Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome.

Background: Restless legs syndrome (RLS) is a prevalent sensorimotor nervous system disorder in patients accompanied with insomnia, blood pressure fluctuation, and sympathetic dysfunction. These symptoms may disrupt cerebral hemodynamics. Dynamic cerebral autoregulation (dCA) describes the temporary response of cerebrovascular system to abrupt fluctuations in blood pressure, which keep cerebral blood flow stable and serve as a marker of cerebrovascular system ability. Objective: This research aimed to assess dCA in RLS patients. Methods: In this study, RLS patients were recruited and subsequently classified into four groups (mild, moderate, severe, and very severe) based on the International RLS Rating Scale (IRLS). Healthy controls matched for age and sex were enrolled. All participants were evaluated dCA by assessing phase difference (PD). A portion of patients with RLS was reassessed for dCA after one month of medication therapy (pramipexole [0.125 mg/day] and gabapentin [300 mg/day]). Results: There were altogether 120 patients with RLS and 30 controls completed the polysomnography and dCA assessment. PD was lower in the moderate, severe, and very severe RLS groups than that in the controls and mild RLS groups. Periodic limb movement index (PLMI), arousal index, and IRLS all showed a linear correlation with PD in RLS patients. Additionally, PD increased in RLS patients after therapy. Conclusion: The dCA was compromised in moderate, severe, and very severe RLS patients and was negatively correlated with the IRLS, arousal index, and PLMI. After 1 month of therapy, dCA improved in RLS patients.

Phenotypic comparison and the potential antitumor function of immortalized bone marrow-derived macrophages (iBMDMs).

Introduction: Macrophages are an important component of innate immunity and involved in the immune regulation of multiple diseases. The functional diversity and plasticity make macrophages to exhibit different polarization phenotypes after different stimuli. During tumor progression, the M2-like polarized tumor-associated macrophages (TAMs) promote tumor progression by assisting immune escape, facilitating tumor cell metastasis, and switching tumor angiogenesis. Our previous studies demonstrated that functional remodeling of TAMs through engineered-modifying or gene-editing provides the potential immunotherapy for tumor. However, lack of proliferation capacity and maintained immune memory of infused macrophages restricts the application of macrophage-based therapeutic strategies in the repressive tumor immune microenvironment (TIME). Although J2 retrovirus infection enabled immortalization of bone marrow-derived macrophages (iBMDMs) and facilitated the mechanisms exploration and application, little is known about the phenotypic and functional differences among multi kinds of macrophages. Methods: HE staining was used to detect the biosafety of iBMDMs, and real-time quantitative PCR, immunofluorescence staining, and ELISA were used to detect the polarization response and expression of chemokines in iBMDMs. Flow cytometry, scratch assay, real-time quantitative PCR, and crystal violet staining were used to analyze its phagocytic function, as well as its impact on tumor cell migration, proliferation, and apoptosis. Not only that, the inhibitory effect of iBMDMs on tumor growth was detected through subcutaneous tumor loading, while the tumor tissue was paraffin sectioned and flow cytometry was used to detect its impact on the tumor microenvironment. Results: In this study, we demonstrated iBMDMs exhibited the features of rapid proliferation and long-term survival. We also compared iBMDMs with RAW264.7 cell line and mouse primary BMDMs with in vitro and in vivo experiments, indicating that the iBMDMs could undergo the same polarization response as normal macrophages with no obvious cellular morphology changes after polarization. What's more, iBMDMs owned stronger phagocytosis and pro-apoptosis functions on tumor cells. In addition, M1-polarized iBMDMs could maintain the anti-tumor phenotypes and domesticated the recruited macrophages of receptor mice, which further improved the TIME and repressed tumor growth. Discussion: iBMDMs can serve as a good object for the function and mechanism study of macrophages and the optional source of macrophage immunotherapy.

Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

IMPORTANCE: Postoperative delirium is a common and impactful neuropsychiatric complication in patients undergoing coronary artery bypass grafting surgery. Cognitive training may enhance cognitive reserve, thereby reducing postoperative delirium. OBJECTIVE: To determine whether preoperative cognitive training reduces the incidence of delirium in patients undergoing coronary artery bypass grafting. DESIGN, SETTING, and PARTICIPANTS: This prospective, single-blind, randomized clinical trial was conducted at 3 university teaching hospitals in southeastern China with enrollment between April 2022 and May 2023. Eligible participants included those scheduled for elective coronary artery bypass grafting who consented and enrolled at least 10 days before surgery. INTERVENTIONS: Participating patients were randomly assigned 1:1, stratified by site, to either routine care or cognitive training, which included substantial practice with online tasks designed to enhance cognitive functions including memory, imagination, reasoning, reaction time, attention, and processing speed. MAIN OUTCOMES AND MEASURES: The primary outcome was occurrence of delirium during postoperative days 1 to 7 or until hospital discharge, diagnosed using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Units. Secondary outcomes were postoperative cognitive dysfunction, delirium characteristics, and all-cause mortality within 30 days following the operation. RESULTS: A total of 218 patients were randomized and 208 (median [IQR] age, 66 [58-70] years; 64 female [30.8%] and 144 male [69.2%]) were included in final analysis, with 102 randomized to cognitive training and 106 randomized to routine care. Of all participants, 95 (45.7%) had only a primary school education and 54 (26.0%) had finished high school. In the cognitive training group, 28 participants (27.5%) developed delirium compared with 46 participants (43.4%) randomized to routine care. Those receiving cognitive training were 57% less likely to develop delirium compared with those receiving routine care (adjusted odds ratio [aOR] 0.43; 95% CI, 0.23-0.77; P = .007). Significant differences were observed in the incidence of severe delirium (aOR, 0.46; 95% CI, 0.25-0.82; P = .01), median (IQR) duration of delirium (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .008), and median (IQR) number of delirium-positive days (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .007). No other secondary outcomes differed significantly. CONCLUSIONS AND RELEVANCE: In this randomized trial of 208 patients undergoing coronary artery bypass grafting, preoperative cognitive training reduced the incidence of postoperative delirium. However, our primary analysis was based on fewer than 75 events and should therefore be considered exploratory and a basis for future larger trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200058243.

Evaluation of a Novel Drilling Approach for Dynamic Navigation-Aided Endodontic Microsurgery: A Surgical Simulation Comparison Study.

INTRODUCTION: This study investigated the feasibility of a novel drilling approach that integrates a pilot trephine into dynamic navigation (DN) for guided osteotomy and root-end resection (RER) with unimanual operation in endodontic microsurgery. METHODS: Two operators with varying levels of DN experience performed guided osteotomy and RER using 2 unimanual drilling methods with DN-aided operation on 3-dimensional printed jaw models. Method 1 (M1) involved drilling with a conventional trephine. Method 2 (M2) involved drilling with a pilot trephine, followed by drilling with a conventional trephine. Accuracy, time, and safety of M1 and M2 were compared. Accuracy measurements included platform deviation (PD), end deviation (ED), angular deviation (AD), resection length deviation (RLD), and resection bevel angle (RBA). Additional parameters included osteotomy and RER time (OT) and bur slippage number (BSN). Statistical analyses were conducted using a 2-sample t-test or Mann-Whitney U test, with the significance level set at .05. RESULTS: The PD, AD, RBA, and BSN in the M2 group were significantly less than in the M1 group (P < .05). For M1, the novice operator (NO) exhibited significantly higher values of PD, ED, OT, and BSN than the experienced operator (EO) (P < .05). For M2, the NO exhibited significantly higher value of ED only (P < .05), and drilling depth >7 mm was significantly associated with a longer OT (P < .05). CONCLUSION: In this surgical simulation comparison study, the incorporation of a pilot drill improved the accuracy and safety of DN-aided endodontic microsurgery.

Clinical features, polysomnography, and genetics association study of restless legs syndrome in clinic based Chinese patients: A multicenter observational study.

STUDY OBJECTIVES: To systemically describe the clinical features, polysomnography (PSG) finding, laboratory tests and single-nucleotide polymorphisms (SNPs) in a clinic based Chinese primary restless legs syndrome (RLS) population. METHODS: This observational study, conducted from January 2020 to October 2021 across 22 sleep labs in China, recruited 771 patients diagnosed with RLS following the 2014 RLSSG criteria. Clinical data, PSG testing, and laboratory examination and SNPs of patients with RLS were collected. A total of 32 SNPs in 24 loci were replicated using the Asian Screening Array chip, employing data from the Han Chinese Genomes Initiative as controls. RESULTS: In this study with 771 RLS patients, 645 had primary RLS, and 617 has DNA available for SNP study. Among the 645 primary RLS, 59.7% were women. 33% had a family history of RLS, with stronger familial influence in early-onset cases. Clinical evaluations showed 10.4% had discomfort in body parts other than legs. PSG showed that 57.1% of RLS patients had periodic leg movement index (PLMI) of >5/h and 39.1% had PLMI >15/h, respectively; 73.8% of RLS patients had an Apnea-Hypopnea Index (AHI) > 5/h, and 45.3% had an AHI >15/h. The laboratory examinations revealed serum ferritin levels <75 ng/ml in 31.6%, and transferrin saturation (TSAT) of <45% in 88.7% of RLS patients. Seven new SNPs in 5 genes showed a significant allelic association with Chinese primary RLS, with one previously reported (BTBD9) and four new findings (TOX3, PRMT6, DCDC2C, NOS1). CONCLUSIONS: Chinese RLS patients has specific characters in many aspects. A high family history with RLS not only indicates strong genetic influence, but also reminds us to consider the familial effect in the epidemiological study. Newly developed sequencing technique with large samples remains to be done.

Long-range connections damage in white matter hyperintensities affects information processing speed.

White matter hyperintensities, one of the major markers of cerebral small vessel disease, disrupt the integrity of neuronal networks and ultimately contribute to cognitive dysfunction. However, a deeper understanding of how white matter hyperintensities related to the connectivity patterns of brain hubs at the neural network level could provide valuable insights into the relationship between white matter hyperintensities and cognitive dysfunction. A total of 36 patients with moderate to severe white matter hyperintensities (Fazekas score ≥ 3) and 34 healthy controls underwent comprehensive neuropsychological assessments and resting-state functional MRI scans. The voxel-based graph-theory approach-functional connectivity strength was employed to systematically investigate the topological organization of the whole-brain networks. The white matter hyperintensities patients performed significantly worse than the healthy controls in episodic memory, executive function and information processing speed. Additionally, we found that white matter hyperintensities selectively affected highly connected hub regions, predominantly involving the medial and lateral prefrontal, precuneus, inferior parietal lobule, insula and thalamus. Intriguingly, this impairment was connectivity distance-dependent, with the most prominent disruptions observed in long-range connections (e.g. 100-150 mm). Finally, these disruptions of hub connectivity (e.g. the long-range functional connectivity strength in the left dorsolateral prefrontal cortex) positively correlated with the cognitive performance in white matter hyperintensities patients. Our findings emphasize that the disrupted hub connectivity patterns in white matter hyperintensities are dependent on connection distance, especially longer-distance connections, which in turn predispose white matter hyperintensities patients to worse cognitive function.

An alfalfa MYB-like transcriptional factor MsMYBH positively regulates alfalfa seedling drought resistance and undergoes MsWAV3-mediated degradation.

Drought is a major threat to alfalfa (Medicago sativa L.) production. The discovery of important alfalfa genes regulating drought response will facilitate breeding for drought-resistant alfalfa cultivars. Here, we report a genome-wide association study of drought resistance in alfalfa. We identified and functionally characterized an MYB-like transcription factor gene (MsMYBH), which increases the drought resistance in alfalfa. Compared with the wild-types, the biomass and forage quality were enhanced in MsMYBH overexpressed plants. Combined RNA-seq, proteomics and chromatin immunoprecipitation analysis showed that MsMYBH can directly bind to the promoters of MsMCP1, MsMCP2, MsPRX1A and MsCARCAB to improve their expression. The outcomes of such interactions include better water balance, high photosynthetic efficiency and scavenge excess H2O2 in response to drought. Furthermore, an E3 ubiquitin ligase (MsWAV3) was found to induce MsMYBH degradation under long-term drought, via the 26S proteasome pathway. Furthermore, variable-number tandem repeats in MsMYBH promoter were characterized among a collection of germplasms, and the variation is associated with promoter activity. Collectively, our findings shed light on the functions of MsMYBH and provide a pivotal gene that could be leveraged for breeding drought-resistant alfalfa. This discovery also offers new insights into the mechanisms of drought resistance in alfalfa.

Anxiety and depression among patients with insomnia during the first wave and the release of the COVID-19 in Northeast China: A cross-sectional survey.

BACKGROUND: The global coronavirus disease 2019 (COVID-19) pandemic seriously affected people's lives. We evaluated anxiety and depression among patients with insomnia in northeast China during the first wave and release of COVID-19, providing a basis for the clinical diagnosis and treatment of insomnia. METHODS: We enrolled 4211 patients with insomnia from January 2016 to February 2020, August 2020 to February 2022, August 2022 to December 2022, and January 2023 to February 2023, from our institution. Sleep quality was evaluated using the Athens Insomnia Scale, Insomnia Severity Index (ISI), and Pittsburgh sleep quality index (PSQI), while mood disorder and fatigue were evaluated using the Hhospital anxiety and depression scale (HAD), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder (GAD-7), and Fatigue Scale-14 (FS-14). RESULTS: Insomnia with depression increased in prevalence after COVID-19 compared with before (12.8 % vs. 15.3 %, P < 0.05), while the age of patients decreased [(50.2 ± 15.2) vs. (47.5 ± 16.8), P < 0.05]. The number of patients with insomnia and severe depression increased compared with before COVID-19 (20.3 % vs. 25.3 %, P < 0.05). A higher proportion of patients with insomnia for >2 years had depression (P < 0.05). As the epidemic subsided, insomnia increased among young and male patients (young patients: 55.2 % vs. 37.0 %; male patients: 41 % vs. 27.4 %, respectively; P < 0.05). The proportion of patients with insomnia with anxiety and depression increased (53.8 % vs. 51.8 %，P < 0.05), the proportion with moderate to severe anxiety increased (7.6 % vs. 13.5 %, P < 0.05), and moderate and severe depression decreased (moderate: 25.6 % vs. 19.1 %, severe: 25.8 % vs. 20.3 %, P < 0.05, respectively). Middle-aged and elderly patients had higher PQSI scores in sleep latency, habitual sleep efficiency, subjective sleep quality, and use of sleep medications than young patients (P < 0.05). The PSQI score was positively correlated with the PHQ-9 score (r = 0.526), GAD-7 score (r = 0.563), and FS-14 score (r = 0.316) (P < 0.05). LIMITATIONS: The study was single-center, the sample size was small, and assessment data were lacking from early in the epidemic. The scale is subjective, which may affect the accuracy. CONCLUSION: Insomnia with depression increased during COVID-19. The patients were younger than before the epidemic, and a higher proportion with insomnia for >2 years had depression. The proportion of patients with insomnia with anxiety and depression was higher after the epidemic period, and the degree worsened. The proportion of insomnia with depression decreased after the epidemic period, and the degree alleviated. The proportion of young male patients with insomnia increased. Middle aged and elderly patients with insomnia had poor sleep quality, which was positively correlated with anxiety, depression, and fatigue.

The chromosome-level assembly of the wild diploid alfalfa genome provides insights into the full landscape of genomic variations between cultivated and wild alfalfa.

Alfalfa (Medicago sativa L.) is one of the most important forage legumes in the world, including autotetraploid (M. sativa ssp. sativa) and diploid alfalfa (M. sativa ssp. caerulea, progenitor of autotetraploid alfalfa). Here, we reported a high-quality genome of ZW0012 (diploid alfalfa, 769 Mb, contig N50 = 5.5 Mb), which was grouped into the Northern group in population structure analysis, suggesting that our genome assembly filled a major gap among the members of M. sativa complex. During polyploidization, large phenotypic differences occurred between diploids and tetraploids, and the genetic information underlying its massive phenotypic variations remains largely unexplored. Extensive structural variations (SVs) were identified between ZW0012 and XinJiangDaYe (an autotetraploid alfalfa with released genome). We identified 71 ZW0012-specific PAV genes and 1296 XinJiangDaYe-specific PAV genes, mainly involved in defence response, cell growth, and photosynthesis. We have verified the positive roles of MsNCR1 (a XinJiangDaYe-specific PAV gene) in nodulation using an Agrobacterium rhizobia-mediated transgenic method. We also demonstrated that MsSKIP23_1 and MsFBL23_1 (two XinJiangDaYe-specific PAV genes) regulated leaf size by transient overexpression and virus-induced gene silencing analysis. Our study provides a high-quality reference genome of an important diploid alfalfa germplasm and a valuable resource of variation landscape between diploid and autotetraploid, which will facilitate the functional gene discovery and molecular-based breeding for the cultivars in the future.

Connectomics-based resting-state functional network alterations predict suicidality in major depressive disorder.

Suicidal behavior is a major concern for patients who suffer from major depressive disorder (MDD). However, dynamic alterations and dysfunction of resting-state networks (RSNs) in MDD patients with suicidality have remained unclear. Thus, we investigated whether subjects with different severity of suicidal ideation and suicidal behavior may have different disturbances in brain RSNs and whether these changes could be used as the diagnostic biomarkers to discriminate MDD with or without suicidal ideation and suicidal behavior. Then a multicenter, cross-sectional study of 528 MDD patients with or without suicidality and 998 healthy controls was performed. We defined the probability of dying by the suicide of the suicidality components as a 'suicidality gradient'. We constructed ten RSNs, including default mode (DMN), subcortical (SUB), ventral attention (VAN), and visual network (VIS). The network connections of RSNs were analyzed among MDD patients with different suicidality gradients and healthy controls using ANCOVA, chi-squared tests, and network-based statistical analysis. And support vector machine (SVM) model was designed to distinguish patients with mild-to-severe suicidal ideation, and suicidal behavior. We found the following abnormalities with increasing suicidality gradient in MDD patients: within-network connectivity values initially increased and then decreased, and one-versus-other network values decreased first and then increased. Besides, within- and between-network connectivity values of the various suicidality gradients are mainly negatively correlated with HAMD anxiety and positively correlated with weight. We found that VIS and DMN-VIS values were affected by age (p < 0.05), cingulo-opercular network, and SUB-VAN values were statistically influenced by sex (p < 0.05). Furthermore, the SVM model could distinguish MDD patients with different suicidality gradients (AUC range, 0.73-0.99). In conclusion, we have identified that disrupted brain connections were present in MDD patients with different suicidality gradient. These findings provided useful information about the pathophysiological mechanisms of MDD patients with suicidality.

Human umbilical cord mesenchymal stem cell-derived exosomes promote microcirculation in aged diabetic mice by TGF-ß1 signaling pathway.

BACKGROUND: Microvascular dysfunction is one of the most common pathological characteristics in Type 2 diabetes. Human mesenchymal stem cell-derived exosomes (hUCMSCs-Exo) have diverse functions in improving microcirculation; however, the molecular mechanism of hUCMSCs-Exo in regulating burn-induced inflammation is not well understood. METHODS: hUCMSCs-Exo were extracted by hypervelocity centrifugation method, and exosome morphology was observed by transmission electron microscopy, exosome diameter distribution was detected by particle size analysis, and exosome specific proteins were identified by Western blot.2. DB/DB mice were randomly divided into exosomes group and PBS group. Exosomes and PBS were injected into the tail vein, respectively, and the calf muscle tissue was taken 28 days later. 0.5% Evans blue fluorescence assessment microvascular permeability. The expression of CD31 was detected by immunofluorescence.The morphology and function of microvessels in muscle tissue of lower limbs was evaluated by transmission electron microscopy.3. TMT proteomics was used to detect the changes of differential protein expression in lower limb muscle tissues of the PBS group and the exosome group, and data analysis was performed to screen key signal molecules and their involved biological pathways. Key signal molecules CD105 were verified by Western blot. The expression of TGF-ß1 in exosomes were evaluated by Western blot. RESULTS: Electron microscopy showed that hUCMSCs-Exo presented a uniform vesicle structure, and NTA showed that its diameter was about 160 nm. Western blot showed positive expression of specific proteins CD9, CD81 and TSG101 on exosomes.2. There is no significant change in blood glucose and body weight before and after the exosome treatment. The exosome group can significantly reduce the exudation of Evans blue. Compared with the PBS group. Meanwhile, CD31 immunofluorescence showed that the red fluorescence of exosome treatment was significantly increased, which was higher than that of PBS group. Transmission electron microscopy showed smooth capillary lumen and smooth and complete surface of endothelial cells in the exosome group, while narrow capillary lumen and fingerlike protrusion of endothelial cells in the PBS group.3.Quantitative analysis of TMT proteomics showed that there were 82 differential proteins, including 49 down-regulated proteins and 33 up-regulated proteins. Go enrichment analysis showed that the differential proteins were involved in molecular function, biological process, cell components,among which CD105 was one of the up-regulated proteins. Through literature search, CD105 was found to be related to endothelial cell proliferation. Therefore, this study verified the changes of CD105 in the exosome group, and it was used as the mechanism study of this study. 4. Western blot analysis showed that the expression of CD105 protein in lower limb muscle tissue of exosome group was significantly increased compared with that of PBS group. Based on the fact that CD105 is a component of the TGF-ß1 receptor complex and exosomes are rich in growth factors and cytokines, this study further examined the expression of TGF-ß1 in exosomes, and the results showed that exosomes had high expression of TGF-ß1. CONCLUSION: By improving the integrity of microvascular endothelial cells, hUCMSCs-Exo can improve the permeability of microvessels in diabetic lower muscle tissue, further promote the proliferation of lower limb muscle cells and inhibit the apoptosis of tissue cells. The mechanism may be associated with exosomes rich in TGF-ß1, which is likely to promote endothelial cell proliferation and improve permeability through binding to the endothelial CD105/TßR-II receptor complex, while promoting angiogenesis and protecting skeletal muscle cells from apoptosis.

Facile synthesis of wide bandgap ZrS2 colloidal quantum dots for solution processed solar-blind UV photodetectors.

We present a facile one-pot method for the successful synthesis of heavy metal-free ZrS2 colloidal quantum dots (QDs) with a wide bandgap. To achieve this, we employed 1-dodecanethiol (DT) as a sulfur precursor, enabling the controlled release of H2S in situ during the reaction at temperatures exceeding 195 °C. This approach facilitated the synthesis of small-sized ZrS2 QDs with precise control.

Electrolytic Characteristics of Microhole Array Manufacturing Using Polyacrylamide Electrolyte in 304 Stainless Steel.

Because of the ease with which oxide films form on its surfaces, stainless steel has strong corrosion resistance and excellent processing performance. Electrochemical machining (ECM) is a flexible process that can create microstructures on stainless steel (SS304); however, with traditional masked ECM, the efficiency and accuracy of microstructure machining are low. Proposed here is the use of a non-Newtonian fluid [polyacrylamide (PAM)] as the electrolyte. To date, there have been few papers on the electrochemical dissolution behavior of stainless-steel micromachining with a non-Newtonian fluid as the electrolyte. The aims of the study reported here were to investigate the electrochemical properties of SS304 with PAM and PAM-NaOH as electrolytes, and to explain their electrochemical corrosion mechanisms. The effects of different electrolytes were compared, and the polarization curves of SS304 in PAM and PAM-NaOH electrolyte solutions with different components were analyzed and compared with that in NaNO3 electrolyte. Then, the effects of the main processing parameters (pulse voltage, frequency, and duty ratio) on the machining performance were investigated in detail. A microhole array was obtained with a good quality comprising an average diameter of 330.11 µm, an average depth of 16.13 µm, and a depth-to-diameter ratio of 0.048. Using PAM to process microstructures on stainless-steel surfaces was shown to be feasible, and experiments indicated that the mixed electrolyte (PAM-NaOH) had not only the physical characteristics of a non-Newtonian fluid but also the advantages of a traditional electrolyte to dissolve processing products, and it effectively improved the processing accuracy of masked ECM for SS304.

The Abnormal Alternations of Brain Imaging in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review.

Background: Cognitive impairment (CI) is an important extrapulmonary complication in patients with chronic obstructive pulmonary disease (COPD). Multimodal Neuroimaging Examination can display changes in brain structure and functions in patients with COPD. Objective: The purpose of this systematic review is to provide an overview of the variations in brain imaging in patients with COPD and their potential relationship with CI. Furthermore, we aim to provide new ideas and directions for future research. Methods: Literature searches were performed using the electronic databases PubMed, Scopus, and ScienceDirect. All articles published between January 2000 and November 2021 that met the eligibility criteria were included. Results: Twenty of the 23 studies focused on changes in brain structure and function. Alterations in the brain's macrostructure are manifested in the bilateral frontal lobe, hippocampus, right temporal lobe, motor cortex, and supplementary motor area. The white matter microstructural changes initially appear in the bilateral frontal subcortical region. Regarding brain function, patients with COPD exhibited reduced frontal cerebral perfusion and abnormal alterations in intrinsic brain activity in the bilateral posterior cingulate cortex, precuneus, right lingual gyrus, and left anterior central gyrus. Currently, there is limited research related to brain networks. Conclusion: CI in patients with COPD may present as a type of dementia different from Alzheimer's disease, which tends to manifest as frontal cognitive decline early in the disease. Further studies are required to clarify the neurobiological pathways of CI in patients with COPD from the perspective of brain connectomics based on the whole-brain system in the future.

Efficacy and safety of perampanel as early add-on therapy in Chinese patients with focal-onset seizures: a multicenter, open-label, single-arm study.

Background: No interventional study has been conducted in China to assess efficacy and safety of perampanel in treating Chinese patients with epilepsy, nor has there been any study on perampanel early add-on therapy in China. This interventional study aimed to assess efficacy and safety of perampanel as an early add-on treatment of focal-onset seizures (FOS) with or without focal-to-bilateral tonic-clonic seizures (FBTCS) in Chinese patients. Methods: In this multicenter, open-label, single-arm, phase 4 interventional study, Chinese patients ≥ 12 years old with FOS with or without FBTCS who failed anti-seizure medication (ASM) monotherapy from 15 hospitals in China were enrolled and treated with perampanel add-on therapy (8-week titration followed by 24-week maintenance). The primary endpoint was 50% responder rate. Secondary endpoints included seizure-freedom rate and changes in seizure frequency from baseline. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were recorded. Results: The full analysis set included 150 patients. The mean maintenance perampanel dose was 5.9 ± 1.5 mg/day and the 8-month retention rate was 72%. The 50% responder rate and seizure-freedom rate for all patients during maintenance were 67.9 and 30.5%, respectively. Patients with FBTCS had higher 50% responder rate (96.0%) and seizure-freedom rate (76.0%) during maintenance. Patients on concomitant sodium valproate had a significantly higher seizure-freedom rate than those on concomitant oxcarbazepine. Eight-six (55.1%) patients experienced treatment-related TEAEs, and the most common TEAEs were dizziness (36.5%), hypersomnia (11.5%), headache (3.9%), somnolence (3.2%), and irritability (3.2%). Withdrawal due to TEAEs occurred to 14.7% of the patients. Conclusion: Perampanel early add-on was effective and safe in treating Chinese patients≥12 years old with FOS with or without FBTCS.Clinical trial registrationwww.chictr.org.cn, Identifier ChiCTR2000039510.

MsCYP71 is a positive regulator for drought resistance in alfalfa.

Cytochrome P450 (CYP450) family proteins play key roles in plant growth, development, stress responses, and other physiological processes. Here, we cloned the cytochrome P450 gene MsCYP71 in alfalfa and found that the expression of MsCYP71 was induced by drought stress. Silencing the MsCYP71 gene using virus-induced gene silencing technology significantly decreased the drought resistance of alfalfa, as indicated by their lower relative water content, net photosynthetic rate, and chlorophyll fluorescence maximum (Fm); further, the heterologous overexpression of MsCYP71 in tobacco significantly enhanced the drought resistance and Fm of transgenic tobacco. Furthermore, the expression of MsCYP71 across 45 alfalfa accessions under drought stress was investigated. A significant positive correlation between drought resistance and MsCYP71 expression was observed. The 45 alfalfa accessions were clustered into four groups, and drought resistance, Fm, and MsCYP71 were higher in group I than in the other groups, indicating that group I accessions can be used as candidate germplasm resources for the breeding of drought-resistant alfalfa varieties. Overall, our findings indicated that MsCYP71 is a positive regulator of drought resistance in alfalfa, and its expression can be used to evaluate the drought resistance of alfalfa.

Milletdb: a multi-omics database to accelerate the research of functional genomics and molecular breeding of millets.

Millets are a class of nutrient-rich coarse cereals with high resistance to abiotic stress; thus, they guarantee food security for people living in areas with extreme climatic conditions and provide stress-related genetic resources for other crops. However, no platform is available to provide a comprehensive and systematic multi-omics analysis for millets, which seriously hinders the mining of stress-related genes and the molecular breeding of millets. Here, a free, web-accessible, user-friendly millets multi-omics database platform (Milletdb, http://milletdb.novogene.com) has been developed. The Milletdb contains six millets and their one related species genomes, graph-based pan-genomics of pearl millet, and stress-related multi-omics data, which enable Milletdb to be the most complete millets multi-omics database available. We stored GWAS (genome-wide association study) results of 20 yield-related trait data obtained under three environmental conditions [field (no stress), early drought and late drought] for 2 years in the database, allowing users to identify stress-related genes that support yield improvement. Milletdb can simplify the functional genomics analysis of millets by providing users with 20 different tools (e.g., 'Gene mapping', 'Co-expression', 'KEGG/GO Enrichment' analysis, etc.). On the Milletdb platform, a gene PMA1G03779.1 was identified through 'GWAS', which has the potential to modulate yield and respond to different environmental stresses. Using the tools provided by Milletdb, we found that the stress-related PLATZs TFs (transcription factors) family expands in 87.5% of millet accessions and contributes to vegetative growth and abiotic stress responses. Milletdb can effectively serve researchers in the mining of key genes, genome editing and molecular breeding of millets.

Clinical and radiological outcomes of dynamic navigation in endodontic microsurgery: a prospective study.

OBJECTIVES: This study was aimed at evaluating the clinical and radiological outcomes of novel dynamic navigation (DN)-aided endodontic microsurgery (EMS), with an analysis of potential prognostic factors. MATERIALS AND METHODS: Forty-six teeth from 32 patients who received DN-aided EMS were included. Clinical and radiographic assessments were performed at least 1 year postoperatively. Two calibrated endodontists assessed radiological outcomes according to two-dimensional (2D) periapical radiography (PA) and three-dimensional (3D) cone-beam computed tomography (CBCT) imaging using Rud's and Molven's criteria and modified PENN 3D criteria, respectively. Fisher's exact test was used for statistical analysis of the predisposing factors. RESULTS: Of the 32 patients with 46 treated teeth, 28 with 40 teeth were available for follow-up. Of the 28 patients, four (five teeth) refused to undergo CBCT and only underwent clinical and PA examinations, and the remaining 24 (35 teeth) underwent clinical, PA, and CBCT examinations. Combined clinical and radiographic data revealed a 95% (38/40) success rate in 2D healing evaluations and a 94.3% (33/35) success rate in 3D healing evaluations. No significant effect was found in sex, age, tooth type, arch type, preoperative lesion volume, preoperative maximum lesion size, presence/absence of crown and post, and the root canal filling state on the outcome of DN-aided EMS. CONCLUSIONS: DN-aided EMS has a favorable prognosis and could be considered an effective and reliable treatment strategy. Further investigations with larger sample sizes are required to confirm these results. CLINICAL RELEVANCE: DN-aided EMS could be considered an effective and reliable treatment strategy.

APE1 promotes embryonic stem cell proliferation and teratoma formation by regulating GDNF/GFRα1 axis.

The teratomas formation has severely hindered the application of embryonic stem cells (ESCs) in clinical trials. Apurinic/apyrimidinic endonuclease 1 (APE1) is strongly involved in the development of tumors and differentiation process of stem cells. However, the role of APE1 in teratomas remains unknown. The expression of APE1 was examined in mouse ESCs (mESCs) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The role and mechanism of APE1 in the proliferation, pluripotency and differentiation of E14 cells were determined by cell counting, flow cytometry and western blot assays. Besides, the role of APE1 in teratomas was also probed in xenografted mice. The expression of APE1 was upregulated in mESCs with differentiation. Knockdown of APE1 reduced the cell numbers, induced the arrest of the G2/M phase, and decreased the expression of cell cycle-related proteins in E14 cells. Besides, loss- and gain-of-function assays revealed that APE1 enhanced the levels of proteins involved in pluripotency, reduced the protein expression of ectoderm markers, and increased the protein levels of endoderm markers in E14 cells. Mechanically, inhibition of APE1 downregulated the expression of GDNF and GFRα1 in E14 cells. GDNF reversed the role of APE1 in the proliferation, pluripotency and embryogenesis of E14 cells. Moreover, suppression of APE1 reduced the teratoma volume and the relative protein expression of endoderm markers, but increased the relative protein expression of ectoderm markers in xenografted mice. Collectively, knockdown of APE1 attenuated proliferation, pluripotency and embryogenesis of mESCs via GDNF/GFRα1 axis.

Disconnection of Network Hubs Underlying the Executive Function Deficit in Patients with Ischemic Leukoaraiosis.

BACKGROUND: Cognitive impairment is the most common clinical manifestation of ischemic leukoaraiosis (ILA), but the underlying neurobiological pathways have not been well elucidated. Recently, it was thought that ILA is a "disconnection syndrome". Disorganized brain connectome were considered the key neuropathology underlying cognitive deficits in ILA patients. OBJECTIVE: We aimed to detect the disruption of network hubs in ILA patients using a new analytical method called voxel-based eigenvector centrality (EC) mapping. METHODS: Subjects with moderate to severe white matters hyperintensities (Fazekas score ≥3) and healthy controls (HCs) (Fazekas score = 0) were included in the study. The resting-state functional magnetic resonance imaging and the EC mapping approach were performed to explore the alteration of whole-brain network connectivity in ILA patients. RESULTS: Relative to the HCs, the ILA patients exhibited poorer cognitive performance in episodic memory, information processing speed, and executive function (all ps < 0.0125). Additionally, compared with HCs, the ILA patients had lower functional connectivity (i.e., EC values) in the medial parts of default-mode network (i.e., bilateral posterior cingulate gyrus and ventral medial prefrontal cortex [vMPFC]). Intriguingly, the functional connectivity strength at the right vMPFC was positively correlated with executive function deficit in the ILA patients. CONCLUSION: The findings suggested disorganization of the hierarchy of the default-mode regions within the whole-brain network in patients with ILA and advanced our understanding of the neurobiological mechanism underlying executive function deficit in ILA.