Multifunctional metamaterial device based on VO2 and the equivalent diode.

This paper proposes a switchable multifunctional metamaterial device operating in the terahertz (THz) band. The device is loaded with an equivalent diode and utilizes vanadium dioxide (V O 2). The middle layer of the whole device, a metal layer, divides the device into the I side and the II side. When the diode is ON, the I side can achieve dual-band absorption at 1.975 and 4.345 THz. When the diode is OFF, the I side can achieve single-band absorption at 4.28 THz. In the case of V O 2 being insulating, the II side can achieve linear-to-linear (LTL) polarization conversion at 2.342-4.18 THz. In the case of V O 2 being conductive, the II side can realize linear-to-circular (LTC) polarization conversion at 2.105-3.283 THz. The device provides a new strategy for the subsequent combination of multiple functions. The device can be used in electromagnetic stealth, intelligent applications, radiometers, and sensors and has relatively large application potential in miniaturized multifunctional metamaterials and THz band research.

BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease.

INTRODUCTION: The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. METHODS: To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology. RESULTS: The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant. DISCUSSION: The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. HIGHLIGHTS: BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

The Abca7V1613M variant reduces Aß generation, plaque load, and neuronal damage.

BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS: Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

Flexible strain sensor based on a frequency selective surface.

Frequency selective surfaces (FSSs), modern artificial materials, show great potential in engineering applications due to their excellent frequency selection capabilities. In this paper, we introduce a flexible strain sensor based on FSS reflection characteristics, which can be well conformally attached to the surface of an object and bear mechanical deformation from a certain load. When the FSS structure changes, the original working frequency will be shifted. By measuring the difference in electromagnetic performance, the strain degree of the object can be monitored in real-time. In this study, we designed an FSS sensor with a working frequency of 31.4 GHz and amplitude that reaches -35 dB that exhibits favorable resonance properties in the Ka-band. The quality factor of FSS is 16.2, which indicates that the sensor has excellent sensing performance. The sensor was applied in the strain detection of a rocket engine case through statics and electromagnetic simulations. The analysis showed that the working frequency of the sensor shifted by approximately 200 MHz for 1.64% radial expansion of the engine case and the frequency shift exhibits an excellent linear relationship with the deformation in diverse loads, so it can be used for accurate strain detection of the case. Based on experiments, we carried out the uniaxial tensile test of the FSS sensor in this study. The sensor's sensitivity was 1.28 GHz/mm when the FSS was stretched by 0-3 mm in the test. Therefore, the FSS sensor has high sensitivity and strong mechanical properties, which verifies the practical value of the FSS structure designed in this paper. It has a broad development space in this field.

Multifunctional terahertz metamaterial based on vanadium dioxide and silicon.

This paper proposes a multifunctional metamaterial device operating in the terahertz (THz) band. The metamaterial device can switch functions by using the phase transition properties of vanadium dioxide (V O 2) and the photoconductive effect of silicon. An intermediate metal layer divides the device into the I side and II side. When V O 2 is in the insulating state, the I side can achieve polarization conversion from linear polarization waves to linear polarization waves at 0.408-0.970 THz. When V O 2 is in the metal-like state, the I side can perform polarization conversion from linear polarization waves to circular polarization waves at 0.469-1.127 THz. When silicon is not excited in the absence of light, the II side can perform polarization conversion from linear polarization waves to linear polarization waves at 0.799-1.336 THz. As the light intensity increases, the II side can realize stable broadband absorption at 0.697-1.483 THz when silicon is in the conductive state. The device can be applied to wireless communications, electromagnetic stealth, THz modulation, THz sensing, and THz imaging. Moreover, it provides a fresh idea for the design of multifunctional metamaterial devices.

Evaluation of a rat model of exercise-induced fatigue using treadmill running with progressively increasing load.

The mechanism behind exercise-induced fatigue is a significant topic in the field of sports physiology. Therefore, establishing and evaluating an acute exercise-induced fatigue animal model that explores the limits of the motor system may provide greater insight into these mechanisms. Heart rate is an important quantitative parameter that accurately reflects the immediate change in physical function due to exercise load. And there is likely to be an important correlation between heart rate and behavioral performance. In this study, changes in heart rate and behavioral indexes during exercise-induced fatigue were quantitatively analyzed in rats using heart rate telemetry and video methods respectively. The behavioral indexes were used as independent variables and the degree of fatigue was used as the forecast value. Ternary quadratic function curve fitting was used to deduce a formula to calculate a fatigue score: Y = 15.2548+0.4346∙xa-0.1154∙xb+0.6826∙xc+0.0044∙xa∙xb-0.0021∙xb∙xc-0.0013∙xc∙xa-0.0023∙xa2-0.0016∙xb2 (r2=0.906). It identified a linear relationship between heart rate and exercise intensity, with a plateau in heart rate occurring during difference periods. It will serve as an effective reference for the modeling of exercise-induced fatigue. In addition, it also provides a theoretical method for analyzing the correlation between peripheral and central parameters.

Treadmill Exercise Improves Motor Dysfunction and Hyperactivity of the Corticostriatal Glutamatergic Pathway in Rats with 6-OHDA-Induced Parkinson's Disease.

Hyperactivity in the corticostriatal glutamatergic pathway (CGP) induces basal ganglia dysfunction, contributing to parkinsonian syndrome (PS). Physical exercise can improve PS. However, the effect of exercise on the CGP, and whether this pathway is involved in the improvement of PS, remains unclear. Parkinson's disease (PD) was induced in rats by 6-hydroxydopamine injection into the right medial forebrain bundle. Motor function was assessed using the cylinder test. Striatal neuron (SN) spontaneous and evoked firing activity was recorded, and the expression levels of Cav1.3 and CaMKII in the striatum were measured after 4 weeks of treadmill exercise. The motor function in PD rats was improved by treadmill exercise. SN showed significantly enhanced excitability, and treadmill exercise reduced SN excitability in PD rats. In addition, firing activity was evoked in SNs by stimulation of the primary motor cortex, and SNs exhibited significantly decreased stimulus threshold, increased firing rates, and reduced latency. The expression of Cav1.3 and p-CaMKII (Thr286) in the striatum were enhanced in PD rats. However, these effects were reversed by treadmill exercise. These findings suggest that treadmill exercise inhibits CGP hyperactivity in PD rats, which may be related to improvement of PS.

The neuromechanical of Beta-band corticomuscular coupling within the human motor system.

Beta-band activity in the sensorimotor cortex is considered a potential biomarker for evaluating motor functions. The intricate connection between the brain and muscle (corticomuscular coherence), especially in beta band, was found to be modulated by multiple motor demands. This coherence also showed abnormality in motion-related disorders. However, although there has been a substantial accumulation of experimental evidence, the neural mechanisms underlie corticomuscular coupling in beta band are not yet fully clear, and some are still a matter of controversy. In this review, we summarized the findings on the impact of Beta-band corticomuscular coherence to multiple conditions (sports, exercise training, injury recovery, human functional restoration, neurodegenerative diseases, age-related changes, cognitive functions, pain and fatigue, and clinical applications), and pointed out several future directions for the scientific questions currently unsolved. In conclusion, an in-depth study of Beta-band corticomuscular coupling not only elucidates the neural mechanisms of motor control but also offers new insights and methodologies for the diagnosis and treatment of motor rehabilitation and related disorders. Understanding these mechanisms can lead to personalized neuromodulation strategies and real-time neurofeedback systems, optimizing interventions based on individual neurophysiological profiles. This personalized approach has the potential to significantly improve therapeutic outcomes and athletic performance by addressing the unique needs of each individual.

Physical exercise for brain plasticity promotion an overview of the underlying oscillatory mechanism.

The global recognition of the importance of physical exercise (PE) for human health has resulted in increased research on its effects on cortical activity. Neural oscillations, which are prominent features of brain activity, serve as crucial indicators for studying the effects of PE on brain function. Existing studies support the idea that PE modifies various types of neural oscillations. While EEG-related literature in exercise science exists, a comprehensive review of the effects of exercise specifically in healthy populations has not yet been conducted. Given the demonstrated influence of exercise on neural plasticity, particularly cortical oscillatory activity, it is imperative to consolidate research on this phenomenon. Therefore, this review aims to summarize numerous PE studies on neuromodulatory mechanisms in the brain over the past decade, covering (1) effects of resistance and aerobic training on brain health via neural oscillations; (2) how mind-body exercise affects human neural activity and cognitive functioning; (3) age-Related effects of PE on brain health and neurodegenerative disease rehabilitation via neural oscillation mechanisms; and (4) conclusion and future direction. In conclusion, the effect of PE on cortical activity is a multifaceted process, and this review seeks to comprehensively examine and summarize existing studies' understanding of how PE regulates neural activity in the brain, providing a more scientific theoretical foundation for the development of personalized PE programs and further research.

Aerobic exercise improves motor dysfunction in Parkinson's model mice via differential regulation of striatal medium spiny neuron.

The striatum plays a crucial role in providing input to the basal ganglia circuit and is implicated in the pathological process of Parkinson's disease (PD). Disruption of the dynamic equilibrium in the basal ganglia loop can be attributed to the abnormal functioning of the medium spiny neurons (MSNs) within the striatum, potentially acting as a trigger for PD. Exercise has been shown to mitigate striatal neuronal dysfunction through neuroprotective and neurorestorative effects and to improve behavioral deficits in PD model mice. In addition, this effect is offset by the activation of MSNs expressing dopamine D2 receptors (D2-MSNs). In the current study, we investigated the underlying neurobiological mechanisms of this effect. Our findings indicated that exercise reduces the power spectral density of the beta-band in the striatum and decreases the overall firing frequency of MSNs, particularly in the case of striatal D2-MSNs. These observations were consistent with the results of molecular biology experiments, which revealed that aerobic training specifically enhanced the expression of striatal dopamine D2 receptors (D2R). Taken together, our results suggest that aerobic training aimed at upregulating striatal D2R expression to inhibit the functional activity of D2-MSNs represents a potential therapeutic strategy for the amelioration of motor dysfunction in PD.

APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.

Background: Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. Methods: We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial transcriptomics and proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau. Results: In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Conclusions: These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

Goal-directed and habitual control: from circuits and functions to exercise-induced neuroplasticity targets for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and cognitive impairments. The progressive depletion of dopamine (DA) is the pathological basis of dysfunctional goal-directed and habitual control circuits in the basal ganglia. Exercise-induced neuroplasticity could delay disease progression by improving motor and cognitive performance in patients with PD. This paper reviews the research progress on the motor-cognitive basal ganglia circuit and summarizes the current hypotheses for explaining exercise intervention on rehabilitation in PD. Studies on exercise mediated mechanisms will contribute to the understanding of networks that regulate goal-directed and habitual behaviors and deficits in PD, facilitating the development of strategies for treatment of PD.

Transient targeting of BIM-dependent adaptive MCL1 preservation enhances tumor response to molecular therapeutics in non-small cell lung cancer.

Despite remarkable efficacy, targeted treatments often yield a subpopulation of residual tumor cells in part due to non-genetic adaptions. Previous mechanistic understanding on the emergence of these drug-tolerant persisters (DTPs) has been limited to epigenetic and transcriptional reprogramming. Here, by comprehensively interrogating therapy-induced early dynamic protein changes in diverse oncogene-addicted non-small cell lung cancer models, we identified adaptive MCL1 increase as a new and universal mechanism to confer apoptotic evasion and DTP formation. In detail, acute MAPK signaling disruption in the presence of genotype-based tyrosine kinase inhibitors (TKIs) prompted mitochondrial accumulation of pro-apoptotic BH3-only protein BIM, which sequestered MCL1 away from MULE-mediated degradation. A small-molecule combination screen uncovered that PI3K-mTOR pathway blockade prohibited MCL1 upregulation. Biochemical and immunocytochemical evidence indicated that mTOR complex 2 (mTORC2) bound and phosphorylated MCL1, facilitating its interaction with BIM. As a result, short-term polytherapy combining antineoplastic TKIs with PI3K, mTOR or MCL1 inhibitors sufficed to prevent DTP development and promote cancer eradication. Collectively, these findings support that upfront and transient targeting of BIM-dependent, mTORC2-regulated adaptive MCL1 preservation holds enormous promise to improve the therapeutic index of molecular targeted agents.

Flavonoids from Scutellaria likiangensis Diels and their antimalarial activities.

Two new flavonoid glycosides scutelikiosides A and B (13 and 23), along with twenty-one known compounds from the 75% ethanol extract of roots of Scutellaria likiangensis Diels. Their structures were determined by the comprehensive analyses of the spectroscopic data (1D NMR, 2D NMR, HRESIMS, and CD) and physicochemical properties. Compounds 4-14, 17-19, 21, and 22 were evaluated for their in vivo antimalarial activities against Plasmodium yoelii BY265RFP in mice. Compound 17 exhibited significant activity close to artemisinin with an inhibition ratio of 29.2%, and compounds 6, 9-12, 14, 18, 19, and 22 exhibited moderate antimalarial activities with inhibition ratios ranging from 10.2% to 20.0% at a dose of 25 mg/kg/day. In addition, a summary of preliminary structure-activity relationship of isolated flavonoids for in vivo antimalarial activity was described.

A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques.

BACKGROUND: The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. METHODS: Trem2R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain's response to plaques. RESULTS: Trem2R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2R47H NSS (5xFAD/Trem2R47H NSS) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2R47H NSS mice also display LTP deficits and postsynaptic loss. CONCLUSIONS: The Trem2R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.

Comparison of male chimeric mice generated from microinjection of JM8.N4 embryonic stem cells into C57BL/6J and C57BL/6NTac blastocysts.

To identify ways to improve the efficiency of generating chimeric mice via microinjection of blastocysts with ES cells, we compared production and performance of ES-cell derived chimeric mice using blastocysts from two closely related and commonly used sub-strains of C57BL/6. Chimeras were produced by injection of the same JM8.N4 (C57BL/6NTac) derived ES cell line into blastocysts of mixed sex from either C57BL/6J (B6J) or C57BL/6NTac (B6NTac) mice. Similar efficiency of production and sex-conversion of chimeric animals was observed with each strain of blastocyst. However, B6J chimeric males had fewer developmental abnormalities involving urogenital and reproductive tissues (1/12, 8%) compared with B6NTac chimeric males (7/9, 78%). The low sample size did not permit determination of statistical significance for many parameters. However, in each category analyzed the B6J-derived chimeric males performed as well, or better, than their B6NTac counterparts. Twelve of 14 (86%) B6J male chimeras were fertile compared with 6 of 11 (55%) B6NTac male chimeras. Ten of 12 (83%) B6J chimeric males sired more than 1 litter compared with only 3 of 6 (50%) B6NTac chimeras. B6J male chimeras produced more litters per productive mating (3.42 ± 1.73, n = 12) compared to B6NTac chimeras (2.17 ± 1.33, n = 6). Finally, a greater ratio of germline transmitting chimeric males was obtained using B6J blastocysts (9/14; 64%) compared with chimeras produced using B6NTac blastocysts (4/11; 36%). Use of B6J host blastocysts for microinjection of ES cells may offer improvements over blastocysts from B6NTac and possibly other sub-strains of C57BL/6 mice.

Nicandra physalodes Extract Exerts Antiaging Effects in Multiple Models and Extends the Lifespan of Caenorhabditis elegans via DAF-16 and HSF-1.

The development of safe and effective therapeutic interventions is an important issue for delaying aging and reducing the risk of aging-related diseases. Chinese herbal medicines for the treatment of aging and other complex diseases are desired due to their multiple components and targets. Through screening for effects on lifespan of 836 Chinese herbal medicine extracts, Nicandra physalodes extract (HL0285) was found to exhibit lifespan extension activity in Caenorhabditis elegans (C. elegans). In further experiments, HL0285 improved healthspan, enhanced stress resistance, and delayed the progression of neurodegenerative diseases in C. elegans. Additionally, it ameliorated senescence in human lung fibroblasts (MRC-5 cells) and reversed liver function damage and reduced senescence marker levels in doxorubicin- (Dox-) induced aging mice. In addition, the longevity effect of HL0285 in C. elegans was dependent on the DAF-16 and HSF-1 signaling pathways, as demonstrated by the results of the mutant lifespan, gene level, and GFP level assays. In summary, we discovered that HL0285 had an antiaging effect in C. elegans, MRC-5 cells, and Dox-induced aging mice and deserves to be explored in the future studies on antiaging agents.

Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer.

Therapeutic perturbation of cyclin-dependent kinase 12 (CDK12) is proposed to have pleiotropic effects in ovarian cancer, including direct cytotoxicity against tumor cells and indirect induction of immunogenicity that confer synthetic sensitivity to immune-based treatment. However, formal testing of this hypothesis has been hindered by an insufficient mechanistic understanding of CDK12 and its close homolog CDK13, as well as generally unfavorable pharmacokinetics of available CDK12/CDK13 covalent inhibitors. In this study, we used an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitors ZSQ836 exerted potent anticancer activity in cell culture and mouse models and induced transcriptional reprogramming, including downregulation of DNA damage response genes. CDK12 and CDK13 were both ubiquitously expressed in primary and metastatic ovarian cancer, and the two kinases performed independent and synergistic functions to promote tumorigenicity. Unexpectedly, although ZSQ836 triggered genomic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T-cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simultaneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharmacologically target CDK12. SIGNIFICANCE: This study dissects the specific roles of CDK12 and CDK13 in ovarian cancer and develops a CDK12/CDK13 inhibitor that impairs both tumor and immune cells, which could guide future CDK12 inhibitor development.

SOX17 and PAX8 constitute an actionable lineage-survival transcriptional complex in ovarian cancer.

Müllerian tissue-specific oncogenes, prototyped by PAX8, underlie ovarian tumorigenesis and represent unique molecular vulnerabilities. Further delineating such lineage-dependency factors and associated therapeutic implications would provide valuable insights into ovarian cancer biology and treatment. In this study, we identified SOX17 as a new lineage-survival master transcription factor, which shared co-expression pattern with PAX8 in epithelial ovarian carcinoma. Genetic disruption of SOX17 or PAX8 analogously inhibited neoplastic cell viability and downregulated a spectrum of lineage-related transcripts. Mechanistically, we showed that SOX17 physically interacted with PAX8 in cultured cell lines and clinical tumor specimens. The two nuclear proteins bound to overlapping genomic regions and regulated a common set of downstream genes, including those involved in cell cycle and tissue morphogenesis. In addition, we revealed that small-molecule inhibitors of transcriptional cyclin-dependent kinases (CDKs) effectively reduced SOX17 and PAX8 expression. ZSQ1722, a novel orally bioavailable CDK12/13 covalent antagonist, exerted potent anti-tumor activity in xenograft models. These findings shed light on an actionable lineage-survival transcriptional complex in ovarian cancer, and facilitated drug discovery by generating a serial of candidate compounds to pharmacologically target this difficult-to-treat malignancy.

Exercise Improves Movement by Regulating the Plasticity of Cortical Function in Hemiparkinsonian Rats.

Aberrant cortical spike-local field potential (LFP) coupling leads to abnormal basal ganglia activity, disruption of cortical function, and impaired movement in Parkinson's disease (PD). Here, the primary motor cortex mediated plasticity mechanism underlying behavioral improvement by exercise intervention was investigated. Exercise alleviates motor dysfunction and induces neuroplasticity in PD. In this study, Sprague-Dawley (SD) rats were injected with 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Two weeks later, a 4-week exercise intervention was initiated in the PD + exercise (Ex) group. Multichannel recording technology recorded spikes and LFPs in rat motor cortices, and balanced ability tests evaluated behavioral performance. The balanced ability test showed that the total crossing time/front leg error/input latency time was significantly lower in PD + Ex rats than in PD rats (P < 0.05). Scalograms and LFP power spectra indicated increased beta-range LFP power in lesioned hemispheres, with exercise reducing LFP power spectral density. Spike-triggered LFP waveform averages showed strong phase-locking in PD motor cortex cells, and exercise reduced spike-LFP synchronization. Our results suggest that exercise can suppress overexcitability of LFPs and minimize spike-LFP synchronization in the motor cortex, leading to motor-improving effects in PD.