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Autism spectrum disorder (ASD) is a major neurodevelopmental disorder in which patients present with core symptoms of social communication impairment, restricted interest, and repetitive behaviors. Although various studies have been performed to identify ASD-related mechanisms, ASD pathology is still poorly understood. CNTNAP2 genetic variants have been found that represent ASD genetic risk factors, and disruption of Cntnap2 expression has been associated with ASD phenotypes in mice. In this study, we performed an integrative multi-omics analysis by combining quantitative proteometabolomic data obtained with Cntnap2 knockout (KO) mice with multi-omics data obtained from ASD patients and forebrain organoids to elucidate Cntnap2-dependent molecular networks in ASD. To this end, a mass spectrometry-based proteometabolomic analysis of the medial prefrontal cortex in Cntnap2 KO mice led to the identification of Cntnap2-associated molecular features, and these features were assessed in combination with multi-omics data obtained on the prefrontal cortex in ASD patients to identify bona fide ASD cellular processes. Furthermore, a reanalysis of single-cell RNA sequencing data obtained from forebrain organoids derived from patients with CNTNAP2-associated ASD revealed that the aforementioned identified ASD processes were mainly linked to excitatory neurons. On the basis of these data, we constructed Cntnap2-associated ASD network models showing mitochondrial dysfunction, axonal impairment, and synaptic activity. Our results may shed light on the Cntnap2-dependent molecular networks in ASD.

Sarcopenia is a new and emerging risk factor aggravating the quality of life of elderly population. Because Korean Red Ginseng (RG) is known to have a great effect on relieving fatigue and enhancing physical performance, it is invaluable to examine its potential as an anti-sarcopenic drug.Anti-sarcopenic effect of non-saponin fraction of Korean Red Ginseng (RGNS) was evaluated in C2C12 myoblasts treated with C2-ceramide to induce senescence phenotypes, and 22-month-old mice fed with chow diet containing 2% RGNS (w/w) for 4 further months.The RGNS treatment significantly alleviated cellular senescence indicated by intracellular lipid accumulation, increased amount of lysosomal β-galactosidase, and reduced proliferative capacity in C2C12 myoblasts. This effect was not observed with saponin fraction. In an aged mouse, the 4-month-RGNS diet significantly improved aging-associated loss of muscle mass and strength, assessed by the weights of hindlimb skeletal muscles such as tibialis anterior (TA), extensor digitorum longus (EDL), gastrocnemius (GN) and soleus (SOL), and the cross-sectional area (CSA) of SOL muscle, and the behaviors in grip strength and hanging wire tests, respectively. During the same period, an aging-associated shift of fast-to slow-twitch muscle in SOL muscle was also retarded by the RGNS treatment.These findings suggested that the long-term diet of RGNS significantly prevented aging-associated muscle atrophy and reduced physical performance, and thus RGNS has a strong potential to be developed as a drug that prevents or improves sarcopenia.

In this study, the possibility of the industrial application of terahertz (THz) imaging technology was verified. It was applied to the inspection of voids in multistack semiconductors that require safe inspection and to the high-resolution detection and inspection of foreign substances in tablets in the pharmaceutical field. To acquire a high-resolution THz image, a resonant slit probe operating in the THz region was designed, and a high-speed scanning system was established. For the inspection of a multistack semiconductor, a lateral scan method was proposed, and voids with a diameter of 0.5 mm in the multistack semiconductor were detected. In addition, the proposed probe even enables the distinguishment of the positions of voids in the multistack semiconductor. For pharmaceutical inspection, we investigated the application of THz imaging to detect mixed foreign objects frequently occurring in the tablet manufacturing process. For metals, plastics, and rubber, which are the most frequently mixed materials in the tablet manufacturing process, the foreign objects were identified in tablets using a transmission THz system. The measured THz image was compared with the conventional X-ray test result to confirm the potential of THz inspection. In the X-ray image, only metal and some polymer foreign objects were detected. In contrast, in the THz image, although the materials could not be distinguished, most foreign substances were detected. Consequently, the THz imaging test was verified as a possible new tool in fields where X-ray or existing tests are not possible.

Background Initial D-dimer level is a well-known prognostic parameter in patients with acute ischemic stroke (AIS). However, there have been no studies on the clinical significance of follow-up D-dimer levels. In this study, we evaluated the association between initial and follow-up D-dimer levels and early neurological deterioration (END) in patients with AIS. Methods We included consecutive patients with AIS who had a positive initial D-dimer test (> 0.55 mg/L) between March 2021 and November 2022. The follow-up D-dimer test was performed on the 7th day after hospitalization and on the day of discharge if discharged earlier. END was defined as an increase of ≥ 2 in the total NIHSS score, or ≥ 1 in the motor NIHSS score within the first 7 days of admission. As medical conditions closely associated with the initial and follow-up D-dimer levels in AIS patients, we also evaluated the history of cancer, active cancer, and venous thromboembolism (VTE) that occurred during hospitalization together. Results A total of 246 patients with AIS were evaluated (median age: 87 years, male: 56.5%). In multivariable logistic regression analysis, the initial D-dimer level was closely associated with END after adjusting for confounders (adjusted odds ratio [aOR]: 1.48, 95% CI: 1.06–2.05). The follow-up D-dimer level also showed a close correlation with END (aOR: 1.60, 95% CI: 1.16–2.20). Regarding the analysis of the association between D-dimer levels and underlying cancer or VTE, the initial D-dimer level showed a statistically significant positive relationship only with active cancer (P = 0.024). On the other hand, the follow-up D-dimer level was found to be statistically significantly associated with a history of cancer (P = 0.024), active cancer (P = 0.001), and VTE (P = 0.001). Conclusions Initial and follow-up D-dimer levels were associated with END in AIS patients. Particularly, the follow-up D-dimer level showed a clear correlation not only with END but also with the underlying cancer or the occurrence of VTE during the acute period.

(1) Background: The lymphocyte-to-monocyte ratio (LMR), one of the systemic inflammatory markers, has been shown to be associated with prognosis of various solid tumors. However, no study has reported clinical utility of the LMR of malignant body fluid (mLMR) (2) Methods: We retrospectively analyzed clinical data of the final 92 patients of a total of 197 patients with advanced ovarian cancer newly diagnosed from November 2015 and December 2021 using our institute big data. (3) Results: Patients were divided into three groups according to their combined bLMR and mLMR scores (bmLMR score): 2, both bLMR and mLMR were elevated; 1, bLMR or mLMR was elevated; and 0, neither bLMR nor mLMR was elevated. A multivariable analysis confirmed that the histologic grade (p = 0.001), status of residual disease (p < 0.001), and bmLMR score (p < 0.001) were independent predictors of disease progression. A low combined value of bLMR and mLMR was strongly associated with a poor prognosis in patients with ovarian cancer. (4) Conclusions: Although further studies are required to apply our results clinically, this is the first study to validate the clinical value of mLMR for predicting prognosis of patients with advanced ovarian cancer.

Although Toll-like receptors have been widely identified and functionally characterized in mammalian models and Drosophila, the immunological function of these receptors in other insects remains unclear. Here, we explored the relevant innate immune response of Tenebrio molitor (T. molitor) Toll-3 against Gram-negative bacteria, Gram-positive bacteria, and fungal infections. Our findings indicated that TmToll-3 expression was mainly induced by Candida albicans infections in the fat bodies, gut, Malpighian tubules, and hemolymph of young T. molitor larvae. Surprisingly, Escherichia coli systemic infection caused mortality after TmToll-3 knockdown via RNA interference (RNAi) injection, which was not observed in the control group. Further analyses indicated that in the absence of TmToll-3, the final effector of the Toll signaling pathway, antimicrobial peptide (AMP) genes and relevant transcription factors were significantly downregulated after E. coli challenge. Our results indicated that the expression of almost all AMP genes was suppressed in silenced individuals, whereas the expression of relevant genes was positively regulated after fungal injection. Therefore, this study revealed the immunological involvement of TmToll-3 in T. molitor in response to systematic infections.

Figure S1 (Related to Fig. 1). Low expression of SPIN90 in cancer stroma and CAFs. Figure S2 (Related to Fig. 2). CAFs derived from Spin90-/- mice show increased activation. Figure S3 (Related to Fig. 3). Loss of SPIN90 induces CAF differentiation. Figure S4 (Related to Fig. 4). Recruitment of mDia2 to acetylated microtubules regulates CAF differentiation. Figure S5 (Related to Fig. 5). Acetylated α-tubulin enhances nuclear translocation of YAP on 0.5 kPa PAGs. Figure S6 (Related to Fig. 6). Increased α-tubulin acetylation in Spin90-/- mice induces cancer progression. Table S1. Primers used for RT-PCR

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710–22. ©2017 AACR.

In single subcortical infarction (SSI), changes in lesion size are a major determinant of early neurological deterioration. We evaluated the association between END and infarct growth velocity (IGV) in patients with SSI. We included consecutive patients with SSI who underwent MRI within 24 h of symptom onset between 2010 and 2020. END was defined as an increase of ≥ 2 in the total National Institutes of Health Stroke Scale (NIHSS) score or ≥ 1 in the motor NIHSS score. IGV was calculated using the following formula: IGV (mL/h) = diffusion-weighted imaging volume (mL)/time to MRI (h). A total of 604 patients with SSI were evaluated. Multivariable logistic regression analysis showed that IGV remained significant after adjusting for confounders (aOR = 1.34, 95% CI 1.12–1.61). In a subgroup analysis based on the type of SSI, only patients with distal SSI showed an association between IGV and END (aOR = 1.64, 95% CI 1.24–2.16). In patients with proximal SSI, IGV did not show any statistical association with END. In conclusion, IGV was positively associated with END in patients with SSI. IGV should be interpreted differently in clinical settings depending on the location of the SSI lesion.

Background Dung beetles recycle organic matter through the decomposition of feces and support ecological balance. However, these insects are threatened by the indiscriminate use of agrochemicals and habitat destruction. Copris tripartitus Waterhouse (Coleoptera: Scarabaeidae), a dung beetle, is listed as a class-II Korean endangered species. Although the genetic diversity of C. tripartitus populations has been investigated through analysis of mitochondrial genes, genomic resources for this species remain limited. In this study, we analyzed the transcriptome of C. tripartitus to elucidate functions related to growth, immunity and reproduction for the purpose of informed conservation planning. Results The transcriptome of C. tripartitus was generated using next-generation Illumina sequencing and assembled de novo using a Trinity-based platform. In total, 98.59% of the raw sequence reads were processed as clean reads. These reads were assembled into 151,177 contigs, 101,352 transcripts, and 25,106 unigenes. A total of 23,450 unigenes (93.40%) were annotated to at least one database. The largest proportion of unigenes (92.76%) were annotated to the locally curated PANM-DB. A maximum of 5,512 unigenes had homologous sequences in Tribolium castaneum. Gene Ontology (GO) analysis revealed a maximum of 5,174 unigenes in the Molecular function category. Further, in Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, a total of 462 enzymes were associated with established biological pathways. Based on sequence homology to known proteins in PANM-DB, representative immunity, growth, and reproduction-related genes were screened. Potential immunity-related genes were categorized into pattern recognition receptors (PRRs), the Toll-like receptor signaling pathway, the MyD88- dependent pathway, endogenous ligands, immune effectors, antimicrobial peptides, apoptosis, and adaptation-related transcripts. Among PRRs, we conducted detailed in silico characterization of TLR-2, CTL, and PGRP_SC2-like. Repetitive elements such as long terminal repeats, short interspersed nuclear elements, long interspersed nuclear elements and DNA elements were enriched in the unigene sequences. A total of 1,493 SSRs were identified among all unigenes of C. tripartitus. Conclusions This study provides a comprehensive resource for analysis of the genomic topography of the beetle C. tripartitus. The data presented here clarify the fitness phenotypes of this species in the wild and provide insight to support informed conservation planning.

Most commonly used behavioral measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal’s residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal’s performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (NS; Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of NS, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the MWM into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.

Background and Purpose: Patients with single subcortical infarctions (SSIs) have relatively a favorable prognosis, but they often experience early neurological deterioration (END). In this study, we compared the predictors for END in patients with SSI according to the location of the lesion. Methods: We included consecutive patients with SSIs within 72 hours of symptom onset presenting between 2010 and 2016. END was defined as an increase of ≥2 in the total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 in the motor NIHSS score within the first 72 hours of admission. Along with the analysis of all patients with SSI, we also analyzed the predictors for END in proximal/distal SSI patients and anterior/posterior circulation SSI patients. Results: A total of 438 patients with SSI were evaluated. In multivariable analysis, initial NIHSS score (adjusted odds ratio, 1.36 [95% CI, 1.15–1.60]), pulsatility index (adjusted odds ratio, 1.25 [95% CI, 1.03–1.52]), parent artery disease (adjusted odds ratio, 2.14 [95% CI, 1.06–4.33]), and neutrophil-to-lymphocyte ratio (adjusted odds ratio, 1.24 [95% CI, 1.04–1.49]) were positively associated with END. In patients with proximal SSI, initial NIHSS score, pulsatility index, parent artery disease, and neutrophil-to-lymphocyte ratio showed positive associations with END. Meanwhile, no variable related to END was found in the distal SSI group. When we compared the predictors for END based on the involved vascular territory, higher initial NIHSS score and neutrophil-to-lymphocyte ratio were significantly associated with END in patients with anterior circulation SSIs. On the contrary, higher pulsatility index values and the presence of parent artery disease were independent predictors for END in patients with SSIs in the posterior circulation. Conclusions: Initial NIHSS score, pulsatility index, parent artery disease, and neutrophil-to-lymphocyte ratio are associated with END in patients with SSIs. The frequency and predictors for END differ depending on the location of the SSI.

Background We compared the prevalence of periodic leg movements during sleep (PLMS) according to two different scoring rules of the American Academy of Sleep Medicine (AASM) 2012 and World Association of Sleep Medicine (WASM) 2016 and determined their association with depressed mood in patients with obstructive sleep apnea (OSA). Methods PLMS, defined as a periodic leg movements index of >15, were diagnosed on a diagnostic and continuous positive airway pressure (CPAP) titration polysomnography using the AASM 2012 and WASM 2016 rules. The Beck Depression Inventory (BDI) and Epworth Sleepiness Scale (ESS) were used, and multiple regression analyses were performed. Results Among 160 OSA patients, the proportion with PLMS scored by the WASM 2016 criteria was significantly higher than that scored by the AASM 2012 criteria in a diagnostic study (20.6% vs. 16.3%, respectively; P = 0.016) but not in CPAP titration study and only in patients with severe OSA. In adjusted models, PLMS were positively associated with BDI scores and a BDI of ≥10 on both diagnostic and CPAP titration studies when scored by the WASM 2016. By contrast, when scored by the AASM 2012, PLMS were associated with BDI scores (but not BDI of ≥10) only in a CPAP titration study. Conclusions There are significant differences in the prevalence of PLMS and their association with depressed mood depending on the scoring rules in patients with OSA. The current AASM scoring criteria underestimate the prevalence of PLMS, and PLMS are more likely associated with depressed mood according to the WASM scoring criteria.

Recent evidence indicates that ultraviolet (UV) exposure of the skin can affect brain functions such as learning and memory, addictive behavior, and hippocampal neurogenesis. These changes are closely associated with hippocampal function, which plays a pivotal role in learning and memory formation. However, the molecular mechanisms underlying these UV-induced skin-brain interactions remain unclear. To elucidate the molecular signature associated with UV-induced neurobehavioral changes, we analyzed the hippocampal transcriptome in a well-established mouse skin aging model, which showed thickened skin and impaired hippocampal memory. Transcriptome analysis revealed that significantly downregulated genes in UV-irradiated mice are enriched in neuroimmune-related signaling pathways. Furthermore, cell-type analysis showed that DEGs are also enriched in microglia. Consistently, immunofluorescence imaging showed an increased number of Iba1-positive microglia in the hippocampi of UV-irradiated mice. Collectively, our findings highlight that chronic UV irradiation of the skin causes significant changes in the neuroimmune system in the hippocampus, accompanied by microglial dysfunction and cognitive impairment.

The antimicrobial roles of Toll-like receptors have been mainly identified in mammalian models and

Purpose Recently, high-precision radiotherapy systems have been developed by integrating computerized tomography or magnetic resonance imaging to enhance the precision of radiotherapy. For integration with additional imaging systems in a limited space, miniaturization and weight reduction of the linear accelerator (linac) system have become important. The aim of this work is to develop a compact medical linac based on 9.3 GHz X-band RF technology instead of the S-band RF technology typically used in the radiotherapy field. Methods The accelerating tube was designed by 3D finite-difference time-domain and particle-in-cell simulations because the frequency variation resulting from the structural parameters and processing errors is relatively sensitive to the operating performance of the X-band linac. Through the 3D simulation of the electric field distribution and beam dynamics process, we designed an accelerating tube to efficiently accelerate the electron beam and used a magnetron as the RF source to miniaturize the entire linac. In addition, a side-coupled structure was adopted to design a compact linac to reduce the RF power loss. To verify the performance of the linac, we developed a beam diagnostic system to analyze the electron beam characteristics and a quality assurance (QA) experimental environment including 3D lateral water phantoms to analyze the primary performance parameters (energy, dose rate, flatness, symmetry, and penumbra) The QA process was based on the standard protocols AAPM TG-51, 106, 142 and IAEA TRS-398. Results The X-band linac has high shunt impedance and electric field strength. Therefore, even though the length of the accelerating tube is 37 cm, the linac could accelerate an electron beam to more than 6 MeV and produce a beam current of more than 90 mA. The transmission ratio is measured to be approximately 30% ~ 40% when the electron gun operates in the constant emission region. The percent depth dose ratio at the measured depths of 10 and 20 cm was approximately 0.572, so we verified that the photon beam energy was matched to approximately 6 MV. The maximum dose rate was measured as 820 cGy/min when the source-to-skin distance was 80 cm. The symmetry was smaller than the QA standard and the flatness had a higher than standard value due to the flattening filter-free beam characteristics. In the case of the penumbra, it was not sufficiently steep compared to commercial equipment, but it could be compensated by improving additional devices such as multileaf collimator and jaw. Conclusions A 9.3 GHz X-band medical linac was developed for high-precision radiotherapy. Since a more precise design and machining process are required for X-band RF technology, this linac was developed by performing a 3D simulation and ultraprecision machining. The X-band linac has a short length and a compact volume, but it can generate a validated therapeutic beam. Therefore, it has more flexibility to be coupled with imaging systems such as CT or MRI and can reduce the bore size of the gantry. In addition, the weight reduction can improve the mechanical stiffness of the unit and reduce the mechanical load.

The triglyceride-glucose (TyG) index has been associated with various metabolic, cardiovascular, and cerebrovascular diseases. We evaluated the association between the TyG index and early recurrent ischemic lesions (ERILs) in patients with acute ischemic stroke (AIS). We included consecutive patients diagnosed with AIS between 2010 and 2016. ERILs were defined as new diffusion-weighted imaging lesions outside the initial symptomatic lesion area. The TyG index was calculated using the following formula: log scale of fasting triglyceride × fasting glucose/2. A total of 176 patients with AIS were evaluated. In the multivariable analysis, the TyG index remained significant (adjusted odds ratio [aOR] 2.63, 95% confidence interval [CI] 1.34–5.15). This close correlation between the TyG index and ERIL was pronounced in ERIL-same group (aOR 2.84, 95% CI 1.40–5.78), but not in ERIL-different group. When comparing the relationship between the TyG index and ERIL by stroke mechanisms, only the intracranial- and extracranial-large artery atherosclerosis groups showed significantly higher TyG index values in patients with ERIL than those without. In conclusion, a higher TyG index was associated with ERIL, especially ERIL-same, in patients with AIS. The TyG index appears to be involved in ERIL occurrence by a mechanism related to atherosclerosis.

Guanine nucleotide exchange factors (GEFs) play multiple functional roles in neurons. In a previous study, we reported that Arhgef4 (Rho guanine nucleotide exchange factor 4) functioned as a negative regulator of the excitatory synaptic function by sequestering postsynaptic density protein 95 (PSD-95). However, the role of Arhgef4 in behavior has not been examined. We performed comprehensive behavioral tests in knockout (KO) mice to investigate of the effects of Arhgef4 deficiency. We found that the expressed PSD-95 particle size was significantly increased in hippocampal neuronal cultures from Arhgef4 KO mice, which is consistent with the previous in vitro findings. Arhgef4 KO mice exhibited general motor activity and anxiety-like behavior comparable to those of the wild type littermates. However, spatial memory and object recognition memory were significantly enhanced in the Arhgef4 KO mice. Taken together, these data confirm the role of Arhgef4 as a negative synaptic regulator at the behavioral level.

Micron-sized Ni–Al alloy powders (Ni–x wt.%Al, x = 40, 50, 60) were synthesized using the low-temperature chemical alloying (LTCA) at 500 °C. The three different as-prepared Ni–Al alloy powders were composed of Ni2Al3 and/or NiAl3 phases while achieving thermodynamic equilibrium compositions (Ni–40 wt%Al, Ni2Al3; Ni–50 wt%Al, the coexistence of Ni2Al3 and NiAl3; Ni–60 wt%Al, NiAl3). The LTCA method demonstrates that it is capable of producing Al-rich Ni–Al alloy powders while maintaining a particle size similar to that of the starting Ni particles. The three Ni–Al alloy powders were used as precursor materials to fabricate porous nickel catalysts through a selective aluminum leaching process, followed by the enlargement of the surface area. Alteration of the material characteristics with respect to the leaching time was investigated using XRD, FESEM-EDS, TEM, XPS, TPR, BET, and particle size analysis. The nickel skeletal catalysts with the increased BET-surface areas (50–111 m2/g) displayed high reactivity toward ammonia decomposition.

The cerebellum improves motor performance by adjusting motor gain appropriately. As de novo protein synthesis is essential for the formation and retention of memories, we hypothesized that motor learning in the opposite direction would induce a distinct pattern of protein expression in the cerebellum. We conducted quantitative proteomic profiling to compare the level of protein expression in the cerebellum at 1 and 24 h after training from mice that underwent different paradigms of cerebellum-dependent oculomotor learning from specific directional changes in motor gain. We quantified a total of 43 proteins that were significantly regulated in each of the three learning paradigms in the cerebellum at 1 and 24 h after learning. In addition, functional enrichment analysis identified protein groups that were differentially enriched or depleted in the cerebellum at 24 h after the three oculomotor learnings, suggesting that distinct biological pathways may be engaged in the formation of three oculomotor memories. Weighted correlation network analysis discovered groups of proteins significantly correlated with oculomotor memory. Finally, four proteins (Snca, Sncb, Cttn, and Stmn1) from the protein group correlated with the learning amount after oculomotor training were validated by Western blot. This study provides a comprehensive and unbiased list of proteins related to three cerebellum-dependent motor learning paradigms, suggesting the distinct nature of protein expression in the cerebellum for each learning paradigm. The proteomics data have been deposited to the ProteomeXchange Consortium with identifiersPXD008433.

Clinical studies have revealed that the cerebellum is activated by noxious stimuli or pathological pain, and its removal results in somatosensory dysfunction. However, the neural circuits and molecular mechanisms underlying the processing of noxious information in the cerebellum remain unknown. Using two-photon microscopy and optogenetics in mice, we found that the locus coeruleus (LC) terminals in the cerebellar cortex release noradrenaline (NA) in response to cutaneous noxious electrical stimuli. Most Bergmann glia (BG) accumulated this LC-NA noxious information by increasing intracellular calcium in an integrative manner. This global calcium activation of BG, referred to as “flare,” was also elicited in response to an intraplantar capsaicin injection. Chemogenetic inactivation of LC terminals or BG in the cerebellar cortex suppressed BG flares and reduced licking, a nocifensive behavior associated with capsaicin-induced pain. BG-specific knockdown of α-1 adrenergic receptors also suppressed capsaicin-induced BG flares and licking. Chemogenetic activation of BG or an intraplantar capsaicin injection reduced Purkinje cell firings, which disinhibited the output activity of the deep cerebellar nuclei. These results suggest that BG in the cerebellar cortex play an essential role in computing noxious information ascending from the LC and modulate pain-related behaviors by controlling the activity of the cerebellar neural circuits.One Sentence SummaryBergmann glia mediate noxious information processing in the cerebellum

Background: Although widely used in clinical fields, real-world data on the role of warfarin and non-vitamin K oral anticoagulants (NOACs) for the secondary prevention of thromboembolic complications in ischemic stroke patients with nonvalvular atrial fibrillation (NVAF) are scarce. Aims: This retrospective cohort study compared the effectiveness and safety of secondary prevention of NOAC and warfarin in ischemic stroke patients with NVAF. Methods: From the Korean National Health Insurance Service Database, we included 16,762 oral anticoagulants-naive acute ischemic stroke patients with NVAF between July 2016 and June 2019. The main outcomes included ischemic stroke, systemic embolism, major bleeding, and all-cause of death. Results: In total, 1717 warfarin and 15,025 NOAC users were included in the analysis. After 1:8 propensity score matching, during the observation period, all types of NOACs had a significantly lower risk of ischemic stroke and systemic embolism than warfarin (edoxaban: adjusted hazard ratio [aHR], 0.80; 95% confidence interval [CI], 0.68–0.93, rivaroxaban: aHR, 0.82; 95% CI, 0.70–0.96, apixaban: aHR, 0.79; 95% CI, 0.69–0.91, and dabigatran: aHR, 0.82; 95% CI, 0.69–0.97). Edoxaban (aHR, 0.77; 95% CI, 0.62–0.96), apixaban (aHR, 0.73; 95% CI, 0.60–0.90), and dabigatran (aHR, 0.66; 95% CI, 0.51–0.86) had lower risks of major bleeding and all-cause of death. Conclusions: All NOACs were more effective than warfarin in the secondary prevention of thromboembolic complications in ischemic stroke patients with NVAF. Except for rivaroxaban, most NOACs demonstrated a lower risk of major bleeding and all-cause of death than warfarin.

The purpose of this study is to evaluate the mechanical properties and clinical fitness of 3D-printed bioglass porcelain fused to metal (PFM) dental crowns. To evaluate the mechanical properties, tensile strength, Vickers microhardness, shear bond strength, and surface roughness tests of the SLM printed Co-Cr alloy was conducted. A right mandibular 1st molar tooth was prepared for a single dental crown (n = 10). For a three-unit metal crown and bridge, the right mandibular first premolar and first molar were prepared. Bioglass porcelain was fired to fabricate PFM dental restorations. A clinical gap was observed and measured during each of the four times porcelain was fired. A statistical analysis was conducted. The SLM technique showed the largest statistically significant tensile strength and a 0.2% yield strength value. The milling technique had the lowest statistically significant compressive strength value. The shear bond strength and surface roughness showed no statistically significant difference between the fabricated method. There was a statistically significant change in marginal discrepancy according to the porcelain firing step. The casting technique showed the greatest statistically significant margin discrepancy value. The SLM method showed better fitness than the traditional casting method and showed better mechanical properties as a dental material.