ADAR1 promotes cisplatin resistance in intrahepatic cholangiocarcinoma by regulating BRCA2 expression through A-to-I editing manner.

Aberrant A-to-I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A-to-I editing in BRCA2 3'UTR, inhibiting miR-3157-5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.

Sequence characteristics, genetic diversity and phylogenetic analysis of the Cucurbita ficifolia (Cucurbitaceae) chloroplasts genome.

BACKGROUND: Curcubita ficifolia Bouché (Cucurbitaceae) has high value as a food crop and medicinal plant, and also has horticultural value as rootstock for other melon species. China is home to many different cultivars, but the genetic diversity of these resources and the evolutionary relationships among them, as well as the differences between C. ficifolia and other Cucurbita species, remain unclear. RESULTS: We investigated the chloroplast (cp) genomes of 160 C. ficifolia individuals from 31 populations in Yunnan, a major C. ficifolia production area in China. We found that the cp genome of C. ficifolia is ~151 kb and contains 128 genes, of which 86 are protein coding genes, 34 encode tRNA, and eight encode rRNAs. We also identified 64 SSRs, mainly AT repeats. The cp genome was found to contain a total of 204 SNP and 57 indels, and a total of 21 haplotypes were found in the 160 study individuals. The reverse repeat (IR) region of C. ficifolia contained a few differences compared with this region in the six other Cucurbita species. Sequence difference analysis demonstrated that most of the variable regions were concentrated in the single copy (SC) region. Moreover, the sequences of the coding regions were found to be more similar among species than those of the non-coding regions. The phylogenies reconstructed from the cp genomes of 61 representative species of Cucurbitaceae reflected the currently accepted classification, in which C. ficifolia is sister to the other Cucurbita species, however, different interspecific relationships were found between Cucurbita species. CONCLUSIONS: These results will be valuable in the classification of C. ficifolia genetic resources and will contribute to our understanding of evolutionary relationships within the genus Cucurbita.

Pyramidal and parvalbumin neurons modulate the process of electroacupuncture stimulation for stroke rehabilitation.

Electroacupuncture (EA) stimulation has been shown to be beneficial in stroke rehabilitation; however, little is known about the neurological mechanism by which this peripheral stimulation approach treats for stroke. This study showed that both pyramidal and parvalbumin (PV) neuronal activity increased in the contralesional primary motor cortex forelimb motor area (M1FL) after ischemic stroke induced by focal unilateral occlusion in the M1FL. EA stimulation reduced pyramidal neuronal activity and increased PV neuronal activity. These results were obtained by a combination of fiber photometry recordings, in vivo and in vitro electrophysiological recordings, and immunofluorescence. Moreover, EA was found to regulate the expression/function of N-methyl-D-aspartate receptors (NMDARs) altered by stroke pathology. In summary, our findings suggest that EA could restore disturbed neuronal activity through the regulation of the activity of pyramidal and PV neurons. Furthermore, NMDARs we shown to play an important role in EA-mediated improvements in sensorimotor ability during stroke rehabilitation.

Factors affecting local alveolar bone thickness in unilateral maxillary canine-lateral incisor transposition.

INTRODUCTION: This study aimed to use 3-dimensional data to investigate the factors affecting local alveolar bone thickness in unilateral maxillary canine-lateral incisor transposition. METHODS: Pretreatment cone-beam computed tomography data of 34 patients with unilateral maxillary canine-lateral transposition were imported into Dolphin Imaging software (version 11.8; Dolphin Imaging and Management Solutions, Chatsworth, Calif) for 3-dimensional reconstruction. The age, gender, and type of transposition at the beginning of treatment were recorded. The thickness and height of the transposed canine, the labiopalatal and distomedial distance from the transposed canine to the apex of the lateral incisor, the inclination of the transposed lateral incisor, the apical height of the lateral incisor, and the alveolar bone thickness in the apical plane were measured. Multiple linear regression analyses were applied to investigate the factors affecting alveolar bone thickness in the apical plane of the transposed lateral incisor. Two sample t test were applied to assess the difference of alveolar bone thickness in patients of different ages. RESULTS: The 10 boys and 24 girls had a mean age of 12.26 ± 2.34 years. In all 34 participants, the apical alveolar bone thickness of transposed lateral incisors was significantly higher than that of the unaffected side (P <0.05). Based on multiple regression analyses, factors associated with a wider alveolar bone thickness were as follows: age (ß = -0.237; P = 0.008), the labiopalatal distance from the transposed canine to the apex of the lateral incisor (ß = 0.675; P <0.001), and the inclination of the transposed lateral incisor (ß = 0.048; P = 0.032). Patients aged <11 years had significantly thicker alveolar bone than that of patients aged >11 years (P <0.05). CONCLUSIONS: Patients with younger age, greater lateral incisor inclination, and greater labiopalatal distance between canine and lateral incisor had more alveolar bone thickness. Early treatment permits tooth movement within the thicker alveolar bone.

Cortical activity in patients with high-functioning ischemic stroke during the Purdue Pegboard Test: insights into bimanual coordinated fine motor skills with functional near-infrared spectroscopy.

After stroke, even high-functioning individuals may experience compromised bimanual coordination and fine motor dexterity, leading to reduced functional independence. Bilateral arm training has been proposed as a promising intervention to address these deficits. However, the neural basis of the impairment of functional fine motor skills and their relationship to bimanual coordination performance in stroke patients remains unclear, limiting the development of more targeted interventions. To address this gap, our study employed functional near-infrared spectroscopy to investigate cortical responses in patients after stroke as they perform functional tasks that engage fine motor control and coordination. Twenty-four high-functioning patients with ischemic stroke (7 women, 17 men; mean age 64.75 ± 10.84 years) participated in this cross-sectional observational study and completed four subtasks from the Purdue Pegboard Test, which measures unimanual and bimanual finger and hand dexterity. We found significant bilateral activation of the sensorimotor cortices during all Purdue Pegboard Test subtasks, with bimanual tasks inducing higher cortical activation than the assembly subtask. Importantly, patients with better bimanual coordination exhibited lower cortical activation during the other three Purdue Pegboard Test subtasks. Notably, the observed neural response patterns varied depending on the specific subtask. In the unaffected hand task, the differences were primarily observed in the ipsilesional hemisphere. In contrast, the bilateral sensorimotor cortices and the contralesional hemisphere played a more prominent role in the bimanual task and assembly task, respectively. While significant correlations were found between cortical activation and unimanual tasks, no significant correlations were observed with bimanual tasks. This study provides insights into the neural basis of bimanual coordination and fine motor skills in high-functioning patients after stroke, highlighting task-dependent neural responses. The findings also suggest that patients who exhibit better bimanual performance demonstrate more efficient cortical activation. Therefore, incorporating bilateral arm training in post-stroke rehabilitation is important for better outcomes. The combination of functional near-infrared spectroscopy with functional motor paradigms is valuable for assessing skills and developing targeted interventions in stroke rehabilitation.

Isovitexin alleviates hepatic fibrosis by regulating miR-21-mediated PI3K/Akt signaling and glutathione metabolic pathway: based on transcriptomics and metabolomics.

BACKGROUND: Effective drugs for the treatment of hepatic fibrosis have not yet been identified. Isovitexin (IVT) is a promising hepatoprotective agent owing to its efficacy against acute liver injury. However, the role of IVT in liver fibrosis has not been reported. PURPOSE: To explore the effect of IVT on liver fibrosis both in vitro and in vivo. STUDY DESIGN AND METHODS: A mouse model of liver fibrosis induced by carbon tetrachloride (CCl4) and two types of hepatic stellate cell models induced by platelet-derived growth factor-BB (PDGF-BB) were established to evaluate the effect of IVT on hepatic fibrosis. Transcriptomics and metabolomics were used to predict the underlying targets of IVT and were validated by a combination of in vitro and in vivo experiments. Exploration of miRNA and N6-methyladenosine (m6A) modifications was also carried out to detect the key upstream targets of the above targets. RESULTS: IVT reduced collagen deposition and hepatic stellate cell activation to alleviate liver fibrosis. The transcriptomics and metabolomics analyses showed that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling and the glutathione (GSH) metabolic pathway may be the main regulatory processes of IVT in hepatic fibrosis. Both the in vitro and in vivo experiments confirmed the inhibitory effect of IVT on the PTEN-PI3K-Akt-mTOR axis and activation of the GSH metabolic pathway. A miR-21 mimic inhibited the effects of IVT on these two pathways, suggesting that miR-21 is the hub for IVT regulation of PI3K-Akt signaling and the GSH metabolic pathway. IVT also increased pri-miR-21 level and reduced the m6A enrichment of pri-miR-21, demonstrating that IVT may regulate pri-miR-21 through m6A modification, thereby affecting the maturation of miR-21. CONCLUSION: This study is the first to propose a protective effect of IVT against liver fibrosis. The mechanism of IVT against hepatic fibrosis is based on the regulation of miR-21, targeting PTEN-Akt signaling and the GSH metabolic pathway, which is also a novel discovery.

Effect of smoking on thrombotic antiphospholipid syndrome: a 10-year prospective cohort study.

OBJECTIVES: Cigarette smoking is an established risk factor for autoimmune diseases. However, whether smoking plays a clear role in thrombotic antiphospholipid syndrome (TAPS) has not been determined. We aimed to investigate the effects of smoking on clinical characteristics and prognosis of TAPS. METHODS: This was a prospective cohort study from 2013 to 2022. During the study period, 297 patients were diagnosed with TAPS, including 82 smokers and 215 non-smokers. After propensity score matching, 57 smokers and 57 non-smokers matched by age and sex were analysed. RESULTS: Overall, smokers with TAPS had more cardiovascular risk factors (CVRFs) than non-smokers, including hypertension (36.59% vs. 14.42%, P<0.001), obesity (15.85% vs. 7.44%, P=0.029), dyslipidaemia (64.63% vs. 48.37%, P=0.012), and hyperhomocysteinaemia (62.20% vs. 36.28%, P<0.001). Arterial thrombotic events were more common in smokers at diagnosis (62.20% vs. 46.05%, P=0.013), especially myocardial infarction, visceral thrombosis, and peripheral vascular thrombosis. After matching, smokers showed balanced CVRFs with non-smokers at baseline, but retained a higher prevalence of arterial thrombosis (59.65% vs. 33.33%, P=0.005), mainly distributed in cerebral vascular, cardiovascular, and retinal vascular territories. During follow-up, smokers presented a tendency for more recurrent arterial thrombosis and less recurrent venous thrombosis. Smokers had significantly poorer outcomes for organ damage with higher DIAPS (median, 2.00 vs. 1.00, P=0.008), especially in the cardiovascular (26.32% vs. 3.51%, P=0.001), gastrointestinal (15.79% vs. 1.75%, P=0.016), and ophthalmologic (10.53% vs. 00.00%, P=0.027) systems. CONCLUSION: Smoking is related to increased arterial events and poor prognosis in TAPS patients. Patients with TAPS should be fully encouraged to avoid smoking.

Modulated effectiveness of rehabilitation motivation by reward strategies combined with tDCS in stroke: study protocol for a randomized controlled trial.

Background: Stroke survivors often exhibit low motivation for rehabilitation, hindering their ability to effectively complete rehabilitation training task effectively and participate in daily activities actively. Reward strategies have been identified as an effective method for boosting rehabilitation motivation, but their long-term efficacy remains uncertain. Transcranial direct current stimulation (tDCS) has been recognized as a technique that facilitates plastic changes and functional reorganization of cortical areas. Particularly, tDCS can improve the functional connectivity between brain regions associated with goal-directed behavior when applied to the left dorsolateral prefrontal cortex (dlPFC). Combing reward strategies with tDCS (RStDCS) has been shown to motivate healthy individuals to exert more effort in task performance. However, research exploring the combined and sustained effects of these strategies on rehabilitation motivation in stroke survivors is lacking. Methods and design: Eighty-seven stroke survivors with low motivation and upper extremity dysfunction will be randomized to receive either conventional treatment, RS treatment, or RStDCS treatment. The RStDCS group will receive reward strategies combined with anodal tDCS stimulation of the left dlPFC. The RS group will receive reward strategies combined with sham stimulation. The conventional group will receive conventional treatment combined with sham stimulation. tDCS stimulation is performed over 3 weeks of hospitalization, 20 min/time, five times a week. Reward strategies refers to personalized active exercise programs for patients during hospitalization and at home. Patients can voluntarily choose tasks for active exercise and self-report to the therapist so as to punch a card for points and exchange gifts. The conventional group will receive home rehabilitation instructions prior to discharge. Rehabilitation motivation, measured using RMS. RMS, FMA, FIM, and ICF activity and social engagement scale will be compared at baseline, 3 weeks, 6 weeks, and 3 months post-enrollment to evaluate patients' multifaceted health condition based on the ICF framework. Discussion: This study integrates knowledge from social cognitive science, economic behavioral science, and other relevant fields. We utilize straightforward and feasible reward strategies, combined with neuromodulation technology, to jointly improve patients' rehabilitation motivation. Behavioral observations and various assessment tools will be used to monitor patients' rehabilitation motivation and multifaceted health condition according to the ICF framework. The aim is to provide a preliminary exploration path for professionals to develop comprehensive strategies for improving patient rehabilitation motivation and facilitating a complete "hospital-home-society" rehabilitation process. Clinical trial registration: https://www.chictr.org.cn/showproj.aspx?proj=182589, ChiCTR2300069068.

Morphometric evaluation of alveolar bone after orthodontic treatment of multiple impacted teeth in the unilateral maxillary anterior region.

INTRODUCTION: This study aimed to investigate the height and thickness of alveolar bone by cone-beam computed tomography imaging after orthodontic treatment in the unilateral maxillary anterior region and speculate on reasons for the difference in alveolar bone morphology. METHODS: This study selected 11 patients (3 males and 8 females; mean age, 9.42 ± 1.45 years). Cone-beam computed tomography was performed for these 11 patients before and after treatment using Dolphin Imaging software (Dolphin Imaging and Management Solutions, Chatsworth, Calif). Labial and palatal alveolar bone thickness (BT) at root apices and different levels along the roots and loss of alveolar bone height was measured for each impacted tooth and its contralateral homonymous tooth. RESULTS: After orthodontic therapy, all 3 impacted anterior teeth had different degrees of loss of labial alveolar bone height compared with the normal side (central incisor: -1.5 mm, P <0.005; lateral incisor: -1.06 mm, P <0.01; canine: -0.59 mm, P < 0.01). The lateral incisors also showed palatal alveolar bone height loss compared with the unaffected side (-0.8 mm, P <0.005). Alveolar BT at root apices of impacted canines was 1.14 mm thicker than the normal side (P <0.005). Central and lateral incisors were similar to the normal side. The thickness of the alveolar bone at 8, 10, and 12 mm of the impacted canine position was still larger than that on the healthy side, whereas the difference in average thickness between the healthy and affected side had been significantly reduced compared with pretreatment measurements. CONCLUSIONS: There is satisfactory retention of alveolar bone height in canines after orthodontic treatment; however, alveolar bone loss is slightly worse at central and lateral incisors. Retention of alveolar BT was normal for impacted anterior teeth, whereas excess apical alveolar BT at the canines, although still present, was substantially less significant than had been observed before treatment.

Asiatic acid ameliorates rifampicin- and isoniazid-induced liver injury in vivo by regulating sphingolipid metabolism and mitogen-activated protein kinase signalling pathways.

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen-activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4-desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH-induced liver injury.

Broadband spectral combining of three pulse-shaped fiber amplifiers with 42fs compressed pulse duration.

We demonstrate ultra-broadband spectral combining of ultrashort pulses from Yb-doped fiber amplifiers, with coherently spectrally synthesized pulse shaping, to achieve tens-of-fs pulses. This method can fully compensate for gain narrowing and high order dispersion over broad bandwidth. We produce 42fs pulses by spectrally synthesizing three chirped-pulse fiber amplifiers and two programmable pulse shapers across an 80nm overall bandwidth. To the best of our knowledge, this is the shortest pulse duration achieved from a spectrally combined fiber system at one-micron wavelength. This work provides a path toward high-energy, tens-of-fs fiber chirped-pulse amplification systems.

ATM Inhibition-Induced ISG15/IFI27/OASL Is Correlated with Immunotherapy Response and Inflamed Immunophenotype.

Immune checkpoint blockade (ICB) therapy can improve the survival of cancer patients with a high tumor mutation burden (TMB-H) or deficiency in DNA mismatch repair (dMMR) in their tumors. However, most cancer patients without TMB-H and dMMR do not benefit from ICB therapy. The inhibition of ATM can increase DNA damage and activate the interferon response, thus modulating the tumor immune microenvironment (TIME) and the efficacy of ICB therapy. In this study, we showed that ATM inhibition activated interferon signaling and induced interferon-stimulated genes (ISGs) in cisplatin-resistant and parent cancer cells. The ISGs induced by ATM inhibition were correlated with survival in cancer patients who received ICB therapy. In oral cancer, high expressions of ISG15, IFI27, and OASL were associated with low expressions of ATM, the activation of inflamed immune pathways, and increased tumor-infiltrating scores of CD8+ T, natural killer, and dendritic cells. The high expressions of ISG15, IFI27, and OASL were also correlated with complete remission in patients with cervical cancer treated with cisplatin. These results suggest that ATM inhibition can induce the interferon response and inflamed TIME, which may benefit ICB therapy.

One-year myopia control efficacy of cylindrical annular refractive element spectacle lenses.

PURPOSE: To evaluate the 1-year myopia control efficacy of a spectacle lens with annular cylindrical microstructures. METHODS: A total of 118 consecutive eligible children aged 8-12 years with -1.00 D to -4.00 D of spherical component myopia and <1.50 D astigmatism were enrolled between August 2020 and November 2020 at the Eye Hospital of Wenzhou Medical University. Participants were randomly assigned to wear cylindrical annular refractive element (CARE) (n = 61) or single-vision (n = 57) spectacle lenses. Cycloplegic autorefraction (spherical equivalent refraction [SER]) and axial length (AL) were measured at baseline and 6-month intervals. Adaptation and compliance questionnaires were administered during all visits. RESULTS: Among 118 randomized participants, 96 (81.4%) were included in the analyses (mean [SE] age, 10.4 [0.6] years; 49 [51.0%] were female; mean [SE] spherical equivalent refractive error, -2.67 [0.66] D; mean [SE] axial length, 24.75 [0.77] mm). Adjusted 1-year myopia progression was -0.56 D for CARE and -0.71 D for single-vision spectacle lenses. The difference in progression was 0.14 D (95% CI, -0.04 to 0.32) for CARE vs single vision. Adjusted 1-year eye growth was 0.27 mm for CARE and 0.35 mm for single vision. The difference in eye growth was 0.09 mm (95% CI, -0.15 to -0.02) for CARE vs single vision. All groups adapted to their lenses with no reported adverse events, complaints, or discomfort. CONCLUSIONS: Among children with myopia, treatment with cylindrical annular refractive element spectacle lenses significantly reduced the rate of axial elongation over 1 year compared with single-vision spectacle lenses.

A fully-mapped and energy-efficient FPGA accelerator for dual-function AI-based analysis of ECG.

In this paper, a fully-mapped field programmable gate array (FPGA) accelerator is proposed for artificial intelligence (AI)-based analysis of electrocardiogram (ECG). It consists of a fully-mapped 1-D convolutional neural network (CNN) and a fully-mapped heart rate estimator, which constitute a complementary dual-function analysis. The fully-mapped design projects each layer of the 1-D CNN to a hardware module on an Intel Cyclone V FPGA, and a virtual flatten layer is proposed to effectively bridge the feature extraction layers and fully-connected layer. Also, the fully-mapped design maximizes computational parallelism to accelerate CNN inference. For the fully-mapped heart rate estimator, it performs pipelined transformations, self-adaptive threshold calculation, and heartbeat count on the FPGA, without multiplexed usage of hardware resources. Furthermore, heart rate calculation is elaborately analyzed and optimized to remove division and acceleration, resulting in an efficient method suitable for hardware implementation. According to our experiments on 1-D CNN, the accelerator can achieve 43.08× and 8.38× speedup compared with the software implementations on ARM-Cortex A53 quad-core processor and Intel Core i7-8700 CPU, respectively. For the heart rate estimator, the hardware implementations are 25.48× and 1.55× faster than the software implementations on the two aforementioned platforms. Surprisingly, the accelerator achieves an energy efficiency of 63.48 GOPS/W, which obviously surpasses existing studies. Considering its power consumption is only 67.74 mW, it may be more suitable for resource-limited applications, such as wearable and portable devices for ECG monitoring.

Surface astigmatism correction using segmented freeform surfaces for a progressive addition lens.

The undesired distribution of irregular surface astigmatism (SA) on the freeform surface has been the major concern of progressive addition lens (PAL) design. Herein, we proposed a segmented freeform surface (SFS) construction method, which relies on the lines of curvature to rule the surface segmentation and then eliminates the difference between principal curvatures to correct the SA. Based on ray tracing and numerical simulation results, the SFS-PAL design has superior performance in image quality within a dynamic field of view over the conventional freeform PAL. To verify the feasibility and the real performance of the new design, we used the diamond turning method with a fast tool servo to realize the rapid prototyping, and then used injection molding for the mass production of the high-quality SFS-PALs.

Gradually or immediately? The effects of ad type and fresh start mindset on health persuasion.

As a necessary means of encouraging individuals to adopt healthy behaviors, improving the persuasiveness of ads related to health has been a major topic of common concern in both academic and practical circles. However, scant attention has been given to how consumers' fresh start mindset (FSM) may influence the effect of ad types on health persuasion. Based on the construal level theory (CLT), the current research investigates the interplay of ad type (progression ad vs. before/after ad) and FSM (weak vs. strong) on the persuasiveness of health ads and the mechanisms underlying it. Across three studies, we demonstrated that progression ads are more effective when consumers have a weak FSM, whereas a before/after ad will be more persuasive when consumers hold a strong FSM. More importantly, consumers' perceived feasibility and desirability drive the interactive effect of ad type and FSM, such that perceived feasibility mediates the positive effect of progression ads on persuasion among consumers with a weaker FSM, while perceived desirability mediates the positive effect of before/after ads on persuasion among consumers with a stronger FSM. Our findings extend the existing literature streams on the fresh start effect, message persuasion, and construal level theory and provide practical insights for health product manufacturers and policymakers concerned about public health.

Study protocol of a randomized controlled trial for the synergizing effects of rTMS and Tui Na on upper limb motor function and cortical activity in ischemic stroke.

Upper limb motor dysfunction after stroke is a serious threat to the living quality of patients and their families. Recovery of upper limb motor function after stroke largely relies on the activation and remodeling of neural circuits. rTMS (repetitive transcranial magnetic stimulation) has been proved to promote the reconstruction of neural synapses and neural circuits. However, there are still a large number of patients who cannot fully recover and leave behind varying degrees of dysfunction. Considering the systemic pathology after stroke, in addition to focal brain injury, stroke can also cause extensive dysfunction of peripheral organs. The rehabilitation strategy for stroke should combine the treatment of primary brain lesions with the intervention of secondary systemic damage. The aim of this trial is to verify the efficacy of rTMS synergize with Tui Na (Chinese Massage) on upper limb motor function after ischemic stroke, and to explore the mechanism of activation and remodeling of sensorimotor neural circuits with functional near-infrared spectroscopy. Ninety patients will be randomly assigned to either rTMS + Tui Na + conventional rehabilitation group (the experimental group) or rTMS + conventional rehabilitation group (the control group) in 1:1 ratio. Intervention is conducted five sessions a week, with a total of twenty sessions. The primary outcome is Fugl-Meyer Assessment, and the secondary outcomes include Muscle Strength, Modified Ashworth Assessment, Modified Barthel Index Assessment, motor evoked potentials and functional near-infrared spectroscopy. There are four time points for the evaluation, including baseline, 2 weeks and 4 weeks after the start of treatment, and 4 weeks after the end of treatment. This study is a randomized controlled trial. This study was approved by Institutional Ethics Committee of Shanghai Third Rehabilitation Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (approval No. SH3RH-2021-EC-012) on December, 16th, 2021. The protocol was registered with Chinese Clinical Trial Registry (ChiCTR2200056266), on February 3th, 2022. Patient recruitment was initiated on February 10th, 2022, and the study will be continued until December 2023.

Multiple Calcium Channel Types with Unique Expression Patterns Mediate Retinal Signaling at Bipolar Cell Ribbon Synapses.

Retinal bipolar cells (BCs) compose the canonical vertical excitatory pathway that conveys photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca2+ influx through voltage-gated Ca2+ (CaV) channels mediating L-type currents, the molecular identity of CaV channels in BCs is uncertain. Therefore, we combined molecular and functional analyses to determine the expression profiles of CaV α1, ß, and α2δ subunits in mouse rod bipolar (RB) cells, BCs from which the dynamics of synaptic transmission are relatively well-characterized. We found significant heterogeneity in CaV subunit expression within the RB population from mice of either sex, and significantly, we discovered that transmission from RB synapses was mediated by Ca2+ influx through P/Q-type (CaV2.1) and N-type (CaV2.2) conductances as well as the previously-described L-type (CaV1) and T-type (CaV3) conductances. Furthermore, we found both CaV1.3 and CaV1.4 proteins located near presynaptic ribbon-type active zones in RB axon terminals, indicating that the L-type conductance is mediated by multiple CaV1 subtypes. Similarly, CaV3 α1, ß, and α2δ subunits also appear to obey a "multisubtype" rule, i.e., we observed a combination of multiple subtypes, rather than a single subtype as previously thought, for each CaV subunit in individual cells.SIGNIFICANCE STATEMENT Bipolar cells (BCs) transmit photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca2+ influx through L-type voltage-gated Ca2+ (CaV) channels, the molecular identity of CaV channels in BCs is uncertain. Here, we report unexpectedly high molecular diversity of CaV subunits in BCs. Transmission from rod bipolar (RB) cell synapses can be mediated by Ca2+ influx through P/Q-type (CaV2.1) and N-type (CaV2.2) conductances as well as the previously-described L-type (CaV1) and T-type (CaV3) conductances. Furthermore, CaV1, CaV3, ß, and α2δ subunits appear to obey a "multisubtype" rule, i.e., a combination of multiple subtypes for each subunit in individual cells, rather than a single subtype as previously thought.

YTHDF2 promotes intrahepatic cholangiocarcinoma progression and desensitises cisplatin treatment by increasing CDKN1B mRNA degradation.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with exceedingly poor prognosis, and chemoresistance is a huge challenge for treatment. N6-methyladenosine (m6 A) modification plays an important role in the progression and chemoresistance of cancers. We aimed to investigate the oncogenic function and therapeutic significance of the m6 A binding protein, YTH domain family 2 (YTHDF2), in ICC progression and cisplatin-based chemotherapy. METHODS: Several independent data sets were used to assess the expression of YTHDF2 in ICC, particularly in chemoresistant ICC. Knockdown and overexpression were used to evaluate the effects of YTHDF2 on tumourigenesis and cisplatin response in ICC. Multi-omics sequencing was performed to identify target genes. RIP, dual luciferase reporter, RNA stability experiment and loss-of-function assays were conducted to study the mechanisms underlying the oncogenic function of YTHDF2. Furthermore, patient-derived xenograft (PDX) model was established to determine the effect of combination treatment of YTHDF2 siRNA and cisplatin in ICC. RESULTS: Our study showed that YTHDF2 was upregulated in ICC tissues, particularly in chemoresistant ICC tissues, and correlated with poor prognosis. Furthermore, silencing YTHDF2 led to inhibited proliferation, promoted apoptosis and G0/G1 cell cycle arrest. Its downregulation also enhanced DNA damage and sensitised ICC cells to cisplatin. YTHDF2 overexpression exerted the opposite results. Integration analysis using RNA-seq, MeRIP-seq and anti-YTHDF2 RIP-seq elucidated the role of YTHDF2 in tumourigenesis and cisplatin-desensitising function by promoting the degradation of cyclin-dependent kinase inhibitor 1B (CDKN1B) mRNA in an m6 A-dependent manner. Downregulation of CDKN1B increased the YTHDF2 silencing-induced influence on tumourigenesis and cisplatin response to ICC. In addition, the combination treatment of YTHDF2 siRNA and cisplatin significantly enhanced the anti-tumour effect of cisplatin in a chemoresistant ICC PDX model. CONCLUSIONS: YTHDF2 exhibits tumour oncogenic and cisplatin-desensitising properties, which may offer insight into the development of novel combination therapeutic strategies for ICC.

Effectiveness and Success Factors of Bilateral Arm Training After Stroke: A Systematic Review and Meta-Analysis.

Bilateral arm training (BAT) presents as a promising approach in upper extremity (UE) rehabilitation after a stroke as it may facilitate neuroplasticity. However, the effectiveness of BAT is inconclusive, and no systematic reviews and meta-analyses have investigated the impact of different factors on the outcomes of BAT. This systematic review and meta-analysis aimed to (1) compare the effects of bilateral arm training (BAT) with unilateral arm training (UAT) and conventional therapy (CT) on the upper limb (UL) motor impairments and functional performance post-stroke, and (2) investigate the different contributing factors that may influence the success of BAT. A comprehensive literature search was performed in five databases. Randomized control trials (RCTs) that met inclusion criteria were selected and assessed for methodological qualities. Data relating to outcome measures, characteristics of participants (stroke chronicity and severity), and features of intervention (type of BAT and dose) were extracted for meta-analysis. With 25 RCTs meeting the inclusion criteria, BAT demonstrated significantly greater improvements in motor impairments as measured by Fugl-Meyer Assessment of Upper Extremity (FMA-UE) than CT (MD = 3.94, p = < 0.001), but not in functional performance as measured by the pooled outcomes of Action Research Arm Test (ARAT), Box and Block Test (BBT), and the time component of Motor Function Test (WMFT-time) (SMD = 0.28, p = 0.313). The superior motor impairment effects of BAT were associated with recruiting mildly impaired individuals in the chronic phase of stroke (MD = 6.71, p < 0.001), and applying a higher dose of intervention (MD = 6.52, p < 0.001). Subgroup analysis showed that bilateral functional task training (BFTT) improves both motor impairments (MD = 7.84, p < 0.001) and functional performance (SMD = 1.02, p = 0.049). No significant differences were detected between BAT and UAT for motor impairment (MD = -0.90, p = 0.681) or functional performance (SMD = -0.09, p = 0.457). Thus, our meta-analysis indicates that BAT may be more beneficial than CT in addressing post-stroke UL motor impairment, particularly in the chronic phase with mild UL paresis. The success of BAT may be dose-dependent, and higher doses of intervention may be required. BFTT appears to be a valuable form of BAT that could be integrated into stroke rehabilitation programs. BAT and UAT are generally equivalent in improving UL motor impairments and functional performance.