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Unroofed coronary sinus (UCS) is a rare cardiac anomaly that results in communication between the coronary sinus and the left atrium. We described an unusual presentation of UCS in a 48-year-old female that was not corrected during an initial secundum ASD repair 22 years ago. [ABSTRACT FROM AUTHOR]

Oral Diseases (2012) 19, 73-79 Objectives: Glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling mediates osteogenesis in response to mechanical loading. We tested the hypothesis that local administration of a GSK-3β inhibitor could stimulate new bone formation in the expanding premaxillary suture. Materials and methods: Thirty-five Sprague-Dawley rats were subjected to premaxillary suture expansion using a helix spring. The experimental rats were given one or two local injections of SB-415286, a small-molecule GSK-3β inhibitor. Animals were administered calcein and sacrificed on day 7 to quantify new bone formation. To evaluate the proliferation and differentiation of osteoblasts, rats were labeled with bromodeoxyuridine on day 1 and sacrificed on day 2 or 4. β-catenin expression was evaluated by immunohistochemical staining. Results: Two injections of SB-415286 led to an elevation of β-catenin expression and an increase in the number of proliferating osteoblasts in expanding sutures on day 2 and day 4. Consequently, new bone formation in the suture increased significantly on day 7. Conclusions: These results suggest that local delivery of a GSK-3β inhibitor could stimulate bone formation in the expanding premaxillary suture by eliciting β-catenin signaling. GSK-3β could be a pharmaceutical target for improving the effect of orthodontic treatments such as rapid palatal expansion. [ABSTRACT FROM AUTHOR]

Objective: Midpalatal expansion (MPE) is routinely employed to treat transverse maxillary arch deficiency. Neutrophils are indispensable for recruiting bone marrow stromal cells (BMSCs) at the initial stage of bone regeneration. This study aimed to explore whether neutrophils participate in MPE and how they function during bone formation under mechanical stretching., Materials and Methods: The presence and phenotype of neutrophils in the midpalatal suture during expansion were detected by flow cytometry and immunofluorescence staining. The possible mechanism of neutrophil recruitment and polarization was explored in vitro by exposing vascular endothelial cells (VECs) to cyclic tensile strain., Results: The number of neutrophils in the distracted suture peaked on Day 3, and N2-type neutrophils significantly increased on Day 5 after force application. The depletion of circulatory neutrophils reduced bone volume by 43.6% after 7-day expansion. The stretched VECs recruited neutrophils via a CXCR2 mechanism in vitro, which then promoted BMSC osteogenic differentiation through the VEGFA/VEGFR2 axis. Consistently, these neutrophils showed higher expression of canonical N2 phenotype genes, including CD206 and Arg1., Conclusions: These results suggested that neutrophils participated in early bone formation during MPE. Based on these findings, we propose that stretched VECs recruited and polarized neutrophils, which, in turn, induced BMSC osteogenic differentiation., (© 2023 Wiley Periodicals LLC.)

International societies have conflicting recommendations on whether bone marrow aspirate/biopsy (BMB) is needed during workup for isolated thrombocytopenia. Our objective was to determine if thrombocytopenia in patients aged ≥60 years is associated with an increased incidence of haematological malignancy. We performed a retrospective population-based cohort study in patients aged ≥60 years between January 1, 2009 to December 31, 2019. Exposed patients had specialist consultation for thrombocytopenia, with platelet count <100 × 10 9 /L, but normal haemoglobin and white blood cell count. Unexposed patients were those who never had specialist consultation for thrombocytopenia and whose platelets were ≥100 × 10 9 /L. The primary outcome was the diagnosis of haematological malignancy using a competing risk of death model. During 4.0 years (IQR 2.2-6.7) of follow-up, 378/4930 exposed (19.1/1000PY, 95% CI 17.1-21.0), and 204/17556 unexposed patients (2.5/1000PY, 95% CI 2.2-2.8) were diagnosed with haematological malignancy (HR 15.5 (95% CI 11.3-21.4, p < 0.0001) in year 1, and 5.3 (95% CI 4.4-6.6, p < 0.0001) in years 2+). This finding persisted in analyses stratified by sex, age, severity, or duration of thrombocytopenia, and treatment with corticosteroids within 2 weeks of consultation. This study found a strong association between isolated thrombocytopenia and haematological malignancy in patients ≥60 years, supporting consideration of diagnostic testing including BMB during outpatient specialist consultation., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Three new meroterpenoids (1-3) and ten known ones (4-13) were obtained from the endophytic fungus Talaromyces primulinus H21 isolated from the plant of Euphorbia sikkimensis. Their structures including their absolute configurations were elucidated by extensive analysis of spectroscopic data such as HR-ESI-MS, 1D/2D NMR, and X-ray diffraction of single crystal together with comparison of experimental ECD with calculated ECD. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 3, 9, 12, and 13 exhibited certain inhibition on NO production, with IC 50 values of 27.19, 41.55, 25.23, and 24.71 μM, respectively., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Iron deficiency anemia (IDA) and non-anemic iron deficiency (NAID) are highly prevalent among non-pregnant females of reproductive age. Canada has no national screening guidelines for this population. Screening, when performed, is often with a complete blood count alone without ferritin or iron indices. The primary objective was to determine the prevalence of screening for NAID and IDA over a 3-year period in non-pregnant females of reproductive age who had tests performed at outpatient laboratories in Ontario, Canada. Retrospective cohort study of non-pregnant females ages 15-54 in Ontario, from 2017 to 2019. NAID was defined as ferritin <30 μg/L, anemia as hemoglobin <120 g/L, and IDA as ferritin <30 μg/L and hemoglobin <120 g/L. Annual household income was estimated using patient postal codes. A total of 784 132 non-pregnant females were included. The 82.1% were screened for iron deficiency, 38.3% had NAID and 13.1% had IDA; 55.6% with IDA had normal mean corpuscular volumes. The median household income was $89454.80 compared with a provincial median of $65285.00. Patients in the lowest income quintile had the highest odds of being anemic, and the lowest odds of having a ferritin checked. A large proportion of non-pregnant females of reproductive age in this cohort were screened for iron deficiency. In this relatively privileged cohort, NAID affected nearly 40%, and IDA 13%. Most patients with IDA did not have microcytosis. Low household income was associated with the greatest odds of anemia and the lowest odds of being screened, highlighting inequitable access to screening for IDA in Ontario, Canada., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Three new prenylated dihydroflavones, moralbaflavones A-C ( 1 - 3 ), together with four known ones ( 4a/4b , 5 , and 6 ) were isolated from the root barks of Morus alba L. Their structures including the absolute configurations were determined by the analysis of HRMS, NMR, and ECD data. The neuroprotective properties of these prenylated dihydroflavones were screened at the concentration of 10  µ M in the sodium nitroprusside-induced rat pheochromocytoma PC-12 cells, and the results showed moralbaflavone C ( 3 ) possessed significant neuroprotective activity, being more potent than the positive control edaravone.

The radiative cooling has great potential for electronic device cooling without requiring any energy consumption. However, a low thermal conductivity of most radiative cooling materials limits their application. Herein, a multishape codoping strategy was proposed to achieve collaborative enhancement of thermal conductivity and radiative properties. The hBN-coated hollow SiO 2 particles were prepared based on electrostatic self-assembly technology, which were then mixed with hBN platelets and doped into a poly(vinylidene fluoride- co -hexafluoropropylene) substrate. Discrete dipole approximation theory was employed to reveal the mechanism and optimize the particle size. The results showed that the multishape codoping method can significantly improve the radiative performance, with 94.9% reflectivity and 91.2% emissivity. In addition, this zero-dimensional and two-dimensional composite doping structure facilitated the formation of a thermal conduction network, which enhanced the thermal conductivity of the film up to 1.32 W m -1 K -1 . The high thermal conductivity radiative cooling film can decrease the heater temperature from 58.8 to 31.3 °C, with a further reduction of temperature by 7.2 °C compared to the radiative cooling substrates with low thermal conductivity. The net cooling power of the film can reach 102.5 W m -2 under direct sunlight. This work provides a novel strategy for high-efficiency electronic device cooling.

The inhibition of cell surface crystal adhesion and an appropriate increase in crystal endocytosis contribute to the inhibition of kidney stone formation. In this study, we investigated the effects of different degrees of carboxymethylation on these processes. An injury model was established by treating human renal proximal tubular epithelial (HK-2) cells with 98.3 ± 8.1 nm calcium oxalate dihydrate (nanoCOD) crystals. The HK-2 cells were protected with carboxy (-COOH) Desmodium styracifolium polysaccharides at 1.17% (DSP0), 7.45% (CDSP1), 12.2% (CDSP2), and 17.7% (CDSP3). Changes in biochemical indexes and effects on nanoCOD adhesion and endocytosis were detected. The protection of HK-2 cells from nanoCOD-induced oxidative damage by carboxymethylated Desmodium styracifolium polysaccharides (CDSPs) is closely related to the protection of subcellular organelles, such as mitochondria. CDSPs can reduce crystal adhesion on the cell surface and maintain appropriate crystal endocytosis, thereby reducing the risk of kidney stone formation. CDSP2 with moderate -COOH content showed the strongest protective activity among the CDSPs., (© 2024 Wiley Periodicals LLC.)

Tranexamic acid is safe and effective for the treatment of heavy vaginal bleeding during menstruation and childbirth. It improves the quality of life, facilitates participation in school and work, and reduces the risk of death from postpartum hemorrhage. Despite its well-established benefits, individual- and structural-level barriers preclude its widespread utilization, hindering effective patient care and perpetuating health inequities in women's health. We first describe the evidence for the use of tranexamic acid in treating heavy menstrual bleeding and postpartum hemorrhage. Barriers to tranexamic acid use, including structural sexism, period poverty, misinformation in product monograph labeling, stigmatization of vaginal blood loss, and drug access, are then discussed. Finally, we summarize relevant data presented during the 2023 International Society on Thrombosis and Haemostasis Congress., (© 2024 The Author(s).)

Phytochemical investigation on the plant endophytic fungus Penicillium ferraniaense GE-7 led to the isolation of 18 compounds including one new α -pyrone derivative, peniferranige A ( 1 ). The structure including the absolute configuration of compound 1 was elucidated by NMR, HRMS, and ECD data. Demethoxyfumitremorgin C ( 16 ) and meleagrin ( 17 ) possessed moderate activities against the human lung cancer cell line H1975 with IC 50 values of 28.52 ± 1.07 and 13.94 ± 1.92 μM, respectively.

Phytochemical investigation on the plant of Wikstroemia alternifolia led to the isolation of 26 compounds including two new ones, wikstralternifols A and B ( 1 and 7 ). Their structures including the absolute configuration were elucidated by spectroscopic data together with analysis of experimental and calculated ECD data. All compounds were isolated from this plant for the first time, and their main structural types were lignans, sesquiterpenoids, and flavonoids. In the sodium nitroprusside-induced rat pheochromocytoma PC-12 cell model, the neuroprotective activities of the selected sesquiterpenoids ( 1 and 4 ) and lignans ( 7  -  14 ) were screened at the concentration of 10  µ M, and 7  -  14 displayed better activities than the positive control edaravone.

Iron deficiency is the most common and widespread nutritional deficiency in the world. For women, the risk of iron deficiency and iron deficiency anemia increases due to iron demands during pregnancy and regular iron losses due to menstruation during reproductive years. These interrelated conditions are of public health concern as they are highly prevalent, and the negative consequences such as chronic fatigue, cognitive impairment and poor quality of life are broad and multifaceted. People of low socioeconomic status are at higher risk of iron deficiency due to low intake of expensive iron-rich foods, and decreased access to healthcare. In this review, we applied a health equity lens to describe the current state of care for women with iron deficiency with or without anemia. We have highlighted several structural challenges that span from the laboratory diagnosis, inconsistent screening guidelines, and stigma associated with heavy menstrual bleeding, to treatment barriers., Competing Interests: Declaration of Competing Interest: Grace Tang – None to declare. Michelle Sholzberg reports research funding from: Octapharma, Pfizer; honoraria: Octapharma, Pfizer, Takeda., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Thirteen new Euphorbia diterpenoids, euphylonanes A-M ( 1 - 13 ), and eight known ones were isolated from the whole plants of Euphorbia hylonoma . Compounds 1 and 2 are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound 3 represents the first example of a 9,10-epoxy tigliane, while 4 - 21 are typical ingenanes varying with substituents. Structures were elucidated using a combination of spectroscopic, computational, and chemical methods. Most ingenanes exerted a significant antiadipogenic effect in 3T3-L1 adipocytes, among which 4 was the most active with an EC 50 value of 0.60 ± 0.27 μM. Mechanistic study revealed that 4 inhibited the adipogenesis and lipogenesis in adipocytes via activation of the AMPK signaling pathway.

Nuclear transporter importin- β 1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin- β 1 inhibitor DD1 to afford an improved analog DD1 -Br with better tolerability (>25 folds) and oral bioavailability. DD1 -Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin- β 1, DD1 -Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin- β 1., Competing Interests: The authors declare no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

A pair of undescribed dihydrobenzofuran neolignan enantiomers, (+/-)-phybrenan A ( 1a / 1b ), two new benzofuran neolignans, phybrenan B and C ( 2 and 3 ), along with four known neolignans ( 4  -  7 ) were obtained from the plants of Phyllanthodendron breynioides P. T. Li. The planar structures of all isolates were demonstrated by the analysis of detailed spectroscopic evidence (NMR, HRMS, and IR), and the absolute configurations of novel neolignans were elucidated by combined calculated and experimental ECD data analysis. The neuroprotective activities of all benzofuran neolignans against sodium nitroprusside (SNP)-induced cell death were examined in rat pheochromocytoma PC12 cells. The results exhibited that three compounds ( 4  -  6 ) possessed remarkable neuroprotective activities at 10  µ M, better than the positive drug edaravone.

Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE., Competing Interests: Declaration of Competing Interest None of the authors have any competing interests., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Endocrine therapy is the frontline treatment for estrogen receptor (ER) positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy drugs remain as a major challenge in the clinic. Here, this work identifies an estrogen-induced lncRNA, LINC02568, which is highly expressed in ER-positive breast cancer and functional important in cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy drug resistance. Mechanically, this work demonstrates that LINC02568 regulates estrogen/ERα-induced gene transcriptional activation in trans by stabilizing ESR1 mRNA through sponging miR-1233-5p in the cytoplasm. Meanwhile, LINC02568 contributes to tumor-specific pH homeostasis by regulating carbonic anhydrase CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy drug resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo. Furthermore, combination treatment with ASO targeting LINC02568 and endocrine therapy drugs or CA12 inhibitor U-104 exhibits synergistic effects on tumor growth. Taken together, the findings reveal the dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER-positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in the clinic., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Patient blood management (PBM) programs are effective at reducing transfusion-associated mortality and morbidity; however, patient engagement within the realm of PBM remains relatively unstudied. Our objectives were to develop a novel educational tool utilizing animation to educate preoperative patients about anemia and to evaluate the effectiveness of this intervention., Study Design and Methods: We created a patient-facing animation for preoperative surgical patients. The animation addressed characters' health journeys from diagnosis to treatment, addressing the role of PBM. We utilized the concept of patient activation as a means to empower patients, and developed the animation to be as accessible as possible. Post-viewing, patients provided feedback utilizing an electronic survey., Results: A final version of the animation can be found here: https://vimeo.com/495857315. A total of 51 participants viewed our animation, the majority of whom were planned to undergo joint replacement or cardiac surgery. Almost all (94%, N = 4) agreed that taking an active role in their health was the most important factor in determining their ability to function. The video was felt to be easy to understand (96%, N = 49), and 92% (N = 47) agreed that they had a better understanding of anemia and its treatment. After watching the animation, patients felt more certain that they could follow through with their PBM plan (98%, N = 50)., Discussion: To the best of our knowledge, there are no other PBM-specific patient education animations. Patients enjoyed learning about PBM though animation, and patient education may lead to better uptake of PBM interventions. We hope that other hospitals will be inspired to pursue this approach., (© 2023 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Three new halimane furanoditerpenoids (1-3) and three new clerodane furanoditerpenoids (4-6), along with seven known terpenoids including four pimarane diterpenoids (7-10) and three norisoprenoids (11-13) were isolated from the 95% EtOH extracts of the plants of Croton cnidophyllus. The 2D structures including absolute configuration of new furanoditerpenoids (1-6) were elucidated by analysis of their HRMS and NMR data as well as comparison of experimental and calculated ECD curves. Bioassay revealed that two compounds (8 and 9) possessed certain inhibitory effects against NO production stimulated by LPS, with IC 50 values of 19.00 ± 1.76 and 21.61 ± 1.11 μM, respectively., (© 2023. The Author(s).)

Introduction: Von Willebrand Disease is the most common inherited bleeding disorder. Paradoxically, affected individuals are often misdiagnosed and experience substantial diagnostic delay. There are sex-specific health disparities in VWD rooted in the stigmatization of vaginal bleeding, which leads to symptom dismissal, lack of timely access to care and lower health-related quality of life., Areas Covered: Following the core elements of patient-centered care - respect for patient preferences, values, and needs, we describe the current state of VWD care. Challenges of diagnostic delay, serial misrecognition of abnormal bleeding, and symptom dismissal are barriers that disproportionately affect women with VWD. These negative effects are further amplified in individuals living in low- and middle-income countries. We describe the importance of coordinated multidisciplinary care, as well as the need for patient education and empowered self-advocacy., Expert Opinion: While tremendous work has been done to improve the diagnosis and management of VWD, timely and high-quality research is urgently needed to address care gaps. Systemic changes such as resource investment, dedicated research funding for novel treatment modalities, and effective knowledge translation strategies to address structural barriers are needed to facilitate effective patient-centered care for VWD.

Objective: To investigate the effects of two-step retraction and en-masse retraction on tooth movement pattern of anterior teeth and posterior anchorage with clear aligners using three-dimensional finite element analysis. Methods: A finite element model of maxillary first premolar extraction case undergoing clear aligner treatment was established based on maxillofacial cone-beam CT data of a 24-year-old adult male with individual normal occlusion, who visited Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine for impacted mandibular third molar in June, 2022. The initial tooth displacement of five anterior retraction protocols (two-step with canine retraction, two-step with incisor bodily retraction, two-step with incisor retraction-overtreatment, en-masse bodily retraction, and en-masse retraction-overtreatment) were evaluated. Results: Two step with canine retraction caused distal tipping of the canine and labial tipping of the incisors (0.18° for central incisor and 0.13° for lateral incisor). Two step with incisor retraction caused mesial tipping of the canine. In two step with bodily retraction protocol, uncontrolled lingual tipping was found in central incisor (0.29°) and lateral incisor (0.32°). In two-step with incisor retraction-overtreatment protocol, the movement pattern of the incisors didn't change, but the inclinations reduced to 0.21° and 0.18°. En-masse retraction caused distal tipping of the canine. In en-masse bodily retraction protocol, uncontrolled lingual tipping was also found in central incisor (0.19°) and lateral incisor (0.27°). In en-masse retraction-overtreatment protocol, the central incisor showed controlled lingual tipping (0.02°) and the lateral incisor showed palatal root movement (0.03° labial inclination). Posterior teeth exhibited mesial tipping in all five protocols. Conclusion: En-masse retraction with incisor overtreatment was beneficial to incisor torque control in clear aligner treatment.

Background: Early and accurate diagnosis of infection-induced osteomyelitis, which often involves increased PD-L1 expression, is crucial for better treatment outcomes. Radiolabeled anti-PD-L1 nuclear imaging allows for sensitive and non-invasive whole-body assessments of PD-L1 expression. This study aimed to compare the efficacy of 18 F-FDG and an 18 F-labeled PD-L1-binding peptide probe ( 18 F-PD-L1P) in PET imaging of implant-associated Staphylococcus aureus osteomyelitis (IAOM)., Methods: In this study, we synthesized an anti-PD-L1 probe and compared its efficacy with 18 F-FDG and 18 F-PD-L1P in PET imaging of implant-associated Staphylococcus aureus osteomyelitis (IAOM). The %ID/g ratios (i.e., radioactivity ratios between the infected and non-infected sides) of both probes were evaluated for sensitivity and accuracy in post-infected 7-day tibias and post-infected 21 days, and the intensity of 18 F-PD-L1P uptake was compared with pathological changes measured by PD-L1 immunohistochemistry (IHC)., Results: Compared with 18 F-FDG, 18 F-PDL1P demonstrated higher %ID/g ratios for both post-infected 7-day tibias (P=0.001) and post-infected 21 days (P=0.028). The intensity of 18 F-PD-L1P uptake reflected the pathological changes of osteomyelitic bones. In comparison to 18 F-FDG, 18 F-PDL1P provides earlier and more sensitive detection of osteomyelitis caused by S. aureus., Conclusion: Our findings suggest that the 18 F-PDL1P probe is a promising tool for the early and accurate detection of osteomyelitis caused by S. aureus., 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 © 2023 Ren, Ma, Fu, Hu, Liang, Yu and Tang.)

Objectives: To study the clinical and genetic features of Joubert syndrome (JS) in children., Methods: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022., Results: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1 , RPGRIP1L , MKS1 , CC2D2A , CEP120 , and AHI1 genes., Conclusions: For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.

Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c (5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1c is a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1c could block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARγ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1c as the first Raptor inhibitor may provide a new therapeutic option for these conditions.

Chromatographic fractionation of the 95% EtOH extract of the roots of Stellera chamaejasme yielded 20 sesquiterpenoids of four different types, guaiane-, carotane-, sesquicarane-, and alpiniane-types. Among them, sesquistrachanoids A-F were previously undescribed ones, whose structures including absolute configurations were elucidated by spectroscopic methods, the Mo 2 (OAc) 4 -induced ECD experiment, and analysis of experimental and calculated 1D NMR and ECD data. Sesquistrachanoid A is a 2,3-seco-guaiane-type sesquiterpenoid with a α-pyrone core and sesquistrachanoid B is the first example of 8,9-seco-guaiane-type sesquiterpenoid featured with an 1,8-δ-lactone core. Sesquistrachanoid C is a guaiane sesquiterpenoid characterized by a peroxide bridge between C-8 and C-10. All sesquiterpenoids were evaluated for their neuroprotective effects on cell damage induced by sodium nitroprusside in PC-12 cells. The bioassay results showed that six compounds at 10 μM could restore the cell viability, being comparable to that of the positive control edaravone. The mechanistic study on the most pronounced activity compound, stelleraguaianone B, demonstrated that it played a neuroprotective role by promoting the mRNA expression of antioxidant enzymes to reduce oxidative stress., 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 © 2023 Elsevier Ltd. All rights reserved.)

The restoration of mangrove in coastal wetlands of China has been started since the 1990s. However, various pollutants, especially for heavy metals (HMs), contained in wastewater might present a significant risk to mangrove forests during the restoration. In this study, sediments of five typical mangrove wetlands with varying restoration years and management measures in the Greater Bay Area were collected to evaluate the distribution fractions and potential ecological risk of HMs. Cd (0.2-1.6 mg/kg) was found in high concentrations in the exchangeable fraction (37.8-71.5%), whereas Cu (54.2-94.8 mg/kg), Zn (157.6-332.6 mg/kg), Cr (57.7-113.6 mg/kg), Pb (36.5-89.9 mg/kg), and Ni (29.7-69.5 mg/kg) primarily presented in residual fraction (30.8-91.9%). According to the geo-accumulation index (I geo ) analysis, sediment Cd presented a high level of pollution (3 ≤ I geo  ≤ 4), while Zn and Cu were associated with moderately pollution (1 ≤ I geo  ≤ 2). Besides, high ecological risk of Cd was found in sediments of five mangroves, with risk assessment code (RAC) ranging from 45.9 to 84.2. Redundancy analysis revealed that the content of NO 3 - -N was closely related to that of HMs in sediments and, pH value and NO 3 - -N concentration affected the distribution of HMs geochemical fractions. High concentration of HMs in QA and NS sampling sites was caused by the formerly pollutants discharge, resulting in these sediments still with a higher HM pollution level after the plant of mangrove for a long period. Fortunately, strict drainage standards for industrial activities in Shenzhen significantly availed for decreasing HMs contents in mangrove sediments. Therefore, future works on mangrove conversion and restoration should be linked to the water purification in the GBA., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bio-toxic inorganic pollutants, e.g., fluorine (F) and heavy metals (HMs), in wastewaters are the potential threats to nitrate (NO 3 - -N) reduction by microorganisms in constructed wetlands (CWs). Selection of suitable substrate with high F and HMs adsorption efficiency and capacity is a potential alternative for simultaneous removal of these pollutants in CWs. Herein, this study investigated the feasibility of applying hydroxyapatite (HA)-gravel media for F and HMs adsorption and its effect on NO 3 - -N reduction in CWs (HA CWs) by comparing the CWs filled with gravel substrate (CK CWs). The results indicated that the removal efficiency of F, Cr, As, and NO 3 - -N in HA CWs increased by 113.6-, 3.3-, 2.7-, and 0.6-folds, respectively, compared to CK CWs. The NO 3 - -N reduction rate decreased by 11-46% in CK CWs after the presence of F and HMs in influent, while for HA CWs, it was only 13-22%. Excellent F and HMs adsorption capacity of HA substrate availed for wetland plants resisting F/HMs toxicity and making catalase activity lower. The HA substrate in CWs resulted in the certain succession of nitrogen-transforming bacteria, e.g., nitrifiers (Nitrospira) and denitrifiers (Thiobacillus and Desulfobacterium). More importantly, key functional genes, including nirK/nirS, korA/korB, ChrA/ChrD, arsA/arsB, catalyzing the processes of nitrogen biotransformation, energy metabolism, NO 3 - -N and metal ions reduction were also enriched in HA CWs. This study highlights HA substrate reduce the inhibitive effect of F and HMs on NO 3 - -N reduction, and provides new insights into how microbiota structurally and functionally respond to different substrates in CWs., 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 © 2022 Elsevier B.V. All rights reserved.)

Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) ( 1 ) and OA methyl ester ( 2 ), were isolated from the cultured microalgae strain Prorocentrum lima PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound ( 3 ) and four new derivatives ( 4 - 7 ). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC 50 = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound 7 promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.

Biscroyunoid A ( 1 ), a 19- nor -clerodane diterpenoid dimer featuring a unique C-16-C-12' linkage and containing an unusual 4,7-dihydro-5 H -spiro[benzofuran-6,1'-cyclohexane] motif, together with its biosynthetic precursor, croyunoid A ( 2 ), were isolated from Croton yunnanensis . Their structures were determined by spectroscopic, computational, and single-crystal X-ray diffraction methods. Compound 1 exerted an antihepatic fibrosis effect in LX-2 cells via inhibition of TGFβ-Smad2/3 signaling.

Five new toosendanin limonoids with highly oxidative furan ring walsurobustones A-D (1-4), and one new furan ring degraded limonoid walsurobustone E (5) together with one known compound toonapubesic acid B (6) were isolated from the leaves of Walsura robusta. Their structures were elucidated by NMR and MS data. Especially, the absolute configuration of toonapubesic acid B (6) was confirmed by X-ray diffraction study. Compounds 1-6 exhibited good cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480., (© 2023. The Author(s).)

Background: Vascular dementia (VD) is a disease that affects brain function through cerebrovascular disease. Due to its complex pathogenesis, there is no effective drug treatment for VD. The present study aimed to evaluate the role of acupoint catgut embedding in the treatment of rats with VD and its possible molecular mechanism., Methods: A modified 4 vessel occlusion (4-VO) method was used to establish a VD model rat, and spatial learning and memory ability was assessed using the Morris water maze (MWM) test. The protein expression levels were detected by Western blot. Hematoxylin and eosin (HE) staining was used for histological analysis and enzyme-linked immunosorbent assay (ELISA) was applied for analysis of serum inflammatory factors., Results: We successfully constructed VD model rats with spatial learning and memory impairment, hippocampus injury, and high inflammatory response. Treatment of VD rats with acupoint catgut embedding significantly reduced escape latency and increased the time in the target quadrant and platform crossing times. VD-mediated hippocampal tissue damage and inflammatory reaction [down-regulating interleukin-1β (IL-1β), interleukin-6 (IL-6)] were significantly alleviated by acupoint catgut embedding treatment. In addition, further mechanism exploration found that acupoint catgut embedding treatment could improve the activity of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. In summary, acupoint catgut embedding treatment improved spatial learning and memory loss, alleviated pathological damage of the hippocampus, and inhibited inflammation response in VD rats, which was probably related to the inhibition of the TLR4/MyD88/NF-κB signaling pathway., Conclusions: Acupoint catgut embedding may warrant further study as an adjuvant therapy for the treatment of VD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6402/coif). The authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Euphylonoids A ( 1 ) and B ( 2 ), two highly modified jatrophane diterpenoids, were isolated from Euphorbia hylonoma . 1 represents a new 9(10→18)- abeo -8,12-cyclojatrophane skeleton containing a cage-like 3,8-dioxatricyclo[5.1.2.0 4,9 ]decane core, while 2 is a 14(13→20)- abeo -8,12-cyclojatrophane featuring an unusual 17-oxatetracyclo[12.2.1.0 1,5 .0 9,13 ]heptadecane framework. Their structural elucidation was completed by spectroscopic, chemical, computational, and single-crystal X-ray diffraction means. 2 significantly inhibited early adipogenesis in 3T3-L1 adipocytes via activating AMP-activated protein kinase signaling.

Tigliane and rhamnofolane diterpenoids bearing glycosyl substituents are rarely found in nature. In the current study, seven new tigliane glycosides, euphorwallsides A - G (1-7), and five new rhamnofolane glycosides, euphorwallsides H - L (8-12), were isolated from the whole plants of Euphorbia wallichii. Their structures were elucidated by a combination of spectroscopic, computational, and chemical means. The aglycones of 1-5 represent a rare class of 13-deoxygenated tiglianes, while those of 8-12 represent the first examples of 4-deoxygenated rhamnofolanes. 2, 3, 5, 7, 8, and 12 showed significant neuroprotective effects on sodium nitroprusside (SNP)-induced neuronal death in pheochromocytoma cell line PC-12 at 10 μM, being more active than the clinical drug, edaravone. Mechanistic study revealed that the most active compound, 3, could inhibit reactive oxygen species (ROS) accumulation and restore the mitochondrial membrane potential via modulating the Nrf2 signaling pathway in PC-12 cells., 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 © 2022 Elsevier Inc. All rights reserved.)

Understanding of mechanisms in nitrous oxide (N 2 O) emission from constructed wetland (CW) is particularly important for the establishment of related strategies to reduce greenhouse gas (GHG) production during its wastewater treatment. However, plant biomass accumulation, microbial communities and nitrogen transformation genes distribution and their effects on N 2 O emission from CW as affected by different nitrogen forms in aquatic environment have not been reported. This study investigated the interactive effects of aquatic nitrogen and plant biomass on N 2 O emission from subsurface CW with NH 4 + -N (CW-A) or NO 3 - -N (CW-B) wastewater. The experimental results show that NH 4 + -N and NO 3 - -N removal efficiencies from CW mesocosms were 49.4% and 87.6%, which indirectly lead to N 2 O emission fluxes of CW-A and CW-B maintained at 213 ± 67 and 462 ± 71 μg-N/(m 2 ·h), respectively. Correlation analysis of nitrogen conversion dynamic indicated that NO 2 - -N accumulation closely related to N 2 O emission from CW. Aquatic NH 4 + -N could up-regulate plant biomass accumulation by intensifying citric acid cycle, glycine-serine-threonine metabolism etc., resulting in more nitrogen uptake and lower N 2 O emission/total nitrogen (TN) removal ratio of CW-A compared to CW-B. Although the abundance of denitrifying bacteria and N 2 O reductase nosZ in CW-B were significantly higher than that of CW-A, after fed with mixed NH 4 + -N and NO 3 - -N influent, N 2 O fluxes and N 2 O emission/TN removal ratio in CW-A were extremely close to that of CW-B, suggesting that nitrogen form rather than nitrogen transformation microbial communities and N 2 O reductase nosZ determines N 2 O emission from CW. Hence, the selection of nitrate-loving plants will play an important role in inhibiting N 2 O emission from CW., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Five tigliane ( 1 - 5 ) and one ingenane ( 6 ) diterpenoids were isolated from the ethanol extract of Euphorbia tirucalli . The structures of these compounds were identified based on analysis of their spectroscopic data. Among them, compound 12- O -(2 E ,4 E ,6 E ,8 E -tetradecatetraenoyl)-13- O -isobutyroyl-4 β -deoxyphorbol ( 1 ) was a new tigliane. The Rho123 effluxion assay showed that tiglianes with a trans -fused 5/7 ring system such as compounds 1 , 2 , and 4 had potent inhibitory activity against P-glycoprotein in HepG2/ADR cells.

Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-β1 inhibitor, daphnane diterpenoid DD1 . DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-β1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-β1 abolished this anti-CRPC effect. These findings suggest that importin-β1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-β1 inhibitor to date can be developed as therapeutics for treatment of this disease.

Mulberry Diels-Alder-type adducts (MDAAs) are unique phenolic natural products biosynthetically derived from the intermolecular [4 + 2]-cycloaddition of dienophiles (mainly chalcones) and dehydroprenylphenol dienes, which are exclusively distributed in moraceous plants. A total of 166 MDAAs with diverse skeletons have been isolated and identified since 1980. Structurally, the classic MDAAs characterized by the chalcone-skeleton dienophiles can be divided into eight groups (Types A - H), while others with non-chalcone dienophiles or some variations of classic MDAAs are non-classic MDAAs (Type I). These compounds have attracted significant attention of natural products and synthetic chemists due to their complex architectures, remarkable biological activities, and synthetic challenges. The present review provides a comprehensive summary of the structural properties, bioactivities, and syntheses of MDAAs. Cited references were collected between 1980 and 2021 from the SciFinder, Web of Science, and China National Knowledge Internet (CNKI)., (© 2022. The Author(s).)

Objective: Desmodium styracifolium is the best traditional medicine for treating kidney calculi in China. This study is aimed at increasing the carboxyl (-COOH) content of D. styracifolium polysaccharide (DSP0) and further increasing its antistone activity., Methods: DSP0 was carboxymethylated with chloroacetic acid at varying degrees. Then, oxalate-damaged HK-2 cells were repaired with modified polysaccharide, and the changes in biochemical indices before and after repair were detected., Results: Three modified polysaccharides with 7.45% (CDSP1), 12.2% (CDSP2), and 17.7% (CDSP3) -COOH are obtained. Compared with DSP0 (-COOH content = 1.17%), CDSPs have stronger antioxidant activity in vitro and can improve the vitality of damaged HK-2 cells. CDSPs repair the cell morphology and cytoskeleton, increase the cell healing ability, reduce reactive oxygen species and nitric oxide levels, increase mitochondrial membrane potential, limit autophagy level to a low level, reduce the eversion of phosphatidylserine in the cell membrane, weaken the inhibition of oxalate on DNA synthesis, restore cell cycle to normal state, promote cell proliferation, and reduce apoptosis/necrosis., Conclusion: The carboxymethylation modification of DSP0 can improve its antioxidant activity and enhance its ability to repair damaged HK-2 cells. Among them, CDSP2 with medium -COOH content has the highest activity of repairing cells, whereas CDSP3 with the highest -COOH content has the highest antioxidant activity. This difference may be related to the active environment of polysaccharide and conformation of the polysaccharide and cell signal pathway. This result suggests that Desmodium styracifolium polysaccharide with increased -COOH content may have improved potential treatment and prevention of kidney calculi., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Gu-Hua Tang et al.)

Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg -1 . d -1 , ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Crotonianoids A-C ( 1 - 3 ), three unusual tigliane diterpenoids, were isolated from the seeds of Croton tiglium . Compound 1 is a 13,14:13,15- diseco -tigliane featuring a unique spiro[bicyclo[5.3.0]decane-2,5'-2'(3' H ,4' H )-furanone] core; 2 is a 13,15- seco -tigliane incorporating a rare peroxide bridge between C-13 and C-15; and 3 is the first example of a phorbol ester with a 10 R -configuration. Their structures were determined by spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 markedly inhibited the growth and survival of prostate cancer cell C4-2B at micromolar concentrations and induced cell apoptosis. Mechanistic study revealed that 1 and 2 could suppress androgen receptor (AR) signaling pathway by promoting the degradation of AR protein.

Thermoelectric effects in quantum systems have been focused in recent years. Thermoelectric energy conversion study of systems with edge states, such as quantum Hall insulators and quantum spin Hall insulators, is one of the most important frontier topics in material science and condensed-matter physics. Based on the previous paper (Gresta in Phys Rev Lett 123:186801, 2019), we further investigated the linear and nonlinear thermoelectric transport properties of helical edge states of the quantum spin Hall insulators coupled with double nanomagnet, calculated the Seebeck coefficients [Formula: see text] and the thermoelectrical figure of merit ZT, discussed the influence of the length of the nanomagnet and the relative tilt angle of component of the magnetization perpendicular on the thermoelectric coefficients ([Formula: see text] and ZT), and summarized some meaningful conclusions in the linear response regime. In the nonlinear regime, we calculated the equivalent figure of merit [Formula: see text] and the power-generation efficiency [Formula: see text] in different length of the nanomagnet, obtain the temperature difference of achieving optimal thermoelectricity. The results of this paper further confirm that the setup can indeed be used as a device for achieving high performance thermoelectric., (© 2022. The Author(s).)

Recently discovered topological nodal-line semimetals (TNLSMs) have received considerable research interest due to their rich physical properties and potential applications. TNLSMs have the particular band structure to lead to many novel properties. Here we theoretically study the thermoelectric transport of a two-terminal pristine TNLSM nanowires and TNLSMs p - n - p junctions. The Seebeck coefficients S c and the thermoelectrical figure of merit ZT are calculated based on the Landauer-Büttiker formula combined with the nonequilibrium Green's function method. In pristine TNLSM nanowires, we discuss the effect of the magnetic fields φ , the disorder D , the on-site energy µ z , and the mass term m on the thermoelectric coefficient and find that the transport gap can lead to a large S c and ZT . When transmission coefficient jumps from one integer plateau to another, S c and ZT show a series of peaks. The peaks of S c and ZT are determined by the jump of the transmission coefficient plateau and are not associated with the plateau itself. For TNLSMs p - n - p junctions, S c and ZT strongly depend on the parameter ξ of potential well. We can get a large ZT by adjusting the parameter ξ and magnetic field φ . In TNLSMs p - n - p junctions, ZT has the large value and is easily regulated. This setup has promising application prospects as a thermoelectric device., (© 2022 IOP Publishing Ltd.)