SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay.

SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.

Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target.

RNA-binding proteins can regulate nucleotide metabolism and gene expression. UPF3B regulator of nonsense mediated mRNA decay (UPF3B) exhibits dysfunction in cancers. However, its role in the progression of hepatocellular carcinoma (HCC) is still insufficiently understood. Here, we found that UPF3B was markedly upregulated in HCC samples and associated with adverse prognosis in patients. UPF3B dramatically promoted HCC growth both in vivo and in vitro. Mechanistically, UPF3B was found to bind to PPP2R2C, a regulatory subunit of PP2A, boosting its mRNA degradation and activating the PI3K/AKT/mTOR pathway. E2F transcription factor 6 (E2F6) directly binds to the UPF3B promoter to facilitate its transcription. Together, the E2F6/UPF3B/PPP2R2C axis promotes HCC growth through the PI3K/AKT/mTOR pathway. Hence, it could be a promising therapeutic target for treating HCC.

Molecular design, construction and analgesic mechanism insights into the novel transdermal fusion peptide ANTP-BgNPB.

Toad venom, a traditional Chinese medicine, exhibits remarkable medicinal properties of significant therapeutic value. The peptides present within toad venom possess a wide range of biological functions, yet the neuropeptide B (NPB) and it modification requires further exploration to comprehensively understand its mechanisms of action and potential applications. In this study, a fusion peptide, ANTP-BgNPB, was designed to possess better analgesic properties through the transdermal modification of BgNPB. After optimizing the conditions, the expression of ANTP-BgNPB was successfully induced. The molecular dynamics simulations suggested that the modified protein exhibited improved stability and receptor binding affinity compared to its unmodified form. The analysis of the active site of ANTP-BgNPB and the verification of mutants revealed that GLN3, SER38, and ARG42 were crucial for the protein's recognition and binding with G protein-coupled receptor 7 (GPR7). Moreover, experiments conducted on mice using the hot plate and acetic acid twist body models demonstrated that ANTP-BgNPB was effective in transdermal analgesia. These findings represent significant progress in the development of transdermal delivery medications and could have a significant impact on pain management.

3D-DESS MRI with CAIPIRINHA two- and fourfold acceleration for quantitatively assessing knee cartilage morphology.

OBJECTIVES: This study aimed to assess the diagnostic image quality and compare the knee cartilage segmentation results using a controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA)-accelerated 3D-dual echo steady-state (DESS) research package sequence in the knee. MATERIALS AND METHODS: A total of 64 subjects underwent both two- and fourfold CAIPIRINHA-accelerated 3D-DESS and DESS without parallel acceleration technique of the knee on a 3.0 T system. Two musculoskeletal radiologists evaluated the images independently for image quality and diagnostic capability following randomization and anonymization. The consistency of automatic segmentation results between sequences was explored using an automatic knee cartilage segmentation research application. The descriptive statistics and inter-observer and inter-method concordance of various acceleration sequences were investigated. P values < .05 were considered significant. RESULTS: For image quality evaluation, the image signal-to-noise ratio and contrast-to-noise ratio decreased with the decrease in scanning time. However, it is accompanied by the reduction of artifacts. Using 3D-DESS without parallel acceleration technique as the standard for cartilage grading diagnosisand the diagnostic agreement of two- and fourfold CAIPIRINHA-accelerated 3D-DESS was good, kappa value was 0.860 (P < .001) and 0.804 (p < 0.001), respectively. Regarding cartilage defects, the sensitivity and specificity of the twofold acceleration 3D-CAIPIRINHA-DESS were 95.56% and 97.70%, and the fourfold CAIPIRINHA-accelerated 3D-DESS were 91.49% and 97.65%, respectively. The intraclass correlation coefficients of various sequences in cartilage segmentation were almost all greater than 0.9. CONCLUSION: The CAIPIRINHA-accelerated 3D-DESS sequence maintained comparable diagnostic and segmentations performance of knee cartilage after a 60% scan time reduction.

Exchange-Driven Intermixing of Bulk and Topological Surface States by Chiral Excitons in Bi_{2}Se_{3}.

Topological surface states (TSS) in the prototypical topological insulator (TI) Bi_{2}Se_{3} are frequently characterized using optical probes, but electron-hole interactions and their effect on surface localization and optical response of the TSS remain unexplored. Here, we use ab initio calculations to understand excitonic effects in the bulk and surface of Bi_{2}Se_{3}. We identify multiple series of chiral excitons that exhibit both bulk and TSS character, due to exchange-driven mixing. Our results address fundamental questions about the degree to which electron-hole interactions can relax the topological protection of surface states and dipole selection rules for circularly polarized light in TIs by elucidating the complex intermixture of bulk and surface states excited in optical measurements and their coupling to light.

Multi-echo in steady-state acquisition improves MRI image quality and lumbosacral radiculopathy diagnosis efficacy compared with T2 fast spin-echo sequence.

PURPOSE: This study compares the performance of a 4-min multi-echo in steady-state acquisition (MENSA) with a 6-min fast spin echo with variable flip angle (CUBE) protocol for the assessment of lumbosacral plexus nerve root lesions. METHODS: Seventy-two subjects underwent MENSA and CUBE sequences on a 3.0-T MRI scanner. Two musculoskeletal radiologists independently assessed the images for quality and diagnostic capability. A qualitative assessment scoring system for image quality and quantitative nerve signal-to-noise ratio (SNR) and iliac vein and muscle contrast-to-noise ratios (CNR) was applied. Using surgical reports as the reference, sensitivity, specificity, accuracy, and area under the receiver operating characteristic curves (AUC) were evaluated. Intraclass correlation coefficients (ICC) and weighted kappa were used to calculate reliability. RESULTS: MENSA image quality rating (3.679 ± 0.47) was higher than for CUBE images (3.038 ± 0.68), and MENSA showed higher mean nerve root SNR (36.935 ± 8.33 vs. 27.777 ± 7.41), iliac vein CNR (24.678 ± 6.63 vs. 5.210 ± 3.93), and muscle CNR (19.414 ± 6.07 vs. 13.531 ± 0.65) than CUBE (P < 0.05). Weighted kappa and ICC values indicated good reliability. Sensitivity, specificity, and accuracy of diagnosis based on MENSA images were 96.23%, 89.47%, and 94.44%, respectively, and AUC was 0.929, compared with 92.45%, 84.21%, 90.28%, and 0.883 for CUBE images. The two correlated ROC curves were not significantly different. Weighted kappa values for intraobserver (0.758) and interobserver (0.768-0.818) reliability were substantial to perfect. CONCLUSION: A time-efficient 4-min MENSA protocol exhibits superior image quality and high vascular contrast with the potential to produce high-resolution lumbosacral nerve root images.

Comparison of CAIPIRINHA-accelerated 3D fat-saturated-SPACE MRI with 2D MRI sequences for the assessment of shoulder pathology.

OBJECTIVES: To compare the performance of 6-min MRI with a fat-saturated 3D-controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) Sampling perfection with application-optimized contrast using different flip angle evolution (SPACE) TSE protocol with 10-min 2D TSE MRI protocol for assessment of abnormalities of the shoulder. METHODS: Forty-nine subjects underwent both 3D fat-saturated-CAIPIRINHA SPACE and 2D TSE sequences of the shoulder on a 3.0-T system. Following randomization and anonymization, two musculoskeletal radiologists evaluated the 2D and 3D images independently for image quality and diagnostic capability. Descriptive statistics, inter-observer, and inter-method concordance were investigated. p values < 0.05 were considered significant. RESULTS: For image quality assessment, 2D images were similar to 3D CAIPIRINHA SPACE images (p = 0.05). 3D had lower noise standard deviation (SD) and higher fluid CNR than 2D images (p = 0.00). For diagnostic capability assessment, using 2D TSE as a standard of reference, sensitivity, specificity, and accuracy of 3D SPACE were, respectively, 94.81%, 94.12%, and 94.39% for tendon abnormalities; 97.06%, 80.00%, and 91.84% for acromioclavicular joint abnormalities; 88.89%, 100.00%, and 93.89% for adjacent bone alterations; and 97.30%, 100%, and 97.96% for joint fluid/effusion assessment. The inter-method concordance was moderate to almost perfect. The inter-observer-concordance of the shoulder assessment was also moderate to almost perfect, with SSP lesions demonstrating the greatest concordance. CONCLUSIONS: The performance of 6-min 3D fat-saturated-CAIPIRINHA SPACE MRI for shoulder MRI is similar to that of 10-min 2D TSE MRI. 3D fat-saturated-CAIPIRINHA SPACE MRI can be utilized to reduce scan time without degradation in image quality. KEY POINTS: • CAIPIRINHA acceleration 3D fat-saturated-MRI of the shoulder is achievable in 6 min with high spatial resolution. • 3D fat-saturated CAIPIRINHA MRI is similar to 2D MRI in the shoulder assessment. • 3D CAIPIRINHA MRI images enable rapid diagnosis of shoulder abnormalities without image quality degradation.

Comparison of zero echo time MRI with T1-weighted fast spin echo for the recognition of sacroiliac joint structural lesions using CT as the reference standard.

OBJECTIVES: To evaluate the diagnostic performance of zero echo time (ZTE) MRI in the depiction of structural lesions of sacroiliac joints (SIJs) in patients with the suspicion of sacroiliitis compared with T1-weighted fast spin echo (T1 FSE), using CT as the reference standard. METHODS: Forty patients with suspicion of sacroiliitis underwent both CT and MR scans of SIJs with 80 SIJs (160 bone articular surfaces) included for analysis. Two readers independently scored SIJs for structural lesions on CT and MR images. The diagnostic capability of ZTE MRI and T1 FSE were compared by the McNemar test, using CT as the reference standard. Agreements of diagnosis and sum scores of lesions between MR sequences and CT as well as between readers were also investigated using Cohen's κappa tests and intraclass correlation coefficients. RESULTS: Diagnostic accuracy of ZTE MRI was higher than that of T1 FSE for erosions, sclerosis, and joint space changes (e.g., joint space changes: 91.3% vs 75.0%). ZTE MRI also improved sensitivity for detection of erosions and sclerosis (e.g., erosions at the joint level: 98.2% vs 80.0%) as well as specificity for detection of joint space changes (93.0% vs 67.4%). ZTE MRI had more consistency with CT than T1 FSE for both diagnosis and sum scores. Inter-reader agreements were higher for CT and ZTE MRI than those for T1 FSE. CONCLUSIONS: ZTE MRI showed superior diagnostic performance in the depiction of SIJ structural lesions compared with routine T1-weighted MRI and had reliability comparable to CT. KEY POINTS: • ZTE MRI can provide CT-like bone contrast for the depiction of osseous structural lesions of the sacroiliac joints. • ZTE MRI showed superior diagnostic performance than conventional T1 FSE in the detection of osseous structural lesions of sacroiliitis, using CT as the reference standard. • In terms of inter-reader reliability, ZTE MRI performed comparably to CT and better than conventional T1 FSE.

The diagnostic value of T2 map, diffusion tensor imaging, and diffusion kurtosis imaging in differentiating dermatomyositis from muscular dystrophy.

BACKGROUND: Dermatomyositis (DM) and muscular dystrophy are clinically difficult to differentiate. PURPOSE: To confirm the feasibility and assess the accuracy of conventional magnetic resonance imaging (MRI), T2 map, diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DKI) in the differentiation of DM from muscular dystrophy. MATERIAL AND METHODS: Forty-two patients with DM proven by diagnostic criteria were enrolled in the study along with 23 patients with muscular dystrophy. Conventional MR, T2 map, DTI, and DKI images were obtained in the thigh musculature for all patients. Intramuscular T2 value, apparent diffusion coefficient (ADC), fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values were compared between the patients with DM and muscular dystrophy. Student's t-tests and receiver operating characteristic (ROC) curve analyses were performed for all parameters. P values < 0.05 were considered statistically significant. RESULTS: The intramuscular T2, ADC, FA, MD, and MK values within muscles were statistically significantly different between the DM and muscular dystrophy groups (P<0.01). The MK value was statistically significantly different between the groups in comparison with T2 and FA value. As a supplement to conventional MRI, the parameters of MD and MK differentiated DM and muscular dystrophy may be valuable. The optimal cut-off value of ADC and MD values (with respective AUC, sensitivity, and specificity) between DM and muscular dystrophy were 1.698 ×10-3mm2/s (0.723, 54.1%, and 78.1%) and 1.80 ×10-3mm2/s (61.9% and 70.2%), respectively. CONCLUSION: Thigh muscle ADC and MD parameters may be useful in differentiating patients with DM from those with muscular dystrophy.

Evaluation of the degenerative lumbar osseous morphology using zero echo time magnetic resonance imaging (ZTE-MRI).

PURPOSE: To determine and compare the performance of zero echo imaging (ZTE) with conventional MRI sequences on lumbar osseous morphology in patients suspected with lumbar degeneration with multi-slice computed tomography (MSCT) as standard reference. METHODS: 22 subjects with concerned lumbar degeneration were recruited. All subjects were scanned with ZTE sequence after routine conventional MR sequences on a 3.0 T system and also received MSCT examination. Image quality was assessed. The quantitative and qualitative parameters of lumbar osseous morphology on MSCT, ZTE and MRI images were evaluated by three musculoskeletal radiologists independently. Inter-reader and inter-modality reliability and the difference between the modalities were calculated. RESULTS: There was no difference for the osseous parameters between modalities, including axial orientation (p = 0.444), IAD (p = 0.381), lateral recess (p = 0.370), pedicle width (p = 0.067), pedicle height (p = 0.056), and osteophyte grade (p = 0.052). The measurement of the foramina diameter was statistically different between conventional MRI and MSCT (p < 0.05) but not between the MSCT and ZTE (p = 0.660). Conventional MRI was more likely to miss cortical bone abnormalities. ZTE appeared blurrier in cortical bone than MSCT, especially in cases with severe lumbar degeneration. The inter-reader agreement between MSCT and ZTE-MRI was higher than between MSCT and conventional MRI. CONCLUSIONS: ZTE-MRI could offer more cortical bone details than conventional MRI images and might be a valid alternative to CT for lumbar osseous morphology assessment to some extent.

Multi-Source Coupling Based Analysis of the Acoustic Radiation Characteristics of the Wheel-Rail Region of High-Speed Railways.

Based on elastic mechanics, the fluid-structure coupling theory and the finite element method, a high-speed railway wheel-rail rolling-aerodynamic noise model is established to realize the combined simulation and prediction of the vibrations, rolling noise and aerodynamic noise in wheel-rail systems. The field test data of the Beijing-Shenyang line are considered to verify the model reliability. In addition, the directivity of each sound source at different frequencies is analyzed. Based on this analysis, noise reduction measures are proposed. At a low frequency of 300 Hz, the wheel-rail area mainly contributes to the aerodynamic noise, and as the frequency increases, the wheel-rail rolling noise becomes dominant. When the frequency is less than 1000 Hz, the radiated noise fluctuates around the cylindrical surface, and the directivity of the sound is ambiguous. When the frequency is in the middle- and high-frequency bands, exceeding 1000 Hz, both the rolling and total noise exhibit a notable directivity in the directions of 20-30° and 70-90°, and thus, noise reduction measures can be implemented in these directions.

Feasibility study for evaluating lumbar intervertebral disc degeneration using histogram analysis of T2* values.

PURPOSE: To evaluate the feasibility of histogram analysis of T2* value for the detection and grading of degenerative lumbar intervertebral discs (IVDs) and for the characterization of microstructural heterogeneity of discs. METHODS: Two hundred fourteen lumbar IVDs of 44 subjects with chronic low back pain were examined using sagittal T2WI and axial T2* mapping. All IVDs were classified according to the Pfirrmann grade on T2WI. The correlations between histogram-derived parameters based on T2* values (T2*-HPs) of IVDs and Pfirrmann grade as well as between "red zone ratio" (area of "red zone" on T2* color maps over cross-sectional area of corresponding IVDs) and Pfirrmann grade were calculated. RESULTS: The agreement for Pfirrmann grade of IVDs was excellent (κ = 0.808, P < 0.001). The consistency of the measured T2*-HPs was excellent, with ICCs ranging from 0.828-0.960. Each histogram-derived parameter had a statistically significant relationship with Pfirrmann grade (P < 0.001). The bright "red zone" on T2* color maps of IVDs displayed as a separated peak relative to the rest of voxels in histograms. The mean area ratio of "red zone" over the corresponding IVD was 9.234% ± 6.680 and ranged from 0.517% to 30.598%. The "red zone ratio" was highly related to Pfirrmann grade (r = - 0.732, P < 0.001). CONCLUSION: Histogram analysis of T2* value is an effective tool for the detection and grading of degenerative IVDs. Identification of the "red zone" may provide new breakthroughs in the study of disc degeneration initiation and generate new hypotheses in anatomical and histological studies of IVDs.

Landmark-Based Inertial Navigation System for Autonomous Navigation of Missile Platform.

As a new information provider of autonomous navigation, the on-orbit landmark observation offers a new means to improve the accuracy of autonomous positioning and attitude determination. A novel autonomous navigation method based on the landmark observation and the inertial system is designed to achieve the high-accuracy estimation of the missile platform state. In the proposed method, the navigation scheme is constructed first. The implicit observation equation about the deviation of the inertial system output is derived and the Kalman filter is applied to estimate the missile platform state. Moreover, the physical observability of the landmark and the mathematical observability of the navigation system are analyzed. Finally, advantages of the proposed autonomous navigation method are demonstrated through simulations compared with the traditional celestial-inertial navigation system and the deeply integrated celestial-inertial navigation system.

Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus.

Men are generally superior to women in remembering spatial relationships, whereas the reverse holds for semantic information, but the neurobiological bases for these differences are not understood. Here we describe striking sexual dimorphism in synaptic mechanisms of memory encoding in hippocampal field CA1, a region critical for spatial learning. Studies of acute hippocampal slices from adult rats and mice show that for excitatory Schaffer-commissural projections, the memory-related long-term potentiation (LTP) effect depends upon endogenous estrogen and membrane estrogen receptor α (ERα) in females but not in males; there was no evident involvement of nuclear ERα in females, or of ERß or GPER1 (G-protein-coupled estrogen receptor 1) in either sex. Quantitative immunofluorescence showed that stimulation-induced activation of two LTP-related kinases (Src, ERK1/2), and of postsynaptic TrkB, required ERα in females only, and that postsynaptic ERα levels are higher in females than in males. Several downstream signaling events involved in LTP were comparable between the sexes. In contrast to endogenous estrogen effects, infused estradiol facilitated LTP and synaptic signaling in females via both ERα and ERß. The estrogen dependence of LTP in females was associated with a higher threshold for both inducing potentiation and acquiring spatial information. These results indicate that the observed sexual dimorphism in hippocampal LTP reflects differences in synaptic kinase activation, including both a weaker association with NMDA receptors and a greater ERα-mediated kinase activation in response to locally produced estrogen in females. We propose that male/female differences in mechanisms and threshold for field CA1 LTP contribute to differences in encoding specific types of memories.SIGNIFICANCE STATEMENT There is good evidence for male/female differences in memory-related cognitive function, but the neurobiological basis for this sexual dimorphism is not understood. Here we describe sex differences in synaptic function in a brain area that is critical for learning spatial cues. Our results show that female rodents have higher synaptic levels of estrogen receptor α (ERα) and, in contrast to males, require membrane ERα for the activation of signaling kinases that support long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. The additional requirement of estrogen signaling in females resulted in a higher threshold for both LTP and hippocampal field CA1-dependent spatial learning. These results describe a synaptic basis for sexual dimorphism in encoding spatial information.

Maximum Correntropy Unscented Kalman Filter for Ballistic Missile Navigation System based on SINS/CNS Deeply Integrated Mode.

Strap-down inertial navigation system/celestial navigation system ( SINS/CNS) integrated navigation is a high precision navigation technique for ballistic missiles. The traditional navigation method has a divergence in the position error. A deeply integrated mode for SINS/CNS navigation system is proposed to improve the navigation accuracy of ballistic missile. The deeply integrated navigation principle is described and the observability of the navigation system is analyzed. The nonlinearity, as well as the large outliers and the Gaussian mixture noises, often exists during the actual navigation process, leading to the divergence phenomenon of the navigation filter. The new nonlinear Kalman filter on the basis of the maximum correntropy theory and unscented transformation, named the maximum correntropy unscented Kalman filter, is deduced, and the computational complexity is analyzed. The unscented transformation is used for restricting the nonlinearity of the system equation, and the maximum correntropy theory is used to deal with the non-Gaussian noises. Finally, numerical simulation illustrates the superiority of the proposed filter compared with the traditional unscented Kalman filter. The comparison results show that the large outliers and the influence of non-Gaussian noises for SINS/CNS deeply integrated navigation is significantly reduced through the proposed filter.

Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats.

Positive allosteric modulators of AMPA-type glutamate receptors (ampakines) have been shown to rescue synaptic plasticity and reduce neuropathology in rodent models of cognitive disorders. Here we tested whether chronic ampakine treatment offsets age-related dendritic retraction in middle-aged (MA) rats. Starting at 10 months of age, rats were housed in an enriched environment and given daily treatment with a short half-life ampakine or vehicle for 3 months. Dendritic branching and spine measures were collected from 3D reconstructions of Lucifer yellow-filled CA1 pyramidal cells. There was a substantial loss of secondary branches, relative to enriched 2.5-month-old rats, in apical and basal dendritic fields of vehicle-treated, but not ampakine-treated, 13-month-old rats. Baseline synaptic responses in CA1 were only subtly different between the two MA groups, but long-term potentiation was greater in ampakine-treated rats. Unsupervised learning of a complex environment was used to assess treatment effects on behavior. Vehicle- and drug-treated rats behaved similarly during a first 30 min session in the novel environment but differed markedly on subsequent measures of long-term memory. Markov sequence analysis uncovered a clear increase in the predictability of serial movements between behavioral sessions 2 and 3 in the ampakine, but not vehicle, group. These results show that a surprising degree of dendritic retraction occurs by middle age and that this can be mostly offset by pharmacological treatments without evidence for unwanted side effects. The functional consequences of rescue were prominent with regard to memory but also extended to self-organization of behavior. SIGNIFICANCE STATEMENT: Brain aging is characterized by a progressive loss of dendritic arbors and the emergence of impairments to learning-related synaptic plasticity. The present studies show that dendritic losses are evident by middle age despite housing in an enriched environment and can be mostly reversed by long-term, oral administration of a positive allosteric modulator of AMPA-type glutamate receptors. Dendritic recovery was accompanied by improvements to both synaptic plasticity and the encoding of long-term memory of a novel, complex environment. Because the short half-life compound had no evident negative effects, the results suggest a plausible strategy for treating age-related neuronal deterioration.

Causal effects of body mass index, education, and lifestyle behaviors on intervertebral disc disorders: Mendelian randomization study.

This study aimed to investigate the causal risk factors for intervertebral disc disorders (IVDD) to help establish prevention strategies for IVDD-related diseases. We performed two-sample Mendelian randomization analyses to investigate the causal effects of body mass index (BMI), education, and lifestyle behaviors (sedentary behavior, smoking, and sleeping) on thoracic/thoracolumbar/lumbosacral IVDD (TTL-IVDD) and cervical IVDD. The inverse-variance weighted (IVW) method was conducted as the primary model to pool effect sizes using odds ratio and 95% confidence interval. The strength of causal evidence was evaluated from the effect size and different Mendelian randomization methods (MR-Egger/weighted median/weighted mode method, Cochran's Q test, leave-one-out analysis, MR Steiger, MR-PRESSO and radial IVW analyses). We found strong evidence for the causal associations between IVDD and BMI (TTL-IVDD, 1.27 [1.18, 1.37], p = 2.40 × 10-10 ; cervical IVDD, 1.24 [1.12, 1.37, p = 6.58 × 10-5 ), educational attainment (TTL-IVDD, 0.57 [0.51, 0.64], p = 9.64 × 10-21 ; cervical IVDD, 0.58 [0.49, 0.68], p = 1.78 × 10-10 ), leisure television watching (TTL-IVDD, 1.54 [1.29, 1.84], p = 7.80 × 10-6 ; cervical IVDD, 1.65 [1.29, 2.11], p = 0.0001), smoking initiation (TTL-IVDD, 1.37 [1.25, 1.50], p = 1.78 × 10-10 ; cervical IVDD, 1.32 [1.16, 1.51], p = 6.49 × 10-5 ), short sleep (TTL-IVDD, 1.28 [1.09, 1.49], p = 0.0027; cervical IVDD, 1.53 [1.21, 1.94], p = 0.0008), or frequent insomnia (TTL-IVDD, 1.20 [1.11, 1.30], p = 1.54 × 10-5 ; cervical IVDD, 1.37 [1.20, 1.57], p = 7.80 × 10-6 ). This study provided genetic evidence that increased BMI, low educational attainment, sedentary behavior by leisure television watching, smoking initiation, short sleep, and frequent insomnia were causal risk factors for IVDD. More efforts should be directed toward increasing public awareness of these modifiable risk factors and mobilizing individuals to adopt healthy lifestyles.

Lithiation Induced Phases in 1T'-MoTe2 Nanoflakes.

Multiple polytypes of MoTe2 with distinct structures and intriguing electronic properties can be accessed by various physical and chemical approaches. Here, we report electrochemical lithium (Li) intercalation into 1T'-MoTe2 nanoflakes, leading to the discovery of two previously unreported lithiated phases. Distinguished by their structural differences from the pristine 1T' phase, these distinct phases were characterized using in situ polarization Raman spectroscopy and in situ single-crystal X-ray diffraction. The lithiated phases exhibit increasing resistivity with decreasing temperature, and their carrier densities are two to 4 orders of magnitude smaller than the metallic 1T' phase, as probed through in situ Hall measurements. The discovery of these gapped phases in initially metallic 1T'-MoTe2 underscores electrochemical intercalation as a potent tool for tuning the phase stability and electron density in two-dimensional (2D) materials.

KCNQ2 channels regulate the population activity of neonatal GABAergic neurons ex vivo.

Over the last decade KCNQ2 channels have arisen as fundamental and indispensable regulators of neonatal brain excitability, with KCNQ2 loss-of-function pathogenic variants being increasingly identified in patients with developmental and epileptic encephalopathy. However, the mechanisms by which KCNQ2 loss-of-function variants lead to network dysfunction are not fully known. An important remaining knowledge gap is whether loss of KCNQ2 function alters GABAergic interneuron activity early in development. To address this question, we applied mesoscale calcium imaging ex vivo in postnatal day 4-7 mice lacking KCNQ2 channels in interneurons (Vgat-ires-cre;Kcnq2f/f;GCamp5). In the presence of elevated extracellular potassium concentrations, ablation of KCNQ2 channels from GABAergic cells increased the interneuron population activity in the hippocampal formation and regions of the neocortex. We found that this increased population activity depends on fast synaptic transmission, with excitatory transmission promoting the activity and GABAergic transmission curtailing it. Together, our data show that loss of function of KCNQ2 channels from interneurons increases the network excitability of the immature GABAergic circuits, revealing a new function of KCNQ2 channels in interneuron physiology in the developing brain.

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation.

The present study investigated the effect of transcription factor yin yang 1 (YY1) on aerobic glycolysis and cell proliferation in neuroblastoma and its mechanism. Neuroblastoma cell lines were used to investigate the association between YY1 and lactate dehydrogenase A (LDHA) expression. Cell Counting Kit (CCK)-8 and clone formation experiments were used to detect the cell viability. The interaction of YY1 and LDHA was detected using chromatin immunoprecipitation assay. Glucose uptake, intra/extracellular lactate and pyruvate and LDHA expression were evaluated using standard methods. Reverse transcription quantitative PCR, western blotting and gene overexpression or silencing were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. The results demonstrated that YY1 was significantly upregulated in neuroblastoma cell lines. The results of aerobic glycolysis and CCK-8 indicated that YY1 significantly promoted the proliferation and aerobic glycolysis of neuroblastoma cells. In addition, chromatin immunoprecipitation-PCR results demonstrated that YY1 was directly bound to the promoter LDHA. Overexpression of LDHA could reverse the inhibitory effect of sh-YY1 on aerobic glycolysis and proliferation of neuroblastoma cells. In conclusion, YY1 could induce aerobic glycolysis and proliferation of neuroblastoma cell lines, and may directly mediate the regulation of LDHA. These findings may provide novel insight for the treatment of neuroblastoma.