Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity.

Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling.

N1-methyladenosine (m1A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels. Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.

Topological disruption of low- and high-order functional networks in presbycusis.

Prior efforts have manifested that functional connectivity (FC) network disruptions are concerned with cognitive disorder in presbycusis. The present research was designed to investigate the topological reorganization and classification performance of low-order functional connectivity (LOFC) and high-order functional connectivity (HOFC) networks in patients with presbycusis. Resting-state functional magnetic resonance imaging (Rs-fMRI) data were obtained in 60 patients with presbycusis and 50 matched healthy control subjects (HCs). LOFC and HOFC networks were then constructed, and the topological metrics obtained from the constructed networks were compared to evaluate topological differences in global, nodal network metrics, modularity and rich-club organization between patients with presbycusis and HCs. The use of HOFC profiles boosted presbycusis classification accuracy, sensitivity and specificity compared to that using LOFC profiles. The brain networks in both patients with presbycusis and HCs exhibited small-world properties within the given threshold range, and striking differences between groups in topological metrics were discovered in the constructed networks (LOFC and HOFC). NBS analysis identified a subnetwork involving 26 nodes and 23 signally altered internodal connections in patients with presbycusis in comparison to HCs in HOFC networks. This study highlighted the topological differences between LOFC and HOFC networks in patients with presbycusis, suggesting that HOFC profiles may help to further identify brain network abnormalities in presbycusis.

Erratum: Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma: Erratum.

[This corrects the article DOI: 10.7150/ijbs.54014.].

The construction of a stable hydrogen-bonded organic framework for the photocatalytic reduction and removal of uranium.

An imidazolyl hydrogen-bonded organic framework (HOF-T) with outstanding thermal and water stability was constructed by C-H⋯N hydrogen bonding and C-H⋯π interactions. UO22+ can be selectively captured by the imidazole group of HOF-T and rapidly reduced to UO2 under visible light irradiation, realizing exceptional uranium removal with high capacity and fast kinetics.

Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a formidable cancer type that poses significant treatment challenges, including radiotherapy (RT) resistance. The metabolic characteristics of tumors present substantial obstacles to cancer therapy, and the relationship between RT and tumor metabolism in HNSCC remains elusive. Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Here, we report that after RT, glutamine levels rise in HNSCC, and the glutamine transporter protein SLC1A5 is upregulated. Notably, blocking glutamine significantly enhances the therapeutic efficacy of RT in HNSCC. Furthermore, inhibition of glutamine combined with RT triggers immunogenic tumor ferroptosis, a form of nonapoptotic regulated cell death. Mechanistically, RT increases interferon regulatory factor (IRF) 1 expression by activating the interferon signaling pathway, and glutamine blockade augments this efficacy. IRF1 drives transferrin receptor expression, elevating intracellular Fe2+ concentration, disrupting iron homeostasis, and inducing cancer cell ferroptosis. Importantly, the combination treatment-induced ferroptosis is dependent on IRF1 expression. Additionally, blocking glutamine combined with RT boosts CD47 expression and hinders macrophage phagocytosis, attenuating the treatment effect. Dual-blocking glutamine and CD47 promote tumor remission and enhance RT-induced ferroptosis, thereby ameliorating the tumor microenvironment. Our work provides valuable insights into the metabolic and immunological mechanisms underlying RT-induced ferroptosis, highlighting a promising strategy to augment RT efficacy in HNSCC.

Intracerebral hemodynamic abnormalities in patients with Parkinson's disease: Comparison between multi-delay arterial spin labelling and conventional single-delay arterial spin labelling.

PURPOSE: The purpose of this study was to analyze the intracerebral abnormalities of hemodynamics in patients with Parkinson's disease (PD) through arterial spin labelling (ASL) technique with multi-delay ASL (MDASL) and conventional single-delay ASL (SDASL) protocols and to verify the potential clinical application of these features for the diagnosis of PD. MATERIALS AND METHODS: Perfusion data of the brain obtained using MDASL and SDASL in patients with PD were compared to those obtained in healthy control (HC) subjects. Intergroup comparisons of z-scored cerebral blood flow (zCBF), arterial transit time (zATT) and cerebral blood volume (zCBV) were performed via voxel-based analysis. Performance of these perfusion metrics were estimated using area under the receiver operating characteristic curve (AUC) and compared using Delong test. RESULTS: A total of 47 patients with PD (29 men; 18 women; mean age, 69.0 ± 7.6 (standard deviation, [SD]) years; range: 50.0-84.0 years) and 50 HC subjects (28 men; 22 women; mean age, 70.1 ± 6.2 [SD] years; range: 50.0-93.0 years) were included. Relative to the uncorrected-zCBF map, the corrected-zCBF map further refined the distributed brain regions in the PD group versus the HC group, manifested as the extension of motor-related regions (PFWE < 0.001). Compared to the HC subjects, patients with PD had elevated zATT and zCBV in the right putamen, a shortened zATT in the superior frontal gyrus, and specific zCBV variations in the left precuneus and the right supplementary motor area (PFWE < 0.001). The corrected-zCBF (AUC, 0.90; 95% confidence interval [CI]: 0.84-0.96) showed better classification performance than uncorrected-zCBF (AUC, 0.84; 95% CI: 0.75-0.92) (P = 0.035). zCBV achieved an AUC of 0.89 (95% CI: 0.82-0.96) and zATT achieved an AUC of 0.66 (95% CI: 0.55-0.77). The integration model of hemodynamic features from MDASL provided improved performance (AUC, 0.97; 95% CI: 0.95-0.98) for the diagnosis of PD by comparison with each perfusion model (P < 0.001). CONCLUSION: ASL identifies impaired hemodynamics in patients with PD including regional abnormalities of CBF, CBV and ATT, which can better be mapped with MDASL compared to SDASL. These findings provide complementary depictions of perfusion abnormalities in patients with PD and highlight the clinical feasibility of MDASL.

Rationally designed nanotrap structures for efficient separation of rare earth elements over a single step.

Extracting rare earth elements (REEs) from wastewater is essential for the growth and an eco-friendly sustainable economy. However, it is a daunting challenge to separate individual rare earth elements by their subtle differences. To overcome this difficulty, we report a unique REE nanotrap that features dense uncoordinated carboxyl groups and triazole N atoms in a two-fold interpenetrated metal-organic framework (named NCU-1). Notably, the synergistic effect of suitable pore sizes and REE nanotraps in NCU-1 is highly responsive to the size variation of rare-earth ions and shows high selectivity toward light REE. As a proof of concept, Pr/Lu and Nd/Er are used as binary models, which give a high separation factor of SFPr/Lu = 796 and SFNd/Er = 273, demonstrating highly efficient separation over a single step. This ability achieves efficient and selective extraction and separation of REEs from mine tailings, establishing this platform as an important advance for sustainable obtaining high-purity REEs.

The risk of concurrent malignancies in patients with multiple endocrine neoplasia type 1: insights into clinical characteristics of those with multiple endocrine neoplasia type 1.

OBJECTIVE: Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. METHODS: Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. RESULTS: A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. CONCLUSION: Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.

Optimization of structural connectomes and scaled patterns of structural-functional decoupling in Parkinson's disease.

Parkinson's disease (PD) is manifested with disrupted topology of the structural connection network (SCN) and the functional connection network (FCN). However, the SCN and its interactions with the FCN remain to be further investigated. This multimodality study attempted to precisely characterize the SCN using diffusion kurtosis imaging (DKI) and further identify the neuropathological pattern of SCN-FCN decoupling, underscoring the neurodegeneration of PD. Diffusion-weighted imaging and resting-state functional imaging were available for network constructions among sixty-nine patients with PD and seventy demographically matched healthy control (HC) participants. The classification performance and topological prosperities of both the SCN and the FCN were analyzed, followed by quantification of the SCN-FCN couplings across scales. The SCN constructed by kurtosis metrics achieved optimal classification performance (area under the curve 0.89, accuracy 80.55 %, sensitivity 78.40 %, and specificity 80.65 %). Along with diverse alterations of structural and functional network topology, the PD group exhibited decoupling across scales including: reduced global coupling; increased nodal coupling within the sensorimotor network (SMN) and subcortical network (SN); higher intramodular coupling within the SMN and SN and lower intramodular coupling of the default mode network (DMN); decreased coupling between the modules of DMN-fronto-parietal network and DMN-visual network, but increased coupling between the SMN-SN module. Several associations between the coupling coefficient and topological properties of the SCN, as well as between network values and clinical scores, were observed. These findings validated the clinical implementation of DKI for structural network construction with better differentiation ability and characterized the SCN-FCN decoupling as supplementary insight into the pathological process underlying PD.

Explorative research on glucolipid metabolism and levels of adipokines in pseudohypoparathyroidism type 1 patients.

BACKGROUND: Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH resistant have been widely studied, glucolipid metabolism abnormalities observed in PHP1 patients have received little attention. The aim of this research is to explore the glucolipid metabolism features in a rather large cohort of PHP1 patient. In the current study, PHP1 patients and primary hyperparathyroidism patients as well as normal control were recruited for the investigation. Glucolipid metabolic indices as well as the level of four adipokines were examined. RESULTS: A total of 49 PHP1 patients, 64 PHPT patients and 30 healthy volunteers were enrolled. A trend of higher HOMA-ß index was found in PHP1 patients than normal controls (median 97.08% vs 68.19%, p = 0.060). Both the PHP1 and PHPT group presented with significantly lower TNFα level compared to normal controls (average 10.74 pg/ml and 12.53 pg/ml vs 15.47 pg/ml, p = 0.002 and 0.041, respectively). FGF21 level was significantly higher in PHPT group than in PHP1 group (median 255.74 pg/ml vs 167.46 pg/ml, p = 0.019). No significant difference in glucolipid metabolic indices and adipokines was found between PHP1A or PHP1B patients and normal controls, while overweight/obese PHP1 patients tended to have higher leptin than normal-BMI cases (p = 0.055). Multiple linear regression analysis showed BMI rather than PTH or HOMA-IR to be an independent variable of leptin in PHP1. CONCLUSION: Metabolic stress given upon especially overweight PHP1 patients may resulted in possible ß-cell compensation. Elevated TNFα may be related with hyper-PTH level regardless of calcium level.

Genotype-phenotype correlations in pseudohypoparathyroidism type 1a patients: a systemic review.

BACKGROUND: Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO). OBJECTIVES: To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them. METHODS: Articles pertaining to PHP1a until May, 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them. RESULTS: A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%), and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). Thyroid stimulating hormone resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of the round face (P = .001) and subcutaneous ossifications (P < .001) than those with loss-of-function (non-sense, frameshift, splicing site variants, and large deletions) variants. CONCLUSIONS: This study revealed the correlation between loss-of-function RVs with round faces and subcutaneous ossifications in PHP 1a patients. Further exploration of genotype-phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.

Minichromosome maintenance 6 protects against renal fibrogenesis by regulating DUSP6-mediated ERK/GSK-3ß/Snail1 signaling.

Minichromosome maintenance 6 (MCM6) has been implicated in the progression of various malignant tumors; however, its exact physiological function in kidney diseases remains unclear. Here, we demonstrated that MCM6 levels showed a significant increase in the proximal tubular cells during progressive renal fibrosis in two unrelated in vivo fibrotic models, including unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Depletion of MCM6 aggravated partial epithelial-mesenchymal transition, extracellular matrix accumulation, and myofibroblast activation in the kidneys of UUO or UIRI mice. Conversely, overexpression of MCM6 promoted the recovery of E-cadherin and retarded UUO- or UIRI-induced renal fibrosis. In addition, DUSP6 expression substantially decreased in fibrotic kidneys, and it might be involved in MCM6-induced renal fibrosis by regulating the activation of ERK/GSK-3ß/Snail1 signaling. In conclusion, our results highlight the significance of MCM6 in renal fibrosis, providing a potential therapeutic target for patients with chronic kidney disease.

Integration of AIEgens into covalent organic frameworks for pyroptosis and ferroptosis primed cancer immunotherapy.

Immunogenic programmed cell death, such as pyroptosis and ferroptosis, efficiently induces an acute inflammatory response and boosts antitumor immunity. However, the exploration of dual-inducers, particularly nonmetallic inducers, capable of triggering both pyroptosis and ferroptosis remains limited. Here we show the construction of a covalent organic framework (COF-919) from planar and twisted AIEgen-based motifs as a dual-inducer of pyroptosis and ferroptosis for efficient antitumor immunity. Mechanistic studies reveal that COF-919 displays stronger near-infrared light absorption, lower band energy, and longer lifetime to favor the generation of reactive oxygen species (ROS) and photothermal conversion, triggering pyroptosis. Because of its good ROS production capability, it upregulates intracellular lipid peroxidation, leading to glutathione depletion, low expression of glutathione peroxidase 4, and induction of ferroptosis. Additionally, the induction of pyroptosis and ferroptosis by COF-919 effectively inhibits tumor metastasis and recurrence, resulting in over 90% tumor growth inhibition and cure rates exceeding 80%.

Trabecular Bone Score as a More Sensitive Tool to Evaluate Bone Involvement in MEN1-related Primary Hyperparathyroidism.

CONTEXT: The skeletal involvement of multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) is not exactly the same as that of sporadic primary hyperparathyroidism (SHPT). Trabecular bone score (TBS) as a texture parameter has been reported to reflect trabecular bone damage. OBJECTIVE: This study aimed to compare the clinical characteristics, especially the skeletal involvement, between patients with MHPT and SHPT. METHODS: The clinical characteristics were retrospectively collected in 120 patients with MHPT and compared with 360 patients with SHPT in the same period. Dual-energy X-ray absorptiometry were conducted in some patients with MHPT, in whom bone mineral density (BMD) and calculated TBS derived from lumbar spine dual-energy X-ray absorptiometry images were compared with those of patients with SHPT. RESULTS: Although the duration of disease in the MHPT group was longer, the age at hospital visit was significantly lower than that in the SHPT group (43.5 [interquartile range, 31.5-52.0] vs 52.0 [interquartile range, 40.5-61.0], P < .001). The proportion of skeletal involvement in the MHPT group was significantly lower. However, in the subgroup of MHPT cases (n = 86) with data of BMD, there was no significant difference in skeletal involvement from SHPT cases matched for gender and age. Although the BMD and TBS in the lumbar spines of patients with MHPT were lower than those of patients with SHPT (BMD: 0.91 ± 0.18 g/cm2 vs 1.01 ± 0.17 g/cm2; TBS: 1.22 ± 0.14 vs 1.29 ± 0.11, P < .001). According to TBS, among 34 patients with MHPT with normal BMD, 15 patients had bone microstructure damage. CONCLUSION: The cancellous bone microarchitecture was more severely damaged in patients with MHPT according to TBS, which suggested that TBS could be a sensitive supplemental index in addition to BMD to identify bone-involvement risk in patients with MHPT.

Genetic and clinical screening for hereditary primary hyperparathyroidism in a large Chinese cohort: a single-center study.

Primary hyperparathyroidism (PHPT) includes sporadic PHPT and hereditary PHPT. However, until now, there have been no exact data on the proportion and composition of hereditary PHPT in the Chinese PHPT population. This study aimed to clarify the proportion and composition of hereditary PHPT in patients at a large academic center in Beijing, China, and to analyze genotype-phenotype characteristics. A total of 394 newly diagnosed Han PHPT patients who consented to genetic screening were enrolled. Targeted next-generation sequencing (T-NGS) (including for MEN1, RET, CDKN1B, CaSR, HRPT2/CDC73, GNA11, AP2S1, GCM2), combined with MEN1-multiplex ligation-dependent probe amplification (MLPA) and CDC73-MLPA, was used for genetic screening. Diagnosis of hereditary PHPT was based on clinical manifestations, family history, and genetic screening. Thirty-seven pathogenic (P)/likely pathogenic (LP) variants were detected in 41 patients via T-NGS, and three patients carried long-range deletions of MEN1 or CDC73 detected by MLPA, with a variant detection rate of 11.2% (44/394). In total, 30 patients were clinically diagnosed with MEN1. Combined with genetic and clinical screening, the rate of hereditary PHPT in this study was 18.8% (74/394). For purposes of comparison, the rate of unequivocal nonhereditary PHPT was 66.5% (262/394); 14.7% (58/394) did not exhibit the clinical features of hereditary PHPT but carried variants of uncertain clinical significance and so could not be clearly categorized. Both the age at hospital visit (43.6 ± 14.0 versus 53.7 ± 14.9 years) and age at onset (35.4 ± 13.8 versus 50.6 ± 14.8 years) in the hereditary group (n = 74) were significantly lower than those in the nonhereditary group (n = 262). Higher levels of ionized calcium and serum ß-CTX were observed in the hereditary group; proportions of parathyroid hyperplasia and multigland involvement were also higher. In addition to multigland disease and positive family history, it is recommended that patients with an age of onset less than 38 should be screened for hereditary forms. © 2023 American Society for Bone and Mineral Research (ASBMR).

Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been demonstrated to play a critical role in regulating cholesterol homeostasis and T cell antitumor immunity. However, the expression, function, and therapeutic value of PCSK9 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we found that the expression of PCSK9 was upregulated in HNSCC tissues, and higher PCSK9 expression indicated poorer prognosis in HNSCC patients. We further found that pharmacological inhibition or siRNA downregulating PCSK9 expression suppressed the stemness-like phenotype of cancer cells in an LDLR-dependent manner. Moreover, PCSK9 inhibition enhanced the infiltration of CD8+ T cells and reduced the myeloid-derived suppressor cells (MDSCs) in a 4MOSC1 syngeneic tumor-bearing mouse model, and it also enhanced the antitumor effect of anti-PD-1 immune checkpoint blockade (ICB) therapy. Together, these results indicated that PCSK9, a traditional hypercholesterolemia target, may be a novel biomarker and therapeutic target to enhance ICB therapy in HNSCC.

Drooling disrupts the brain functional connectivity network in Parkinson's disease.

AIMS: This study aimed to investigate the causal interaction between significant sensorimotor network (SMN) regions and other brain regions in Parkinson's disease patients with drooling (droolers). METHODS: Twenty-one droolers, 22 PD patients without drooling (non-droolers), and 22 matched healthy controls underwent 3T-MRI resting-state scans. We performed independent component analysis and Granger causality analysis to determine whether significant SMN regions help predict other brain areas. Pearson's correlation was computed between imaging characteristics and clinical characteristics. ROC curves were plotted to assess the diagnostic performance of effective connectivity (EC). RESULTS: Compared with non-droolers and healthy controls, droolers showed abnormal EC of the right caudate nucleus (CAU.R) and right postcentral gyrus to extensive brain regions. In droolers, increased EC from the CAU.R to the right middle temporal gyrus was positively correlated with MDS-UPDRS, MDS-UPDRS II, NMSS, and HAMD scores; increased EC from the right inferior parietal lobe to CAU.R was positively correlated with MDS-UPDRS score. ROC curve analysis showed that these abnormal ECs are of great significance in diagnosing drooling in PD. CONCLUSION: This study identified that PD patients with drooling have abnormal EC in the cortico-limbic-striatal-cerebellar and cortio-cortical networks, which could be potential biomarkers for drooling in PD.

PriMPSO: A Privacy-Preserving Multiagent Particle Swarm Optimization Algorithm.

Centralized particle swarm optimization (PSO) does not fully exploit the potential of distributed or parallel computing and suffers from single-point-of-failure. Particularly, each particle in PSO comprises a potential solution (e.g., traveling route and neural network model parameters) which is essentially viewed as private data. Unfortunately, previously neither centralized nor distributed PSO algorithms fail to protect privacy effectively. Inspired by secure multiparty computation and multiagent system, this article proposes a privacy-preserving multiagent PSO algorithm (called PriMPSO) to protect each particle's data and enable private data sharing in a privacy-preserving manner. The goal of PriMPSO is to protect each particle's data in a distributed computing paradigm via existing PSO algorithms with competitive performance. Specifically, each particle is executed by an independent agent with its own data, and all agents jointly perform global optimization without sacrificing any particle's data. Thorough investigations show that selecting an exemplar from all particles and updating particles through the exemplar are critical operations for PSO algorithms. To this end, this article designs a privacy-preserving exemplar selection algorithm and a privacy-preserving triple computation protocol to select exemplars and update particles, respectively. Strict privacy analyses and extensive experiments on a benchmark and a realistic task confirm that PriMPSO not only protects particles' privacy but also has uniform convergence performance with the existing PSO algorithm in approximating an optimal solution.