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1.
J Nanosci Nanotechnol ; 20(2): 668-672, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383061

RESUMO

Currently, optical probes with near-infrared (NIR) fluorescence are of great interest in chemical biology. In the present study, we designed and synthesized a novel NIR fluorescent probe, IR789. IR789 has high selectivity and sensitivity for living cells imaging. The stronger excitation and emission characteristics suggested its dominant optical properties over ICG. IR789 also showed a high affinity and inconspicuous cytotoxicity at the cellular level. The results of fluorescent image in living A549 cells (human lung adenocarcinoma epithelial cell line) further demonstrated its potential applications for biomedical diagnosis in biological systems utilization of nanotechnology.

2.
Phys Rev Lett ; 123(6): 067202, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31491175

RESUMO

We report a high-resolution terahertz spectroscopic study of quantum spin dynamics in the antiferromagnetic Heisenberg-Ising spin-chain compound BaCo_{2}V_{2}O_{8} as a function of temperature and longitudinal magnetic field. Confined spinon excitations are observed in an antiferromagnetic phase below T_{N}≃5.5 K. In a field-induced gapless phase above B_{c}=3.8 T, we identify many-body string excitations as well as low-energy fractional psinon or antipsinon excitations by comparing to Bethe ansatz calculations. In the vicinity of B_{c}, the high-energy string excitations are found to have a dominant contribution to the spin dynamics as compared with the fractional excitations.

3.
J Ovarian Res ; 12(1): 80, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31472684

RESUMO

BACKGROUND: Multiple targeted gene sequencing is seldom performed in both germline and somatic testing for ovarian cancer. This study is to evaluate the specific genetic alterations, including both somatic and germline mutations, in Chinese patients with epithelial ovarian cancer (EOC) in a prospective cohort study. MATERIALS AND METHODS: Mutations in a customed 21-gene panel that included BRCA1, BRCA2, and 19 other tumor suppressor genes related to homologous recombination (HR) deficiency or non-HR deficiency were detected by targeted exon capture and next-generation sequencing (NGS) technology across all coding exons and exon-intron (±20 base pairs) boundaries. Patients were enrolled consecutively and unselectively without age or family history consideration. Sixty-two unselected patients with epithelial ovarian cancer were enrolled in our study to be tested for paired somatic and germline mutations. All patients were tested using a 21-gene panel that included BRCA1, BRCA2, CHEK2, PALB2, BRIP1, TP53, PTEN, STK11, CDH1, ATM, BARD1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PMS1, PMS2, RAD50, and RAD51C. RESULTS: Mutation analysis revealed that 77.4% (48/62) of patients carried one or more of 64 identified genetic alterations, including 19 germline and 45 somatic deleterious mutations. Twelve individuals shared both germline and somatic mutations. BRCA mutants existed in 17 of 62 (27.4%) patients. Of the 64 mutations detected, 46 (74.2%) were in 7 other HR or non-HR genes, including TP53, PTEN, ATM, CHEK2, PALB2, RAD51C, and STK11. In somatic mutation analysis, TP53 showed frequent pathogenic or likely pathogenic mutations in 56.5% (35/62) of enrolled cases, among which six cases harbored a loss of heterozygosity. CONCLUSIONS: This is the first report of multi-gene panel testing for germline and somatic mutations among Chinese EOC patients, which revealed a broader deleterious variants than only BRCA testing. REGISTRATION: Registration No. NCT03015376, clinicaltrials.gov , registered on January 10, 2017.

4.
Drug Discov Today ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494187

RESUMO

DNA methyltransferases (DNMTs) are a conserved family of cytosine methylases with crucial roles in epigenetic regulation. They have been considered as promising therapeutic targets for the epigenetic treatment of cancer. Therefore, DNMT inhibitors (DNMTis) have attracted considerable interest in recent years for the modulation of the aberrant DNA methylation pattern in a reversible way. In this review, we provide a structure-based overview of the therapeutic importance of DNMTs against different cancer types, and then summarize recently investigated DNMTis as well as their inhibitory mechanisms, focusing on recent advances in the development of DNMTis with specificity and/or selectivity developed through computational approaches.

5.
PLoS One ; 14(9): e0222151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31504068

RESUMO

In this study, the spatial distribution of the transient pressure and the slipstream caused by a 1/10 scaled metro train passing through a tunnel was studied with moving model test. We hereby investigate the mechanism underlying the mitigation of the transient pressure on both the train surface and tunnel wall, as well as that of the slipstream in the tunnel. Experimental results showed that the airshaft at different locations in a tunnel had different pressure relief effects. The most significant pressure amplitude decreased by 36.0% with the airshaft locating in the middle of the tunnel. Meanwhile, the slipstream speed was also relieved from 0.45 to 0.36 after an airshaft. We also assessed and analyzed the impact of train speed on the transient pressures and slipstream. It was found that the increase of the train speed would increase the transient pressure and slipstream speed, but it did not effect their spatial distribution.

6.
Int J Biol Macromol ; 141: 369-377, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31491514

RESUMO

High-strength and water resistant lignocelluloses based composites (LC) were fabricated using branched polyethylenimine (PEI) as the main bonding agent combined with glutaraldehyde cross-linking reaction and grinding pre-treatment. Physical and mechanical properties of different composites prepared were measured and investigated. It is evident that PEI was efficient in endowing LC with high strength and excellent water resistance. The obtained physical and mechanical properties of LC were complied with the requirement of the Chinese national standard for medium-density fiberboard (MDF). Most notably, the glutaraldehyde cross-linking and grinding pre-treatment could further improve these properties. When 5% PEI and 2.5% glutaraldehyde were incorporated, together with 2-hour grinding treatment, the LC prepared exhibited the optimum modulus of rupture (MOR) 58.1 MPa, modulus of elasticity (MOE) 5077 MPa, internal bonding strength (IB) 2.14 MPa, and thickness swell (TS) 30.2%. The excellent properties obtained could be attributed to the cross-linking effect and Schiff's base addition reaction among lignocelluloses, PEI and glutaraldehyde, which were confirmed by the Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS) analysis. The high-strength LC prepared in this study is expected to be used as load-bearing material in structural application.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31501323

RESUMO

Combination chemotherapy can increase treatment efficacy and suppress drug resistance. Knowledge of how to engineer rational, mechanism-based drug combinations, however, remains lacking. Although studies of drug activity have historically focused on the primary drug-target interaction, growing evidence has emphasized the importance of the subsequent consequences of this interaction. Bedaquiline (BDQ) is the first new drug for tuberculosis (TB) approved in more than 40 y, and a species-selective inhibitor of the Mycobacterium tuberculosis (Mtb) ATP synthase. Curiously, BDQ-mediated killing of Mtb lags significantly behind its inhibition of ATP synthase, indicating a mode of action more complex than the isolated reduction of ATP pools. Here, we report that BDQ-mediated inhibition of Mtb's ATP synthase triggers a complex metabolic response indicative of a specific hierarchy of ATP-dependent reactions. We identify glutamine synthetase (GS) as an enzyme whose activity is most responsive to changes in ATP levels. Chemical supplementation with exogenous glutamine failed to affect BDQ's antimycobacterial activity. However, further inhibition of Mtb's GS synergized with and accelerated the onset of BDQ-mediated killing, identifying Mtb's glutamine synthetase as a collateral, rather than directly antimycobacterial, metabolic vulnerability of BDQ. These findings reveal a previously unappreciated physiologic specificity of ATP and a facet of mode-of-action biology we term collateral vulnerability, knowledge of which has the potential to inform the development of rational, mechanism-based drug combinations.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31388937

RESUMO

PURPOSE: The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen. METHODS: We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded. RESULTS: Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, pdifference < 0.001). Larger mammographic size increased the risk of both upgrading (pheterogeneity = 0.01) and upstaging (pheterogeneity = 0.004). CONCLUSIONS: The risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.

9.
J Biol Chem ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366735

RESUMO

Adenosine deaminases acting on RNA-1 (ADAR1) involves adenosine to inosine RNA editing and microRNA processing. ADAR1 is known to be involved in the replication of various viruses, including hepatitis C and D. However, the role of ADAR1 in hepatitis B virus (HBV) infection has not yet been elucidated. Here, for the first time, we demonstrated ADAR1 antiviral activity against HBV. ADAR1 has two splicing isoforms in human hepatocytes: constitutive p110 protein and interferon-α (IFN-α)-responsive p150 protein. We found that overexpression of ADAR1 decreased HBV RNA in an HBV culture model. A catalytic-site mutant ADAR1 also decreased HBV RNA levels, while another adenosine deaminases that act on RNA (ADAR) family protein, ADAR2, did not. Moreover, the induction of ADAR1 by stimulation with IFN-α also reduced HBV RNA levels. Decreases in endogenous ADAR1 expression by knock-down or knock-out increased HBV RNA levels. A major hepatocyte-specific microRNA, miRNA-122, was found to be positively correlated with ADAR1 expression, and exogenous miRNA-122 decreased both HBV RNA and DNA, while, conversely, transfection with a miRNA-122 inhibitor increased them. The reduction of HBV RNA by ADAR1 expression was abrogated by p53 knock-down, suggesting the involvement of p53 in the ADAR1-mediated reduction of HBV RNA. This study demonstrated, for the first time, that ADAR1 plays an antiviral role against HBV infection by increasing the level of miRNA-122 in hepatocytes.

10.
Nat Commun ; 10(1): 3872, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455804

RESUMO

Molecular self-assembly into crystallised films or wires on surfaces produces a big family of motifs exhibiting unique optoelectronic properties. However, little attention has been paid to the fundamental mechanism of molecular crystallisation. Here we report a biomimetic design of phosphonate engineered, amphiphilic organic semiconductors capable of self-assembly, which enables us to use real-time in-situ scanning probe microscopy to monitor the growth trajectories of such organic semiconducting films as they nucleate and crystallise from amorphous solid states. The single-crystal film grows through an evolutionary selection approach in a two-dimensional geometry, with five distinct steps: droplet flattening, film coalescence, spinodal decomposition, Ostwald ripening, and self-reorganised layer growth. These sophisticated processes afford ultralong high-density microwire arrays with high mobilities, thus promoting deep understanding of the mechanism as well as offering important insights into the design and development of functional high-performance organic optoelectronic materials and devices through molecular and crystal engineering.

11.
Thromb Res ; 181: 127-134, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401416

RESUMO

OBJECTIVE: Venous thromboembolism (VTE) is a common cardiovascular disease, in which pulmonary embolism (PE) is potentially life-threatening. Accurate biological markers for the early diagnosis of VTE are needed. The purpose of this study was to analyze and validate the predictive value of microRNAs for the diagnosis of VTE. METHODS: A comprehensive literature review was conducted using the PubMed, Embase, and Cochrane Library databases and is current through Sep 27, 2018. The diagnostic value of microRNAs for VTE was analyzed by creating a summary receiver operating characteristic curve (SROC) and calculating the area under the curve (AUC). RESULTS: Our analysis included 12 articles assessing a total of 1057 individuals. The most frequently researched microRNA was miR-134, and the pooled results of the predictive ability of this miRNA with 95% confidence intervals (CIs) showed an average sensitivity of 0.82 (0.69-0.91) and an average specificity of 0.83 (0.68-0.92). The average AUC for the SROC curves was 0.89 (0.86-0.92). For other microRNAs, AUC values >0.8 were considered as potential diagnostic indices. These microRNAs included miR-1233, miR-134, miR-145, miR-483-3p, miR-582, miR-532, and miR-195. CONCLUSIONS: MicroRNAs may act as novel diagnostic biomarkers for VTE, and miR-1233, miR-134, miR-145, miR-483-3p, miR-582, miR-532, and miR-195 are prime candidates. Of these, research on miR-134 is the most extensive and reliable.

12.
Mediators Inflamm ; 2019: 5497467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467485

RESUMO

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.

13.
Phys Chem Chem Phys ; 21(35): 18958-18969, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31453590

RESUMO

Enhanced sampling has been extensively used to capture the conformational transitions in protein folding, but it attracts much less attention in the studies of protein-protein recognition. In this study, we evaluated the impact of enhanced sampling methods and solute dielectric constants on the overall accuracy of the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) approaches for the protein-protein binding free energy calculations. Here, two widely used enhanced sampling methods, including aMD and GaMD, and conventional molecular dynamics (cMD) simulations with two AMBER force fields (ff03 and ff14SB) were used to sample the conformations for 21 protein-protein complexes. The MM/PBSA and MM/GBSA calculation results illustrate that the standard MM/GBSA based on the cMD simulations yields the best Pearson correlation (rp = -0.523) between the predicted binding affinities and the experimental data, which is much higher than that given by MM/PBSA (rp = -0.212). Two enhanced sampling methods (aMD and GaMD) are indeed more efficient for conformational sampling, but they did not improve the binding affinity predictions for protein-protein systems, suggesting that the aMD or GaMD sampling (at least in short timescale simulations) may not be a good choice for the MM/PBSA and MM/GBSA predictions of protein-protein complexes. The solute dielectric constant of 1.0 is recommended to MM/GBSA, but a higher solute dielectric constant is recommended to MM/PBSA, especially for the systems with higher polarity on the protein-protein binding interfaces. Then, a preliminary assessment of the MM/GBSA calculations based on a variable dielectric generalized Born (VDGB) model was conducted. The results highlight the potential power of VDGB in the free energy predictions for protein-protein systems, but more thorough studies should be done in the future.

14.
Protein Expr Purif ; 164: 105478, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31421223

RESUMO

A gene encoding 1,4-α-glucan branching enzyme (GBE, EC 2.4.1.18) from the extremely thermophilic bacterium Rhodothermus obamensis STB05 was successfully cloned and expressed in Escherichia coli. Extracellular expression of the recombinant enzyme (R.o-GBE) was achieved with a yield of 1080 mg/L. Then it was purified and further characterized biochemically. R.o-GBE was optimally active at pH 7.0 and 65 °C. It remained stable at temperatures up to 80 °C and had a half-life at 85 °C of approximately 31 min. Far-UV circular dichroism and intrinsic fluorescence analyses revealed that high temperatures reduced its activity by changing the secondary and tertiary structure of R.o-GBE. The enzyme had broad pH stability between pH 3.0 and 11.0 at 4 °C, and preferred weakly acidic conditions at high temperatures. None of the metal ions enhanced the activity of R.o-GBE, but Ca2+ may be required for its activity. Its specific activity with amylopectin was 6651 U/mg, which is much higher than that reported for other GBEs. Its excellent thermostability, broad pH stability, and high specific activity make R.o-GBE highly suitable for industrial applications.

15.
Dalton Trans ; 48(35): 13466-13471, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31451822

RESUMO

Phosphorization engineering is an alternative method to explore highly efficient electrocatalysts for water splitting. Herein, a heterostructure consisting of Ni2P and Ni3S2 supported on commercial nickel foam (Ni3S2-Ni2P/NF) was prepared through the conversion of some Ni3S2 molecules into Ni2P by phosphorization engineering. Electrochemical tests revealed that the partial phosphorization of Ni3S2 effectively enhanced the catalytic activity of the host electrocatalyst towards the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in 1 M KOH; in particular, the Ni3S2-Ni2P/NF electrode exhibited the current density of 50 mA cm-2 at the very low OER overpotential of 287 mV and needed the low overpotential of 130 mV to afford 10 mA cm-2 for the HER. Moreover, the alkaline electrolyzer assembled by two Ni3S2-Ni2P/NF electrodes could deliver 10 mA cm-2 at the low voltage of 1.58 V and exhibited excellent durability during electrolysis for 15 h. Therefore, our study opens up an attractive fabrication strategy for highly active heterostructure electrocatalysts.

16.
Pharmacol Res ; 147: 104355, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386886

RESUMO

Convallatoxin (CNT) is a cardiac glycoside isolated from Adonis amurensis Regel et Radde and has both anti-inflammatory and anti-proliferative properties. In the present study, the anti-inflammatory mechanisms of action of CNT was investigated in vitro and in vivo. Stimulation of mouse macrophages with lipopolysaccharide induced secretion of proinflammatory cytokines via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) and activation of nuclear factor-κB (NF-κB), two transcription factors implicated in many inflammatory diseases. Notably, the effects of lipopolysaccharide were reversed by concomitant treatment of macrophages with CNT. Knockdown of PPARγ by siRNA inhibited the effect of convallatoxin on NF-κB activation. Because these transcription factors play a role in the development of ulcerative colitis in humans, the mice with experimental colitis induced by dextran sodium sulfate (DSS) was employed. Indeed, concomitant treatment with CNT ameliorated DSS-induced colitis symptoms, tissue damage, inflammatory cell infiltration, and proinflammatory cytokine production in the colon, and also reversed the activation of NF-κB and suppression of PPARγ. Collectively, these data indicate that CNT ameliorates colitic inflammation via activation of PPARγ and suppression of NF-κB, and suggest that CNT may be a promising treatment for inflammatory bowel disease (IBD).

17.
Insect Biochem Mol Biol ; 113: 103215, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31449847

RESUMO

In this study, two novel antibacterial peptide genes, termed lugensin A and B were identified and characterized from a rice sap-sucking hemipteran insect pest, the brown planthopper, Nilaparvata lugens. Lugensin gene expression was significantly induced by Gram-negative and Gram-positive bacterial stains under the regulation of a signal receptor, the long peptidoglycan recognition protein (PGRP-LC) in the IMD pathway. Knockdown of PGRP-LC by RNAi eliminated bacterium induced Lugensin gene expression. Lugensins had the apparent antibacterial activities against Escherichia coli K12, Bacillus subtilis and the rice bacterial brown stripe pathogen Acidovorax avenae subsp. avenae (Aaa) strain RS-1. Lugensins inhibited bacterial proliferation by disrupting the integrity of the bacterial membranes. Scanning electron microscopy revealed abnormal membrane morphology of the recombinant Lugensin-treated bacteria. Lugensins induced complete cell disruption of E. coli K12 and B. subtilis strains while formed the holes on the cell surface of Aaa RS-1 strain. Immunofluorescence showed that Lugensins localized in the cell membrane of E. coli K12 while accumulated in the cytosol of B. subtilis. Differently, Lugensins remained in both the cell membrane and the cytosol of Aaa RS-1 strain, suggesting different action modes of Lugensins to different microbes. This is the first report of the novel antibacterial peptides found in the rice sap-sucking hemipteran insect species.

19.
Mol Nutr Food Res ; : e1900603, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31433910

RESUMO

SCOPE: Age-related degeneration is associated with imbalances of gut microbiota and its related immune system, thereby gut microbiota dysbiosis is considered to be a key target to improve senescence. The potential roles of probiotics on physiological function and cognitive ability in aged mice were investigated in this study. METHODS AND RESULTS: Lactobacillus casei LC122 or Bifidobacterium longum BL986, were orally administrated for 12 weeks, and the anti-aging effects, as well as the composition and function of gut microbiota were investigated in aged mice. Probiotics supplementation ameliorated hepatic lipid accumulation, enhanced muscle strength and function, attenuated oxidative stress and inflammation in peripheral tissues and improved gut barrier function. These results were associated with improved learning and memory ability as assessed by behavioral tests and up-regulation of neurodegenerative and neurotrophic factors expressions in hippocampus. Moreover, the diversity and composition of gut microbiota were altered in aged mice, and both probiotics treatment displayed distinguished features of gut microbiota. Comparisons of two probiotic strains revealed significant differences in the taxa at family and genus level, leading to the functional profile change of the microbial community. CONCLUSION: Lactobacillus casei LC122 and Bifidobacterium longum BL986 might be used as novel and promising anti-aging agent in human. This article is protected by copyright. All rights reserved.

20.
J Dermatol ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31435946

RESUMO

Hailey-Hailey disease (HHD) is a rare autosomal dominant inherited keratosis caused by mutations in ATP2C1. The aim of our study was to identify and analyze the features of the mutations in HHD. We examined 52 Chinese Han cases which were diagnosed as HHD based on their clinical and histological findings. Genomic DNA polymerase chain reaction and direct sequencing of ATP2C1 were performed from peripheral blood samples of the patients and 100 unrelated healthy controls. Twenty-five novel mutations and 14 recurrent mutations were identified, including 11 (28.2%) missense mutations, nine (23.1%) frame-shift deletion mutations, eight (20.5%) nonsense mutations, seven (17.9%) splicing mutations and four (10.3%) frame-shift insertion mutations. Together with ours, all 209 mutations showed a uniform distribution without hotspots or clusters. In addition, there is no specific genotype-phenotype correlation in HHD. Our findings update the spectrum of mutations in ATP2C1.

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