Background: Obsessive-compulsive disorder (OCD) remains refractory to conventional pharmacological and psychotherapeutic treatments in a substantial proportion of patients. Neuromodulation has emerged as a promising intervention, but optimal neural circuit targets remain unclear. This systematic review and meta-analysis aimed to evaluate the efficacy of invasive and non-invasive neuromodulation for OCD using a circuit-based framework and to translate these findings into clinical practice. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials investigating neuromodulation for OCD. PubMed/MEDLINE, Web of Science, and the Cochrane Library were searched from database inception to December 2023. Eligible studies included adult patients with a primary diagnosis of OCD receiving invasive or non-invasive neuromodulation, with symptom outcomes assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Random-or fixed-effects meta-analyses were performed using mean differences or standardized mean differences, depending on heterogeneity. The review was registered in PROSPERO (CRD42024518326). Results: Twenty-seven randomized controlled trials involving 868 patients met inclusion criteria. Overall, neuromodulation significantly reduced OCD symptoms compared with control conditions. Circuit-based subgroup analyses indicated that modulation of the fronto-limbic circuit--primarily via invasive deep brain stimulation--was associated with the largest and most consistent Y-BOCS improvements, while sensorimotor, dorsal cognitive, and ventral affective circuits also demonstrated significant but more heterogeneous effects. Invasive neuromodulation showed greater efficacy than non-invasive approaches. These findings informed a translational multi-target deep brain stimulation case, demonstrating clinically meaningful symptom improvement (Y-BOCS decreased from 25 to 16 after 6 months). Limitations: Heterogeneity across non-invasive studies, short follow-up durations, and limited circuit-specific data constrain interpretation of long-term and symptom-domain-specific effects. Conclusions: This systematic review, meta-analysis, and case study suggest that circuit-based neuromodulation--particularly targeting the fronto-limbic circuit--may offer the most consistent benefit for treatment-refractory OCD. Larger, longer-term, and circuit-informed trials are needed to optimize individualized neuromodulation strategies.

Neuroinflammation plays a key role in exacerbating dopaminergic neuron loss in Parkinson's disease (PD). We identified TAB2 as an early-stage biomarker, which was elevated in PD patients' microglia. However, the role of TAB2 in the pathogenesis of PD remains unknown. In this study, we found that Tab2 knockdown inhibited the activation of microglia and protected neurons in PD models. STAT3, as a transcription factor for TAB2, regulated TAB2 expression. Mechanistically, TAB2 interacted with α-synuclein and facilitated the recognition of K63-linked ubiquitin chains, leading to the formation of the TAK1-TABs complex and activation of TAK1, which was ultimately followed by activation of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, microglia-specific knockdown of Tab2 significantly inhibited microglia activation, protected dopaminergic neurons, improved motor function, and attenuated anxiety-like behaviors in PD mouse model. We further showed that the FDA-approved drug, lumacaftor, suppressed microglial TAB2 expression and had potent anti-inflammatory and neuroprotective effects in PD models. Taken together, our study reveals that the STAT3-TAB2-NF-κB-IL-1β positive feedback axis in microglia is a crucial checkpoint that exacerbates neuroinflammation in PD. Therefore, these findings identify a pivotal role of TAB2 in regulating microglia-mediated neuroinflammation, suggesting that targeting TAB2 may be a possible therapeutic strategy for PD.

Abstract Understanding how plants adapt to extreme cold and ripen fruit is a key question in plant biology. Lonicera caerulea (blue honeysuckle), a cold-tolerant berry species native to the northern temperate zone, is valued as a ‘noble fruit’ for its rich nutrient profile, and serves as an ideal model for studies due to its unique ability to thrive in low temperatures and ripen fruit during early spring. Here, we generated a chromosome-level genome assembly for wild L. caerulea from the Changbai Mountain region. We integrated it with transcriptomic and metabolomic analyses to explore its molecular cold adaptation mechanisms. We found that L. caerulea achieves cold tolerance and fruit ripening through dynamic regulation of two important metabolic pathways. Under cold stress, the LcODO1/LcMYB15–LcSLAS module promotes iridoids accumulation, while the LcbHLH62/LcMYB3R5–LcF3GT module enhances anthocyanin biosynthesis-jointly increasing plant cold resistance. During fruit maturation, metabolite profiles show dynamic reprogramming: anthocyanin levels rise in both pulp and peel, while the content of bitter iridoids markedly decreases in the pulp. This work provides a comprehensive genomic framework for understanding cold adaptation mechanisms, offering valuable gene resources and a theoretical foundation for improving cold resistance and fruit quality in breeding programs.

To investigate the effect of sorbitol feeding on immune responses and its underlying mechanism, this study employed crabapple (Malus micromalus), a species native to China, as the experimental material. Detached leaves were subjected to sorbitol feeding experiments, with water feeding as the control. The dynamic changes in lesion area and cell membrane permeability were measured across four groups of leaves following feeding and fungal inoculation, and transcriptome sequencing was performed on these four groups. The results revealed that compared to the control group, leaves fed with sorbitol prior to inoculation exhibited significantly reduced lesion areas and decreased cell membrane permeability. Transcriptome and KEGG pathway analyses indicated that differentially expressed genes were significantly enriched in the phenylpropanoid biosynthesis pathway. HPLC results demonstrated that quercetin and isorhamnetin contents increased significantly after sorbitol feeding, and both compounds were shown to inhibit the mycelial growth of Alternaria alternata, thereby enhancing the disease resistance of crabapple leaves. Among the associated genes, MmF3H1, which regulates the synthesis of quercetin and isorhamnetin, showed the highest level of enrichment. Co-expression trend analysis and qPCR results revealed that MmNAC17 and MmbZIP1 exhibited strong co-expression relationships with MmF3H1 and responded to sorbitol regulation. Functional validation was conducted by constructing overexpression and silencing vectors for MmNAC17/MmbZIP1 and performing transient transformation, thereby elucidating the molecular and biochemical mechanisms underlying the response of M. micromalus to A. alternata. This study provides a theoretical reference for breeding crabapple varieties with enhanced resistance to leaf spot disease.

We investigated the impact of visual states on basal ganglia oscillatory biomarkers, comparing local field potentials (LFPs) dynamics between Parkinson’s disease (PD) and dystonia and developing a decoding model for state identification. Simultaneous LFPs recordings from the subthalamic nucleus (STN) or globus pallidus internus (GPi), and cortex were obtained from 18 PD and 18 dystonia patients. In the eyes-closed state, theta and alpha power increased in the basal ganglia, with stronger coherence to the central cortex, more pronounced in the STN than in the GPi. Machine learning models identified the eyes-closed state with 88% accuracy for STN and 77% for GPi. The sensorimotor STN and GPi were most informative. The present findings provide proof-of-concept that basal ganglia LFPs can reliably predict a physiological state, highlighting the potential influence of physiological oscillatory activity on pathological bands and its relevance for adaptive stimulation paradigms.

Deep brain stimulation (DBS) has emerged as a transformative neuromodulation therapy for a variety of neurological and psychiatric disorders, including Parkinson’s disease, epilepsy, and obsessive-compulsive disorder. Despite its widespread clinical use, the precise mechanisms underlying these therapeutic effects remain incompletely understood. This review provides a comprehensive examination of DBS, from its historical development and underlying mechanisms to its diverse clinical applications in 16 diseases. The historical context traces the evolution of DBS technology from early stereotactic techniques to contemporary advances that allow for more precise targeting and adaptive stimulation. Mechanistically, DBS influences neural activity through a combination of depolarization block, informational lesion, and network reconfiguration via induced neuroplasticity. Each mechanism may contribute uniquely to symptom mitigation and therapeutic outcome. The most advanced and widely studied clinical applications of DBS are alleviating motor symptoms in Parkinson’s disease, managing refractory epilepsy, and addressing treatment-resistant psychiatric conditions. While highlighting these three major application conditions, we also map therapeutic interventions across a broader spectrum of emerging indications. The future of DBS lies in adaptive systems that optimize stimulation based on real-time neural feedback, as well as in expanding applications to other disorders and targets. Continued research and technological advancements are crucial for enhancing the efficacy, precision, and accessibility of DBS, thereby broadening its therapeutic potential.

Rapid climate shifts in high-latitude regions profoundly impact the geographical distribution boundaries and molecular adaptive strategies of cold-tolerant plants. Lonicera caerulea, known for its excellent cold tolerance, provides an ideal model for exploring the molecular mechanisms of climate adaptation and trait formation. To elucidate the ecological and molecular mechanisms of climate adaptation in L. caerulea, we integrated species distribution modeling with multi-tissue transcriptome profiling. Distribution modeling identified temperature and precipitation as primary constraints on its current range, with projections suggesting a significant poleward expansion under future warming scenarios. At the molecular level, we identified 19 LcSWEET genes exhibiting functional differentiation. Rather than listing specific candidates, our findings highlight that certain LcSWEET members are transcriptionally activated during fruit maturation, while others are significantly upregulated in response to cold stress, underscoring their dual roles in plant reproduction and ecological adaptation. This study revealed that the LcSWEET gene family exhibits functional diversification in tissue-specific expression and low-temperature stress response. It provides molecular candidates that may inform future studies on plant adaptive response under climate change and lays a theoretical foundation for germplasm conservation and high-quality breeding of L. caerulea.

AimDeep brain stimulation of the nucleus basalis of Meynert (NBM-DBS) represents an emerging therapeutic strategy for Alzheimer’s disease (AD), yet clinical outcomes have been inconsistent and its mechanistic underpinnings are not fully elucidated. This study aimed to assess the cognitive and psychobehavioral effects of NBM-DBS and to explore its potential impact on systemic inflammatory markers.MethodsIn this open-label trial, nine individuals with moderate-to-severe AD underwent bilateral NBM-DBS. Six participants (four with moderate and two with severe AD) completed the full 12-month protocol, which included serial neuropsychiatric assessments and serum cytokine profiling.ResultsStratification by baseline disease severity revealed divergent cognitive trajectories. Patients with moderate AD (CDR = 2) maintained their preoperative performance on the Montreal Cognitive Assessment (MoCA) and Boston Naming Test (BNT) over the 12-month follow-up. In contrast, patients with severe AD (CDR = 3) experienced significant decline on these measures. Serum analyses demonstrated a significant immunomodulatory effect, characterized by elevated levels of the anti-inflammatory cytokines IL-10 and IL-27, and reduced levels of the pro-inflammatory chemokines CXCL10 and RANTES at the 12-month timepoint.ConclusionOur findings indicate that NBM-DBS may be associated with stabilization of cognitive function in patients with moderate AD, potentially through the modulation of inflammation. The therapeutic benefit appears to be more pronounced in the moderate stage of the disease.

Soil salinization significantly limits agricultural yields; therefore, it is crucial to analyze grape salt tolerance mechanisms to better strategically place grape industries in saline–alkali soils. This study employed four grape varieties, including ’Kyoho’ , ’Beibinghong’ , ’Thompson Seedless’ and ’Muscat Hamburg’ to investigate salt stress. The results indicated that ’Kyoho’ grapes had the highest salt tolerance, while ’Beibinghong’ showed the lowest tolerance. Furthermore, ’Thompson Seedless’ and ’Muscat Hamburg’ were classified as moderately salt-tolerant and salt-sensitive varieties, respectively. Moreover, transcriptome sequencing was performed to evaluate the molecular mechanisms of grape salt tolerance using leaves of the four varieties at 0, 1, 3, and 5 days post-salt stress. The results showed that VvMYB308 and VvCHI2 are key enzymes associated with flavonoid synthesis and respond to salt stress in grapes. Similarly, physiological analysis indicated substantially increased Quercitrin levels in the salt-tolerant’Kyoho’variety under salt stress. Subcellular localization analysis showed that VvMYB308 resides in the nucleus and interacts with the VvCHI2 promoter. Similarly, transient transformation assays revealed that VvMYB308 positively modulates salt tolerance in grape tissue-cultured seedlings. This study indicated that the VvMYB308-VvCHI2 pathway modulates grape salt tolerance by promoting Quercitrin synthesis. These findings provide theoretical evidence for the breeding of salt-tolerant grape varieties and their cultivation in saline‐alkali soils.

Sorbitol is a major primary metabolite in Malus species, serving as the primary product of photosynthesis and the main form of carbon translocation. It also functions as a signaling molecule that regulates plant growth, development, and stress responses. Fungal foliar diseases are widespread in Malus and can cause substantial economic losses, yet the molecular mechanism underlying sorbitol-mediated disease resistance remains poorly understood. This study focused on Malus resistance to Alternaria alternata Mr1 and found that sorbitol markedly increased the accumulation of flavonoids, including phlorizin, phloretin, and catechin, enhancing disease resistance. Based on our previous transcriptome data, transcriptome analysis identified the chromatin remodeling factor LFR as a susceptibility-associated gene. LFR was transcriptionally downregulated by sorbitol and negatively regulated flavonoid biosynthesis. This study further identified the transcription factor MYBR1, whose expression showed a negative correlation with that of LFR. MYBR1 was activated by sorbitol and facilitated flavonoid accumulation, and its overexpression restored resistance to Alternaria alternata Mr1 in plants with high LFR expression. Collectively, sorbitol suppresses LFR expression, relieving its inhibitory effect on MYBR1, which in turn enhances flavonoid accumulation and boosts resistance to Alternaria alternata Mr1 in Malus.

BACKGROUND:Cognitive decline in Parkinson's disease (PD) is associated with pathological alterations within the thalamus. Nevertheless, volumetric changes in the specific subnuclei of the thalamus in PD patients with dementia (PD-D) remain inadequately characterized. Furthermore, the clinical challenges of diagnosing PD-D at an individual level and forecasting the trajectory of cognitive decline persist. METHODS:This study acquired structural magnetic resonance imaging (MRI) data from 60 healthy normal controls (NC), 63 PD patients without dementia (PD-nD), and 57 PD-D patients. The volumes of 25 thalamic subnuclei were quantified using FreeSurfer and a novel thalamic segmentation algorithm. Subsequently, individual PD-D diagnosis and severity prediction of cognitive impairment were performed using support vector machines (SVMs). RESULTS:Our findings demonstrated atrophy in seven out of 25 left and two out of 25 right thalamic subnuclei in PD-D patients relative to PD-nD patients. When compared to NC subjects, the PD-D group exhibited volume reductions in two left and one right subnuclei, alongside enlargement in several others. Within the PD cohort, the volumes of four left thalamic subnuclei showed a negative correlation with cognitive impairment severity. Machine learning models achieved high accuracy in differentiating PD-nD from NC (89.19%), PD-D from NC (94.29%), and PD-D from PD-nD (83.33%). Moreover, the prediction of Mini-Mental State Examination (MMSE) scores yielded a Pearson correlation coefficient of 0.7568. CONCLUSION:Specific thalamic subnuclei undergo atrophy in PD-D, and these morphological changes are linked to cognitive deficit severity. Leveraging these features with machine learning enables accurate individual diagnosis and severity prediction.

OBJECTIVE:Research on freezing of gait (FOG) in Parkinson's disease (PD) has identified relevant electrophysiological markers. However, their brief temporal windows limit their utility for individualized deep brain stimulation (DBS). This study explored gait performance and neural features in freezing-susceptible walking to develop novel FOG-predictive biomarkers. METHODS:Gait kinematics and local field potentials (LFP) from the cortex and subthalamic nucleus (STN) were simultaneously acquired in FOG patients during walking. Using the gait cycle as the analytic unit, we compared freezing trials (FOGT) and non-freezing trials (nFOGT) under the no-intervention condition (OFF) to identify gait parameters and neural features associated with FOG risk. Subsequently, we assessed the modulatory effects of high-frequency (HFS) and low-frequency (LFS) STN-DBS on abnormal gait and cortical power. Finally, we analyzed changes in abnormal gait and cortico-STN coherence after levodopa administration. RESULTS:FOGT showed aberrant gait parameters compared to nFOGT, along with disrupted lowbeta oscillations in primary somatosensory cortex (S1) and superior parietal lobule (SPL). Both HFS and LFS mitigated gait impairment and freezing severity, with LFS exerting broader effects: HFS reversed pathological lowbeta power reduction in SPL during the double support phase, while LFS restored phase-dependent oscillations between the stance phase and swing phase in S1. Additionally, abnormal theta coherence between S1 and STN could be modulated by levodopa, accompanied by gait recovery. CONCLUSION:This study identifies gait-cycle-locked cortico-STN signatures for FOG, which have extended temporal windows and are modulable by DBS, suggesting the gait cycle as a promising intervention target.

ABSTRACT Objective Deep brain stimulation offers a unique opportunity to record neural activity of the basal ganglia. While much work in dystonia has focused on the globus pallidus internus, expanding research to investigate subthalamic nucleus (STN) activity in various dystonia types is critical to provide a comprehensive understanding of dystonia pathophysiology. Methods STN and cortex activity were recorded from 17 patients with cervical dystonia (CD), 19 with Meige syndrome, and 9 with generalized dystonia (GD) during the lead externalized period. We investigated local and network oscillatory characteristics, including power, bursts, and coherence. Additionally, we explored the relationship between these features and the severity of dystonic symptoms within each group and conducted a comparative analysis across the different dystonia types. Results Peaks of low‐frequency (4–13 Hz) and beta (14–30 Hz) power were present in the STN of all patients; most of the beta peaks are distributed in the high beta range (20–30 Hz). The CD and GD groups showed longer low‐frequency bursts and greater high beta power in STN than the Meige group. Interestingly, the CD group showed stronger STN‐cortex low‐frequency coherence, while the GD group had stronger STN‐cortex high beta coherence. Combined, low‐frequency and beta features could predict symptom severity with a performance of 73% in the CD group and 82% in the GD group. Interpretation Low‐frequency and high‐beta oscillations are present in the STN across all three types of dystonia. The distinct patterns may be associated with different underlying pathological mechanisms.

Blue honeysuckle (Lonicera caerulea L.) is an important cash crop growing in freezing regions with high freezing tolerance. Previous studies have shown that reactive oxygen species (ROS) play an important role in plant defense against low-temperature stress, however, the regulatory mechanism of freezing resistance network formed during the long evolutionary evolution of blue honeysuckle is not clear. By treating blue honeysuckles at -4 °C for 0 h, 12 h, 24 h, and 48 h, it was found that the contents of ROS and malondialdehyde increased as well as the activities of antioxidant enzymes were enhanced. Analysis of the transcriptome data revealed a large number of differentially expressed genes enriched in the glutathione metabolic pathway. Among them, LcGST, LcGSS, LcGGT, LcGSR, LcGPX genes were differentially expressed and enriched in the glutathione synthesis pathway under low-temperature stress in blue honeysuckle. The transient overexpression of transcription factor LcERF107 demonstrated the transcriptional regulation of glutathione metabolism pathway genes and its ability to increase the activities of antioxidant enzymes such as CAT, APX, SOD and POD to increase the scavenging capacity of reactive oxygen species to improve the tolerance to low-temperature stress. In this study, we demonstrated that the transcription factor LcERF107 activated the expression of genes related to oxygen glutathione metabolism and significantly enhanced the activities of antioxidant enzymes, which led to the accumulation of ROS and reactive oxygen species in the body, thus improving the freezing tolerance of blue honeysuckles under low-temperature stress.

Pyroptosis is strongly associated with refractory epilepsy. However, the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various neurological disorder processes by regulating programmed cell death. In this study, we identified a novel lncRNA, lncMCL1, by high-throughput screening, which suppresses NLRP3 inflammasome-dependent neural pyroptosis in epilepsy. We demonstrated that lncMCL1 is aberrantly underexpressed in the hippocampus and cortex of epilepsy patients, a phenomenon that was validated in various mouse and rat epilepsy models. Through CRISPR/Cas9, siRNA, and viral manipulation, gain- and loss-of-function experiments confirmed that lncMCL1 inhibits neuronal pyroptosis in vivo and in vitro and exerts antiepileptic effects. Mechanistically, lncMCL1 acts as a scaffold to modulate DDX3X protein stabilization by enhancing NEDD4-mediated DDX3X K48 ubiquitination, thereby inhibiting neural pyroptosis through the suppression of NLRP3 inflammasome signalling. Additionally, IL-18/IL-1β, downstream cytokines of pyroptosis, inhibit lncMCL1 expression through the activation of a shared pathway, the STAT3 pathway, forming a feedback loop. Our findings identify lncMCL1 as a critical regulator of neural cell pyroptosis and a promising therapeutic target for refractory epilepsy.

Introduction: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for Parkinson's disease (PD); however, long-term motor outcomes vary, affecting patients' quality of life. Identifying the factors that influence these heterogeneous motor outcomes is essential. This study investigated the factors influencing heterogeneous motor outcomes in patients with PD after STN-DBS and developed predictive models using preoperative demographic and clinical factors. Methods: We studied 92 patients with PD who underwent bilateral STN-DBS at the Beijing Tiantan Hospital between 2020 and 2022. Motor outcomes were assessed preoperatively and 1 and 12 months postoperatively. Patients were grouped based on different motor outcomes (change in Unified Parkinson's Disease Rating Scale Part III scores) between the 12- and 1-month assessments: those achieving minimal clinically significant motor improvement (MCID+) and those who did not (MCID-). Machine-learning models were used to predict outcomes based on preoperative factors. Results: The MCID+ group (n = 46) showed significantly better motor outcomes at the 1-year follow-up than the MCID- group (n = 46, mean difference 10.47, p < 0.001). A lower levodopa equivalent daily dose (p < 0.01), reduced anxiety (p < 0.05), reduced depression (p < 0.001), and milder freezing of gait (p < 0.05) were associated with better motor outcomes. Predictive models using logistic regression and XGBoost achieved a high accuracy (82%) in forecasting motor outcomes. Conclusions: Preoperative non-motor factors, particularly emotional status, significantly affected motor outcomes following STN-DBS. Machine-learning models enhance prognostic accuracy and offer the potential for personalized treatment strategies.

Microglia-mediated neuroinflammation plays a crucial role in the progression of Parkinson’s disease (PD). Dysregulation of lipid droplet homeostasis is a significant factor affecting microglial inflammatory responses, but the mechanisms underlying lipid droplet imbalance in PD are currently unclear. Here, we report a subtype of microglia characterized by high expression of long-chain acyl-CoA synthetase 1 (ACSL1) through single-nucleus RNA sequencing analysis and machine learning algorithms, linking lipid metabolism to PD neuroinflammation. The results of multiple loss- and gain-of-function experiments indicate that ACSL1 localized to the endoplasmic reticulum (ER) promotes lipid droplet accumulation to exacerbate microglial activation and dopaminergic neurons death. Mechanistically, activation of TANK-binding kinase 1 (TBK1) leads to the enrichment of ACSL1 on the endoplasmic reticulum, which generates acyl-CoA that are channelled for lipid droplet biogenesis. Additionally, high expression of ACSL1 promotes activation of TBK1 through Nrdp1-mediated K63 ubiquitination of TBK1, which triggers the amplification of the aforementioned biological effects. Moreover, NF-κB directly binds to the ACSL1 promoter and positively regulates its transcription, resulting in increased ACSL1 expression in microglia. Our findings suggest that manipulating lipid droplet biogenesis by modulating ACSL1 may be a potential strategy for treating neuroinflammation in PD patients.

Sorbitol is an important primary metabolite that serves as both a carbon source and signal to pathogens. The leaf diseases caused by Alternata alternata are particularly serious in crabapple (Malus micromalus). Here, we found that sorbitol can enhance the resistance of crabapple to A. alternata R1 by increasing the content of flavonoid catechin. Nanomaterials as an emerging technology tool can efficiently deliver lncRNA to target cells. Here, we found nanoencapsulated lncRNA809 (SPc/lncRNA809) exhibits significant resistance to R1strain. To elucidate the effect of SPc/lncRNA809 on flavonoids catechin synthesis, we observed the expression of lncRNA809 was consistent with that of MmNAC17 which regulates the synthesis of catechin and both could jointly respond to sorbitol. MmNAC17 induced the accumulation of catechin in vivo by directly activating the expression of catechin synthase genes MmF3H and MmLAR. Correspondingly, overexpression of lncRNA809 significantly upregulated the expression of MmNAC17 and enhanced the disease resistance. This study reveals for the first time that sorbitol positively regulates the expression of MmNAC17 through lncRNA809, promoting the accumulation of catechin via the expression of MmF3H and MmLAR, ultimately improving the defense response of M. micromalus. This research provides a crucial foundation for the establishment and application of sorbitol-based signaling regulatory networks.

BackgroundEpidemiologic researches show that short sleep duration may affect feeding behaviors resulting in higher energy intake and increased risk of obesity, but the further mechanisms that can interpret the causality remain unclear. The circadian rhythm is fine-tuned by the suprachiasmatic nucleus (SCN) as the master clock, which is essential for driving rhythms in food intake and energy metabolism through neuronal projections to the arcuate nucleus (ARC) and paraventricular nucleus (PVN).ResultsWe showed that chronic SD-induced aberrant expressions of AgRP/NPY and POMC attributed to compromised JAK/STAT3 signals and reduced energy expenditure in the mice, which can be rescued with AAV-genetic overexpression of BMAL1 into SCN. The potential mechanism may be related to the disruptions of SCN efferent mediated by BMAL1.ConclusionsChronic SD impairs energy balance through directly dampening BMAL1 expression, probably in the transcription level, in the SCN, which in turn affects the neuron projections to ARC and PVN. Remarkably, we provide evidence that may explain the causal mechanisms associated with sleep curtailment and obesity in adolescents.

BACKGROUND:Adaptive changes in the endometrial immune microenvironment during the luteal phase are essential for pregnancy, and their abnormalities are associated with recurrent pregnancy loss (RPL). Nevertheless, the specific mechanism is still unknown. Cuprotosis, an innovatively discovered type of programmed cell death, provides us with a pioneering perspective to decipher the landscape of luteal-phase endometrial immune microenvironment in RPL. This study aimed to analyze the immune landscape of luteal-phase endometrial microenvironment in RPL and explore the association of cuprotosis with it through integrative bioinformatics analysis.METHODS:The microarrays involving the luteal phase endometrial tissue of RPL were obtained from the GEO database. Differentially expressed genes (DEGs) of RPL were screened and key modules were detected by WGCNA. GO, KEGG, and GSEA immune enrichment analyses were performed on the DEGs in the most relevant modules to RPL. Then, the endometrial immune microenvironment landscape of RPL was analyzed, including immune infiltration analysis and correlation analysis between immune cells or immune functions. The interaction of cuprotosis-related genes (CRGs), the expression level between groups, the immune localization and their correlation with immune cells and immune function were analyzed. LASSO regression and Nomogram evaluated the diagnostic value of immune-related CRGS in RPL. Functional enrichment analysis was performed on the RPL signature CRGs. And RPL samples were grouped according to the expression of 7 RPL signature CRGs through unsupervised clustering analysis. After that, we analyzed the expression level of CRGs and immune infiltration, as well as performed immune function enrichment analysis in subtypes. In addition, we also screened potential drugs that might act on CRGs to improve the pathological mechanism of RPL.RESULTS:In this study, we uncovered that DEGs and genes in key modules derived from weighted gene co-expression network analysis (WGCNA) were involved in immune regulation. And the immune infiltration landscape of RPL was significantly different from healthy controls. Furthermore, six hub genes were screened from CRGs based on Cytohubba, and their expression profilings were verified in RPL and normal mouse samples. Besides, seven CRGs closely associated with the immune regulation of RPL were identified by Spearman correlation analysis, including SLC31A1, LIAS, DLD, DLAT, DBT, ATP7B, and ATP7A, named as immune-related CRGs. Furthermore, three subgroups clustered according to these seven genes showed significant differences in immune landscape, suggesting a remarkable effect of CRGs on immune regulation. Last but not least, we analyzed the regulation network of transcription factors, miRNAs, and CRGs, and screened potential compounds for the treatment of RPL by targeting CRGs.CONCLUSIONS:The abnormal endometrial immune microenvironment in the luteal phase was associated with the pathomechanism of RPL, and cuprotosis was closely involved in the immune microenvironment in the luteal phase endometrium of RPL. Collectively, this study revealed the potential contribution of CRGs to the pathogenesis of RPL, providing a novel breakthroughs in insights into the pathogenesis, diagnosis, and treatment of RPL.