N6-methyladenine DNA Modification in Glioblastoma.

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N6-mA.

Yet more evidence that non-aqueous myelin lipids can be directly imaged with ultrashort echo time (UTE) MRI on a clinical 3T scanner: a lyophilized red blood cell membrane lipid study.

Direct imaging of semi-solid lipids, such as myelin, is of great interest as a noninvasive biomarker of neurodegenerative diseases. Yet, the short T2 relaxation times of semi-solid lipid protons hamper direct detection through conventional magnetic resonance imaging (MRI) pulse sequences. In this study, we examined whether a three-dimensional ultrashort echo time (3D UTE) sequence can directly acquire signals from membrane lipids. Membrane lipids from red blood cells (RBC) were collected from commercially available blood as a general model of the myelin lipid bilayer and subjected to D2O exchange and freeze-drying for complete water removal. Sufficiently high MR signals were detected with the 3D UTE sequence, which showed an ultrashort T2* of ∼77-271 µs and a short T1 of ∼189 ms for semi-solid RBC membrane lipids. These measurements can guide designing UTE-based sequences for direct in vivo imaging of membrane lipids.

10 W super-wideband ultra-low-intensity-noise single-frequency fiber laser at 1 µm.

A 10 W super-wideband ultra-low-intensity-noise single-frequency fiber laser (SFFL) at 1 µm is experimentally demonstrated, based on dual gain saturation effects from semiconductors and optical fibers, together with an analog-digital hybrid optoelectronic feedback loop. Three intensity-noise-inhibited units synergistically work, which actualizes a connection of effective bandwidth and enhancement of noise-suppressing amplitude. With the cascade action of the semiconductor optical amplifier and optical fiber amplifier, the laser power is remarkably boosted. Eventually, an SFFL with an output power of 10.8 W and a relative intensity noise (RIN) below -150 dB/Hz at the frequency range over 1 Hz is realized. More meaningfully, within the total frequency range of 10 Hz to 10 GHz exceeding 29 octaves, the RIN is controlled to below -160 dB/Hz, approaching the shot-noise limit (SNL) level. To the best of our knowledge, this is the lowest RIN result of SFFL within such an extensive frequency range, and this is the highest output power of the near-SNL super-wideband SFFL. Furthermore, a linewidth of less than 0.8 kHz, a long-term stable polarization extinction ratio of 20 dB, and an optical signal-to-noise ratio of over 60 dB are obtained simultaneously. This start-of-the-art SFFL has provided a systematic solution for high-power and low-noise light sources, which is competitive for sophisticated applications, such as free-space laser communication, space-based gravitational wave detection, and super-long-distance space coherent velocity measurement and ranging.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Frequency-stabilized improvement of saturated absorption spectroscopy based on laser linewidth-control strategy.

Single-frequency fiber lasers (SFFLs), 1083 nm, have been extensively applied in 4He optical pumping magnetometers (OPMs) for magnetic field detection. However, the sensitivity and accuracy of OPMs are constrained by the frequency stability of SFFLs. Focusing on this concern, the frequency-stabilized performance of the 1083 nm SFFLs is successfully improved by externally tailoring the laser linewidth to match the spectral width of the error signal in saturated absorption spectroscopy. Thereinto, a high-intensity error signal of saturated absorption is generated as a large number of 4He atoms with a wide range of velocities interacting with the 1083 nm laser. Consequently, the root mean square value of the fluctuating frequency after locking is effectively decreased from 24.6 to 13.6 kHz, which achieves a performance improvement of 44.7%. Such a strategy can provide a technical underpinning for effectuating an absolute frequency stabilization with higher precision based on atomic and molecular absorption spectroscopy techniques.

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

A study on pulmonary function in children with obstructive sleep apnea hypopnea syndrome.

OBJECTIVE: To investigate the pulmonary function of children with obstructive sleep apnea syndrome. METHODS: A total of 328 children aged 3 to 12 years old who were evaluated for a sleep disorder from January 2022 to June 2023 were selected as the observation group, classified into mild, moderate, and severe categories based on the apnea hypopnea index. The number of children with mild, moderate, and severe obstructive sleep apnea is 228, 62, and 28 respectively. Additionally, 126 healthy individuals aged 3 to 13 years old undergoing health examinations during the same period were selected as the control group. All subjects underwent sleep respiratory monitoring, pulmonary function tests, and impulse oscillometry. Comparative analysis was performed on pulmonary function indices (forced vital capacity, maximum ventilation, inspiratory capacity, total lung capacity, and inspiratory reserve volume), and respiratory impedance indices (resonant frequency, total respiratory impedance, viscous resistance at 5 Hz, 20 Hz, and 35 Hz). Pulmonary function indices were also compared among patients in the observation group with mild, moderate, and severe conditions. RESULTS: In the observation group, the FVC pre% of patients decreased by 10.5 ± 5.99 compared to the control group. The MVV of the control group decreased by 28.10 ± 2.22 compared to patients in the observation group. The IC of the control group decreased by 0.68 ± 0.44 compared to patients in the observation group. The TLC of the control group decreased by 1.354 ± 0.51 compared to patients in the observation group. The ERV of the control group decreased by 0.53 ± 0.30 compared to patients in the observation group. Additionally, the Fres, Zrs, R5, R20, and R35 of the observation group were higher than those of the control group by 10.73 ± 0.18, 1.78 ± 0.24, 0.11 ± 0.17, 0.86 ± 0.13, and 0.02 ± 0.21, respectively. In sum, the pulmonary function indices of the observation group were significantly lower than those of the control group, while the respiratory impedance indices were higher (P < 0.05). Within the observation group, the pulmonary function indices of severe patients were lower than those of moderate and mild patients, and moderate patients had lower pulmonary function indices than mild patients (P < 0.05). CONCLUSION: The pulmonary function of children with obstructive sleep apnea syndrome is impaired and varies in severity. There are significant differences in pulmonary function, underscoring the importance of monitoring pulmonary function in these children for clinical assessment and treatment prognosis.

Rapamycin facilitates healing of the tendon-bone interface in an aging rat model of chronic rotator cuff injury.

BACKGROUND: Tendon-bone interface (TBI) healing in chronic rotator cuff injury (CRCI) in older individuals is a common clinical challenge due to cellular senescence, as well as decreased tissue repair and regeneration. Many studies have demonstrated the antiaging, improved tissue repair, and bone regeneration properties of rapamycin (RPM) in multiple age-related diseases. This study aimed to explore the effects of RPM on TBI healing after CRCI in an aging rat model. METHODS: A CRCI model was established in 60 Sprague-Dawley rats (24 months old). Rats were then randomly allocated into the control, 0.1 µg RPM, and 1 µg RPM groups. At 4 and 8 weeks postreconstructive surgery, the supraspinatus tendon-humerus complexes were harvested for biomechanical, microimaging, histological, and immunohistochemical evaluations. RESULTS: Biomechanical testing results demonstrated that the failure load, ultimate strength, and stiffness of the 2 RPM groups were significantly higher than those of the control group at 4 and 8 weeks postoperatively. Microradiographically, both RPM groups had significantly higher values of bone mineral density and the ratio of trabecular bone volume to total volume than controls at each time point. Moreover, the RPM groups had higher histological scores and showed better regenerated TBI, characterized by better organizational tissue, more fibrocartilage cells, and more bone formation. Immunohistochemical evaluations showed that RUNX2-, SOX9-, and SCX-positive cells were significantly more in the 2 RPM groups than in the controls at each time point. CONCLUSIONS: RPM may effectively enhance CRCI healing after reconstruction by facilitating osteogenesis, tenogenesis, and fibrocartilage reformation at the TBI, as well as improving biomechanical properties.

Cast versus Kirschner wire fixation in type II paediatric phalangeal neck fractures.

PURPOSE: To compare the outcomes of type II pediatric phalangeal neck fractures (PPNFs) treated with closed reduction and cast immobilization (CRCI) versus closed reduction percutaneous pinning (CRPP), and evaluated the clinical efficacy of conservative versus surgical treatment of type II PPNFs via meta-analysis. METHODS: Patients aged ≤ 14 years with type II PPNFs were divided into conservative (CRCI) and operative (CRPP) groups. Radiographs measured angulation and translation; hand function was assessed with total active range of motion (TAM) and Quick-DASH. Complication rates were also compared between the groups. A meta-analysis of conservative versus operative treatment confirmed the clinical results. Statistical analysis was performed using SPSS 26.0 and R studio 3.0 with two-tailed, chi-squared, and Mann-Whitney U or t-tests, P < 0.05. Meta-analysis used fixed or random effects models, calculating mean differences and odds ratios for outcomes, and assessing heterogeneity with I2 and Q tests. RESULTS: Final angulation (3.4° ± 3.7° and 4.9° ± 5.4° vs. 3.6° ± 3.7° and 4.2° ± 4.3°) and displacement (6.3% ± 5.8% and 5.7% ± 4.7% vs. 5.8% ± 5.5% and 3.2% ± 4.2%) in the coronal and sagittal planes were not different statistically between the conservative and surgical groups (P > 0.05), but improved significantly compared to preoperative values (P < 0.05). Although Quick-DASH scores were comparable in both groups (P = 0.105), conservatively treated patients had a significantly better TAM at the last follow-up visit (P = 0.005). The complication rates were 24.2% and 41.7% in the surgical and conservatively treated groups respectively (P = 0.162). However, the latter primarily experienced imaging-related complications, whereas the former experienced functional complications (P = 0.046). Our meta-analysis (n = 181 patients) also showed comparable functional (P = 0.49) and radiographic (P = 0.59) outcomes and complication rates (P = 0.21) between the surgical (94 patients) and conservative (87 patients) groups. CONCLUSIONS: Conservative and surgical treatments are both reliable and safe approaches for managing type II PPNF in children. However, conservatively treated patients generally experience similar radiographic outcomes, lower complication rates, and better functional outcomes than surgically treated ones.

Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach.

E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of Vss in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (Cmax) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.

[FeIIICl(TMPPH2)][FeIIICl4]2: A Stand-Alone Molecular Nanomedicine That Induces High Cytotoxicity by Ferroptosis.

Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [FeIIICl(TMPPH2)][FeIIICl4]2 (Fe-TMPP) exhibits a superior anticancer performance on a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC50) values in the range of 0.098-3.97 µM (0.066-2.68 µg mL-1), comparable to the best-reported medicines. Fe-TMPP can form stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H2O2, converting H2O2 to the cytotoxic •OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.

[Experimental study on improvement of cognitive impairment in Alzheimer's disease by different degrees of steaming and sunning of Polygoni Multiflori Radix based on fecal metabolomics].

The fecal metabolomics method was employed to investigate the cognitive improvement mechanism of Polygoni Multiflori Radix in Alzheimer's disease(AD) and examine the effects of different degrees of steaming and sunning on cognitive function in AD model mice. Additionally, the processing principle of Polygoni Multiflori Radix was discussed. Forty-eight 5-month-old APP/PS1 mice were randomly assigned to the following groups: model group, positive group, raw product group, three-steaming and three-sunning product group, six-steaming and six-sunning product group, and nine-steaming and nine-sunning product group. Seven negative control mice from the same litter were included as the blank group. After 150 days of intragastric administration, the learning and memory abilities of mice in each group were assessed by using the Barnes maze and dark avoidance tests. Fecal samples were collected for extensive targeted metabolomics testing. Principal component analysis(PCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and other multivariate statistical methods were utilized to analyze metabolites in mouse feces. Comparison of behavioral results between the model group and different product groups demonstrated that the six-steaming and six-sunning product group exhibited significantly reduced latency in the Barnes maze positioning and navigation test(P<0.05), as well as a notable decrease in the number of errors in the space exploration experiment(P<0.05). Moreover, the latency of mice entering the dark box for the first time in the dark avoidance experiment was significantly prolonged(P<0.05), indicating the best overall improvement in the learning and memory ability of AD model mice. Metabolomics results revealed that compared with the model group, the differential metabolites in other groups in descending order were as follows: six-steaming and six-sunning product group > nine-steaming and nine-sunning product group > raw product group > three-steaming and three-sunning product group, encompassing 146, 120, 95, and 81 potential biomarkers, respectively. Among them, 16 differential metabolites were related to AD disease. Further comparisons based on the degree of processing indicated that the six-steaming and six-sunning product group exhibited the most significant adjustments in total metabolic pathways, particularly regulating the interconversion of pentose and glucuronic acid, as well as amino acid anabolism and other pathways. In summary, the mechanism of Polygoni Multiflori Radix after processing in enhancing the learning and memory ability of APP/PS1 mice may be associated with improved amino acid metabolism and increased energy metabolism in the body. The six-steaming and six-sunning yielded the best outcomes.

Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial macrophages.

BACKGROUND: Disruption of N6 methyl adenosine (m6A) modulation hampers gene expression and cellular functions, leading to various illnesses. However, the role of m6A modification in osteoarthritis (OA) synovitis remains unclear. This study aimed to explore the expression patterns of m6A regulators in OA synovial cell clusters and identify key m6A regulators that mediate synovial macrophage phenotypes. METHODS: The expression patterns of m6A regulators in the OA synovium were illustrated by analyzing bulk RNA-seq data. Next, we built an OA LASSO-Cox regression prediction model to identify the core m6A regulators. Potential target genes of these m6A regulators were identified by analyzing data from the RM2target database. A molecular functional network based on core m6A regulators and their target genes was constructed using the STRING database. Single-cell RNA-seq data were collected to verify the effects of m6A regulators on synovial cell clusters. Conjoint analyses of bulk and single-cell RNA-seq data were performed to validate the correlation between m6A regulators, synovial clusters, and disease conditions. After IGF2BP3 was screened as a potential modulator in OA macrophages, the IGF2BP3 expression level was tested in OA synovium and macrophages, and its functions were further tested by overexpression and knockdown in vitro. RESULTS: OA synovium showed aberrant expression patterns of m6A regulators. Based on these regulators, we constructed a well-fitting OA prediction model comprising six factors (FTO, YTHDC1, METTL5, IGF2BP3, ZC3H13, and HNRNPC). The functional network indicated that these factors were closely associated with OA synovial phenotypic alterations. Among these regulators, the m6A reader IGF2BP3 was identified as a potential macrophage mediator. Finally, IGF2BP3 upregulation was verified in the OA synovium, which promoted macrophage M1 polarization and inflammation. CONCLUSIONS: Our findings revealed the functions of m6A regulators in OA synovium and highlighted the association between IGF2BP3 and enhanced M1 polarization and inflammation in OA macrophages, providing novel molecular targets for OA diagnosis and treatment.

Cerebellar connectome alterations and associated genetic signatures in multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND: The cerebellum plays key roles in the pathology of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but the way in which these conditions affect how the cerebellum communicates with the rest of the brain (its connectome) and associated genetic correlates remains largely unknown. METHODS: Combining multimodal MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls and brain-wide transcriptional data, this study characterized convergent and divergent alterations in within-cerebellar and cerebello-cerebral morphological and functional connectivity in MS and NMOSD, and further explored the association between the connectivity alterations and gene expression profiles. RESULTS: Despite numerous common alterations in the two conditions, diagnosis-specific increases in cerebellar morphological connectivity were found in MS within the cerebellar secondary motor module, and in NMOSD between cerebellar primary motor module and cerebral motor- and sensory-related areas. Both diseases also exhibited decreased functional connectivity between cerebellar motor modules and cerebral association cortices with MS-specific decreases within cerebellar secondary motor module and NMOSD-specific decreases between cerebellar motor modules and cerebral limbic and default-mode regions. Transcriptional data explained > 37.5% variance of the cerebellar functional alterations in MS with the most correlated genes enriched in signaling and ion transport-related processes and preferentially located in excitatory and inhibitory neurons. For NMOSD, similar results were found but with the most correlated genes also preferentially located in astrocytes and microglia. Finally, we showed that cerebellar connectivity can help distinguish the three groups from each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases. CONCLUSIONS: We demonstrate convergent and divergent cerebellar connectome alterations and associated transcriptomic signatures between MS and NMOSD, providing insight into shared and unique neurobiological mechanisms underlying these two diseases.

Simultaneous achievement of power boost and low-frequency intensity noise suppression in a bidirectional pumping fiber amplifier based on saturated even-distribution gain.

An optimized bidirectional pumping fiber amplifier is demonstrated to achieve low-frequency intensity noise suppression and effective power enhancement simultaneously. Based on the concept analysis of the gain saturation effect, the influence of input signal power and pump power on intensity noise suppression is investigated and optimized systematically. Further combining with the optimization of the pumping configuration to achieve the even-distribution gain, the relative intensity noise (RIN) of 1083 nm single-frequency fiber laser (SFFL) is suppressed with 9.1 dB in the frequency range below 10 kHz. Additionally, the laser power is boosted from 10.97 dBm to 25.02 dBm, and a power instability of ±0.31% is realized. This technology has contributed to simultaneously improving the power and noise performance of the 1083 nm SFFL, which can be applied to a multi-channel helium (He) optically pumping magnetometer. Furthermore, this technique has broken the mindset that power amplification of the conventional fiber amplifiers will inevitably cause the degradation of intensity noise property, and provided a valuable guidance for the development of high-performance SFFLs.

Wideband ultra-low intensity noise reduction via joint action of gain saturation and out-of-phase polarization mixing effect from a semiconductor optical amplifier.

In this article, the vector dynamics of semiconductor optical amplifiers (SOAs) are systematically analyzed and developed to explore its mechanism of intensity noise suppression. First, theoretical investigation on the gain saturation effect and carrier dynamics is performed via a vectorial model, and the calculated result unravels desynchronized intensity fluctuations of two orthogonal polarization states. Particularly, it predicts an out-of-phase case, which allows the cancellation of the fluctuations via adding up the orthogonally-polarized components, then establishes a synthetic optical field with stable amplitude and dynamic polarization, and thereby enables a remarkable relative intensity noise (RIN) reduction. Here, we term this approach of RIN suppression as out-of-phase polarization mixing (OPM). To validate the OPM mechanism, we conduct an SOA-mediated noise-suppression experiment based on a reliable single-frequency fiber laser (SFFL) with the presence of relaxation oscillation peak, and subsequently carry out a polarization resolvable measurement. By this means, out-of-phase intensity oscillations with respect to the orthogonal polarization states are clearly demonstrated, and consequently enable a maximum suppression amplitude of >75 dB. Notably, the RIN of 1550-nm SFFL, suppressed by joint action of OPM and gain saturation effect, is dramatically reduced to -160 dB/Hz in a wideband of 0.5 MHz∼10 GHz, and the performance of which is excellent by comparing with the corresponding shot noise limit of -161.9 dB/Hz. The proposal of OPM here not only facilitates us to dissect the vector dynamics of SOA but also offers a promising solution to realize wideband near-shot-noise-limited SFFL.

Ultrafine electro-optical frequency comb based on cascade phase modulation with cyclic frequency shifting.

An ultrafine electro-optical frequency comb (EOFC) with plentiful comb teeth is demonstrated. Adopting a single-frequency fiber laser as a light source, cascade phase modulation based on a sinusoidal signal and a frequency-time transformation (FTT) signal is executed to generate the EOFC with high fineness. Meanwhile, a cyclic fast frequency shifting strategy is introduced to boost the number of comb teeth and the bandwidth of the EOFC. As a result, an EOFC with 12600 comb lines covering a broad bandwidth from -6.3 GHz to 6.3 GHz is established, corresponding to an ultrafine comb space of 1 MHz. Moreover, the power fluctuation of a comb tooth is less than 0.5 dBm. This state-of-the-art EOFC has significant potential in the field of precision spectroscopy.

Brain age gap in neuromyelitis optica spectrum disorders and multiple sclerosis.

OBJECTIVE: To evaluate the clinical significance of deep learning-derived brain age prediction in neuromyelitis optica spectrum disorder (NMOSD) relative to relapsing-remitting multiple sclerosis (RRMS). METHODS: This cohort study used data retrospectively collected from 6 tertiary neurological centres in China between 2009 and 2018. In total, 199 patients with NMOSD and 200 patients with RRMS were studied alongside 269 healthy controls. Clinical follow-up was available in 85 patients with NMOSD and 124 patients with RRMS (mean duration NMOSD=5.8±1.9 (1.9-9.9) years, RRMS=5.2±1.7 (1.5-9.2) years). Deep learning was used to learn 'brain age' from MRI scans in the healthy controls and estimate the brain age gap (BAG) in patients. RESULTS: A significantly higher BAG was found in the NMOSD (5.4±8.2 years) and RRMS (13.0±14.7 years) groups compared with healthy controls. A higher baseline disability score and advanced brain volume loss were associated with increased BAG in both patient groups. A longer disease duration was associated with increased BAG in RRMS. BAG significantly predicted Expanded Disability Status Scale worsening in patients with NMOSD and RRMS. CONCLUSIONS: There is a clear BAG in NMOSD, although smaller than in RRMS. The BAG is a clinically relevant MRI marker in NMOSD and RRMS.

The relationship between homocysteine and cardiopulmonary exercise testing in patients with acute coronary syndrome after percutaneous coronary intervention.

OBJECTIVE: The purpose of this study was to investigate the relationship between homocysteine (Hcy) levels and cardiopulmonary exercise testing (CPET) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). We also explored the relationship between Hcy levels and cardiac ultrasonography. METHODS: This study comprised 261 patients with ACS who underwent coronary angiography and PCI at Yulin First Hospital from January 2020 to June 2021. All subjects completed basic data collection, laboratory examination, CPET and cardiac ultrasonography. The CPET includes the peak oxygen uptake (peak VO2), anaerobic threshold (AT), metabolic equivalents (METs), exercise load (load), oxygen pulse (O2 pulse), end-tidal CO2 partial pressure (PETCO2), ventilatory equivalents for carbon dioxide (VE/VCO2) and Oxygen uptake efficiency (OUES). Cardiac ultrasonography was used to evaluate the left ventricular end diastolic diameter (LVEDD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT) and left ventricular ejection fraction (LVEF). A serum Hcy level ≥ 15 µmol/L was defined as hyperhomocysteinemia (HHcy). The patients were divided into the Hcy < 15 µmol/L group (n = 189) and the Hcy ≥ 15 µmol/L group (n = 72). RESULTS: The average age of the participating patients was 58.9 ± 10.1 years. The majority of participants were male (86.6%). The CPET indices of METs, load, VO2/kg, and PETCO2 were significantly decreased in the Hcy ≥ 15 µmol/L group compared with the Hcy < 15 µmol/L group. Additionally, the CPET index of the VE/VCO2 slope and the cardiac ultrasonography indices of IVST and LVPWT were significantly increased in the Hcy ≥ 15 µmol/L group compared with the Hcy < 15 µmol/L group. These differences were statistically significant (P < 0.05). Correlation analysis showed that Hcy levels were negatively correlated with METs, VO2/kg and PETCO2 and positively correlated with the VE/VCO2 slope (P < 0.05). Partial correlation analysis showed that Hcy levels were negatively correlated with METs and VO2/kg in the AT state. The correlation coefficients were - 0.172 and - 0.172, respectively (P < 0.05). Hcy levels were negatively correlated with METs, VO2/kg and PETCO2 in the peak state. The correlation coefficients were - 0.177, -0.153 and - 0.129, respectively (P < 0.05). After further adjustment for confounders, multiple linear regression analysis showed that Hcy levels were negatively correlated with METs and VO2/kg in the AT state and peak state. The standardized regression coefficients were - 0.035, -0.122, -0.048 and - 0.128, respectively (P < 0.05). Correlation analysis showed that Hcy levels were positively correlated with the IVST and LVPWT (P < 0.05), but after adjusting for confounding factors, partial correlation analysis showed that there was no correlation between them. CONCLUSION: A high Hcy level is associated with lower METs and VO2/kg and worse cardiopulmonary function in patients with ACS after PCI.

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ß-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.