Publications by authors named "Jian Li"

5,560 Publications

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Deletion of inhibits neointima formation by enhancing KAT2A/GCN5-mediated acetylation of TUBA/α-tubulin .

Autophagy 2021 May 14:1-18. Epub 2021 May 14.

Center of Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia.

ULK1 (unc-51 like autophagy activating kinase) has a central role in initiating macroautophagy/autophagy, a process that contributes to atherosclerosis and neointima hyperplasia, or excessive tissue growth that leads to vessel dysfunction. However, the role of ULK1 in neointima formation remains unclear. We aimed to determine how deletion affected neointima formation and to investigate the underlying mechanisms. We measured autophagy activity, vascular smooth muscle cell (VSMC) migration and neointima hyperplasia in cultured VSMCs and ligation-injured mouse carotid arteries from male wild-type (WT, C57BL/6 J) and VSMC-specific knockout ( KO) mice. Carotid artery ligation in WT mice increased ULK1 protein expression, and concurrently increased autophagic flux and neointima formation. Treating human aortic smooth muscle cells (HASMCs) with PDGF (platelet derived growth factor) increased ULK1 expression, activated autophagy, and promoted cell migration. Further, smooth muscle cell-specific deletion of suppressed autophagy, inhibited VSMC migration, and impeded neointima hyperplasia. Mechanistically, deletion inhibited autophagic degradation of histone acetyltransferase protein KAT2A/GCN5 (K[lysine] acetyltransferase 2A), resulting in accumulation of KAT2A that directly acetylated TUBA/α-tubulin and subsequently increased protein levels of acetylated TUBA. The acetylation of TUBA increased microtubule stability and inhibited VSMC directional migration and neointima formation. Finally, local transfection of siRNA decreased TUBA acetylation and prevented the attenuation of vascular injury-induced neointima formation in KO mice. These findings suggest that deletion inhibits neointima formation by reducing autophagic degradation of KAT2A and increasing TUBA acetylation in VSMCs. ACTA2/α-SMA: actin, alpha 2, smooth muscle, aorta; ACTB: actin beta; ATAT1: alpha tubulin acetyltransferase 1; ATG: autophagy related; BECN1: beclin 1; BP: blood pressure; CAL: carotid artery ligation; CQ: chloroquine diphosphate; EC: endothelial cells; EEL: external elastic layer; FBS: fetal bovine serum; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; HASMCs: human aortic smooth muscle cells; HAT1: histone acetyltransferase 1; HDAC: histone deacetylase; IEL: inner elastic layer; IP: immunoprecipitation; KAT2A/GCN5: K(lysine) acetyltransferase 2A; KAT8/hMOF: lysine acetyltransferase 8; MAP1LC3: microtubule associated protein 1 light chain 3; MYH11: myosin heavy chain 11; PBS: phosphate-buffered saline; PDGF: platelet derived growth factor; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; RAC3: Rac family small GTPase 3; SIRT2: sirtuin 2; SPP1/OPN: secreted phosphoprotein 1; SQSTM1/p62: sequestosome 1; TAGLN/SM22: transgelin; TUBA: tubulin alpha; ULK1: unc-51 like autophagy activating kinase; VSMC: vascular smooth muscle cell; VVG: Verhoeff Van Gieson; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2021.1911018DOI Listing
May 2021

Imaging modeling and error analysis of the star sensor under rolling shutter exposure mode.

Opt Express 2021 May;29(10):15478-15496

As the star sensor works under high dynamic conditions, the spot formed by the star on the imaging plane will become a tail, which directly reduces the accuracy of centroid positioning. In addition, the imaging quality of the star sensor is seriously hit by the rolling shutter effect in the rolling shutter exposure mode, which further increases positioning error. Considering the diffusion radius and the dynamic tailing of the star spot, the imaging trajectory and the energy distribution models of the star spot under the rolling shutter exposure mode are established in this paper. Furthermore, based on the purposed models, the influence of the starting positions of stars and the dispersion of star spots to the centroid positioning error are analyzed by numerical simulation respectively, from which the variation laws of the two kinds of errors are obtained. Then, the laboratory experiments are implemented to evaluate the latter error; it indicates from the experimental results that the variation of the latter error is consistent with the simulation results, which is simultaneously proved that it cannot be ignored in practical engineering application. These results can be a valuable reference for developing a high precision star sensor. The models proposed in this paper can describe the star imaging process and evaluate the centroid positioning accuracy under the roller shutter exposure mode effectively, which lays a foundation for further eliminating the rolling shutter effect in the following research and improving the dynamic performance of star sensors.
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http://dx.doi.org/10.1364/OE.423219DOI Listing
May 2021

Approach to reduce light field sampling redundancy for flame temperature reconstruction.

Opt Express 2021 Apr;29(9):13094-13114

Flame temperature measurement through a light field camera shows an attractive research interest due to its capabilities of obtaining spatial and angular rays' information by a single exposure. However, the sampling information collected by the light field camera is vast and most of them are redundant. The reconstruction process occupies a larger computing memory and time-consuming. We propose a novel approach i.e., feature rays under-sampling (FRUS) to reduce the light field sampling redundancy and thus improve the reconstruction efficiency. The proposed approach is evaluated through numerical and experimental studies. Effects of under-sampling methods, flame dividing voxels, noise levels and light field camera parameters are investigated. It has been observed that the proposed approach provides better anti-noise ability and reconstruction efficiency. It can be valuable not only for the flame temperature reconstruction but also for other applications such as particle image velocimetry and light field microscope.
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http://dx.doi.org/10.1364/OE.424112DOI Listing
April 2021

Directional PCA for Fast Detection and Accurate Diagnosis: A Unified Framework.

IEEE Trans Cybern 2021 May 13;PP. Epub 2021 May 13.

Many methods for monitoring multivariate processes are built on principal component analysis (PCA), which, however, simply tells whether the process is faulty or not. In fact, there is still room for the improvement of the early detection performance by exploiting fully the information given by fault directions. To this end, this article proposes a novel directional PCA (diPCA) approach. First, by narrowing down faults to a specified direction or composite mutually orthogonal directions, diPCA can speed fault detection and facilitate accurate fault diagnosis. It also has good theoretical properties that guarantee concise control limits. Second, with appropriate fault directions, diPCA provides a unified framework for process monitoring and includes existing monitoring indices, such as Hotelling's T² and the squared prediction error (SPE), as special cases. Third, diPCA also naturally results in a new combined monitoring statistic, which is composed of both T² and SPE, and provides an optimal ratio of their combination. The Monte Carlo simulation results have demonstrated the power of the proposed monitoring and diagnostic methods stemming from diPCA. The proposed methods have also been implemented into the Tennessee Eastman process.
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http://dx.doi.org/10.1109/TCYB.2021.3070590DOI Listing
May 2021

Diastereoselective Synthesis of Tetracyclic Tetrahydroquinoline Derivative Enabled by Multicomponent Reaction of Isocyanide, Allenoate, and 2-Aminochalcone.

Org Lett 2021 May 13. Epub 2021 May 13.

Department of Chemistry, College of Sciences & Institute for Sustainable Energy, Shanghai University, 99 Shangda Road, Shanghai 200444, People's Republic of China.

We report here a multicomponent protocol to assemble several polycyclic dihydropyran-fused tetrahydroquinoline structures with excellent diastereoselectivity. This procedure employs simple feedstocks to accomplish a series of diverse structures, which is difficult to attain by traditional sequences.
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http://dx.doi.org/10.1021/acs.orglett.1c00912DOI Listing
May 2021

Impact of on the Development of High Level Colistin Resistance in and .

Front Microbiol 2021 26;12:666782. Epub 2021 Apr 26.

College of Veterinary Medicine, Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, Key Laboratory of Zoonosis of Ministry of Agricultural and Rural Affairs, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.

Plasmid-mediated colistin resistance gene generally confers low-level resistance. The purpose of this study was to investigate the impact of on the development of high-level colistin resistance (HLCR) in and . In this study, -negative and strains and their corresponding -positive transformants were used to generate HLCR mutants multiple passages in the presence of increasing concentrations of colistin. We found that for , HLCR mutants with minimum inhibitory concentrations (MICs) of colistin from 64 to 1,024 mg/L were generated. Colistin MICs increased 256- to 4,096-fold for -negative strains but only 16- to 256-fold for the -harboring transformants. For , colistin MICs increased 4- to 64-folds, but only 2- to 16-fold for their -harboring transformants. Notably, improved the survival rates of both and strains when challenged with relatively high concentrations of colistin. In HLCR mutants, amino acid alterations predominately occurred in , followed by , , , , and , while in mutants, genetic alterations were mostly occurred in and . Additionally, growth rate analyses showed that the coexistence of and chromosomal mutations imposed a fitness burden on HLCR mutants of . In conclusion, HLCR was more likely to occur in strains than strains when exposed to colistin. The gene could improve the survival rates of strains of both bacterial species but could not facilitate the evolution of high-level colistin resistance.
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http://dx.doi.org/10.3389/fmicb.2021.666782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108134PMC
April 2021

A novel SPTB frameshift deletion causing hereditary spherocytosis identified by next-generation sequencing in a Chinese family.

Int J Lab Hematol 2021 May 11. Epub 2021 May 11.

Prenatal Diagnostic Center, Guangzhou Women and Children Medical Center, Guangzhou, China.

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http://dx.doi.org/10.1111/ijlh.13575DOI Listing
May 2021

Large-Scale Bio-Inspired Flexible Antireflective Film with Scale-Insensitivity Arrays.

ACS Appl Mater Interfaces 2021 May 11. Epub 2021 May 11.

Key Laboratory of Bionic Engineering, Ministry of Education, Jilin University, Changchun 130022, China.

Natural creatures can always provide perfect strategies for excellent antireflection (AR), which is valuable for photovoltaic industry, optical devices, and flexible displays. However, limited by precision, it is still difficult to guarantee the consistency between the artificial structures and the original biological structures. Here, a novel large-scale flexible AR film is inspired by the cicada wings and successfully fabricated with a recycled template. On the one hand, the adjustable structures on porous templates make it possible to optimize the design of AR structure parameters toward the practical demand. On the other hand, it breaks the limitation of the biological organism size, accomplishing the replication of AR nanostructure units in a large scale. Interestingly, even if the film is covered by enlarged dome cone arrays, it still maintains almost perfect AR property, achieving excellent scale-insensitivity AR performance. This work numerically and experimentally investigates its scale-insensitivity AR performance in detail. Compared with subwavelength nanocones, enlarged cones change the original optical behaviors, and the proportion of transmitted light is reduced while scattering and absorption increase. Based on this, these bio-inspired scale-insensitivity AR arrays could be used in flexible displays, photothermic conversion, solar cells, and so on.
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http://dx.doi.org/10.1021/acsami.1c02046DOI Listing
May 2021

Decoding brain encoded by genome.

Yi Chuan 2021 May;43(5):393-396

The Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing 210096, China.

Human brain is the most complicated living organ in nature. How the human genome encodes the structure and function of brain is a fundamental question to understand the essence of mind. Currently, it is still an unsolved scientific problem requiring the further breakthrough of comprehensive technologies. Here, we summarize the recent advances in brain development/function OMICS studies, and discuss the huge challenges and prospects in understanding how brain is encoded by genome.
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http://dx.doi.org/10.16288/j.yczz.21-019DOI Listing
May 2021

Pericoronary adipose tissue CT attenuation and volume: Diagnostic performance for hemodynamically significant stenosis in patients with suspected coronary artery disease.

Eur J Radiol 2021 Apr 28;140:109740. Epub 2021 Apr 28.

Department of Radiology, Xijing Hospital, Fourth Military Medical University, 127# West Changle Road, Xi'an 710032, Shaanxi Province, China. Electronic address:

Objectives: The aim of this study was to investigate the diagnostic abilities of both pericoronary adipose tissue (PCAT) CT attenuation and volume for the predication hemodynamic significance of coronary artery stenosis as evaluated by fractional flow reserve (FFR).

Methods: Patients with ≥ 30 % in at least 1 major epicardial coronary artery were retrospectively included. Furthermore, all eligible patients underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) as well as FFR within 1 month. PCAT CT attenuation and volume around ischemic and non-ischemic coronary stenosis were measured and compared. The diagnostic accuracy of PCAT CT attenuation and volume for the identification of hemodynamically significant stenosis was determined against the reference standard of FFR ≤ 0.80.

Results: A total of 61 patients (mean age, 57.8 years ± 11.8) with 77 vessels were included. Average PCAT CT attenuation of all vessels was -70.3 ± 7.4 HU. PCAT CT attenuation in coronary arteries with hemodynamically significant stenosis (FFR ≤ 0.80) (-65.6 ± 5.9 HU) was significantly higher than those with FFR > 0.80 (-75.3 ± 5.4 HU; p = 0.000). There was a strong correlation between FFR and PCAT CT attenuation (r = 0.64, p < 0.001). However, no significant difference in PCAT volume was observed between FFR ≤ 0.8 (5.0 ± 3.5 cm) and FFR > 0.80 (5.5 ± 3.7 cm, p = 0.511). The diagnostic accuracy was significantly higher in the combination of CCTA and PCAT CT attenuation compared with CCTA alone (area under the curve: 0.869 vs. 0.569, p < 0.001).

Conclusions: PCAT CT attenuation but not volume was related to the hemodynamic significance of coronary artery stenosis. For the patients with suspected coronary artery disease, after adding of PCAT CT attenuation to CCTA, the diagnostic ability for the identification of ischemic coronary stenosis was significantly improved.
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http://dx.doi.org/10.1016/j.ejrad.2021.109740DOI Listing
April 2021

Visual Exploration of Large Metabolic Models.

Bioinformatics 2021 May 10. Epub 2021 May 10.

Department of Computer and Information Science, University of Konstanz, Konstanz, Germany.

Motivation: Large metabolic models, including genome-scale metabolic models (GSMMs), are nowadays common in systems biology, biotechnology and pharmacology. They typically contain thousands of metabolites and reactions and therefore methods for their automatic visualisation and interactive exploration can facilitate a better understanding of these models.

Results: We developed a novel method for the visual exploration of large metabolic models and implemented it in LMME (Large Metabolic Model Explorer), an add-on for the biological network analysis tool VANTED. The underlying idea of our method is to analyse a large model as follows. Starting from a decomposition into several subsystems, relationships between these subsystems are identified and an overview is computed and visualised. From this overview, detailed subviews may be constructed and visualised in order to explore subsystems and relationships in greater detail. Decompositions may either be predefined or computed, using built-in or self-implemented methods. Realised as add-on for VANTED, LMME is embedded in a domain-specific environment, allowing for further related analysis at any stage during the exploration. We describe the method, provide a use case, and discuss the strengths and weaknesses of different decomposition methods.

Availability: The methods and algorithms presented here are implemented in LMME, an open-source add-on for VANTED. LMME can be downloaded from www.cls.uni-konstanz.de/software/lmme and VANTED can be downloaded from www.vanted.org. The source code of LMME is available from GitHub, at https://github.com/LSI-UniKonstanz/lmme.
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http://dx.doi.org/10.1093/bioinformatics/btab335DOI Listing
May 2021

LncRNA DANCR regulates lymphatic metastasis of bladder cancer via the miR-335/VEGF-C axis.

Transl Androl Urol 2021 Apr;10(4):1743-1753

Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.

Background: Substantial evidence indicate that long non-coding RNA (lncRNA) and microRNA (miRNA) act as key role in bladder cancer. Differentiation antagonistic ncRNA (DANCR) could be used as a biomarker in the occurrence and development of cancer. This study aims to explore the mechanism of DANCR/miR-335/VEGF-C axis affecting lymphatic metastasis of bladder cancer.

Methods: qRT-PCR detects the expression of DANCR in bladder cancer cell lines (SW780, 5637, T24, UM-UC-3) and normal bladder cell lines (SV-HUC-1), and selects T24 cell lines for subsequent experiments. The expression levels of DANCR, miR-335 and VEGF were measured by qRT-PCR, and the dual luciferase reporter gene verified the targeted regulation of DANCR on miR-335 and miR-335 on VEGF. CCK-8, Transwell and Wound healing assay detect the proliferation, invasion and migration ability of bladder cancer cells, Endothelial cell adhesion assay and Western blot further prove the lymphatic metastasis of bladder cancer.

Results: In this study, DANCR was highly expressed in bladder cancer cell lines. Transfection of si-DANCR significantly inhibits the proliferation, migration, invasion and lymphatic metastasis of bladder cancer cells. Dual luciferase assay confirmed that DANCR targets miR-335/VEGF-C. Transfection of miR-335 mimic promotes the proliferation, migration, invasion and lymphatic metastasis of bladder cancer cells, overexpression of DANCR eliminates the promotion of miR-335 mimic on bladder cancer cells. Further experiments proved that inhibition of miR-335 and overexpression of VEGF-C can reverse the inhibitory effect of silencing DANCR on bladder cancer cells.

Conclusions: In bladder cancer, DARCR plays an important role, which regulates the proliferation, migration, invasion and lymphatic metastasis of bladder cancer cells through the miR-335/VEGF-C molecular axis.
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http://dx.doi.org/10.21037/tau-21-226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100837PMC
April 2021

Arg-Vasotocin Directly Activates Isotocin Receptors and Induces COX2 Expression in Ovoviviparous Guppies.

Front Endocrinol (Lausanne) 2021 23;12:617580. Epub 2021 Apr 23.

Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, China.

Oxytocin (OT) is a crucial regulator of reproductive behaviors, including parturition in mammals. Arg-vasopressin (AVP) is a nonapeptide homologous to Arg-vasotocin (AVT) in teleosts that has comparable affinity for the OT receptor. In the present study, ovoviviparous guppies () were used to study the effect of AVT on delivery mediated by the activation of prostaglandin (PG) biosynthesis isotocin (IT) receptors (ITRs). One copy each of and and two copies of were identified in guppies. The results of the affinity assay showed that various concentrations of AVT and IT (10, 10, and 10 mol/L) significantly activated (P < 0.05). experiments revealed significant upregulation (P < 0.05) of cyclooxygenase 2 (), which is the rate-limiting enzyme involved in PG biosynthesis, and by AVT and IT. Furthermore, dual hybridization detected positive signals for and at the same site, implying that ITR1 may regulate gene expression. Measurement of prostaglandin F (PGF) concentrations showed that AVT induced PGF synthesis (P < 0.05) and that the effect of IT was not significant. Finally, intraperitoneal administration of PGF significantly induced premature parturition of guppies. This study is the first to identify and characterize AVT and ITRs in guppies. The findings suggest that AVT promotes PG biosynthesis ITR and that PGF induces delivery behavior in ovoviviparous guppies.
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http://dx.doi.org/10.3389/fendo.2021.617580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104081PMC
April 2021

High Dose Intravenous Vitamin C for Preventing The Disease Aggravation of Moderate COVID-19 Pneumonia. A Retrospective Propensity Matched Before-After Study.

Front Pharmacol 2021 22;12:638556. Epub 2021 Apr 22.

Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Coronavirus disease 2019 (COVID-19) pandemic is continuing to impact multiple countries worldwide and effective treatment options are still being developed. In this study, we investigate the potential of high-dose intravenous vitamin C (HDIVC) in the prevention of moderate COVID-19 disease aggravation. In this retrospective before-after case-matched clinical study, we compare the outcome and clinical courses of patients with moderate COVID-19 patients who were treated with an HDIVC protocol (intravenous injection of vitamin C, 100 mg/kg/day, 1 g/h, for 7 days from admission) during a one-month period (between March 18 and april 18, 2020, HDIVC group) with a control group treated without the HDIVC protocol during the preceding two months (January 18 to March 18, 2020). Patients in the two groups were matched in a 1:1 ratio according to age and gender. The HDIVC and control groups each comprised 55 patients. For the primary outcomes, there was a significant difference in the number of patients that evolved from moderate to severe type between the two groups (HDIVC: 4/55 vs. control: 12/55, relative risk [RR] = 0.28 [0.08, 0.93], = 0.03). Compared to the control group, there was a shorter duration of systemic inflammatory response syndrome (SIRS) ( = 0.0004) during the first week and lower SIRS occurrence (2/21 vs 10/22, = 0.0086) on Day 7 (6-7 days after admission). In addition, HDIVC group had lower C-reactive protein levels ( = 0.005) and higher number of CD4 T cells from Day 0 (on admission) to Day 7 ( = 0.04)." The levels of coagulation indicators, including activated partial thromboplastin time and D-dimer were also improved in the HDIVC compared to the control group on Day 7. HDIVC may be beneficial in limiting disease aggravation in the early stage of COVID-19 pneumonia, which may be related to its improvements on the inflammatory response, immune function and coagulation function. Further randomized controlled trials are required to augment these findings.
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http://dx.doi.org/10.3389/fphar.2021.638556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100592PMC
April 2021

Involvement of 5-Serotonin and Substance Pathways in Dichroa Alkali Salt-Induced Acute Pica in Rats.

Front Pharmacol 2021 22;12:588837. Epub 2021 Apr 22.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

Dichroa alkali salt (DAS) is the active ingredient of Changshan, a traditional Chinese antimalarial medicine. However, owing to its vomiting side effects, its clinical use is limited. Recently, DAS-induced vomiting has attracted broad attention; however, the mechanisms involved have not yet been elucidated. The present study aimed to explore DAS induced vomiting and decipher the potential role of the 5-serotonin (5-HT) and substance (SP) signaling pathways. We used a combination of approaches in the context of a rat pica model, such as immunoblot analysis, HPLC-ECD, ELISA, quantitative real-time PCR, pharmacological inhibition, and immunohistochemistry assays. We demonstrated that DAS contributed to Changshan-induced vomiting via the activation of the 5-HT and SP signaling pathways. DAS could induce a dose-dependent kaolin intake in the rat pica model. Moreover, DAS caused a similar profile as Cisplatin (DDP): "low-dose double-peak, high-dose single-peak pica phenomenon". Interestingly, treatment with DAS stimulated the peripheral ileum and central medulla oblongata and augmented the release of 5-HT, SP, and preprotachykinin-A and the expression of 5-HT and NK receptors in the two issues in acute phase. Additionally, the 5-HT and NK receptor antagonists effectively alleviated DAS-induced kaolin intake and significantly reduced DAS-induced 5-HT and SP levels in the two issues in acute phase. Similar responses were not observed in the context of dopamine receptor inhibition. This study innovatively revealed that the 5-HT and SP-mediated vomiting network plays an important role in DAS-induced acute vomiting; of note, ondansetron, and aprepitant can effectively antagonize DAS-induced vomiting. Our results suggest a potential therapeutic strategy (based on drugs approved for human use) to prevent the DAS-associated adverse reactions.
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http://dx.doi.org/10.3389/fphar.2021.588837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100679PMC
April 2021

Hepatic Arterioportal Fistula Is Associated with Decreased Future Liver Remnant Regeneration after Stage-I ALPPS for Hepatocellular Carcinoma.

J Gastrointest Surg 2021 May 7. Epub 2021 May 7.

Department of Hepatobiliary Surgery and Liver transplantation, the First Affiliated Hospital of Guangxi Medical University, Shuangrong Raod 6, Nanning, 530021, China.

Background: Hepatocellular carcinoma (HCC) patients often developed hepatic arterioportal fistula (APF). The aim of this study is to evaluate the impact of APF on future liver remnant (FLR) regeneration and surgical outcomes after the first stage of associating liver partition and portal vein ligation for staged hepatectomy (stage-I ALPPS).

Methods: Consecutive HCC patients who underwent ALPPS at our center between March 2017 and May 2019 were retrospectively studied. Data for the association between APF and clinicopathological details, liver volume, and surgical outcomes were analyzed.

Results: The enrolled 35 HCC patients were divided into three groups: 15 patients with preoperative APF were classified as the APF I group, 10 patients developed APF after stage-I ALPPS as the APF II group, whereas the other 10 patients without APF before and after stage-I ALPPS as the control group. After stage-I ALPPS, patients in the APF I and APF II groups had lower kinetic growth rate (KGR) of FLR volume (6.1±3.2%, 11.4±8.4%, 25.0±8.8% per week, respectively, P<0.001) and took longer median time to reach the sufficient FLR volume for stage-II ALPPS (17.5 days, 12 days, 6 days, respectively, P<0.001) than those in the control group. Meanwhile, the incidence of posthepatectomy liver failure (PHLF) in the APF I and APF II groups was significantly higher than that of the control group (P=0.007). There are 27 (77.1%) patients who completed stage-II ALPPS. The overall survival (OS) rates at 1 and 3 years were 59.3% and 35.1%, whereas the disease-free survival (DFS) rates at 1 and 3 years were 44.4% and 22.9%, respectively.

Conclusions: Hepatic APF is significantly associated with decreased FLR regeneration and a higher risk of PHLF after stage-I ALPPS. HCC patients who are to undergo ALPPS may benefit from the timely perioperative intervention of APF.
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http://dx.doi.org/10.1007/s11605-021-05022-0DOI Listing
May 2021

Theory of polymer diffusion in polymer-nanoparticle mixtures: effect of nanoparticle concentration and polymer length.

Soft Matter 2021 May;17(17):4632-4642

Department of Physics, Zhejiang Sci-Tech University, Hangzhou 310018, China.

The dynamics of polymer-nanoparticle (NP) mixtures, which involves multiple scales and system-specific variables, has posed a long-standing challenge on its theoretical description. In this paper, we construct a microscopic theory for polymer diffusion in mixtures based on a combination of the generalized Langevin equation, mode-coupling approach, and polymer physics ideas. The parameter-free theory has an explicit expression and remains tractable on a pair correlation level with system-specific equilibrium structures as input. Taking a minimal polymer-NP mixture as an example, our theory correctly captures the dependence of polymer diffusion on NP concentration and average interparticle distance. Importantly, the polymer diffusion exhibits a power law decay as the polymer length increases at dense NPs and/or a long chain, which marks the emergence of entanglement-like motion. The work provides a first-principles theoretical foundation to investigate dynamic problems in diverse polymer nanocomposites.
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http://dx.doi.org/10.1039/d1sm00226kDOI Listing
May 2021

A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer.

NPJ Precis Oncol 2021 May 4;5(1):36. Epub 2021 May 4.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.

The association between genetic variations and immunotherapy benefit has been widely recognized, while such evidence in gastrointestinal cancer remains limited. We analyzed the genomic profile of 227 immunotherapeutic gastrointestinal cancer patients treated with immunotherapy, from the Memorial Sloan Kettering (MSK) Cancer Center cohort. A gastrointestinal immune prognostic signature (GIPS) was constructed using LASSO Cox regression. Based on this signature, patients were classified into two subgroups with distinctive prognoses (p < 0.001). The prognostic value of the GIPS was consistently validated in the Janjigian and Pender cohort (N = 54) and Peking University Cancer Hospital cohort (N = 92). Multivariate analysis revealed that the GIPS was an independent prognostic biomarker. Notably, the GIPS-high tumor was indicative of a T-cell-inflamed phenotype and immune activation. The findings demonstrated that GIPS was a powerful predictor of immunotherapeutic survival in gastrointestinal cancer and may serve as a potential biomarker guiding immunotherapy treatment decisions.
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http://dx.doi.org/10.1038/s41698-021-00172-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096820PMC
May 2021

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Gastric Cancer 2021 May 4. Epub 2021 May 4.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Hai-Dian District, Fu-Cheng Road 52, Beijing, 100142, China.

Purpose: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.

Patients And Methods: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.

Results: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).

Conclusion: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.

Clinical Trial Information: NCT02881190.
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http://dx.doi.org/10.1007/s10120-021-01168-7DOI Listing
May 2021

Tuning the Topology of Three-Dimensional Covalent Organic Frameworks via Steric Control: From to Unprecedented .

J Am Chem Soc 2021 May 4. Epub 2021 May 4.

Sauvage Center for Molecular Sciences, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China.

Whether or not the topology of three-dimensional covalent organic frameworks (3D COFs) can be tuned via steric control remains a big question and has never been reported. Herein, we describe the designed synthesis of two highly crystalline 3D COFs (3D-TPB-COF-OMe and 3D-TPB-COF-Ph), through the polycondensation of tetra(-aminophenyl)methane and methoxy- or phenyl- substituted 1,2,4,5-tetrakis(4-formylphenyl)benzene on the 3- and 6-positions. Amazingly, by using the continuous rotation electron diffraction technique, 3D-TPB-COF-OMe is determined to have a 5-fold interpenetrated structure with a reported net, while 3D-TPB-COF-Ph adopts an unprecedented self-penetrated topology ( = Luojia Hill) that does not exist in the database of ToposPro. Therefore, by altering the substituents from methoxy to phenyl groups, the topology of designed 3D COFs changes accordingly, and a rare net is now available. This result clearly demonstrates that such COF structures need to be carefully determined due to its complexity, and moreover, it is promising to design 3D COFs with new topology for interesting application by increasing the steric hindrance of molecular building blocks.
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http://dx.doi.org/10.1021/jacs.1c03042DOI Listing
May 2021

Robotic-Assisted versus Video-Assisted Thoracoscopic Lobectomy: Short-Term Results of a Randomized Clinical Trial (RVlob Trial).

Ann Surg 2021 Apr 30. Epub 2021 Apr 30.

Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Department of Thoracic Surgery, University Hospital Leuven, Leuven, Belgium Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA Department of Thoracic Medicine and Surgery, Division of Thoracic Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA Thoracic Surgery Unit, National Cancer Institute, Milan, Italy Department of Minimally Invasive Thoracic Surgery, Fujita Health University Okazaki Medical Center, Okazaki, Japan Division of Thoracic Surgery, Monaldi Hospital, Naples, Italy Department of Perioperative Medicine, Golden Jubilee National Hospital, Clydebank, UK Department of Thoracic Surgery, Ruhrlandklinik, University Medicine Essen, Essen, Germany Clinical Research Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Objective: To determine whether robotic-assisted lobectomy (RAL) affects perioperative outcomes and long-term efficacy in non-small cell lung cancer (NSCLC) patients, compared with traditional video-assisted lobectomy (VAL).

Summary Background Data: RAL is a promising treatment for NSCLC. However, its efficacy has not been fully evaluated.

Methods: A single-center, open-labeled prospective randomized clinical trial was launched in May 2017 to compare the efficacy of RAL and VAL. By May 2020, 320 patients were enrolled. The perioperative results of RAL and VAL were compared.

Results: The 320 enrolled patients were randomly assigned to the RAL group (n = 157) and the VAL group (n = 163). Perioperative outcomes were comparable between the two groups, including the length of hospital stay (P = 0.76) and the rate of postoperative complications (P = 0.45). No perioperative mortality occurred in either group. The total amount of chest tube drainage (830 ml [IQR, 550-1130 ml] vs. 685 ml [IQR, 367.5-1160 ml], P = 0.007) and hospitalization costs ($12821 [IQR, $12145-$13924] vs. $8009 [IQR, $7014-$9003], P < 0.001) were significantly higher in the RAL group. RAL group had a significantly higher number of lymph nodes (LNs) harvested (11 [IQR, 8-15] vs. 10 [IQR, 8-13], P = 0.02), higher number of N1 LNs (6 [IQR, 4-8] vs. 5 [IQR, 3-7], P = 0.005), and more LN stations examined (6 [IQR, 5-7] vs. 5 [IQR, 4-6], P < 0.001).

Conclusions: Both RAL and VAL are safe and feasible for the treatment of NSCLC. RAL achieved similar perioperative outcomes, together with higher LN yield. Further follow-up investigations are required to evaluate the long-term efficacy of RAL. (ClinicalTrials.gov identifier: NCT03134534).
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http://dx.doi.org/10.1097/SLA.0000000000004922DOI Listing
April 2021

Comparative Effectiveness of Lobectomy, Segmentectomy, and Wedge Resection for Pathological Stage I Non-small Cell Lung Cancer in Elderly Patients: A Population-Based Study.

Front Surg 2021 15;8:652770. Epub 2021 Apr 15.

Department of Thoracic Surgery, Peking University First Hospital, Beijing, China.

This study was designed to assess the long-term survival of lobectomy, segmentectomy, and wedge resection for pathological stage I non-small cell lung cancer (NSCLC) in patients over 75 years of age. Pathological stage I NSCLC patients aged ≥75 years who underwent lobectomy, segmentectomy, or wedge resection were identified from the Surveillance, Epidemiology, and End Results database. Propensity score-matched and competing risks analyses were conducted. The overall survival (OS) rate and lung cancer-specific survival (LCSS) rate were compared among the three groups based on the pathological stage. A total of 3,345 patients were included. In the full cohort, the OS rate and LCSS rate of lobectomy were superior to wedge resection, but not to segmentectomy, the OS advantage diminished when patients were over 85 years old or when at least one lymph node was examined during the procedure. Stratified analyses showed that there was no significant difference in OS and LCSS rates among the three surgical procedures for patients with tumors smaller than 1.0 cm. The OS and LCSS of wedge resection, not segmentectomy, were inferior to lobectomy in stage IA2-IB tumors. Lobectomy should be recognized as the "gold standard" procedure for pathological stage I NSCLC in patients over 75 years of age, and segmentectomy could be considered as an effective alternative. Wedge resection could be considered for patients with compromised cardiopulmonary function or tumors smaller than 1.0 cm, and intraoperative lymph node examination should be conducted.
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http://dx.doi.org/10.3389/fsurg.2021.652770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082105PMC
April 2021

Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB.

Front Oncol 2021 16;11:665832. Epub 2021 Apr 16.

Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ . CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients.
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http://dx.doi.org/10.3389/fonc.2021.665832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087176PMC
April 2021

Metabolic scaling: individual versus intraspecific scaling of Nile tilapia (Oreochromis niloticus).

J Comp Physiol B 2021 May 2. Epub 2021 May 2.

Guangxi Key Laboratory of Beibu Gulf Marine Biodiversity Conservation, Ocean College, Beibu Gulf University, Qinzhou, China.

We examined intraspecific scaling of the resting metabolic rate (RMR) of Nile tilapia (Oreochromis niloticus) under different culture conditions and further explored the allometric relationships between organ mass (heart, liver, brain, gills, viscera, and red muscles) and blood parameters (erythrocyte size and red blood cell counts) and body mass. Oreochromis niloticus were bred in individual and group cultures. The scaling exponent of the RMR in the individual cultures was b = 0.620-0.821 (n = 30) and that in the group culture was b = 0.770 [natural logarithm (ln) RMR = 0.770 ln M - 1.107 (n = 76)]. The results of the two experimental methods were similar and were not significantly different from 0.75 (3/4), as predicted by the metabolic theory of ecology. The active and inactive organs were scaled with body mass by an exponent of 0.940 and 1.012, respectively. There was no significant relationship between the blood parameters and body mass. These results suggest that the differences in the culture methods may not have affected the allometric scaling of O. niloticus metabolism. The proportion of active and inactive organs contributed to allometric changes in the metabolic rate with body mass. Red blood cells in fish are not generally representative, and cell size can only partially explain the allometric scaling of metabolism.
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http://dx.doi.org/10.1007/s00360-021-01376-8DOI Listing
May 2021

Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China.

Malar J 2021 May 1;20(1):209. Epub 2021 May 1.

Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.

Background: Imported malaria parasites with anti-malarial drug resistance (ADR) from Africa is a serious public health challenge in non-malarial regions, including Wuhan, China. It is crucial to assess the ADR status in African Plasmodium falciparum isolates from imported malaria cases, as this will provide valuable information for rational medication and malaria control.

Methods: During 2017-2019, a cross-sectional study was carried out in Wuhan, China. Peripheral blood 3 ml of returned migrant workers from Africa was collected. The target fragments from pfcrt, pfmdr1, and k13 propeller (pfk13) genes were amplified, sequenced, and analysed.

Results: In total, 106 samples were collected. Subsequently, 98.11% (104/106), 100% (106/106), and 86.79% (92/106) of these samples were successfully amplified and sequenced for the pfcrt (72-76), pfmdr1, and pfk13 genes, respectively. The prevalence of the pfcrt 76 T, pfmdr1 86Y, and pfmdr1 184F mutations was 9.62, 4.72, and 47.17%, respectively. At codons 72-76, the pfcrt locus displayed three haplotypes, CVMNK (wild-type), CVIET (mutation type), CV M/I N/E K/T (mixed type), with 87.50%, 9.62%, and 2.88% prevalence, respectively. For the pfmdr1 gene, NY (wild type), NF and YF (mutant type), N Y/F, Y Y/F, and N/Y Y/F (mixed type) accounted for 34.91, 43.40, 3.77, 15.09, 0.94, and 1.89% of the haplotypes, respectively. A total of 83 isolates with six unique haplotypes were found in pfcrt and pfmdr1 combined haplotypes, of which NY-CVMNK and NF-CVMNK accounted for 40.96% (34/83) and 43.37% (36/83), respectively. Furthermore, 90 cases were successfully sequenced (84.91%, 90/106) at loci 93, 97, 101, and 145, and 78 cases were successfully sequenced (73.58%, 78/106) at loci 343, 353, and 356 for pfcrt. However, the mutation was observed only in locus 356 with 6.41%. For pfk13, mutations reported in Southeast Asia (at loci 474, 476, 493, 508, 527, 533, 537, 539, 543, 553, 568, 574, 578, and 580) and Africa (at loci 550, 561, 575, 579, and 589) were not observed.

Conclusions: The present data from pfcrt and pfmdr1 demonstrate that anti-malarial drugs including chloroquine, amodiaquine, and mefloquine, remain effective against malaria treatment in Africa. The new mutations in pfcrt related to piperaquine resistance remain at relatively low levels. Another source of concern is the artemether-lumefantrine resistance-related profiles of N86 and 184F of pfmdr1. Although no mutation in pfk13 is detected, molecular surveillance must continue.
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http://dx.doi.org/10.1186/s12936-021-03737-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087876PMC
May 2021

Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases.

Sci Immunol 2021 Apr;6(58)

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.

Pharmacologically inhibiting nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation results in potent therapeutic effects in a wide variety of preclinical inflammatory disease models. NLRP3 deubiquitination is essential for efficient NLRP3 inflammasome activity, but it remains unclear whether this process can be harnessed for therapeutic benefit. Here, we show that thiolutin (THL), an inhibitor of the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease, blocks NLRP3 inflammasome activation by canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. In addition, THL potently inhibited the activation of multiple NLRP3 mutants linked with cryopyrin-associated periodic syndromes (CAPS). Treatment with THL alleviated NLRP3-related diseases in mouse models of lipopolysaccharide-induced sepsis, monosodium urate-induced peritonitis, experimental autoimmune encephalomyelitis, CAPS, and methionine-choline-deficient diet-induced nonalcoholic fatty liver disease. Mechanistic studies revealed that THL inhibits the BRCC3-containing isopeptidase complex (BRISC)-mediated NLRP3 deubiquitination and activation. In addition, we show that holomycin, a natural methyl derivative of THL, displays an even higher inhibitory activity against NLRP3 inflammasome than THL. Our study validates that posttranslational modification of NLRP3 can be pharmacologically targeted to prevent or treat NLRP3-associated inflammatory diseases. Future clinical development of derivatives of THL may provide new therapies for NLRP3-related diseases.
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http://dx.doi.org/10.1126/sciimmunol.abe2933DOI Listing
April 2021

Altered structural covariance of hippocampal subregions in patients with Alzheimer's disease.

Behav Brain Res 2021 Apr 27;409:113327. Epub 2021 Apr 27.

Department of Radiology, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, Yantai, Shandong, 264000, PR China. Electronic address:

Background And Purpose: Different atrophy of hippocampus subregions is a valuable indicator of patients with Alzheimer's disease (AD). To explore the relationship among the hippocampal subregions of patients with AD, altered gray matter structural covariance of hippocampal subregions in patients with AD was studied.

Materials And Methods: Participants were selected from the Open Access Series of Imaging Studies Database. Pearson correlations among the volume of the hippocampal subregions were generated as structural covariance network. Topological metrics for all selected sparsity ranges were calculated in the healthy controls (HCs) and patients with AD by using the GRETNA software package. Spearman correlation analysis was performed to statistically analyze the volume and Mini-mental State Examination (MMSE) scores of the hippocampal subregions of the patients with AD, with age and gender as interference covariates and corrected for false discovery rate (FDR) (p < 0.05).

Results: The structural covariance network properties of the hippocampal subregions of patients with AD changed. The clustering coefficient (Cp) and network efficiency (Ne) decreased, characteristic path length (Lp) increased, and the hub nodes changed. The volumes of left parasubiculum, right granule cell layer of dentate gyrus (GC-DG), right molecular layer of the hippocampus (molecular_layer_HP), right Cornu Ammonis (CA) regions CA1 of the hippocampus proper, right fimbria and right CA4 were significantly correlated with the MMSE scores.

Conclusions: The structural covariance network of the hippocampal subregions of patients with AD was reorganized, and the transmission efficiency was weakened. This study explored the changes in these subregions from the network level, which may provide a new perspective and theoretical basis for the neurobiological mechanisms of patients with AD.
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http://dx.doi.org/10.1016/j.bbr.2021.113327DOI Listing
April 2021

Inducible knockout of Clec16a in mice results in sensory neurodegeneration.

Sci Rep 2021 Apr 29;11(1):9319. Epub 2021 Apr 29.

The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.

CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16a mice, to investigate the loss of function of CLEC16A. The mice exhibited a neuronal phenotype including tremors and impaired gait that rapidly progressed to dystonic postures. Nerve conduction studies and pathological analysis revealed loss of sensory axons that are associated with this phenotype. Activated microglia and astrocytes were found in regions of the CNS. Several mitochondrial-related proteins were up- or down-regulated. Upregulation of interferon stimulated gene 15 (IGS15) were observed in neuronal tissues. CLEC16A expression inversely related to IGS15 expression. ISG15 may be the link between CLEC16A and downstream autoimmune, inflammatory processes. Our results demonstrate that a whole-body, inducible knockout of Clec16a in mice results in an inflammatory neurodegenerative phenotype resembling spinocerebellar ataxia.
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http://dx.doi.org/10.1038/s41598-021-88895-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084945PMC
April 2021

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Genome Biol 2021 Apr 29;22(1):125. Epub 2021 Apr 29.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.

Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.

Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.
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http://dx.doi.org/10.1186/s13059-021-02352-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082834PMC
April 2021

Cavity-BOX SOI: Advanced Silicon Substrate with Pre-Patterned BOX for Monolithic MEMS Fabrication.

Micromachines (Basel) 2021 Apr 8;12(4). Epub 2021 Apr 8.

The Electronic Components, Technology and Materials (ECTM) Group, Delft University of Technology, Mekelweg 5, 2628 CD Delft, The Netherlands.

Several Silicon on Insulator (SOI) wafer manufacturers are now offering products with customer-defined cavities etched in the handle wafer, which significantly simplifies the fabrication of MEMS devices such as pressure sensors. This paper presents a novel cavity buried oxide (BOX) SOI substrate (cavity-BOX) that contains a patterned BOX layer. The patterned BOX can form a buried microchannels network, or serve as a stop layer and a buried hard-etch mask, to accurately pattern the device layer while etching it from the backside of the wafer using the cleanroom microfabrication compatible tools and methods. The use of the cavity-BOX as a buried hard-etch mask is demonstrated by applying it for the fabrication of a deep brain stimulation (DBS) demonstrator. The demonstrator consists of a large flexible area and precisely defined 80 µm-thick silicon islands wrapped into a 1.4 mm diameter cylinder. With cavity-BOX, the process of thinning and separating the silicon islands was largely simplified and became more robust. This test case illustrates how cavity-BOX wafers can advance the fabrication of various MEMS devices, especially those with complex geometry and added functionality, by enabling more design freedom and easing the optimization of the fabrication process.
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http://dx.doi.org/10.3390/mi12040414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070108PMC
April 2021