Search

Two quinoxaline dyes utilized in copper-electrolyte-based dye-sensitized solar cells (Cu-DSSCs) are theoretically investigated to analyze the impact of alkyl chains on dye performance. The investigation shows that ZS4, known for its record efficiency of up to 13.2 %, exhibits higher electron coupling and fewer binding sites for dye-[Cu(tmby) 2 ] 2+ interaction compared to ZS5. Contrary to common belief, alkyl chains are found to not only provide shielding but also hinder the interaction between dye and [Cu(tmby) 2 ] 2+ by influencing the optimal conformation of dyes, thereby impeding the charge recombination process. It is crucial to consider the influence of alkyl chains on dye conformation when discussing the relationship between dye structure and performance, rather than oversimplifying it as often done traditionally. Building on these findings, eight dyes are strategically designed by adjusting the position of the alkyl chain to further decrease charge recombination compared to ZS4. Theoretical evaluation of these dyes reveals that changing the alkyl chain on the nitrogen atom from 2-ethylhexyl (ZS4) to 1-hexylheptyl (D3-2) not only reduces the charge recombination rate but also enhances light harvesting ability. Therefore, D3-2 shows potential as a candidate for experimental synthesis of high-performance Cu-DSSCs with improved efficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Organic electrode materials (OEMs) have gathered extensive attention for aqueous zinc-ion batteries (AZIBs) due to their structural diversity and molecular designability. However, the reported research mainly focuses on the design of the planar configuration of OEMs and does not take into account the important influence of the spatial structure on the electrochemical properties, which seriously hamper the further performance liberation of OEMs. Herein, this work has designed a series of thioether-linked naphthoquinone-derived isomers with tunable spatial structures and applied them as the cathodes in AZIBs. The incomplete conjugated structure of the elaborately engineered isomers can guarantee the independence of the redox reaction of active groups, which contributes to the full utilization of active sites and high redox reversibility. In addition, the position isomerization of naphthoquinones on the benzene rings changes the zincophilic activity and redox kinetics of the isomers, signifying the importance of spatial structure on the electrochemical performance. As a result, the 2,2'-(1,4-phenylenedithio) bis(1,4-naphthoquinone) (p-PNQ) with the smallest steric hindrance and the most independent redox of active sites exhibits a high specific capacity (279 mAh g -1 ), an outstanding rate capability (167 mAh g -1 at 100 A g -1 ), and a long-term cycling lifetime (over 2800 h at 0.05 A g -1 )., (© 2024 Wiley‐VCH GmbH.)

Backgroup: Currently, aromatherapy is being increasingly utilized in clinical practice, particularly in managing the side effects associated with radiotherapy and chemoradiotherapy. However, it remains to be established whether aromatherapy can effectively alleviate these symptoms., Objective: To investigate the effects of aromatherapy on the physical and mental health of patients with cancer undergoing radiotherapy and chemotherapy., Methods: Seven databases were researched from inception until September 29, 2023, including PubMed, Scopus, and Web of Science, Chinese National Knowledge Infrastructure, Wanfang database, China Biology Medicine disc and VIP Chinese Medical Journal Database. Review Manager version 5.3 was utilized for data analysis. The Cochrane Risk of Bias tool RoB2 was employed to evaluate the quality of the literature included in the study. Evidence quality rating was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach through the GRADEpro GDT online tool., Results: Nineteen studies involving 1,541 patients were included. Aromatherapy can alleviate nausea [relative risk (RR)=0.64, 95% confidence interval (CI): 0.53 to 0.78, P<0.05, I 2 =46%; standardized mean difference (SMD)=-0.86, 95% CI: -1.21 to -0.51, P<0.05, I 2 =64%] and vomiting (RR=0.54, 95% CI: 0.42 to 0.69, P<0.05, I 2 =35%; SMD=-1.28, 95% CI: -1.52 to -1.03, P<0.05, I 2 =92%), improve sleep disorders [mean difference (MD)=-3.39, 95% CI: -3.95 to -2.84, P<0.05, I 2 =0%], relieve pain (SMD=-1.58, 95% CI: -1.96 to -1.21, P<0.05, I 2 =0%), mitigate fatigue (SMD=-1.28, 95% CI: -2.44 to -0.11, P<0.05, I 2 =93%) and enhance quality of life (SMD=0.50, 95% CI: 0.22 to 0.79, P<0.05, I 2 =0%) in cancer patients after radiotherapy and chemotherapy, but it may not have a significant effect on anxiety. The risk of bias was high in the included studies using the Cochrane Risk of Bias tool RoB2, and no studies were considered to be of high grade according to the GRADE system., Conclusions: Aromatherapy is an efficacious, safe and economic adjunctive therapy for cancer patients, which can mend the physical symptoms and mental health of cancer patients. However, more high-quality studies are needed to verify it. (PROSPERO registration No. CRD42023390171)., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The slow reaction kinetics and structural instability of organic electrode materials limit the further performance improvement of aqueous zinc-organic batteries. Herein, we have synthesized a Z-folded hydroxyl polymer polytetrafluorohydroquinone (PTFHQ) with inert hydroxyl groups that could be partially oxidized to the active carbonyl groups through the in situ activation process and then undertake the storage/release of Zn 2+ . In the activated PTFHQ, the hydroxyl groups and S atoms enlarge the electronegativity region near the electrochemically active carbonyl groups, enhancing their electrochemical activity. Simultaneously, the residual hydroxyl groups could act as hydrophilic groups to enhance the electrolyte wettability while ensuring the stability of the polymer chain in the electrolyte. Also, the Z-folded structure of PTFHQ plays an important role in reversible binding with Zn 2+ and fast ion diffusion. All these benefits make the activated PTFHQ exhibit a high specific capacity of 215 mAh g -1 at 0.1 A g -1 , over 3400 stable cycles with a capacity retention of 92 %, and an outstanding rate capability of 196 mAh g -1 at 20 A g -1 ., (© 2023 Wiley-VCH GmbH.)

In additive manufacturing (AM), the mechanical properties of manufactured parts are often insufficient due to complex defects and residual stresses, limiting their use in high-value or mission-critical applications. Therefore, the research and application of nondestructive testing (NDT) technologies to identify defects in AM are becoming increasingly urgent. This article reviews the recent progress in online detection technologies in AM, a special introduction to the high-speed synchrotron X-ray technology for real-time in situ observation, and analysis of defect formation processes in the past 5 years, and also discusses the latest research efforts involving process monitoring and feedback control algorithms. The formation mechanism of different defects and the influence of process parameters on defect formation, important parameters such as defect spatial resolution, detection speed, and scope of application of common NDT methods, and the defect types, advantages, and disadvantages associated with current online detection methods for monitoring three-dimensional printing processes are summarized. In response to the development requirements of AM technology, the most promising trends in online detection are also prospected. This review aims to serve as a reference and guidance for the work to identify/select the most suitable measurement methods and corresponding control strategy for online detection., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Organic materials have attracted much attention in aqueous zinc-ion batteries (AZIBs) due to their sustainability and structure-designable, but their further development is hindered by the high solubility, poor conductivity, and low utilization of active groups, resulting in poor cycling stability, terrible rate capability, and low capacity. In order to solve these three major obstacles, a novel organic host, benzo[b]naphtho[2',3':5,6][1,4]dithiino[2,3-i]thianthrene-5,7,9,14,16,18-hexone (BNDTH), with abundant electroactive groups and stable extended π-conjugated structure is synthesized and composited with reduced graphene oxide (RGO) through a solvent exchange composition method to act as the cathode material for AZIBs. The well-designed BNDTH/RGO composite exhibits a high capacity of 296 mAh g -1 (nearly a full utilization of the active groups), superior rate capability of 120 mAh g -1 , and a long lifetime of 58 000 cycles with a capacity retention of 65% at 10 A g -1 . Such excellent performance can be attributed to the ingenious structural design of the active molecule, as well as the unique solvent exchange composition strategy that enables effective dispersion of excess charge on the active molecule during discharge/charge process. This work provides important insights for the rational design of organic cathode materials and has significant guidance for realizing ideal high performance in AZIBs., (© 2023 Wiley-VCH GmbH.)

Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community., Competing Interests: C.S.G.’s spouse was an employee of Alex’s Lemonade Stand Foundation, which was a sponsor of this research. J.A.S., C.L.S., C.J.B., S.J.S., and J.N.T. are or were employees of Alex’s Lemonade Stand Foundation, a sponsor of this research. A.J.W. is a member of the Scientific Advisory boards for Alexion and DayOne Biopharmaceuticals., (© 2023 The Author(s).)

Objective: To investigate the clinical features of peripherally inserted central catheter (PICC)-related thrombosis (PICCRT) within 2 weeks after PICC placement in cancer patients and its dynamic influence on the blood flow status of veins inserted with catheter, and to provide support for implementing thrombosis prevention and control measures., Methods: Between May 2019 and July 2020, patients who had solid tumors and who had PICC were prospectively enrolled at West China Hospital, Sichuan University. Scheduled color Doppler imaging was performed to examine the status of PICCRT formation at 8 points of time, with the first one conducted one day before the insertion of PICC and the other 7 completed within 2 weeks after the insertion of PICC. Then, based on whether patients had PICCRT, the patients were divided into two groups, a non-PICCRT group and a PICCRT group. The PICCRT group was further divided into two subgroups, an asymptomatic PICCRT group and a symptomatic PICCRT group, according to whether the patients had thrombosis-related symptoms and signs. Comparisons were made to study the incidence of PICCRT and the vascular diameter and the blood flow velocity in the veins inserted with catheters at different points of time in the patients of different groups., Results: Among 173 cancer patients in the cohort, 126 (72.8%) developed PICCRT, all of which occurred within 1 week after PICC insertion. There were 95 cases of asymptomatic PICCRT and 31 cases of symptomatic PICCRT. Before and after PICC insertion, the vascular diameter of both the asymptomatic and symptomatic PICCRT groups was significantly smaller than that of the non-PICCRT group and the blood flow velocity was significantly slower than that of the non-PICCRT group, with the difference continuing to increase with the prolongation of catheter indwelling time., Conclusion: Inserting catheters in veins with bigger vascular diameter and faster blood flow velocity may help reduce the incidence of PICCRT. The first week post catheter insertion is the key intervention period for the prevention of PICCRT., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

To study the quality control of three traditional Chinese medicines derived from Gleditsia sinensis [Gleditsiae Sinensis Fructus(GSF), Gleditsiae Fructus Abnormalis(GFA), and Gleditsiae Spina(GS)], this paper established a multiple reaction monitoring(MRM) approach based on ultra-high performance liquid chromatography-triple quadrupole-linear ion-trap mass spectrometry(UHPLC-Q-Trap-MS). Using an ACQUITY UPLC BEH C&#95;(18) column(2.1 mm × 100 mm, 1.7 μm), gradient elution was performed at 40 ℃ with water containing 0.1% formic acid-acetonitrile as the mobile phase running at 0.3 mL·min~(-1), and the separation and content determination of ten chemical constituents(e.g., saikachinoside A, locustoside A, orientin, taxifolin, vitexin, isoquercitrin, luteolin, quercitrin, quercetin, and apigenin) in GSF, GFA, and GS were enabled within 31 min. The established method could quickly and efficiently determine the content of ten chemical constituents in GSF, GFA, and GS. All constituents showed good linearity(r&gt;0.995), and the average recovery rate was 94.09%-110.9%. The results showed that, the content of two alkaloids in GSF(2.03-834.75 μg·g~(-1)) was higher than that in GFA(0.03-10.41 μg·g~(-1)) and GS(0.04-13.66 μg·g~(-1)), while the content of eight flavonoids in GS(0.54-2.38 mg·g~(-1)) was higher than that in GSF(0.08-0.29 mg·g~(-1)) and GFA(0.15-0.32 mg·g~(-1)). These results provide references for the quality control of G. sinensis-derived TCMs.

The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFβ type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases., (© 2023. The Author(s).)

Pyrolysis is an important technology to achieve the harmlessness and recycling of contaminated biomass. In this study, the effects of oxygen-controlled atmosphere on the component properties and heavy metal accumulation characteristics of contaminated rice straw biochar were studied. The results showed that low-oxygen pyrolysis could effectively produce biochar using contaminated rice straw and improve the stability of heavy metals in biochar. Under the nitrogen atmosphere, the yield of rice straw biochar was 29.4%-34.9%. The aromatization index (SUVA 254 ) of dissolved organic matter (DOM) increased first and then decreased with the increase in pyrolysis temperature, whereas the fluorescent components were mainly humic-like acid substances. Meanwhile, Ca mainly existed in the form of CaCO 3 in biochar. Compared with the pure nitrogen condition, the biochar yield was reduced by 5.6%-13.5% and 14.9%-15.7% under the pyrolysis atmosphere containing 10% and 20% oxygen content, respectively. Ca existed in the form of CaO in biochar, which increased the pH value of the biochar by more than 0.5 units. The oxygen of the pyrolysis atmosphere accelerated the degradation of the lignin component, resulting in the gradual decrease in SUVA 254 of DOM. With the increase in oxygen content in the pyrolysis atmosphere, humic-like acid substances in DOM were transformed into fulvic-like acid substances. Under the conditions of 400℃ and a 10% oxygen-containing atmosphere, the exchangeable fractions of Cu, Cd, Pb, Ni, and As in biochar were decreased by 5.2%, 3.7%, 1.7%, 0.8%, and 0.7%, respectively, indicating that heavy metals are transformed into more stable states. The results suggested that the higher biochar yield and heavy metal stability could be obtained by introducing a proper amount of nitrogen into the air (controlling the oxygen content of approximately 10%) for pyrolysis treatment of contaminated rice straw, providing an economic and feasible technology for the achievement of harmlessness and recovery of contaminated rice straw.

Background and Aims: A key histopathological feature of inflammatory bowel disease is damage to the mucosa, including breakdown of the epithelial barrier. Human enteroids and colonoids are a critical bench-to-bedside tool for studying the epithelium in inflammatory bowel disease. The goal of the current study was to define transcriptional differences in healthy versus diseased subjects that are sustained in enteroids and colonoids, including from disease-spared tissue., Methods: Biopsies and matching enteroid or colonoid cultures from pediatric patients with ileal Crohn disease (N = 6) and control subjects (N = 17) were subjected to RNA sequencing followed by bioinformatic and machine learning analyses. Late passage enteroids were exposed to cytokines to assess durable transcriptional differences., Results: We observed substantial overlap of pathways upregulated in Crohn disease in enteroids and ileal biopsies, as well as colonoids and rectal biopsies. KEGG pathways for cytokine-cytokine receptor interaction, chemokine signaling, protein export, and Toll-like receptor signaling were upregulated in both ileal and rectal biopsies, as well as enteroids and colonoids. In vitro cytokine exposure reactivated genes previously increased in biopsies. Machine learning predicted biopsy location (100% accuracy) and donor disease status (83% accuracy). A random forest classifier generated using ileal enteroids identified rectal colonoids from ileal Crohn disease subjects with 80% accuracy., Conclusion: We confirmed transcriptional profiles of Crohn disease biopsies are expressed in enteroids and colonoids. Furthermore, transcriptomic data from disease-spared rectal tissue can identify patients with ileal Crohn disease. Our data support the use of patient enteroids and colonoids as critical translational tools for the study of inflammatory bowel disease., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.

Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied with a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in 39 pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A (GenBank: NM&#95;001288739.1), which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of enlarged synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.Arg399Trp and p.Gly401Asp, had a similar DEE phenotype. In contrast, one individual with a missense variant affecting exon 10b, p.Pro405Leu, which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants as well as the possibility of splice site variants acting through a dominant-negative mechanism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.

The relationship between hemiplegic shoulder pain (HSP) and subluxation is unclear. This study aimed to determine the differences of magnetic resonance imaging (MRI) findings in HSP patients with or without subluxation after stroke, and to analyze the etiology of shoulder pain. This retrospective study included 53 patients with HSP after stroke from September 2013 to February 2020. Patients underwent MRI of the shoulder because of shoulder pain. Clinical characteristics, including age, sex, stroke duration, body mass index, stroke type, visual analog scale score, Brunnstrom stage, and MRI arthrography findings of the affected shoulder, were recorded. Patients were classified into the glenohumeral subluxation (GHS) group ( n = 27) or non-glenohumeral subluxation (nGHS) group ( n = 26). We found that patients with HSP may be prone to bursa effusion, rotator cuff injury, ligament injury, and cartilage injury, even though there was no significant difference between the GHS and nGHS groups. MRI revealed 14 cases of long bicipital tendon-glenoid labrum injury (51.8%) in the GHS group and 6 cases (23.1%) in the nGHS group ( p = 0.030). We also found 10 cases (37%) of glenoid labrum injury in the GHS group and 2 cases (7.7%) in the nGHS group ( p = 0.026). Eight cases (29.6%) and 1 case (3.8%) of bone marrow edema were found in the GHS and nGHS groups, respectively ( p = 0.033). Compared with painful hemiplegic shoulder patients without subluxation, patients with subluxation may be more susceptible to some injuries, such as long bicipital tendon-glenoid labrum injury, glenoid labrum injury, and bone marrow edema. During rehabilitation, physicians need to pay attention to these injuries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Zhang, Xu, Wang, Wang, Jia and Zhang.)

The objective of this study was to investigate whether brain volume changes occur in patients with chronic ankle instability (CAI) using voxel-based morphometry and assessing correlations with clinical tests. Structural magnetic resonance imaging data were prospectively acquired in 24 patients with CAI and 34 healthy controls. CAI symptoms and pain intensity were assessed using the Foot and Ankle Ability Measure (FAAM), Cumberland Ankle Instability Tool (CAIT), American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, and visual analog scale (VAS). The gray matter volume (GMV) of each voxel was compared between the two groups while controlling for age, sex, weight, and education level. Correlation analysis was performed to identify associations between abnormal GMV regions and the FAAM score, AOFAS score, VAS score, disease duration, and body mass index. Patients with CAI exhibited reduced GMV in the right precentral and postcentral areas, right parahippocampal area, left thalamus, left parahippocampal area, and left postcentral area compared to that of healthy controls. Furthermore, the right parahippocampal (r = 0.642, p = 0.001), left parahippocampal (r = 0.486, p = 0.016), and left postcentral areas (r = 0.521, p = 0.009) were positively correlated with disease duration. The left thalamus was positively correlated with the CAIT score and FAAM activities of daily living score (r = 0.463, p = 0.023 and r = 0.561, p = 0.004, respectively). A significant positive correlation was found between the local GMV of the right and left parahippocampal areas (r = 0.487, p = 0.016 and r = 0.763, p < 0.001, respectively) and the AOFAS score. Neural plasticity may occur in the precentral and postcentral areas, parahippocampal area, and thalamus in patients with CAI. The patterns of structural reorganization in patients with CAI may provide useful information on the neuropathological mechanisms of CAI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Xing, Chen, Zhang, Qiu, Jia, Zhang and Yu.)

Angiosarcoma is a rare, devastating malignancy with few curative options for disseminated disease. We analyzed a recently published genomic data set of 48 angiosarcomas and noticed recurrent amplifications of HOXA -cluster genes in 33% of patients. HOXA genes are master regulators of embryonic vascular development and adult neovascularization, which provides a molecular rationale to suspect that amplified HOXA genes act as oncogenes in angiosarcoma. HOXA amplifications typically affected multiple pro-angiogenic HOXA genes and co-occurred with amplifications of CD36 and KDR, whereas the overall mutation rate in these tumors was relatively low. HOXA amplifications were found most commonly in angiosarcomas located in the breast and were rare in angiosarcomas arising in sun-exposed areas on the head, neck, face and scalp. Our data suggest that HOXA -amplified angiosarcoma is a distinct molecular subgroup. Efforts to develop therapies targeting oncogenic HOX gene expression in AML and other sarcomas may have relevance for HOXA -amplified angiosarcoma.

Objective: The purpose of this study was to investigate the effects of different durations of static progressive stretching (SPS) on posttraumatic knee contracture in rats, including range of motion (ROM), gait analysis, myofibroblast proliferation, and collagen regulation., Methods: The posttraumatic knee contracture model was established, and male Wistar rats were randomly divided into the 20-minute SPS treatment, 30-minute SPS treatment (S30), 40-minute SPS treatment, untreated, immobilization, and control groups. At Week 1, 2, and 4 of treatment intervention, joint ROM and gait were measured and compared. Knee joint samples stained with hematoxylin and eosin and Masson trichrome were used to observe alterations in pathological structures. Collagen density and cell numbers in the posterior joint capsule were used to assess joint capsule fibrosis and inflammation. Immunohistochemistry was used to detect type I collagen and α-smooth muscle actin expression., Results: The S30 group improved the most; ROM, stance, mean intensity, print area, and stride length were 115 (SD = 5) degrees, 0.423 (SD = 0.074) seconds, 156.020 (SD = 7.952), 2.116 (SD = 0.078) cm2, and 11.758 (SD = 0.548) cm, respectively. The numbers of myofibroblasts, fibroblasts, and inflammatory cells decreased, and collagen proliferation was significantly suppressed in the S30 group compared with the other groups., Conclusion: S30 significantly improved posttraumatic knee contracture in rats, with reduced type I collagen and α-smooth muscle actin expression, decreased the numbers of myofibroblasts and inflammatory cells, suppressed fibrotic and inflammatory changes in the joint capsule, and increased joint mobility. This study provided basic evidence for an optimal standard-of-care treatment approach for posttraumatic knee joint contracture in rats, which may have significance for humans., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the effectiveness of mirror therapy (MT) for phantom limb pain (PLP)., Data Sources: PubMed, EMBASE, Ovid MEDLINE, Scopus, Cochrane Library, Physiotherapy Evidence Database, CNKI, and WanFang Data were used to search for studies published up to March 31, 2021., Study Selection: Randomized controlled trials (RCTs) comparing the pain intensity of MT for PLP were performed. A total of 2094 articles were found. Among them, 10 were eligible for the final analysis., Data Extraction: The quality of the RCTs was assessed using the Physiotherapy Evidence Database (PEDro) scale by 2 independent reviewers. Outcome data were pooled according to follow-up intervals (1, 3, 6, and 12mo). Duration times were used as a basis for distinguishing subgroups. The primary evaluation was by visual analog scale. The PEDro scale was used to assess the methodological quality of studies., Data Synthesis: Meta-analysis revealed a statistically significant decrease in pain in the MT group vs the control group within 1 month (I 2 =0%; standardized mean difference [SMD]=-0.46, 95% confidence interval [CI], -0.79 to -0.13; P = .007). The patients with pain for longer than 1 year benefited more from MT (I 2 =0%; SMD=-0.46; 95% CI, -0.85 to -0.07; P = .02)., Conclusions: MT has beneficial effects for patients with PLP in the short-term, as evidenced by their improved pain scores. There was no evidence that MT had a long-term effect, but that may be a product of limited data. For patients with long-term PLP, MT may be an effective treatment., (Copyright © 2021 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Glial cells play an important role in signal transduction, energy metabolism, extracellular ion homeostasis and neuroprotection of the central nervous system. However, few studies have explained the potential effects of exosomes from glial cells on central nervous system health and disease. In this study, the genes expressed in exosomes from astrocytes and microglia were identified by deep RNA sequencing. Kyoto Encyclopedia of Genes and Genomes analysis indicated that several pathways in these exosomes are responsible for promoting neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. Gene ontology analysis showed that extracellular exosome, mitochondrion and growth factor activity were enriched in exosomes from the unique astrocyte group, while extracellular exosome and mitochondrion were enriched in exosomes from the unique microglia group. Next, combined with the screening of hub genes, the protein-protein interaction network analysis showed that exosomes from astrocytes influence neurodegenerative diseases through metabolic balance and ubiquitin-dependent protein balance, whereas exosomes from microglia influence neurodegenerative diseases through immune inflammation and oxidative stress. Although there were differences in RNA expression between exosomes from astrocytes and microglia, the groups were related by the hub genes, ubiquitin B and heat shock protein family A (Hsp70) member 8. Ubiquitin B appeared to be involved in pleiotropic regulatory functions, including immune regulation, inflammation inhibition, protein catabolism, intracellular protein transport, exosomes and oxidative stress. The results revealed the clinical significance of exosomes from glia in neurodegenerative diseases. This study was approved by the Animal Ethics Committee of Nantong University, China (approval No. S20180102-152) on January 2, 2018., Competing Interests: None

Rationale: Hemangioblastomas (HGBMs) are very rare, and the cerebellum is usually the most common site of occurrence. HGBMs with ring-enhanced walls are often misdiagnosed as metastases, abscesses, glioblastomas, tuberculomas, and demyelinating diseases. Thus, we present a rare case of HGBM masquerading as a ring-enhancing lesion in the cerebellum., Patient Concerns: We present a 33-year-old female who was admitted to our department because of headaches, unstable walking, and visual loss in both eyes. Cranial nerve examination revealed deficits in cranial nerve II., Diagnosis: Magnetic resonance imaging revealed 2 cystic lesions in the cerebellum, with irregular ring-enhanced cyst walls composed of smaller nodular parts. Immunohistochemical staining of resected specimens established HGBM., Interventions: The lesions were completely resected using a right retrosigmoid approach., Outcomes: Two years of follow-up revealed no recurrence of her symptoms or tumor. She is currently well and performs her daily duties., Lessons: HGBMs with enhanced cysts are often misdiagnosed by radiology because of their ring-enhanced nature. Computed tomography angiography may be the best modality for differentiating cerebellar HGBM from other ring-enhancing lesions. Surgery is the gold standard of treatment for these lesions., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited BM failure syndromes (iBMFSs). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes BM dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC after HSCT, a hypothesis that could explain morbidity noted after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have also identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and are accentuated by or develop specifically after myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets, including mesenchymal lineage cells, macrophages, and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Rationale: Glioma in the petroclival region is very rare. Also, very few cases of primary gliomas have been reported to have radiographic as well as intraoperative features of extra-axial lesions resulting in diagnostic dilemma in the literature. We present a rare case of petroclival glioma mimicking trigeminal schwannoma in a young female., Patient Concerns: We present a 21-years old female with a 3-month history of pain in the right eye with no visual impairment. Cranial nerves examination revealed mild deficits in the trigeminal nerve, facial nerve, auditory nerve, oculomotor as well as the trochlear nerve., Diagnoses: Magnetic resonance imaging detected an extra-axial mass with mixed signal intensities in the right petroclivus area. Immunohistochemical established glioma with world health organization (WHO) grade II., Interventions: The lesion was resected via 2 successive operations in 6 months interval. The patient was further treated with radiotherapy and post-radiotherapy temozolamide., Outcomes: Two years follow-up revealed no recurrence of the lesions and she is well. Nevertheless, he is still being followed diligently to uncover any recurrence., Lessons: The extra-axial nature as well as petroclival location of the glioma makes our case very unique and very rare. The imaging characteristics were very extraordinary for a glioma which resulted in diagnostic dilemma. Thus, the definitive diagnosis was based on the histopathological evaluation of the excised tumor., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate the effectiveness of botulinum toxin A (BTX-A) in the treatment of hemiplegic shoulder pain., Data Sources: PubMed, EMBASE, Elsevier, Springer, Cochrane Library, Physiotherapy Evidence Database, CNKI, and VIP were researched from the earliest records to September 1, 2020., Study Selection: Randomized controlled trials that compared shoulder BTX-A injections vs a control intervention in patients with a history of hemiplegic shoulder pain after stroke were selected. Among the 620 records screened, 9 trials with 301 eligible patients were included., Data Extraction: Outcome data were pooled according to follow-up intervals (1, 2, 4, and 12 wk). The primary evaluation indices were pain reduction (visual analog scale [VAS] score) and range of motion (ROM) improvement. The second evaluation indices were upper limb functional improvement, spasticity improvement, and incidence of adverse events. Cochrane risk-of-bias was used to assess the methodological quality of studies independently by 2 evaluators., Data Synthesis: Meta-analysis revealed a statistically significant decrease in the VAS score in the BTX group vs the control group at 1, 4, and 12 weeks postinjection (wk 1: standardized mean difference [SMD], 0.91; 95% confidence interval [CI], 0.27 to 1.54; wk 4: SMD, 1.63; 95% CI, 0.76 to 2.51; wk 12: SMD, 1.96; 95% CI, 1.44 to 2.47). Furthermore, the meta-analysis demonstrated a statistically significant increase in abduction at 1, 4, and 12 weeks postinjection (wk 1: SMD, 3.71; 95% CI, 0 to 7.41; wk 4: SMD, 8.8; 95% CI, 2.22 to 15.37; wk 12: SMD, 19.59; 95% CI, 9.05 to 30.13) and external rotation at 1, 2, 4 weeks postinjection (wk 1: SMD, 5.67; 95% CI, 0.88 to 10.47; wk 2: SMD, 9.62; 95% CI, 5.57 to 13; wk 4: SMD, 6.89; 95% CI, 2.45 to 11.33) in the BTX group., Conclusions: BTX-A injection provided greater analgesic effects and increased shoulder abduction and external rotation ROM compared with steroid or placebo injection for the treatment of HSP., (Copyright © 2021 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Developing flexible electrodes with high active materials loading and excellent mechanical stability is of importance to flexible electronics, yet remains challenging. Herein, robust flexible electrodes with an encapsulated core-multishell structure are developed via a spraying-hydrothermal process. The multilayer electrode possesses an architecture of substrate/reduced graphene oxide (rGO)/bimetallic complex/rGO/bimetallic complex/rGO from the inside to the outside, where the cellulosic fibers serve as the substrate, namely, the core; and the multiple layers of rGO and bimetallic complex, are used as active materials, namely, the shells. The inner two rGO interlayers function as the cement that chemically bind to two adjacent layers, while the two outer rGO layers encapsulate the inside structure effectively protecting the electrode from materials detachment or electrolyte corrosion. The electrodes with a unique core-multishell structure exhibit excellent cycle stability and exceptional temperature tolerance (-25 to 40 °C) for lithium and sodium storage. A combination of experimental and theoretical investigations are carried out to gain insights into the synergetic effects of cobalt-molybdenum-sulfide (CMS) materials (the bimetallic complex), which will provide guidance for future exploration of bimetallic sulfides. This strategy is further demonstrated in other substrates, showing general applicability and great potential in the development of flexible energy storage devices., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS ( N = 1472 total cases) and three without 22q11.2DS ( N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.

Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation., Competing Interests: Declaration of interests K.M.B. holds a patent on the use of DOT1L inhibitors for MN1 leukemia. K.M.B. has received research funding from Syndax and has previously consulted for Agios. I.H. received research funding from Bristol-Myers Squibb (BMS), Celgene, Merck Sharpe & Dohme (MSD), Astellas, Otsuka, Ono, Kyowa Kirin, Sanofi, Shionogi, Zenyaku, Daiichi Sankyo, Taiho, Takeda, Chugai, Eli Lilly, Nihon Shinyaku, Novartis, Pfizer, Fujimoto, Tanabe-Mitsubishi, Fukuyu Hospital, and Yamada Yohojo and received honoraria from or holds membership on an entity’s board of directors, speaker’s bureau, or its advisory committees for Celgene, Janssen, Takeda, Ono, BMS, Novartis, Daiichi Sankyo, Kyowa Kirin, Eisai, Nihon-Shinyaku, Pfizer, AbbVie, Otsuka, Shionogi, Mundi, CSL, and MSD. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A-Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A-Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.

Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion ( p < 0.01) and then a backward exclusion procedure ( p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h -1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important., Competing Interests: Y-jZ, H-mX, LL, and DW are employees of Sunshine Lake Pharma Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guan, Tang, Zhang, Xie, Luo, Wu, Chen and Hu.)

Aim: To verify the association between retinopathy, nephropathy, and periodontitis in type 2 diabetic (T2D) patients., Methods: Several electronic databases were available for our comprehensive search including China National Knowledge Infrastructure (CNKI), Chinese VIP Information (VIP), Wanfang, Web of Science, ScienceDirect and PubMed and were queried for relevant citations (updated to Mar. 2019). RevMan was utilized to perform Meta analysis and publication bias detection. After evaluation of the methodological quality of included studies, a fixed or random effect model was utilized to analyze data from included studies., Results: A total of eight articles were finally included in this Meta analysis. In all 3987 subjects, there were 1207 T2D patients accompanying with microvascular complications and 1734 patients with periodontitis as well. The Meta forest plot presented little heterogeneity of the eight studies ( P <0.00001, I 2 =89%). The total effect demonstrated periodontitis was associated with overall microvascular complications (OR: 1.96, 95%CI: 1.67-2.30, Z =8.25, P <0.00001). Subgroup investigations among the studies in Asian (OR: 2.33, 95%CI: 1.91-2.85) and North American (OR: 1.42, 95%CI: 1.08-1.86) populations confirmed the existed association between retinopathy, nephropathy, and periodontitis. While the strength of such associations between periodontitis and diabetic microvascular complications were more obvious in the Asians than North Americans. All the results indicated that periodontitis was associated with diabetic retinopathy (OR: 3.77, 95%CI: 2.71-5.24), diabetic nephropathy (OR: 1.55, 95%CI: 1.24-1.94) in T2D patients., Conclusion: The periodontitis is associated with diabetic retinopathy, diabetic nephropathy among T2D patients and further large sample size clinical trials are in need to confirm the findings., (International Journal of Ophthalmology Press.)

SnS2 as the promising anode for lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs) still encounters the undesirable rate performance and cycle stability. Herein, a unique stable structure is developed, where the SnS2 nanocrystals (NCs) are sturdily encapsulated by carbon shells anchored on a reduced graphene oxide (rGO) via the one-pot solvothermal process. The well-controlled carbon shells provide the enduring protection for SnS2 NCs through C-S covalent bonds from the corrosion of electrolyte and pulverization of structure. Moreover, both experimental results and density functional theory (DFT) calculations demonstrate that the carbon protective shell effectively enhances the structure stability and conductivity of the resulting materials. Interestingly, the size of SnS2 NCs and the thickness of carbon shells are accurately controlled by regulating the content of glucose. Aided by the advanced electron/ion transfer kinetics and structure stability, the SnS2-based electrode exhibits desired lithium/sodium storage performance and unprecedented long-term cycling stability (capacity retention of 74.7% after 1000 cycles at 2 A g-1 for LIBs and 102% after 200 cycles at 500 mA g-1 for SIBs). This work develops a method for promoting the practical applications and large-scale production of SnS2 composites for energy storage devices.

Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.

Investigations were carried out to study the effects of light-emitting diode (LED) lights on growth and development of isosteroidal alkaloids in embryogenic calli of Fritillaria cirrhosa D. Don, an important traditional Chinese medicine herb. Calli were cultured in glass bottles, each containing 100 mL of Murashige and Skoog's basal medium supplemented with 2% sucrose and 0.4% gellan gum powder, a gelling agent. These bottles were incubated in a specially designed plant growth chamber equipped with eight different LED lights consisting of single or combinations of four different light spectra emitting blue (450 nm), green (525 nm), red (660 nm), and far-red (730 nm) light. After three months of incubation, morphological changes in embryogenic calli were recorded, and LC-MS/MS analysis of cultures was carried out for peimisine, sipeimine, peiminine, and peimine. The highest number of somatic embryos and the maximum fresh weight was recorded in calli incubated under red (9R), infrared (9IR), and a combination of red+blue+infrared (3R3B3IR), respectively, in decreasing order. The highest contents of peimisine, peiminine, and peimine were recorded under red (9R) and infrared (9IR) lights, respectively. Eight LED lights had significant effects on the morphogenesis of embryogenic calli of F. cirrhosa D. Don and contents of isosteroidal alkaloids.

To synthesize covalent organic framework (COF) via irreversible reactions is more challenging than by reversible ones. In this work, microwave-assisted synthesis is used to facilitate the nucleophilic substitution of 2,3,5,6-tetrafluoro-4-pyridinecarbonitrile with 2,3,6,7,10,11-hexahydroxy triphenylene. The dioxin-linked COF, named TH-COF, was efficiently synthesized with extraordinarily large surface area of 1254 m 2 g -1 . With its high crystallinity, excellent thermal and chemical stabilities, TH-COF is used as the coating for the solid-phase micro-extraction (SPME) of perfluorinated alkyl substances (PFASs). The adsorptive mechanism was evaluated with adsorption isotherm and kinetic adsorption. Adsorption energies are calculated based on the density functional theory. Following SPME with TH-COF-coated fibers, PFASs were eluted using 1 mL of 0.6% trifluoroacetic acid/methanol and analyzed through the ultra-performance liquid chromatography equipped with triple quadrupole mass spectrometer (UPLC-MS/MS). When applied to spiked real water samples, this method demonstrates good linearity (0.01-1000 ng L -1 ) with R 2 ≥ 0.9945. The TH-COF-SPME-UPLC-MS/MS technique provides low limits of detection (0.0020-0.0045 ng L -1 ), excellent precision (≤ 7.9%), and good fiber-to-fiber reproducibility (≤ 7.1%). The TH-COF-coated fibers can be reused at least 20 times without the loss of extraction performance. In addition, the relative recoveries from spiked real water samples are 89.5%-105%., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Understanding mechanisms of cooperation between oncogenes is critical for the development of novel therapies and rational combinations. Acute myeloid leukemia (AML) cells with KMT2A-fusions and KMT2A partial tandem duplications (KMT2APTD) are known to depend on the histone methyltransferase DOT1L, which methylates histone 3 lysine 79 (H3K79). About 30% of KMT2APTD AMLs carry mutations in IDH1/2 (mIDH1/2). Previous studies showed that 2-hydroxyglutarate produced by mIDH1/2 increases H3K79 methylation, and mIDH1/2 patient samples are sensitive to DOT1L inhibition. Together, these findings suggested that stabilization or increases in H3K79 methylation associated with IDH mutations support the proliferation of leukemias dependent on this mark. However, we found that mIDH1/2 and KMT2A alterations failed to cooperate in an experimental model. Instead, mIDH1/2 and 2-hydroxyglutarate exert toxic effects, specifically on KMT2A-rearranged AML cells (fusions/partial tandem duplications). Mechanistically, we uncover an epigenetic barrier to efficient cooperation; mIDH1/2 expression is associated with high global histone 3 lysine 79 dimethylation (H3K79me2) levels, whereas global H3K79me2 is obligate low in KMT2A-rearranged AML. Increasing H3K79me2 levels, specifically in KMT2A-rearrangement leukemias, resulted in transcriptional downregulation of KMT2A target genes and impaired leukemia cell growth. Our study details a complex genetic and epigenetic interaction of 2 classes of oncogenes, IDH1/2 mutations and KMT2A rearrangements, that is unexpected based on the high percentage of IDH mutations in KMT2APTD AML. KMT2A rearrangements are associated with a trend toward lower response rates to mIDH1/2 inhibitors. The substantial adaptation that has to occur for 2 initially counteracting mutations to be tolerated within the same leukemic cell may provide at least a partial explanation for this observation., (© 2020 by The American Society of Hematology.)

Inhibition of the H3K79 histone methyltransferase DOT1L has exhibited encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has been reported to have preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we observed both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2-mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 chromatin immunoprecipitation sequencing patterns over ribosomal genes were similar to those of the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process-protein synthesis-that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Background: Fritillaria cirrhosa, an important Chinese medicinal herb, is a Class-III protected and highly exploited species by pharmaceutical industry. Dwindling wild populations of species are unable to meet market demand. Therefore, this study was carried out to develop an in vitro propagation method for bulblet production. Also, the study aimed to carry out LC-MS/MS analysis of tissue culture-derived bulblets and callus for the presence of isosteroidal alkaloids (peimissine, verticine, and verticinone), and compare its quantities with commercially available crude drug samples., Results: In vitro seed germination (91%) of F. cirrhosa was achieved on Murashige and Skoog's basal medium (MSBM) supplemented with 6-benzylaminopurine (1 mg L -1 ) and α-naphthalene-acetic-acid (0.4 mg L -1 ). On transfer of germinated seeds from Petri-dishes to glass bottles containing hormone-free MSBM, 37.5% of seedlings developed bulblets after 3 months of incubation. Regeneration and multiplication of bulblets were achieved by culture of transverse sections of bulblets on 1/2 X MSBM. By repeated subcultures at an interval of 2 months, 3072 bulblets weighing 1270 g could be produced at the end of 5th subculture. LC-MS/MS analysis showed a significant presence of peimissine in in vitro bulblets while callus incubated in the dark showed presence of peimissine and verticine., Conclusion: The study reports an efficient in vitro propagation method of bulblets production of F. cirrhosa and presence of some isosteroidal alkaloids in tissue culture-derived bulblets and callus. The study could be of immense help in production of F. cirrhosa bulblets and callus under laboratory conditions round the year. Also, these results can be used further to investigate production of isosteroidal alkaloids in bioreactors at commercial scale using liquid and cell suspension cultures. Thus, we not only can reduce our dependence on collections from natural habitats, but also can help in in situ conservation of this important species.

Objective: To investigate the effect and mechanism of static progressive stretching (SPS) in different durations on traumatic knee contracture in rats., Methods: Seventy male Wistar rats were randomly divided into three groups, including surgical modeling group ( n =50), control group (CON, no surgery, no treatment, n =10) and trauma without immobilization group (TRA, no treatment, n =10). The knee contracture model was established, and 50 surgical modeling rats were randomly divided into five groups including static progressive stretching treatment for 20 minutes group (S20 min, n =10), treatment for 30 minutes group (S30 min, n =10), treatment for 40 minutes group (S40 min, n =10), untreatment group (UNT, no SPS, n =10) and modeling group (MOD, n =10, euthanized after immobilization for histological staining and Western blot). Individuals in the S20 min, S30 min, and S40 min groups were anesthetized and submitted to SPS. One treatment session took place every other day. A total of 8 sessions were given till the final treatment session on the day 16. On the day 0, 8, and 16 of intervention, the range of joint motion (ROM) and gait analysis were measured and compared. After the ROM measurements and gait analysis, the rats were euthanized on the day 16 and the samples were stained with HE and Masson methods. The changes of pathological organization were observed. Western blot was used to detect the expressions of transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6)., Results: ① ROM：the ROM of S30 min group recovered similar to that of the S20 min and S40 min groups after 8 days of treatment ( P >0.05), and was the best among all the surgical modeling groups after 16 d of treatment ( P <0.05). The ROM of S20 min, S30 min and S40 min groups significantly improved on the day 8 and day 16 comparing with that on day 0 ( P <0.01). ② Gait analysis: the stands in the S30min group improved best on the day 8 and day 16 ( P <0.05) , and better than that on day 0 ( P <0.05). The stride length of the S30 min group progressed similar to that of the S40 min group on the day 8 ( P >0.05), and there was no difference among three groups on the day 16 ( P >0.05). The stride length of the S30 min group appeared to recover more quickly on the day 8 ( P <0.05), and those of S20 min and UNT groups recovered significantly on the day 16 ( P <0.05). In addition, the swings in the S30 min group improved best ( P <0.05), and it appeared to recover better on the day 16 ( P <0.05). There was no statistical difference in terms of the swing speed among the four surgical modeling groups on the day 8 ( P >0.05). The swing speed of the S30min group increased most than those of the other three groups ( P <0.05), and it was much better on the day 8 and day 16 comparing with that on the day 0 ( P <0.05 ). ③ HE and Masson staining: the fibrosis and inflammation of the S30min group were significantly suppressed comparing to the other groups on the day 16. ④ Western blot: The protein expression levels of TGF-β1 and IL-6 were significantly lower than those in the other intervention groups including the S20 min, S40 min and UNT groups on the day 16 ( P <0.05)., Conclusion: Static progressive stretching treatment for 30 min could significantly improve the traumatic knee contracture in rats. The mechanism may be that the SPS decreased the expressions of TGF-β1 and IL-6, reduced the adhesion and inflammation of joint capsule. Therefore it relieved the pain and increased the joint mobility by reconstructing the structure of the capsule and suppressing the fibrotic changes., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

The organic fluorescent probes for temperature have received increasing interest due to their extremely high spatial and temporal resolution. A few of triarylboron derivatives, as almost the only molecular probes consisting of a single luminophore, have the ability to change their luminescent color at different temperatures. The mechanism of their luminescence thermochromism is controversial. Herein, several spectral experiments, along with time-dependent density functional theory (TDDFT) and coupled-cluster (CC) calculations, are carried out to elucidate the temperature-dependent luminescence. The CC rather than the TDDFT methods give a relatively reasonable explanation for the experimental results. Consequently, the thermochromism is now considered as the result of conformational thermal equilibria that occur in both the excited and ground states. Besides, an unusual conformer with intramolecular excimer characteristic plays a crucial role in the attractive luminescence behavior.

In this study, data of 19 climatic factors were downloaded from the World Climate website. A total of 233 Cymbidium kanran distribution data were obtained through online review and field visits. Using MaxEnt model and combined with ArcGIS spatial analysis technology, the potential distribution area and distribution pattern of C. kanran in different periods were simulated, as well as its distribution during the last glacial period and 2070. The results showed that the curve indexes (AUC) value of the model training set was 0.957, and the AUC value of the verification set was 0.953, indicating that the prediction accuracy of the model was very high. The current distribution of C. kanran was mostly affected by the driest quarter precipitation, mean annual precipitation, wettest quarter precipitation, and mean annual temperature range. The contribution rates were 50.3%, 15.9%, 8.4% and 4.4%, respectively, with the total contribution rate being 79.0%. In the last glacial period, C. kanran mainly distributed in Wuyi Mountain, Luojing Mountain, Nanling, Taiwan's five major mountains and some hills in the northern part of Guangxi. From now to 2070, the distribution of C. kanran area will decrease by 22.4%. The southwestern part of Guangxi, the central part of Yunnan, and the junctions of Jiangxi, Fujian and Guangdong provinces will expand, while that in eastern Jiangxi, western Fujian, and the border between these two provinces will shrink.

Background and Aim: Salivary characteristics are altered in gastrointestinal diseases and related to oral taste disorder. However, specific salivary biochemical characteristics and their relationships with oral taste disturbances in chronic non-atrophy gastritis (CNAG) remain uncertain., Methods: Seventy patients with CNAG and 70 subjects in healthy control group (HCG) were enrolled in our study. The levels of salivary flow rate (SFR), pH, salivary α-amylase (sAA) activity, total protein density (TPD), chloride concentration, and calcium concentration were determined before and after citric acid stimulation and compared between CNAG with and without oral taste disturbances., Results: Average body mass index (BMI) of CNAG (17.75 ± 2.08) was lower than that of HCG (21.96 ± 1.72, P < 0.01). Compared with HCG, CNAG showed increased TPD and calcium concentration but decreased SFR both before and after acid stimulation (P < 0.01), as well as reduced sAA and salivary chloride responses to acid stimulation (P < 0.01). Compared with CNAG with normal BMI (24.29%, 17/70), sAA activity response to acid stimulation was reduced in those with low BMI (75.71%, 53/70, P < 0.05). Under resting condition, CNAG with dry mouth (55.71%, 39/70) showed increased SFR and decreased TPD (P < 0.05), as compared with CNAG without dry mouth (44.29%, 31/70). Compared with CNAG without bitter taste (57.14%, 40/70), pH was decreased in those with bitter taste (42.86%, 30/70) under both resting and stimulated conditions (P < 0.05)., Conclusion: Decreased sAA activity may reflect malnutrition state and be one potential marker of poor digestion, decreased salivary pH may contribute to bitter taste perception, and reduced TPD might be a cause of dry mouth in CNAG., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Over 50% of patients with 22q11.2 deletion syndrome (DS) have a conotruncal or related cardiac defect (CTRD). We hypothesized that similar genetic variants, developmental pathways and biological functions, contribute to disease risk for CTRD in patients without a 22q11.2 deletion (ND-CTRD) and with a 22q11.2 deletion (DS-CTRD). To test this hypothesis, we performed rare CNV (rCNV)-based analyses on 630 ND-CTRD cases and 602 DS-CTRD cases with comparable cardiac lesions separately and jointly. First, we detected a collection of heart development related pathways from Gene Ontology and Mammalian Phenotype Ontology analysis. We then constructed gene regulation networks using unique genes collected from the rCNVs found in the ND-CTRD and DS-CTRD cohorts. These gene networks were clustered and their predicted functions were examined. We further investigated expression patterns of those unique genes using publicly available mouse embryo microarray expression data from single-cell embryos to fully developed hearts. By these bioinformatics approaches, we identified a commonly shared gene expression pattern in both the ND-CTRD and DS-CTRD cohorts. Computational analysis of gene functions characterized with this expression pattern revealed a collection of significantly enriched terms related to cardiovascular development. By our combined analysis of rCNVs in the ND-CTRD and DS-CTRD cohorts, a group of statistically significant shared pathways, biological functions, and gene expression patterns were identified that can be tested in future studies for their biological relevance., (© 2019 Wiley Periodicals, Inc.)

Aim: To study the effect of an innovative micro-dissection procedure by radiofrequency ablation (MRA) in removing eyelid nevus., Methods: Fifty-six consecutive outpatients with eyelid nevus were treated with MRA using a monopolar device. The effect of MRA was determined after following-up for 6mo to 5y., Results: Fifty-two cases (52 eyes, 92.9%) were cured once, and 4 cases (4 eyes, 7.1%) received second treatment for small residual. All cases healed well after surgery, with no pigmentation, no scars, no loss of eyelashes, no deformation of eyelid margin. There was no visual impairment after healing., Conclusion: MRA of eyelid nevus using the XL-RFA device is highly efficient without significant complications.

Background: The genome of Banana bunchy top virus (BBTV) consists of at least six circular, single-stranded DNA components of ~ 1 kb in length. Some BBTV isolates may also carry satellite DNA molecules that are not essential for BBTV infection. The relation between multipartite DNA virus replication and their transcriptional levels and the underlying mechanism remain unclear., Results: To understand the coordinated replication and transcription of the multiple genomic components, the absolute amounts of each BBTV DNA component were measured by real-time PCR (qPCR), and their transcriptional levels were determined by RNAseq and reverse transcription-qPCR (qRT-PCR). Significant differences were found in the absolute amounts of individual BBTV genomic components. Transcriptional levels of each BBTV genomic component obtained from the RNAseq data matched closely to those obtained from qRT-PCR, but did not correspond to the absolute amount of each DNA component. The ratio of transcript over DNA copies ranged from 46.21 to 1059.44%, which was possibly regulated by the promoter region in the intergenic region of each component. To further determine this speculation, the promoter region of the DNA-S, -M or -N was constructed to the upstream of green fluorescent protein (GFP) gene for transient expression by agrobacterium-mediated transformation method. The qRT-PCR showed the highest transcriptional activity was promoted by DNA-N promoter, about 386.58% activity comparing with CaMV 35S promoter. Confocal microscopy observation showed that the intensity of green fluorescence was corresponding to that of qRT-PCR., Conclusions: Our data clearly showed that BBTV was able to control the transcriptional level of each DNA component independently by through the promoter sequences in the intergenic region. Moreover, a cis-acting element from DNA-N component had a high transcriptional activity.

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Ribosomal protein S6 kinase A6 (RPS6KA6) is a downstream factor of the ERK-MAPK pathway and has been extensively studied in various types of cancer. However, the role of RPS6KA6 in lung squamous cell carcinoma (LUSC) remains unclear. This study investigated expression of the RPS6KA6 and its clinicopathological correlation with LUSC and explored genetic alterations in the ribosomal protein S6 kinase (RSK) family in LUSC and their impact on the survival of patients. Expression of the RPS6KA6 protein in 175 LUSC samples and 30 normal lung tissues samples was determined by immunohistochemistry (IHC). RPS6KA6 protein expression in the LUSC tissues was significantly higher compared with that in the normal lung tissues (P=0.017). Overexpression of RPS6KA6 protein correlated with tumor size (r=0.260, P=0.001), lymph node metastasis (r=0.683, P<0.001), and TNM stage (r=0.378, P<0.001). RPS6KA6 RNA-seq data were obtained from the Cancer Genome Atlas (TCGA) and ONCOMINE database. RPS6KA6 mRNA expression in the LUSC tissues was significantly higher than that in paired noncancerous samples (TCGA: P=0.005; ONCOMINE: P=0.018). According to the cBioPortal online software, three detecting methods, including Seqv2, Array and U133, identified that the frequency of the genetic alterations in the RSKs in LUSC were 77%, 44%, and 42%, respectively. However, survival analysis of LUSC patients with or without RSKs genetic alterations reached no statistical significance. This study suggests that RPS6KA6 may be an oncogene in LUSC, and that expression of the RPS6KA6 protein is associated with the progression of LUSC. The RSK genes are frequently altered in LUSC, but the alterations have no significant effect on the survival of patients., Competing Interests: None., (IJCEP Copyright © 2018.)

Acquired aplastic anemia (aAA) is an acquired deficiency of early hematopoietic cells, characterized by inadequate blood production, and a predisposition to myelodysplastic syndrome (MDS) and leukemia. Although its exact pathogenesis is unknown, aAA is thought to be driven by Human Leukocyte Antigen (HLA)-restricted T cell immunity, with earlier studies favoring HLA class II-mediated pathways. Using whole exome sequencing (WES), we recently identified two aAA patients with somatic mutations in HLA class I genes. We hypothesized that HLA class I mutations are pathognomonic for autoimmunity in aAA, but were previously underappreciated because the Major Histocompatibility Complex (MHC) region is notoriously difficult to analyze by WES. Using a combination of targeted deep sequencing of HLA class I genes and single nucleotide polymorphism array (SNP-A) genotyping we screened 66 aAA patients for somatic HLA class I loss. We found somatic HLA loss in eleven patients (17%), with thirteen loss-of-function mutations in HLA-A *33:03, HLA-A *68:01, HLA-B *14:02 and HLA-B *40:02 alleles. Three patients had more than one mutation targeting the same HLA allele. Interestingly, HLA-B *14:02 and HLA-B *40:02 were significantly overrepresented in aAA patients, compared to ethnicity-matched controls. Patients who inherited the targeted HLA alleles, regardless of HLA mutation status, had a more severe disease course with more frequent clonal complications as assessed by WES, SNP-A, and metaphase cytogenetics, and more frequent secondary MDS. The finding of recurrent HLA class I mutations provides compelling evidence for a predominant HLA class I-driven autoimmunity in aAA, and establishes a novel link between aAA patients' immunogenetics and clonal evolution., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Purpose: Despite substantial progress in sequencing, current strategies can genetically solve only approximately 55-60% of inherited retinal degeneration (IRD) cases. This can be partially attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy-number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs., Methods: Twenty-eight cases previously unsolved with a targeted NGS were investigated with whole-genome single-nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) arrays., Results: Deletions in the IRD genes were detected in 5 of 28 families, including a de novo deletion. We suggest that the de novo deletion occurred through nonallelic homologous recombination (NAHR) and we constructed a genomic map of NAHR-prone regions with overlapping IRD genes. In this article, we also report an unusual case of recessive retinitis pigmentosa due to compound heterozygous mutations in SNRNP200, a gene that is typically associated with the dominant form of this disease., Conclusions: CNV mapping substantially increased the genetic diagnostic rate of IRDs, detecting genetic causality in 18% of previously unsolved cases. Extending the search to other structural variations will probably demonstrate an even higher contribution to genetic causality of IRDs.Genet Med advance online publication 13 October 2016.

Background: Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome., Methods: Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls., Results: Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development., Conclusion: Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)