CIS is a potent checkpoint in NK cell-mediated tumor immunity.

The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

ELI trifocal microscope: a precise system to prepare target cryo-lamellae for in situ cryo-ET study.

Cryo-electron tomography (cryo-ET) has become a powerful approach to study the high-resolution structure of cellular macromolecular machines in situ. However, the current correlative cryo-fluorescence and electron microscopy lacks sufficient accuracy and efficiency to precisely prepare cryo-lamellae of target locations for subsequent cryo-ET. Here we describe a precise cryogenic fabrication system, ELI-TriScope, which sets electron (E), light (L) and ion (I) beams at the same focal point to achieve accurate and efficient preparation of a target cryo-lamella. ELI-TriScope uses a commercial dual-beam scanning electron microscope modified to incorporate a cryo-holder-based transfer system and embed an optical imaging system just underneath the vitrified specimen. Cryo-focused ion beam milling can be accurately navigated by monitoring the real-time fluorescence signal of the target molecule. Using ELI-TriScope, we prepared a batch of cryo-lamellae of HeLa cells targeting the centrosome with a success rate of ~91% and discovered new in situ structural features of the human centrosome by cryo-ET.

Biosynthetic Polymalic Acid as a Delivery Nanoplatform for Translational Cancer Medicine.

Poly(ß-L-malic acid) (PMLA) is a natural polyester produced by numerous microorganisms. Regarding its biosynthetic machinery, a nonribosomal peptide synthetase (NRPS) is proposed to direct polymerization of L-malic acid in vivo. Chemically versatile and biologically compatible, PMLA can be used as an ideal carrier for several molecules, including nucleotides, proteins, chemotherapeutic drugs, and imaging agents, and can deliver multimodal theranostics through biological barriers such as the blood-brain barrier. We focus on PMLA biosynthesis in microorganisms, summarize the physicochemical and physiochemical characteristics of PMLA as a naturally derived polymeric delivery platform at nanoscale, and highlight the attachment of functional groups to enhance cancer detection and treatment.

A chromosome-scale genome of Rhus chinensis Mill. provides new insights into plant-insect interaction and gallotannins biosynthesis.

Rhus chinensis Mill., an economically valuable Anacardiaceae species, is parasitized by the galling aphid Schlechtendalia chinensis, resulting in the formation of the Chinese gallnut (CG). Here, we report a chromosomal-level genome assembly of R. chinensis, with a total size of 389.40 Mb and scaffold N50 of 23.02 Mb. Comparative genomic and transcriptome analysis revealed that the enhanced structure of CG and nutritional metabolism contribute to improving the adaptability of R. chinensis to S. chinensis by supporting CG and galling aphid growth. CG was observed to be abundant in hydrolysable tannins (HT), particularly gallotannin and its isomers. Tandem repeat clusters of dehydroquinate dehydratase/shikimate dehydrogenase (DQD/SDH) and serine carboxypeptidase-like (SCPL) and their homologs involved in HT production were determined as specific to HT-rich species. The functional differentiation of DQD/SDH tandem duplicate genes and the significant contraction in the phenylalanine ammonia-lyase (PAL) gene family contributed to the accumulation of gallic acid and HT while minimizing the production of shikimic acid, flavonoids, and condensed tannins in CG. Furthermore, we identified one UDP glucosyltransferase (UGT84A), three carboxylesterase (CXE), and six SCPL genes from conserved tandem repeat clusters that are involved in gallotannin biosynthesis and hydrolysis in CG. We then constructed a regulatory network of these genes based on co-expression and transcription factor motif analysis. Our findings provide a genomic resource for the exploration of the underlying mechanisms of plant-galling insect interaction and highlight the importance of the functional divergence of tandem duplicate genes in the accumulation of secondary metabolites.

The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15.

The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.

Chromosome-level genome assembly of Hippophae tibetana provides insights into high-altitude adaptation and flavonoid biosynthesis.

BACKGROUND: As an endemic shrub of the Qinghai-Tibetan Plateau (QTP), the distribution of Hippophae tibetana Schlecht. ranges between 2800 and 5200 m above sea level. As the most basal branch of the Hippophae genus, H. tibetana has an extensive evolutionary history. The H. tibetana is a valuable tree for studying the ecological evolution of species under extreme conditions. RESULTS: Here, we generated a high-quality chromosome-level genome of H. tibetana. The total size of the assembly genome is 917 Mb. The phylogenomic analysis of 1064 single-copy genes showed a divergence between 3.4 and 12.8 Mya for H. tibetana. Multiple gene families associated with DNA repair and disease resistance were significantly expanded in H. tibetana. We also identified many genes related to DNA repair with signs of positive selection. These results showed expansion and positive selection likely play important roles in H. tibetana's adaptation to comprehensive extreme environments in the QTP. A comprehensive genomic and transcriptomic analysis identified 49 genes involved in the flavonoid biosynthesis pathway in H. tibetana. We generated transgenic sea buckthorn hairy root producing high levels of flavonoid. CONCLUSIONS: Taken together, this H. tibetana high-quality genome provides insights into the plant adaptation mechanisms of plant under extreme environments and lay foundation for the functional genomic research and molecular breeding of H. tibetana.

Self-Management Support Using Advertising Principles for Older Adults With Low Income at High Cardiovascular Risk: A Randomized Controlled Trial.

BACKGROUND: Self-management education and support (SMES) interventions have modest effects on intermediate outcomes for those at risk of cardiovascular disease, but few studies have measured or demonstrated an effect on clinical end points. Advertising for commercial products is known to influence behavior, but advertising principles are not typically incorporated into SMES design. METHODS: This randomized trial studied the effect of a novel tailored SMES program designed by an advertising firm among a population of older adults with low income at high cardiovascular risk in Alberta, Canada. The intervention included health promotion messaging from a fictitious "peer" and facilitated relay of clinical information to patients' primary care provider and pharmacist. The primary outcome was the composite of death, myocardial infarction, stroke, coronary revascularization, and hospitalizations for cardiovascular-related ambulatory care-sensitive conditions. Rates of the primary outcome and its components were compared using negative binomial regression. Secondary outcomes included quality of life (EQ-5D [EuroQoL 5-dimension] index score), medication adherence, and overall health care costs. RESULTS: We randomized 4761 individuals, with a mean age of 74.4 years, of whom 46.8% were female. There was no evidence of statistical interaction (P=0.99) or of a synergistic effect between the 2 interventions in the factorial trial with respect to the primary outcome, which allowed us to evaluate the effect of each intervention separately. Over a median follow-up time of 36 months, the rate of the primary outcome was lower in the group that received SMES compared with the control group (incidence rate ratio, 0.78 [95% CI, 0.61 to 1.00]; P=0.047). No significant between-group changes in quality of life over time were observed (mean difference, 0.0001 [95% CI, -0.018 to 0.018]; P=0.99). The proportion of participants who were adherent to medications was not different between the 2 groups (P=0.199 for statins and P=0.754 for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers). Overall adjusted health care costs did not differ between those receiving SMES and the control group ($2015 [95% CI, -$1953 to $5985]; P=0.320). CONCLUSIONS: For older adults with low income, a tailored SMES program using advertising principles reduced the rate of clinical outcomes compared with usual care. The mechanisms of improvement are unclear and further studies are required. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02579655.

Eliminating Medication Copayments for Low-Income Older Adults at High Cardiovascular Risk: A Randomized Controlled Trial.

BACKGROUND: One in eight people with heart disease has poor medication adherence that, in part, is related to copayment costs. This study tested whether eliminating copayments for high-value medications among low-income older adults at high cardiovascular risk would improve clinical outcomes. METHODS: This randomized 2×2 factorial trial studied 2 distinct interventions in Alberta, Canada: eliminating copayments for high-value preventive medications and a self-management education and support program (reported separately). The findings for the first intervention, which waived the usual 30% copayment on 15 medication classes commonly used to reduce cardiovascular events, compared with usual copayment, is reported here. The primary outcome was the composite of death, myocardial infarction, stroke, coronary revascularization, and cardiovascular-related hospitalizations over a 3-year follow-up. Rates of the primary outcome and its components were compared using negative binomial regression. Secondary outcomes included quality of life (Euroqol 5-dimension index score), medication adherence, and overall health care costs. RESULTS: A total of 4761 individuals were randomized and followed for a median of 36 months. There was no evidence of statistical interaction (P=0.99) or of a synergistic effect between the 2 interventions in the factorial trial with respect to the primary outcome, which allowed us to evaluate the effect of each intervention separately. The rate of the primary outcome was not reduced by copayment elimination, (521 versus 533 events, incidence rate ratio 0.84 [95% CI, 0.66-1.07], P=0.162). The incidence rate ratio for nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (0.97 [95% CI, 0.67-1.39]), death (0.94 [95% CI, 0.80 to 1.11]), and cardiovascular-related hospitalizations (0.78 [95% CI, 0.57 to 1.06]) did not differ between groups. No significant between-group changes in quality of life over time were observed (mean difference, 0.012 [95% CI, -0.006 to 0.030], P=0.19). The proportion of participants who were adherent to statins was 0.72 versus 0.69 for the copayment elimination versus usual copayment groups, respectively (mean difference, 0.03 [95% CI, 0.006-0.06], P=0.016). Overall adjusted health care costs did not differ ($3575 [95% CI, -605 to 7168], P=0.098). CONCLUSIONS: In low-income adults at high cardiovascular risk, eliminating copayments (average, $35/mo) did not improve clinical outcomes or reduce health care costs, despite a modest improvement in adherence to medications. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02579655.

Temporal interference stimulation targets deep primate brain.

Temporal interference (TI) stimulation, a novel non-invasive stimulation strategy, has recently been shown to modulate neural activity in deep brain regions of living mice. Yet, it is uncertain if this method is applicable to larger brains and whether the electric field produced under traditional safety currents can penetrate deep regions as observed in mice. Despite recent model-based simulation studies offering positive evidence at both macro- and micro-scale levels, the absence of electrophysiological data from actual brains hinders comprehensive understanding and potential application of TI. This study aims to directly measure the spatiotemporal properties of the interfered electric field in the rhesus monkey brain and to validate the effects of TI on the human brain. Two monkeys were involved in the measurement, with implantation of several stereo-electroencephalography (SEEG) depth electrodes. TI stimulation was applied to anesthetized monkeys using two pairs of surface electrodes at differing stimulation parameters. Model-based simulations were also conducted and subsequently compared with actual recordings. Additionally, TI stimulation was administered to patients with motor disorders to validate its effects on motor symptoms. Through the integration of computational electric field simulation with empirical measurements, it was determined that the temporally interfering electric fields in the deep central regions are capable of attaining a magnitude sufficient to induce a subthreshold modulation effect on neural signals. Additionally, an improvement in movement disorders was observed as a result of TI stimulation. This study is the first to systematically measure the TI electric field in living non-human primates, offering empirical evidence that TI holds promise as a more focal and precise method for modulating neural activities in deep regions of a large brain. This advancement paves the way for future applications of TI in treating neuropsychiatric disorders.

Subthalamic and pallidal oscillations and their couplings reflect dystonia severity and improvements by deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) and subthalamic nucleus (STN) is employed for the treatment of dystonia. Pallidal low-frequency oscillations have been proposed as a pathophysiological marker for dystonia. However, the role of subthalamic oscillations and STN-GPi coupling in relation to dystonia remains unclear. OBJECTIVE: We aimed to explore oscillatory activities within the STN-GPi circuit and their correlation with the severity of dystonia and efficacy achieved by DBS treatment. METHODS: Local field potentials were recorded simultaneously from the STN and GPi from 13 dystonia patients. Spectral power analysis was conducted for selected frequency bands from both nuclei, while power correlation and the weighted phase lag index were used to evaluate power and phase couplings between these two nuclei, respectively. These features were incorporated into generalized linear models to assess their associations with dystonia severity and DBS efficacy. RESULTS: The results revealed that pallidal theta power, subthalamic beta power and subthalamic-pallidal theta phase coupling and beta power coupling all correlated with clinical severity. The model incorporating all selected features predicts empirical clinical scores and DBS-induced improvements, whereas the model relying solely on pallidal theta power failed to demonstrate significant correlations. CONCLUSIONS: Beyond pallidal theta power, subthalamic beta power, STN-GPi couplings in theta and beta bands, play a crucial role in understanding the pathophysiological mechanism of dystonia and developing optimal strategies for DBS.

Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

Comparison of children and adults in deep brain stimulation for Tourette Syndrome: a large-scale multicenter study of 102 cases with long-term follow-up.

BACKGROUND: Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring evidence to compare different age categories. METHODS: This retrospective cohort study recruited 102 GTS patients who underwent DBS between October 2006 and April 2022 at two national centers. Patients were divided into two age categories: children (aged < 18 years; n = 34) and adults (aged ≥ 18 years; n = 68). The longitudinal outcomes as tic symptoms were assessed by the YGTSS, and the YBOCS, BDI, and GTS-QOL were evaluated for symptoms of obsessive-compulsive disorder (OCD), depression, and quality of life, respectively. RESULTS: Overall, these included patients who finished a median 60-month follow-up, with no significant difference between children and adults (p = 0.44). Overall, the YGTSS total score showed significant postoperative improvements and further improved with time (improved 45.2%, 51.6%, 55.5%, 55.6%, 57.8%, 61.4% after 6, 12, 24, 36, 48, and ≥ 60 months of follow-up compared to baseline, respectively) in all included patients (all p < 0.05). A significantly higher improvement was revealed in children than adults at ≥ 60 months of follow-up in the YGTSS scores (70.1% vs 55.9%, p = 0.043), and the time to achieve 60% improvement was significantly shorter in the children group (median 6 months vs 12 months, p = 0.013). At the last follow-up, the mean improvements were 45.4%, 48.9%, and 55.9% and 40.3%, 45.4%, and 47.9% in YBOCS, BDI, and GTS-QOL scores for children and adults, respectively, which all significantly improved compared to baseline (all p < 0.05) but without significant differences between these two groups (all p > 0.05), and the children group received significantly higher improvement in GTS-QOL scores than adults (55.9% vs. 47.9%, p = 0.049). CONCLUSIONS: DBS showed acceptable long-term efficacy and safety for both children and adults with GTS. Surgeries performed for patients younger than 18 years seemed to show acceptable long-term efficacy and safety and were not associated with increased risks of loss of benefit compared to patients older than 18 at the time of surgery. However, surgeries for children should also be performed cautiously to ensure their refractoriness and safety.

Translational medicine for acute lung injury.

Acute lung injury (ALI) is a complex disease with numerous causes. This review begins with a discussion of disease development from direct or indirect pulmonary insults, as well as varied pathogenesis. The heterogeneous nature of ALI is then elaborated upon, including its epidemiology, clinical manifestations, potential biomarkers, and genetic contributions. Although no medication is currently approved for this devastating illness, supportive care and pharmacological intervention for ALI treatment are summarized, followed by an assessment of the pathophysiological gap between human ALI and animal models. Lastly, current research progress on advanced nanomedicines for ALI therapeutics in preclinical and clinical settings is reviewed, demonstrating new opportunities towards developing an effective treatment for ALI.

Investigation on the machinability of polycrystalline ZnSe by elliptical vibration diamond cutting.

Polycrystalline zinc selenide is widely used in advanced optical systems due to its superior optical properties. However, the soft and brittle properties bring a challenge for high-quality surface processing. In recent years, elliptical vibration cutting has been proven as a promising method for machining brittle materials. In the present research, a series of grooving and planning experiments were carried out to investigate the machinability of zinc selenide with elliptical vibration cutting. The removal mechanism was analyzed from fracture characteristics, chip morphology, and phase transformation. The results show that elliptical vibration cutting is effective in suppressing cleavage-induced craters. Reducing the nominal cutting speed is beneficial to inhibit the spring back-induced tearing of grains. A 94-time increase in the critical depth of cut was achieved by vibration trajectory optimization compared to ordinary cutting. Moreover, the influence mechanism of feed on the evolution of surface morphology was revealed. Finally, a zinc selenide microlens array was successfully fabricated. The performance was evaluated by geometric parameter measurements and a multiple imaging test. The findings provide a prospective method for ductile regime machining of zinc selenide.

Statistical properties for an optically injected chaotic semiconductor laser with a high-pass filter.

Chaotic waveforms with Gaussian distributions are significant for laser-chaos-based applications such as random number generation. By exploring the injection parameter space of the optical injection semiconductor lasers, we numerically investigate the associated probability density functions of the generated chaotic waveforms when different high-pass filters with different cutoff frequencies are used. Our results demonstrate that the chaotic waveforms with Gaussian probability density functions can be obtained once the cutoff frequency of the high-pass filter is larger than the laser relaxation resonance frequency. Especially, we find that the Gaussian probability density function can reach a superhigh coefficient of determination R2 ≥ 99.5% and an ultralow skewness |S|<0.1 in a large parameter space by jointly controlling the injection parameter and cutoff frequency.

TT-type resonator-based differential photoacoustic spectroscopy for trace gas detection.

A novel TT-type resonator was proposed for the first time, to our knowledge, to realize differential photoacoustic (PA) detection for trace gas measurement. The special design of the TT-type resonator allows us to install the microphone at the resonant center of the acoustic field to maximize the use of the absorption-induced PA signal. To meet the requirement of low gas consumption and easy integration, the TT-type resonator-based PA cell was fabricated as a fiber-coupled module with an inner volume of only 1.1 ml. For validation, the TT-type PA cell was integrated to a photoacoustic spectroscopy (PAS) system for acetylene detection. As a result, a linearity of 0.99999 was achieved in a concentration range from 0 to 5000 ppm with a noise equivalent sensitivity of 101 ppb. The proposed TT-type resonator contributes a new style of PA cell structure to the field of PAS gas detection, combining the advantages of easy integration, low gas consumption, differential detection, and photoacoustic enhancement together.

Neurophysiological features of STN LFP underlying sleep fragmentation in Parkinson's disease.

BACKGROUND: Sleep fragmentation is a persistent problem throughout the course of Parkinson's disease (PD). However, the related neurophysiological patterns and the underlying mechanisms remained unclear. METHOD: We recorded subthalamic nucleus (STN) local field potentials (LFPs) using deep brain stimulation (DBS) with real-time wireless recording capacity from 13 patients with PD undergoing a one-night polysomnography recording, 1 month after DBS surgery before initial programming and when the patients were off-medication. The STN LFP features that characterised different sleep stages, correlated with arousal and sleep fragmentation index, and preceded stage transitions during N2 and REM sleep were analysed. RESULTS: Both beta and low gamma oscillations in non-rapid eye movement (NREM) sleep increased with the severity of sleep disturbance (arousal index (ArI)-betaNREM: r=0.9, p=0.0001, sleep fragmentation index (SFI)-betaNREM: r=0.6, p=0.0301; SFI-gammaNREM: r=0.6, p=0.0324). We next examined the low-to-high power ratio (LHPR), which was the power ratio of theta oscillations to beta and low gamma oscillations, and found it to be an indicator of sleep fragmentation (ArI-LHPRNREM: r=-0.8, p=0.0053; ArI-LHPRREM: r=-0.6, p=0.0373; SFI-LHPRNREM: r=-0.7, p=0.0204; SFI-LHPRREM: r=-0.6, p=0.0428). In addition, long beta bursts (>0.25 s) during NREM stage 2 were found preceding the completion of transition to stages with more cortical activities (towards Wake/N1/REM compared with towards N3 (p<0.01)) and negatively correlated with STN spindles, which were detected in STN LFPs with peak frequency distinguishable from long beta bursts (STN spindle: 11.5 Hz, STN long beta bursts: 23.8 Hz), in occupation during NREM sleep (ß=-0.24, p<0.001). CONCLUSION: Features of STN LFPs help explain neurophysiological mechanisms underlying sleep fragmentations in PD, which can inform new intervention for sleep dysfunction. TRIAL REGISTRATION NUMBER: NCT02937727.