidural lidocaine treatment. Single-cell RNA sequencing unveiled the overrepresentation of calcitonin gene-related peptide receptors in dermal dendritic cell populations of patients with psoriasis. Through disturbing calcitonin gene-related peptide signaling, lidocaine inhibited IL-23 production by dendritic cells cocultured with dorsal root ganglion neurons. Thus, epidural nerve block with lidocaine demonstrates an effective therapy for psoriasis, which suppresses both inordinate sensory nerve growth in the inflamed skin and calcitonin gene-related peptide-mediated IL-23 production from psoriatic dendritic cells., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Nociceptive information is detected and transmitted by neurons in the DRG. Recently, single-cell RNA sequencing has revealed the molecular profile of various cell types, including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation. Here, we found that secreted modular calcium-binding protein 2 (SMOC2) was secreted by fibroblasts to become a component of basement membrane and envelop the unit consisting of DRG neurons and attached satellite glial cells. KO of Smoc2 in both sexes of mice led to increased neuronal clusters and decreased mechanical threshold, but unchanged noxious thermal response. Knockdown of Smoc2 in the DRG phenocopied the behavioral performance by Smoc2 KO in both sexes of mice. In vivo calcium imaging showed that Smoc2 KO increased coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli, which was reversed by DRG injection of SMOC2. Importantly, SMOC2 interacted with P2X7 receptor (P2X7R) and suppressed ATP-induced activation in HEK293 cells expressing this receptor. Injection of A740003, an antagonist of P2X7R, to the DRG reduced coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli but did not further enhance the SMOC2-inhibited effect. Furthermore, peripheral inflammation resulted in a decreased SMOC2 and increased neuronal clusters. DRG injection of SMOC2 inhibited the neuronal coupling resulted from peripheral inflammation. This study reveals a specific role of fibroblastic SMOC2 in suppressing mechanical nociception through inhibiting the communication of adjacent DRG neurons, which provides an important mechanism of fibroblasts in nociceptive regulation. SIGNIFICANCE STATEMENT The function of fibroblastic molecules is rarely noticed in the regulation of nociceptive sensation. Here, we reveal that fibroblastic SMOC2 is secreted to be a component of basement membrane and surrounded the unit consisting of DRG neuron and attached satellite glial cells. SMOC2 is required for maintaining the basal mechanical nociceptive threshold in the DRG. Loss of SMOC2 leads to the increased coupled activation of adjacent DRG neurons induced by noxious mechanical stimuli. Peripheral inflammation causes decreased fibroblast cells and SMOC2, which may result in the increase of coupled activation of adjacent DRG neurons. Mechanistically, SMOC2 interacts with and suppresses satellite glial P2X7 receptor to inhibit the coupled activation of adjacent DRG neurons., (Copyright © 2022 the authors.)

DRG neurons are classified into distinct types to mediate the somatosensation with different modalities. Recently, transcriptional profilings of DRG neurons by single-cell RNA-sequencing have provided new insights into the neuron typing and functional properties. Zinc-finger CCHC domain-containing 12 ( Zcchc12 ) was reported to be the representative marker for a subtype of galanin-positive ( Gal + ) DRG neurons. However, the characteristics and functions of Zcchc12 + neurons are largely unknown. Here, we genetically labeled Zcchc12 + neurons in Zcchc12 -CreERT2::Ai9 mice, and verified that Zcchc12 represented a new subpopulation of DRG neurons in both sexes. Zcchc12 + neurons centrally innervated the superficial laminae in spinal dorsal horn, and peripherally terminated as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. In addition, Zcchc12 + neurons also formed circumferential endings surrounding the hair follicles in hairy skin. Functionally, in vivo calcium imaging in DRGs revealed that Zcchc12 + neurons were polymodal nociceptors and could be activated by mechanical and noxious thermal stimuli. Behavioral tests showed that selective ablation of Zcchc12 + DRG neurons reduced the sensitivity to noxious heat in mice. Together, we identified a new subpopulation of Zcchc12 + nociceptors essential for noxious heat sensation. SIGNIFICANCE STATEMENT Zcchc12 represents a new subpopulation of DRG neurons. The characteristics and functions of Zcchc12 + neurons are largely unknown. Here we genetically labeled Zcchc12 + neurons, and showed that the fibers of Zcchc12 + DRG neurons projected to superficial lamina at spinal dorsal horn, and innervated skin as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Functionally, Zcchc12 + DRG neurons responded to noxious mechanical and heat stimuli. Ablation of Zcchc12 + DRG neurons impaired the sensation of noxious heat in mice. Therefore, we identify a new subpopulation of DRG neurons required for noxious heat sensation., (Copyright © 2022 the authors.)

An ionic cascade insertion/cyclization reaction of thia-/selena-functionalized arylisocyanides has been successfully developed for the efficient and practical synthesis of 2-halobenzothiazole/benzoselenazole derivatives. This synthetic protocol, incorporating a halogen atom when forming the five-membered ring of benzothia/selenazoles, is different from the existing ones, where halogenation of the preformed benzothia/selenazole precursors happens. Additionally, a facile access to 2-aminobenzothiazoles is also achieved by the one-pot cascade reaction of 2-isocyanoaryl thioethers, iodine, and amines.

Microtubules consisting of α/β-tubulin dimers play critical roles in cells. More than seven genes encode α-tubulin in vertebrates. However, the property of microtubules composed of different α-tubulin isotypes is largely unknown. Here, we purified recombinant tubulin heterodimers of mouse α-tubulin isotypes including α1A and α1C with β-tubulin isotype β2A. In vitro microtubule reconstitution assay detected that α1C/β2A microtubules grew faster and underwent catastrophe less frequently than α1A/β2A microtubules. Generation of chimeric tail-swapped and point-mutation tubulins revealed that the carboxyl-terminal (C-terminal) tails of α-tubulin isotypes largely accounted for the differences in polymerization dynamics of α1A/β2A and α1C/β2A microtubules. Kinetics analysis showed that in comparison to α1A/β2A microtubules, α1C/β2A microtubules displayed higher on-rate, lower off-rate, and similar GTP hydrolysis rate at the plus-end, suggesting a contribution of higher plus-end affinity to faster growth and less frequent catastrophe of α1C/β2A microtubules. Furthermore, EB1 had a higher binding ability to α1C/β2A microtubules than to α1A/β2A ones, which could also be attributed to the difference in the C-terminal tails of these two α-tubulin isotypes. Thus, α-tubulin isotypes diversify microtubule properties, which, to a great extent, could be accounted by their C-terminal tails., (© The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

A catalyst-free chemoselective trimerization reaction of readily available isocyanides is described. This domino reaction provides facile access to a wide range of 2-(indol-2-yl)-quinolines and 2-(indol-2-yl)-pyridines in moderate to excellent yields. A "head to head" heterodimerization of two isocyanides is proposed as the key step of this reaction.

Peripheral nerve injury could lead to chronic neuropathic pain. Understanding transcriptional changes induced by nerve injury could provide fundamental insights into the complex pathogenesis of neuropathic pain. Gene expression profiles of dorsal root ganglia (DRG) in neuropathic pain condition have been studied. However, little is known about transcriptomic changes in individual DRG neurons after peripheral nerve injury. Here we performed single-cell RNA sequencing on dissociated mouse DRG cells after spared nerve injury (SNI). In addition to DRG neuron types that are found under physiological conditions, we identified three SNI-induced neuronal clusters (SNIICs) characterized by the expression of Atf3/Gfra3/Gal (SNIIC1), Atf3/Mrgprd (SNIIC2) and Atf3/S100b/Gal (SNIIC3). These SNIICs originated from Cldn9 + /Gal + , Mrgprd + and Trappc3l + DRG neurons, respectively. Interestingly, SNIIC2 switched to SNIIC1 by increasing Gal and reducing Mrgprd expression 2 days after nerve injury. Inferring the gene regulatory networks after nerve injury, we revealed that activated transcription factors Atf3 and Egr1 in SNIICs could enhance Gal expression while activated Cpeb1 in SNIIC2 might suppress Mrgprd expression within 2 days after SNI. Furthermore, we mined the transcriptomic changes in the development of neuropathic pain to identify potential analgesic targets. We revealed that cardiotrophin-like cytokine factor 1, which activates astrocytes in the dorsal horn of spinal cord, was upregulated in SNIIC1 neurons and contributed to SNI-induced mechanical allodynia. Therefore, our results provide a new landscape to understand the dynamic course of neuron type changes and their underlying molecular mechanisms during the development of neuropathic pain., (© 2021. The Author(s), under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.)

Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified post-translational modification involved in mitosis and cytokinesis. However, knowledge about α-TubK40me3 in microtubule function and post-mitotic cells remains largely incomplete. Here, we report that α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation. α-TubK40me3 is enriched in mouse cerebral cortex during embryonic day (E)14 to E16. Knockdown of α-tubulin methyltransferase SETD2 at E14 leads to the defects in neuronal migration, which could be restored by overexpressing either a cytoplasm-localized SETD2 truncation or α-TubK40me3-mimicking mutant. Furthermore, α-TubK40me3 is preferably distributed on polymerized microtubules and potently promotes tubulin nucleation. Downregulation of α-TubK40me3 results in reduced microtubule abundance in neurites and disrupts neuronal polarization, which could be rescued by Taxol. Additionally, α-TubK40me3 is increased after losing α-tubulin K40 acetylation (α-TubK40ac) and largely rescues α-TubK40ac function. This study reveals a critical role of α-TubK40me3 in microtubule formation and neuronal development.

Background and Aims: Emerging evidence points to a link between creeping fat and the pathogenesis of Crohn's disease [CD]. Non-invasive assessment of the severity of creeping fat on cross-sectional imaging modality has seldom been investigated. This study aimed to develop and characterize a novel mesenteric creeping fat index [MCFI] based on computed tomography [CT] in CD patients., Methods: MCFI was developed based on vascular findings on CT in a retrospective cohort [n = 91] and validated in a prospective cohort [n = 30]. The severity of creeping fat was graded based on the extent to which mesenteric fat extended around the intestinal circumference using the vessels in the fat as a marker. The accuracy of MCFI was assessed by comparing it with the degree of creeping fat observed in surgical specimens. The relationship between MCFI and fibrostenosis was characterized by determining if these correlated. The accuracy of MCFI was compared with other radiographic indices [i.e. visceral to subcutaneous fat area ratio and fibrofatty proliferation score]., Results: In the retrospective cohort, MCFI had moderate accuracy in differentiating moderate-severe from mild fibrostenosis (area under the receiver operating characteristic [ROC] curve [AUC] = 0.799; p = 0.000). ROC analysis in the retrospective cohort identified a threshold MCFI of > 3 which accurately differentiated fibrostenosis severity in the prospective cohort [AUC = 0.756; p = 0.018]. An excellent correlation was shown between MCFI and the extent of fat wrapping in specimens in the prospective cohort [r = 0.840, p = 0.000]. Neither visceral to subcutaneous fat area ratio nor fibrofatty proliferation score correlated well with the degree of intestinal fibrosis., Conclusions: MCFI can accurately characterize the extent of mesenteric fat wrapping in surgical specimens. It may become another non-invasive measure of CD fibrostenosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study aimed to evaluate the role of hepatic mosaic enhancement pattern (HMEP) on computed tomography images in the disease activity and therapeutic outcome of Crohn's Disease (CD)., Methods: Twenty-five CD patients with HMEP comprised the HMEP group, and 25 CD patients without HMEP, who had a similar onset age, sex, and disease course with those in the HMEP group, comprised the non-HMEP group. No underlying liver/biliary disease was observed in any of the patients. Clinical characteristics, laboratory test results, Lémann index, and CD endoscopic index of severity (CDEIS) were compared between the groups using the Student t-, Mann-Whitney U, Chi square, or Fisher's exact tests. Patients received top-down, step-up, or traditional treatment during the follow-up period. After the 1-year follow-up, therapeutic outcomes (active inflammation [CDEIS > 3.5 if the endoscopic data were available, or C-reactive protein level > 5 mg/L if the endoscopic data were unavailable] or remission) were evaluated., Results: The occurrence rate of fistulas/abscesses was higher in the HMEP group (84%, 21/25) than in the non-HMEP group (48%, 12/25) with no statistical significance (P = 0.056). The HMEP group showed a higher C-reactive protein level (P = 0.001), erythrocyte sedimentation rate (P = 0.013), and blood platelet count (P = 0.005). There was no significant difference in therapeutic strategies between the groups (P = 0.509). The HMEP group showed a significantly lower remission ratio after anti-inflammatory treatment than the non-HMEP group (P = 0.045)., Conclusions: HMEP was correlated with increased inflammatory activity and adverse therapeutic outcomes in CD. This finding provided insights regarding novel markers of CD diagnosis and treatment.

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5'-untranslated region (5'-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM&#95;001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5'-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5'-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5'-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions., Competing Interests: XP, JZ, ZZ, JC, ZY, YW, MB, YJ, YY, XH, TC, QL, BW, CL, YL, LD, YZ, JP, JZ, HX, ZQ, JL, ZW, JH, LB, XZ No competing interests declared, (© 2021, Pan et al.)

Microtubules (MTs) are regulated by a number of known posttranslational modifications (PTMs) on α/β-tubulin to fulfill diverse cellular functions. Here, we showed that SUMOylation is a novel PTM on α-tubulin in vivo and in vitro. The SUMOylation on α-tubulin mainly occurred at Lys 96 (K96), K166, and K304 of soluble α-tubulin and could be removed by small ubiquitin-related modifier (SUMO)-specific peptidase 1. In vitro experiments showed that tubulin SUMOylation could reduce interprotofilament interaction, promote MT catastrophe, and impede MT polymerization. In cells, mutation of the SUMOylation sites on α-tubulin reduced catastrophe frequency and increased the proportion of polymerized α-tubulin, while upregulation of SUMOylation with fusion of SUMO1 reduced α-tubulin assembly into MTs. Additionally, overexpression of SUMOylation-deficient α-tubulin attenuated the neurite extension in Neuro-2a cells. Thus, SUMOylation on α-tubulin represents a new player in the regulation of MT properties., (© The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Long intergenic noncoding RNAs (lincRNAs) are critical regulators involved in diverse biological processes. However, the roles and related mechanisms of lincRNAs in axon development are largely unknown. Here we report an axon-enriched lincRNA regulating axon elongation, referred to as ALAE. Profiling of highly expressed lincRNAs detected abundant and enriched ALAE in the axons of dorsal root ganglion (DRG) neurons, where it locally promoted axon elongation. Mechanically, ALAE directly interacted with the KH3-4 domains of KH-type splicing regulatory protein (KHSRP) and impeded its association with growth-associated protein 43 (Gap43) mRNA. Knockdown of ALAE reduced the protein but not the mRNA level of GAP43 in the axons of DRG neurons. Furthermore, local disruption of the interaction between ALAE and KHSRP in the axon significantly inhibited Gap43 mRNA translation, impairing axon elongation. This study implies crucial roles of axon-enriched lincRNAs in spatiotemporal regulation of local translation during axon development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the utility of diffusion kurtosis imaging (DKI) for assessing bowel fibrosis and to establish a new magnetic resonance imaging (MRI)-based classification based on DKI and conventional MRI parameters for characterizing intestinal strictures in Crohn's disease (CD) using the histological evaluation of resected intestine samples as the reference standard., Methods: Thirty-one patients with CD undergoing preoperative conventional MRI and diffusion-weighted imaging (DWI) (b values = 0-2000 s/mm 2 ) were consecutively enrolled. We classified the mural T2-weighted signal intensity and arterial-phase enhancement patterns on conventional MRI. We also measured DWI-derived apparent diffusion coefficients (ADCs) and DKI-derived apparent diffusion for non-Gaussian distribution (D app ) and apparent diffusional kurtosis (K app ). A new MRI-based classification was established to characterize intestinal strictures in CD. Its performance was validated in nine additional patients with CD., Results: Histological inflammation grades were significantly correlated to T2-weighted signal intensity (r = 0.477; P < 0.001) and ADC (r = - 0.226; P = 0.044). Histological fibrosis grades were moderately correlated to K app (r = 0.604, P < 0.001); they were also correlated to D app (r = - 0.491; P < 0.001) and ADC (r = - 0.270; P = 0.015). T2-weighted signal intensity could differentiate between no-to-mild and moderate-to-severe bowel inflammation (sensitivity, 0.970; specificity, 0.479). K app could differentiate between no-to-mild and moderate-to-severe bowel fibrosis (sensitivity, 0.959; specificity, 0.781). The agreement between the new MRI-based classification and the histological classification was moderate in the test (κ = 0.507; P < 0.001) and validation (κ = 0.530; P < 0.001) sets., Conclusions: DKI can be used to assess bowel fibrosis. The new MRI-based classification can help to distinguish between fibrotic and inflammatory intestinal strictures in patients with CD.

Itch can be induced by activation of small-diameter DRG neurons, which express abundant intracellular fibroblast growth factor 13 (FGF13). Although FGF13 is revealed to be essential for heat nociception, its role in mediating itch remains to be investigated. Here, we reported that loss of FGF13 in mouse DRG neurons impaired the histamine-induced scratching behavior. Calcium imaging showed that the percentage of histamine-responsive DRG neurons was largely decreased in FGF13-deficient mice; and consistently, electrophysiological recording exhibited that histamine failed to evoke action potential firing in most DRG neurons from these mice. Given that the reduced histamine-evoked neuronal response was caused by knockdown of FGF13 but not by FGF13A deficiency, FGF13B was supposed to mediate this process. Furthermore, overexpression of histamine Type 1 receptor H1R, but not H2R, H3R, nor H4R, increased the percentage of histamine-responsive DRG neurons, and the scratching behavior in FGF13-deficient mice was highly reduced by selective activation of H1R, suggesting that H1R is mainly required for FGF13-mediated neuronal response and scratching behavior induced by histamine. However, overexpression of H1R failed to rescue the histamine-evoked neuronal response in FGF13-deficient mice. Histamine enhanced the FGF13 interaction with Na V 1.7. Disruption of this interaction by a membrane-permeable competitive peptide, GST-Flag-Na V 1.7CT-TAT, reduced the percentage of histamine-responsive DRG neurons, and impaired the histamine-induced scratching, indicating that the FGF13/Na V 1.7 interaction is a key molecular determinant in the histamine-induced itch sensation. Therefore, our study reveals a novel role of FGF13 in mediating itch sensation via the interaction of Na V 1.7 in the peripheral nervous system. SIGNIFICANCE STATEMENT Scratching induced by itch brings serious tissue damage in chronic itchy diseases, and targeting itch-sensing molecules is crucial for its therapeutic intervention. Here, we reveal that FGF13 is required for the neuronal excitation and scratching behavior induced by histamine. We further provide the evidence that the histamine-evoked neuronal response is mainly mediated by histamine Type 1 receptor H1R, and is largely attenuated in FGF13-deficent mice. Importantly, we identify that histamine enhances the FGF13/Na V 1.7 interaction, and disruption of this interaction reduces histamine-evoked neuronal excitation and highly impairs histamine-induced scratching behavior. Additionally, we also find that FGF13 is involved in 5-hydroxytryptamine-induced scratching behavior and hapten 1-fluoro-2,4-dinitrobenzene-induced chronic itch., (Copyright © 2020 the authors.)

The establishment of axon/dendrite polarity is fundamental for neurons to integrate into functional circuits, and this process is critically dependent on microtubules (MTs). In the early stages of the establishment process, MTs in axons change dramatically with the morphological building of neurons; however, how the MT network changes are triggered is unclear. Here we show that CAMSAP1 plays a decisive role in the neuronal axon identification process by regulating the number of MTs. Neurons lacking CAMSAP1 form a multiple axon phenotype in vitro, while the multipolar-bipolar transition and radial migration are blocked in vivo. We demonstrate that the polarity regulator MARK2 kinase phosphorylates CAMSAP1 and affects its ability to bind to MTs, which in turn changes the protection of MT minus-ends and also triggers asymmetric distribution of MTs. Our results indicate that the polarized MT network in neurons is a decisive factor in establishing axon/dendritic polarity and is initially triggered by polarized signals., Competing Interests: The authors declare no competing interest.

Background: Emergency department (ED) overcrowding is a severe health care concern, while anxiety and depression rates among ED patients have been reported to be substantially higher compared to the general population. We hypothesized that anxiety due to over crowdedness may lead to adverse events in EDs., Aim: To investigate correlations between crowdedness in EDs and anxiety of patients and nurses, and to identify factors affecting their anxiety., Methods: In this prospective observational study, a total 43 nurses and 389 emergency patients from two tier III hospitals located in Beijing were included from January 2016 to August 2017. Patients were grouped into inpatients when they were hospitalized after diagnoses, or into outpatients when they were discharged after treatments. The State Trait Anxiety Inventory (STAI Form Y) questionnaire was used to investigate patient and nurse anxieties, while crowdedness of EDs was evaluated with the National Emergency Department Over Crowding Score., Results: The present results revealed that state anxiety scores (49.50 ± 6.00 vs 50.80 ± 2.80, P = 0.005) and trait anxiety scores (45.40 ± 5.70 vs 46.80 ± 2.70, P = 0.002) between inpatients ( n = 173) and outpatients ( n = 216) were significantly different, while the state anxiety of nurses (44.70 ± 5.80) was different from those of both patient groups. Generalized linear regression analysis demonstrated that multiple factors, including crowdedness in the ED, were associated with state and trait anxieties for both inpatients and outpatients. In addition, there was an interaction between state anxiety and trait anxieties. However, multivariable regression analysis showed that while overcrowding in the ED did not directly correlate with patients' and nurses' anxiety levels, the factors that did correlate with state and trait anxieties of inpatients were related to crowdedness. These factors included waiting time in the ED, the number of patients treated, and the number of nurses in the ED, whereas for nurses, only state and trait anxieties correlated significantly with each other., Conclusion: Waiting time, the number of patients treated, and the number of nurses present in the ED correlate with patient anxiety in EDs, but crowdedness has no effect on nurse or patient anxiety., Competing Interests: Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

More than 30% of patients with Crohn's disease (CD) develop fibrotic strictures in the bowel as the disease progresses. Excessive deposition of extracellular matrix components in the submucosa and smooth muscle hypertrophy or hyperplasia are the main features of fibrosis in CD. Cross-sectional imaging technology provides a wealth of information on the anatomy, histological composition, and physiological function of the bowel, allowing for a non-invasive and complete evaluation of associated abnormalities. This review summarizes recent advances in and the potential technologies of cross-sectional imaging for assessing intestinal fibrosis in CD, including ultrasound imaging, computed tomography, and magnetic resonance imaging., (© 2020 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Multisystem manifestations in myotonic dystrophy type 1 (DM1) may be due to dosage reduction in multiple genes induced by aberrant expansion of CTG repeats in DMPK, including DMPK, its neighboring genes (SIX5 or DMWD) and downstream MBNL1. However, direct evidence is lacking. Here, we develop a new strategy to generate mice carrying multigene heterozygous mutations to mimic dosage reduction in one step by injection of haploid embryonic stem cells with mutant Dmpk, Six5 and Mbnl1 into oocytes. The triple heterozygous mutant mice exhibit adult-onset DM1 phenotypes. With the additional mutation in Dmwd, the quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1. Moreover, muscle stem cells in both models display reduced stemness, providing a unique model for screening small molecules for treatment of DM1. Our results suggest that the complex symptoms of DM1 result from the reduced dosage of multiple genes.

Pancreatitis-associated proteins (PAPs) display multiple functions in visceral diseases. Previous studies showed that the expression level of PAP-I was low in the DRG of naive rats but was de novo expressed after peripheral nerve injury. However, its role in neuropathic pain remains unknown. We found that PAP-I expression was continuously upregulated in the DRG neurons from rat spared nerve injury models, and transported toward the spinal dorsal horn to act as a proinflammatory factor. Intrathecal delivery of PAP-I enhanced sensory hyperalgesia, whereas PAP-I deficiency by either gene knockout or antibody application alleviated tactile allodynia at the maintenance phase after spared nerve injury. Furthermore, PAP-I functioned by activating the spinal microglia via C-C chemokine receptor Type 2 that participated in neuropathic pain. Inhibition of either microglial activation or C-C chemokine receptor Type 2 abolished the PAP-I-induced hyperalgesia. Thus, PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury and contributes to the maintenance of neuropathic pain. SIGNIFICANCE STATEMENT Neuropathic pain is maladaptive pain condition, and the maintaining mechanism is largely unclear. Here we reveal that, after peripheral nerve injury, PAP-I can be transported to the spinal dorsal horn and is crucial in the progression of neuropathic pain. Importantly, we prove that PAP-I mainly functions through activating the spinal microglia via the CCR2-p38 MAPK pathway. Furthermore, we confirm that the proinflammatory effect of PAP-I is more prominent after the establishment of neuropathic pain, thus indicating that microglia also participate in the maintenance phase of neuropathic pain., (Copyright © 2020 the authors.)

Background: A validated histopathological tool to precisely evaluate bowel fibrosis in patients with Crohn's disease is lacking. We attempted to establish a new index to quantify the severity of bowel fibrosis in patients with Crohn's disease-associated fibrostenosis., Methods: We analyzed the histopathological data of 31 patients with Crohn's disease strictures undergoing surgical resection. The most representative sections of resected strictured segments were stained with Masson trichrome to manifest bowel fibrosis. The collagen area fraction and histological fibrosis score were simultaneously calculated for the same section to evaluate the severity of bowel fibrosis., Results: Collagen area fraction strongly correlated with histological fibrosis scores (r = 0.733, P < 0.001). It showed a stronger correlation (r = 0.561, P < 0.001) with the degree of bowel strictures than the histological fibrosis score did (r = 0.468, P < 0.001). It was also shown to be more accurate for diagnosing Crohn's disease strictures (area under the receiver operating characteristic curve = 0.815, P < 0.001) compared with the histological fibrosis score (area under the curve = 0.771, P < 0.001). High repeatability was observed for the collagen area fraction, with an intraclass correlation coefficient of 0.915 (P < 0.001)., Conclusions: Collagen area fraction is a simple and reliable index to quantify the severity of bowel fibrosis in patients with Crohn's disease-associated fibrostenosis.

People generally agree that emotion processing differs between male and female. However, current hypothesis of sex differences needs more objective evidence and quantitative assessment. In this paper, we investigate the sex difference in classifying ve emotions from eletroencephalograph and eye movement signals. We adopt two neural-network-based clas-si ers to objectively investigate sex differences from different perspectives. From experimental results, we nd the following three observations: (1) a general higher accuracy of same-sex strategy suggests sex-speci c factors have in uence on emotion classi cation; (2) both blink duration and frequency differ from female to male and they are negatively correlated under different emotional states; and (3) there are larger differences of brain activities in the Theta, Alpha, and Beta bands between male and female for disgust, sad, and neutral emotions.

Alpinia oxyphylla is mainly produced in Hainan,and also one of the four famous traditional Chinese medicines in South China with increasing importance in traditional Chinese medicine industry. Field surveys and literatures show that A. oxyphylla has widely used as a medicinal and edible plant,it is an important raw material for many Chinese patent medicines,health products and food,with a long history of artificial cultivation and application. The future development is prospected on health market. But A. oxyphylla industry has faced a lot of problems,including unreasonable planting layout,lack of good varieties,imperfect seed breeding system,low level of standardization,inconsistent quality of medicinal materials,low level of industry,and so on. The suggestions for sustainable development are listed below.First,it is essential to strengthen the research on the basis and application technology of A. oxyphylla,speed up the selection and breeding of improved varieties,and popularize standardized cultivation techniques. Secondly,it is important to strengthen the research on quality standards,improve the quality evaluation system of medicinal materials. Thirdly,it is necessary to take full advantage of the functional components to develop functional products with Hainan characteristics,find out the unique product characteristics of A. oxyphylla,build a famous brand and improve the product competitiveness in the market. It is also important to strengthen policy support and industrial supervision,promote the healthy and rapid development of A. oxyphylla industry.

Objectives: Although diffusion-weighted imaging (DWI) is reported to be accurate in detecting bowel inflammation in Crohn's disease (CD), its ability to assess bowel fibrosis remains unclear. This study assessed the role of DWI in the characterization of bowel fibrosis using surgical histopathology as the reference standard., Methods: Abdominal DWI was performed before elective surgery in 30 consecutive patients with CD. The apparent diffusion coefficients (ADCs) in pathologic bowel walls were calculated. Region-by-region correlations between DWI and the surgical specimens were performed to determine the histologic degrees of bowel fibrosis and inflammation., Results: ADCs correlated negatively with bowel inflammation (r = - 0.499, p < 0.001) and fibrosis (r = - 0.464, p < 0.001) in 90 specimens; the ADCs in regions of nonfibrosis and mild fibrosis were significantly higher than those in regions of moderate-severe fibrosis (p = 0.008). However, there was a significant correlation between the ADCs and bowel fibrosis (r = - 0.641, p = 0.001) in mildly inflamed segments but not in moderately (r = - 0.274, p = 0.255) or severely (r = - 0.225, p = 0.120) inflamed segments. In the mildly inflamed segments, the ADCs had good accuracy with an area under the receiver-operating characteristic curve of 0.867 (p = 0.004) for distinguishing nonfibrosis and mild fibrosis from moderate-severe fibrosis., Conclusions: ADC can be used to assess bowel inflammation in patients with CD. However, it only enables the accurate detection of the degree of bowel fibrosis in mildly inflamed bowel walls. Therefore, caution is advised when using ADC to predict the degree of intestinal fibrosis., Key Points: • Diffusion-weighted imaging was used to assess bowel inflammation in patients with Crohn's disease. • The ability of diffusion-weighted imaging to evaluate bowel fibrosis decreased with increasing bowel inflammation. • Diffusion-weighted imaging enabled accurate detection of the degree of fibrosis only in mildly inflamed bowel walls.