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Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy‐induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence‐associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)‐related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid‐derived suppressor cells (G‐MDSCs). Moreover, clearance of the TIS cells by αPD‐L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib–palbociclib combination. Further combination with PD‐L1 antibody might be a promising "one‐two punch" therapeutic strategy for colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors represented by sorafenib are the first‐line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain‐point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib‐sensitive and ‐insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib‐insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction‐responsive nanoplatform for systemic co‐delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles‐mediated co‐delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC. [ABSTRACT FROM AUTHOR]

Objective: Increased Toll‐like receptor 7 (TLR‐7) signaling leading to the production of type I interferon (IFN) is an important contributor to human systemic lupus erythematosus (SLE). Protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), a molecule that regulates synaptic vesicle recycling, has been linked to TLR‐7/TLR‐9–mediated type I IFN production in humans and mice, but the underlying mechanism is unknown. We undertook this study to explore the pathogenicity and underlying mechanism of a de novo PACSIN1 missense variant identified in a child with SLE. Methods: PACSIN1 Q59K de novo and null variants were introduced into a human plasmacytoid dendritic cell line and into mice using CRISPR/Cas9 editing. The effects of the variants on TLR‐7/TLR‐9 signaling in human and mouse cells, as well as PACSIN1 messenger RNA and IFN signature in SLE patients, were assessed using real‐time polymerase chain reaction and flow cytometry. Mechanisms were investigated using luciferase reporter assays, RNA interference, coimmunoprecipitation, and immunofluorescence. Results: We established that PACSIN1 forms a trimolecular complex with tumor necrosis factor receptor–associated factor 4 (TRAF4) and TRAF6 that is important for the regulation of type I IFN. The Q59K mutation in PACSIN1 augments binding to neural Wiskott‐Aldrich syndrome protein while it decreases binding to TRAF4, leading to unrestrained TRAF6‐mediated activation of type I IFN. Intriguingly, PACSIN1 Q59K increased TLR‐7 but not TLR‐9 signaling in human cells, leading to elevated expression of IFNβ and IFN‐inducible genes. Untreated SLE patients had high PACSIN1 expression in peripheral blood cells that correlated positively with IFN‐related genes. Introduction of the Pacsin1 Q59K mutation into mice caused increased surface TLR‐7 and TRAIL expression in B cells. Conclusion: PACSIN1 Q59K increases IFNβ activity through the impairment of TRAF4‐mediated inhibition of TLR‐7 signaling, possibly contributing to SLE risk. [ABSTRACT FROM AUTHOR]

Aims: To describe the home care experience, challenges and coping strategies of caregivers with children on automatic peritoneal dialysis (PD) in mainland China during the early stage of the COVID‐19 outbreak. Design: A qualitative descriptive approach was adopted. Semi‐structured telephone interviews were conducted among 14 families with children on automatic peritoneal dialysis from February 2nd to 10th, 2020. The care routine, stress and coping strategies of caregivers of children on peritoneal dialysis were collected. The data were analysed using thematic analysis. Methods: Four key themes were defined: (1) concerns about PD treatment intertwined with worries about COVID‐19; (2) retaining a sense of normality in the middle of the challenges; (3) staying safe; and (4) staying positive and carrying on. Results: Families with children on automatic PD addressed the stress from COVID‐19 and its containment measures by closely adhering to COVID‐19 preventative measures, actively adjusting mentality and maintaining a sense of normality during the outbreak. This implies that healthcare staff need to be more aware of the complex medical needs of families with children on automatic PD, advocate for them and facilitate their navigation through the repurposed healthcare system. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Diabetes is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pancreatic cancer (PAAD) is a highly malignant tumour characterized of high mortality and poor prognosis. Huntingtin‐interacting protein 1‐related (HIP1R) has been recognized as a tumour suppressor in gastric cancer, while its biological function in PAAD remains to be elucidated. In this study, we reported the downregulation of HIP1R in PAAD tissues and cell lines, and the overexpression of HIP1R suppressed the proliferation, migration and invasion of PAAD cells, while silencing HIP1R showed the opposite effects. DNA methylation analysis revealed that the promoter region of HIP1R was heavily methylated in PAAD cell lines when compared to the normal pancreatic duct epithelial cells. A DNA methylation inhibitor 5‐AZA increased the expression of HIP1R in PAAD cells. 5‐AZA treatment also inhibited the proliferation, migration and invasion, and induced apoptosis in PAAD cell lines, which could be attenuated by HIP1R silencing. We further demonstrated that HIP1R was negatively regulated by miR‐92a‐3p, which modulates the malignant phenotype of PAAD cells in vitro and the tumorigenesis in vivo. The miR‐92a‐3p/HIP1R axis could regulate PI3K/AKT pathway in PAAD cells. Taken together, our data suggest that targeting DNA methylation and miR‐92a‐3p‐mediated repression of HIP1R could serve as novel therapeutic strategies for PAAD treatment. [ABSTRACT FROM AUTHOR]

Summary: Plant glandular secretory trichomes (GSTs) produce various specialized metabolites. Increasing GST density represents a strategy to enhance the yield of these chemicals; however, the gene regulatory network that controls GST initiation remains unclear.In a previous study of Artemisiaannua L., we found that a HD‐ZIP IV transcription factor, AaHD1, promotes GST initiation by directly regulating AaGSW2. Here, we identified two AaHD1‐interacting transcription factors, namely AaMIXTA‐like 2 (AaMYB16) and AaMYB5.Through the generation and characterization of transgenic plants, we found that AaMYB16 is a positive regulator of GST initiation, whereas AaMYB5 has the opposite effect. Notably, neither of them regulates GST formation independently. Rather, they act competitively, by interacting and modulating AaHD1 promoter binding activity. Additionally, the phytohormone jasmonic acid (JA) was shown to be associated with the AaHD1‐AaMYB16/AaMYB5 regulatory network through transcriptional regulation via a JASMONATE‐ZIM DOMAIN (JAZ) protein repressor.These results bring new insights into the mechanism of GST initiation through regulatory complexes, which appear to have similar functions in a range of vascular plant taxa. [ABSTRACT FROM AUTHOR]

Summary: Artemisinin, a sesquiterpene lactone widely used in malaria treatment, was discovered in the medicinal plant Artemisia annua. The biosynthesis of artemisinin is efficiently regulated by jasmonate (JA) and abscisic acid (ABA) via regulatory factors. However, the mechanisms linking JA and ABA signalling with artemisinin biosynthesis through an associated regulatory network of downstream transcription factors (TFs) remain enigmatic. Here we report AaTCP15, a JA and ABA dual‐responsive teosinte branched1/cycloidea/proliferating (TCP) TF, which is essential for JA and ABA‐induced artemisinin biosynthesis by directly binding to and activating the promoters of DBR2 and ALDH1, two genes encoding enzymes for artemisinin biosynthesis. Furthermore, AaORA, another positive regulator of artemisinin biosynthesis responds to JA and ABA, interacts with and enhances the transactivation activity of AaTCP15 and simultaneously activates AaTCP15 transcripts. Hence, they form an AaORA‐AaTCP15 module to synergistically activate DBR2, a crucial gene for artemisinin biosynthesis. More importantly, AaTCP15 expression is activated by the multiple reported JA and ABA‐responsive TFs that promote artemisinin biosynthesis. Among them, AaGSW1 acts at the nexus of JA and ABA signalling to activate the artemisinin biosynthetic pathway and directly binds to and activates the AaTCP15 promoter apart from the AaORA promoter, which further facilitates formation of the AaGSW1‐AaTCP15/AaORA regulatory module to integrate JA and ABA‐mediated artemisinin biosynthesis. Our results establish a multilayer regulatory network of the AaGSW1‐AaTCP15/AaORA module to regulate artemisinin biosynthesis through JA and ABA signalling, and provide an interesting avenue for future research exploring the special transcriptional regulation module of TCP genes associated with specialized metabolites in plants. [ABSTRACT FROM AUTHOR]

Combat‐related mild traumatic brain injury (cmTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral disabilities in Veterans and active‐duty military personnel. Accurate diagnosis of cmTBI is challenging since the symptom spectrum is broad and conventional neuroimaging techniques are insensitive to the underlying neuropathology. The present study developed a novel deep‐learning neural network method, 3D‐MEGNET, and applied it to resting‐state magnetoencephalography (rs‐MEG) source‐magnitude imaging data from 59 symptomatic cmTBI individuals and 42 combat‐deployed healthy controls (HCs). Analytic models of individual frequency bands and all bands together were tested. The All‐frequency model, which combined delta‐theta (1–7 Hz), alpha (8–12 Hz), beta (15–30 Hz), and gamma (30–80 Hz) frequency bands, outperformed models based on individual bands. The optimized 3D‐MEGNET method distinguished cmTBI individuals from HCs with excellent sensitivity (99.9 ± 0.38%) and specificity (98.9 ± 1.54%). Receiver‐operator‐characteristic curve analysis showed that diagnostic accuracy was 0.99. The gamma and delta‐theta band models outperformed alpha and beta band models. Among cmTBI individuals, but not controls, hyper delta‐theta and gamma‐band activity correlated with lower performance on neuropsychological tests, whereas hypo alpha and beta‐band activity also correlated with lower neuropsychological test performance. This study provides an integrated framework for condensing large source‐imaging variable sets into optimal combinations of regions and frequencies with high diagnostic accuracy and cognitive relevance in cmTBI. The all‐frequency model offered more discriminative power than each frequency‐band model alone. This approach offers an effective path for optimal characterization of behaviorally relevant neuroimaging features in neurological and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty‐two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium‐creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium‐creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS. [ABSTRACT FROM AUTHOR]

Puerariae Lobatae Radix (PLR) is the dried root of the leguminous plant Pueraria lobata and is a common component of health products and medicines. Although it is considered safe, some studies have reported that PLR has hepatotoxicity and estrogen‐like effects. In this study, the safety of high doses of PLR water extract administered to adolescent SD rats for 30 days was evaluated by biochemical, histopathological, and metabolomic analyses. Overall, there were no significant differences between the low‐dose and blank control groups in parameter values, including organ wet weight, organ coefficient, routine blood indicators, serum biochemical indexes of liver and renal function, levels of estradiol and testosterone, histopathological parameters, and primary differential metabolite profiles. Compared with the blank control group, the high‐dose group may have a certain effect on the liver. These effects might be mediated by abnormal phenylalanine, tyrosine, and tryptophan biosynthesis or phenylalanine metabolism. However, histopathological analyses did not show differences in the liver, kidney, breast, uterus, ovary, testis, and epididymis between the control group and the group treated with a high dose of PLR water extract. PLR water extract did not significantly promote the precocity of male and female sexual organs. Overall, PLR water extract is relatively safe for adolescent SD rats. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory dermatosis with complex genetic basis supported by family investigation. Renal involvement in psoriasis is sparsely studied and its pathogenesis is still unclear. Methods and Results: We describe the case of a 7‐year‐old boy presented new onset of nephropathy two weeks after a flare‐up of psoriasis. His mother had a long history of psoriasis without abnormal urinalysis records. The case showed non‐nephrotic range proteinuria, microscopic hematuria without any other abnormal results including renal function, complement cascade, and ultrasound. Renal pathological demonstrated the diagnosis of C3 glomerulonephritis (C3GN) showing mesangial proliferative glomerulonephritis with C3 staining only, effacement of podocyte process and intramembranous electron dense deposit by electric microscopy. Parent‐child trio WES performed to screening the common variants of psoriasis susceptibility locus and also the rare variants associated with C3GN. We identified a missense single nucleotide polymorphism of CARD14 (*607211, rs34367357, p.Val585Ile) carried by the proband and his mother. Meta‐analysis proved the association of rs34367357 and psoriasis (p = 0.006, OR = 1.23). A hemizygouse mutation of CLCN5 (*300008, c.1904A＞G,p.Asn635Ser) was identified for diagnosis of Dent disease (*300009). Conclusion: The case highlights the genetic study is necessary to facilitate disease differentiation in new onset of nephropathy with psoriasis in children. [ABSTRACT FROM AUTHOR]

Background: Mutations in COQ8B (*615567) as a defect of coenzyme Q10 (CoQ10) cause steroid resistant nephrotic syndrome (SRNS). Methods: To define the clinical course and prognosis of COQ8B nephropathy, we retrospectively assessed the genotype and phenotype in patients with COQ8B mutations from Chinese Children Genetic Kidney Disease Database. We performed the comparing study of renal outcome following CoQ10 treatment and renal transplantation between early genetic detection and delayed genetic detection group. Results: We identified 20 (5.8%) patients with biallelic mutations of COQ8B screening for patients with SRNS, non‐nephrotic proteinuria, or chronic kidney disease (CKD) of unknown origin. Patients with COQ8B mutations showed a largely renal‐limited phenotype presenting with proteinuria and/or advanced CKD at the time of diagnosis. Renal biopsy uniformly showed focal segmental glomerulosclerosis. Proteinuria was decreased, whereas the renal function was preserved in five patients following CoQ10 administration combined with angiotensin‐converting enzyme (ACE) inhibitor. The renal survival analysis disclosed a significantly better outcome in early genetic detection group than in delayed genetic detection group (Kaplan–Meier plot and log rank test, p =.037). Seven patients underwent deceased donor renal transplantation without recurrence of proteinuria or graft failure. Blood pressure showed decreased significantly during 6 to 12 months post transplantation. Conclusions: COQ8B mutations are one of the most common causes of adolescent‐onset proteinuria and/or CKD of unknown etiology in the Chinese children. Early detection of COQ8B nephropathy following CoQ10 supplementation combined with ACE inhibitor could slow the progression of renal dysfunction. Renal transplantation in patients with COQ8B nephropathy showed no recurrence of proteinuria. [ABSTRACT FROM AUTHOR]

Previous neuroimaging studies have mainly focused on alterations of static and dynamic functional connectivity in patients with generalized anxiety disorder (GAD). However, the characteristics of local brain activity over time in GAD are poorly understood. This study aimed to investigate the abnormal time‐varying local brain activity of GAD by using the amplitude of low‐frequency fluctuation (ALFF) method combined with sliding‐window approach. Group comparison results showed that compared with healthy controls (HCs), patients with GAD exhibited increased dynamic ALFF (dALFF) variability in widespread regions, including the bilateral dorsomedial prefrontal cortex, hippocampus, thalamus, striatum; and left orbital frontal gyrus, inferior parietal lobule, temporal pole, inferior temporal gyrus, and fusiform gyrus. The abnormal dALFF could be used to distinguish between patients with GAD and HCs. Increased dALFF variability values in the striatum were positively correlated with GAD symptom severity. These findings suggest that GAD patients are associated with abnormal temporal variability of local brain activity in regions implicated in executive, emotional, and social function. This study provides insight into the brain dysfunction of GAD from the perspective of dynamic local brain activity, highlighting the important role of dALFF variability in understanding neurophysiological mechanisms and potentially informing the diagnosis of GAD. [ABSTRACT FROM AUTHOR]

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context‐dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load‐modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context‐related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context‐dependent connectivity. During encoding, striatal‐prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long‐range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context‐specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory‐related signatures of aberrant cortico–cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory. [ABSTRACT FROM AUTHOR]

Dent disease is a rare X‐linked recessive inherited tubular disease. In this multicenter study, the clinical presentation and genetic background of Chinese children with Dent disease are studied to improve the cognition and diagnostic ability of pediatricians. In this prospective cohort, we described the genotype and phenotype of a national cohort composed of 45 pediatric probands with Dent disease belonging to 45 families from 12 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system. The CLCN5 gene from 32 affected families revealed 28 different mutations. The OCRL gene from 13 affected families revealed 13 different mutations. The incidence of low‐molecular‐weight proteinuria (LMWP) in both Dent disease type 1 populations and Dent disease type 2 populations was 100.0%; however, the incidence of other manifestations was not high, which was similar to previously reported data. Therefore, LMWP is a key clinical feature that should alert clinicians to the possibility of Dent disease. A high amount of LMWP combined with positive gene test results can be used as the diagnostic criteria for this disease. The diagnostic criteria are helpful in reducing the missed diagnosis of this disease and are beneficial for protecting the renal function of these patients through early diagnosis and early intervention. [ABSTRACT FROM AUTHOR]

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole‐exome sequencing (WES) and trio‐WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio‐WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease. [ABSTRACT FROM AUTHOR]

Summary: Glandular trichomes and cuticles are both specialized structures that cover the epidermis of aerial plant organs. The former are commonly regarded as ‘biofactories’ for producing valuable natural products. The latter are generally considered as natural barriers for defending plants against abiotic and biotic stresses. However, the regulatory network for their formation and relationship remains largely elusive. Here we identify a homeodomain‐leucine zipper (HD‐ZIP) IV transcription factor, AaHD8, directly promoting the expression of AaHD1 for glandular trichome initiation in Artemisia annua. We found that AaHD8 positively regulated leaf cuticle development in A. annua via controlling the expression of cuticle‐related enzyme genes. Furthermore, AaHD8 interacted with a MIXTA‐like protein AaMIXTA1, a positive regulator of trichome initiation and cuticle development, forming a regulatory complex and leading to enhanced transcriptional activity in regulating the expression of AaHD1 and cuticle development genes. Our results reveal a molecular mechanism by which a novel HD‐ZIP IV/MIXTA complex plays a significant role in regulating epidermal development, including glandular trichome initiation and cuticle formation. [ABSTRACT FROM AUTHOR]

The glandular secretory trichomes ( GSTs) on Artemisia annua leaves have the capacity to secrete and store artemisinin, a compound which is the most effective treatment for uncomplicated malaria. An effective strategy to improve artemisinin content is therefore to increase the density of GSTs in A. annua. However, the formation mechanism of GSTs remains poorly understood., To explore the mechanisms of GST initiation in A. annua, we screened myeloblastosis ( MYB) transcription factor genes from a GST transcriptome database and identified a MIXTA transcription factor, Aa MIXTA1, which is expressed predominantly in the basal cells of GST in A. annua. Overexpression and repression of Aa MIXTA1 resulted in an increase and decrease, respectively, in the number of GSTs as well as the artemisinin content in transgenic plants., Transcriptome analysis and cuticular lipid profiling showed that Aa MIXTA1 is likely to be responsible for activating cuticle biosynthesis. In addition, dual-luciferase reporter assays further demonstrated that Aa MIXTA1 could directly activate the expression of genes related to cuticle biosynthesis., Taken together, Aa MIXTA1 regulated cuticle biosynthesis and prompted GST initiation without any abnormal impact on the morphological structure of the GSTs and so provides a new way to improve artemisinin content in this important medicinal plant. [ABSTRACT FROM AUTHOR]

Artemisinin is a type of sesquiterpene lactone well known as an antimalarial drug, and is specifically produced in glandular trichomes of Artemisia annua. However, the regulatory network for the artemisinin biosynthetic pathway remains poorly understood. Exploration of trichome-specific transcription factors would facilitate the elucidation of regulatory mechanism of artemisinin biosynthesis., The WRKY transcription factor GLANDULAR TRICHOME- SPECIFIC WRKY 1 ( Aa GSW1) was cloned and analysed in A. annua. Aa GSW1 exhibited similar expression patterns to the trichome-specific genes of the artemisinin biosynthetic pathway and AP2/ ERF transcription factor Aa ORA. A β-glucuronidase (GUS) staining assay further demonstrated that Aa GSW1 is a glandular trichome-specific transcription factor., Aa GSW1 positively regulates CYP71 AV1 and Aa ORA expression by directly binding to the W-box motifs in their promoters. Overexpression of Aa GSW1 in A. annua significantly improves artemisinin and dihydroartemisinic acid contents; moreover, Aa GSW1 can be directly regulated by Aa MYC2 and Aab ZIP1, which are positive regulators of jasmonate ( JA)- and abscisic acid ( ABA)-mediated artemisinin biosynthetic pathways, respectively., These results demonstrate that Aa GSW1 is a glandular trichome-specific WRKY transcription factor and a positive regulator in the artemisinin biosynthetic pathway. Moreover, we propose that two trifurcate feed-forward pathways involving Aa GSW1, CYP71 AV1 and Aa MYC2/ Aab ZIP1 function in the JA/ ABA response in A. annua. [ABSTRACT FROM AUTHOR]

Objectives: To assess the long-term effects of the introduction of China's zero-markup drug policy on hospitalisation expenditure and hospitalisation expenditures after reimbursement.Methods: An interrupted time series was used to evaluate the impact of the zero-markup drug policy on hospitalisation expenditure and hospitalisation expenditure after reimbursement at primary health institutions in Fufeng County of Shaanxi Province, western China. Two regression models were developed. Monthly average hospitalisation expenditure and monthly average hospitalisation expenditure after reimbursement in primary health institutions were analysed covering the period 2009 through to 2013.Results: For the monthly average hospitalisation expenditure, the increasing trend was slowed down after the introduction of the zero-markup drug policy (coefficient = -16.49, P = 0.009). For the monthly average hospitalisation expenditure after reimbursement, the increasing trend was slowed down after the introduction of the zero-markup drug policy (coefficient = -10.84, P = 0.064), and a significant decrease in the intercept was noted after the second intervention of changes in reimbursement schemes of the new rural cooperative medical insurance (coefficient = -220.64, P < 0.001).Conclusions: A statistically significant absolute decrease in the level or trend of monthly average hospitalisation expenditure and monthly average hospitalisation expenditure after reimbursement was detected after the introduction of the zero-markup drug policy in western China. However, hospitalisation expenditure and hospitalisation expenditure after reimbursement were still increasing. More effective policies are needed to prevent these costs from continuing to rise. [ABSTRACT FROM AUTHOR]

• Glandular trichomes are generally considered biofactories that produce valuable chemicals. Increasing glandular trichome density is a very suitable way to improve the productivity of these valuable metabolites, but little is known about the regulation of glandular trichome formation. Phytohormone jasmonate (JA) promotes glandular trichome initiation in various plants, but its mechanism is also unknown. • By searching transcription factors regulated by JA in Artemisia annua, we identified a novel homeodomain-leucine zipper transcription factor, HOMEODOMAIN PROTEIN 1 (AaHD1), which positively controls both glandular and nonglandular trichome initiations. Overexpression of AaHD1 in A. annua significantly increased glandular trichome density without harming plant growth. Consequently, the artemisinin content was improved. • AaHD1 interacts with A. annua jasmonate ZIM-domain 8 (AaJAZ8), which is a repressor of JA, thereby resulting in decreased transcriptional activity. AaHD1 knockdown lines show decreased sensitivity to JA on glandular trichome initiation, which indicates that AaHD1 plays an important role in JA-mediated glandular trichome initiation. • We identified a new transcription factor that promotes A. annua glandular trichome initiation and revealed a novel molecular mechanism by which a homeodomain protein transduces JA signal to promote glandular trichome initiation. Our results also suggested a connection between glandular and nonglandular trichome formations. [ABSTRACT FROM AUTHOR]

Background Perineural invasion has been found in several types of human tumors, and is associated with poor prognosis; however, few studies have examined perineural invasion in lung cancer. We evaluated the relationship between autonomic nervous densities, pathological risk grading, and prognosis in patients with lung adenocarcinoma ( LADC). Methods Neural fiber expression was examined by immunofluorescence in resected lung specimens in control patients ( n = 30), and low-risk ( n = 22), and high-risk LADC patients ( n = 43). The nerve densities of normal lung tissue and abnormal lung tissues in the tumor and surrounding tissues were evaluated by a semi-quantitative score method. Results Increased sympathetic fibers mainly infiltrated the paratumoral area, while increased parasympathetic fibers were largely restricted to the tumor (paratumor vs. tumor, P = 0.000 in high, P = 0.034 in low; each). In addition, high-risk patients presented the highest density of neural fibers, followed by low-risk and control patients ( P = 0.000; each). In Kaplan-Meier survival analysis, the densities of sympathetic fibers in paratumoral tissue and parasympathetic fibers in the tumor, respectively, correlated with poor recurrence-free survival in patients who were not treated with adjuvant therapy ( P < 0.001; each). Further multivariate analysis showed that these two factors were associated with poor prognosis in all LADC patients ( P = 0.024 sympathetic fibers; P = 0.037 parasympathetic fibers). Conclusion These findings reveal a positive correlation between nervous infiltration and risk of poor prognosis in patients with LADC. [ABSTRACT FROM AUTHOR]

The plant Artemisia annua is well known due to the production of artemisinin, a sesquiterpene lactone that is widely used in malaria treatment. Phytohormones play important roles in plant secondary metabolism, such as jasmonic acid ( JA), which can induce artemisinin biosynthesis in A. annua. Nevertheless, the JA-inducing mechanism remains poorly understood., The expression of gene Aa MYC2 was rapidly induced by JA and Aa MYC2 binds the G-box-like motifs within the promoters of gene CYP71 AV1 and DBR2, which are key structural genes in the artemisinin biosynthetic pathway., Overexpression of Aa MYC2 in A. annua significantly activated the transcript levels of CYP71 AV1 and DBR2, which resulted in an increased artemisinin content. By contrast, artemisinin content was reduced in the RNAi transgenic A. annua plants in which the expression of Aa MYC2 was suppressed. Meanwhile, the RNAi transgenic A. annua plants showed lower sensitivity to methyl jasmonate treatment than the wild-type plants., These results demonstrate that Aa MYC2 is a positive regulator of artemisinin biosynthesis and is of great value in genetic engineering of A. annua for increased artemisinin production. [ABSTRACT FROM AUTHOR]

We describe a case of thoracic empyema in a 76-year-old male with complication of diabetes mellitus and hypertension. His chief complaints were fever and chest pain. The patient was diagnosed as pleural infection according to the pulmonary computed tomography ( CT) scan and laboratory results. The patient had persistent fever after the treatment of continuous percutaneous drainage and 1 week of intravenous moxifloxacin. He was then misdiagnosed as tuberculous pleuritis and still had fever after the treatment of 2 weeks' antituberculosis drugs. Repeated cultures of sputum, blood, bronchoalveolar lavage fluid and pleural fluid were all negative. A gram-negative bacillus was found in the pleural pus Gram stain, and it was identified as Prevotella spp. by 16S ribosomal DNA ( rDNA) sequence analysis. The patient recovered after further treatment, including CT-induced pleural drain and intravenous imipenem. Totally, he received 2-week imipenem and 1-month metronidazole therapy from the day he was diagnosed with empyema to the termination of treatment. On the subsequent 2-month and 6-month follow-up visits, no recurrence has been reported for this patient. Routine microbiological methods are important in diagnosis of pleural infection, but they have limitations in some cases, especially for anaerobe. Molecular assay based on 16S rDNA is helpful in detecting causative organisms of thoracic empyema. [ABSTRACT FROM AUTHOR]

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Six transcription factors of APETALA2/ethylene-response factor ( AP2/ ERF) family were cloned and analyzed in Artemisia annua. Real-time quantitative polymerase chain reaction ( RT- Q- PCR) showed that Aa ORA exhibited similar expression patterns to those of amorpha-4,11-diene synthase gene ( ADS), cytochrome P450-dependent hydroxylase gene ( CYP71AV1) and double bond reductase 2 gene ( DBR2) in different tissues of A. annua., Aa ORA is a trichome-specific transcription factor, which is expressed in both glandular secretory trichomes ( GSTs) and nonglandular T-shaped trichomes ( TSTs) of A. annua. The result of subcellular localization shows that Aa ORA is targeted to the nuclei and the cytoplasm., Overexpression and RNA interference ( RNAi) of Aa ORA in A. annua regulated, positively and significantly, the expression levels of ADS, CYP71 AV1, DBR2 and Aa ERF1. The up-regulated or down-regulated expression levels of these genes resulted in a significant increase or decrease in artemisinin and dihydroartemisinic acid. The results demonstrate that Aa ORA is a positive regulator in the biosynthesis of artemisinin., Overexpression of Aa ORA in Arabidopsis thaliana increased greatly the transcript levels of the defense marker genes PLANT DEFENSIN1.2 ( PDF1.2), HEVEIN-LIKE PROTEIN ( HEL) and BASIC CHITINASE ( B-CHI). After inoculation with Botrytis cinerea, the phenotypes of Aa ORA overexpression in A. thaliana and Aa ORA RNAi in A. annua demonstrate that Aa ORA is a positive regulator of disease resistance to B. cinerea. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate the contributions of amyloid-positive (Am+) and medial temporal atrophy–positive (MTA+) scans to the diagnostic classification of prodromal and probable Alzheimer’s disease (AD). Methods: 18F-flutemetamol-labeled amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to classify 10 young normal, 15 elderly normal, 20 amnestic mild cognitive impairment (aMCI), and 27 AD subjects. MTA+ status was determined using a cut point derived from a previous study, and Am+ status was determined using a conservative and liberal cut point. Results: The rates of MRI scans with positive results among young normal, elderly normal, aMCI, and AD subjects were 0%, 20%, 75%, and 82%, respectively. Using conservative cut points, the rates of Am+ scans for these same groups of subjects were 0%, 7%, 50%, and 93%, respectively, with the aMCI group showing the largest discrepancy between Am+ and MTA+ scans. Among aMCI cases, 80% of Am+ subjects were also MTA+, and 70% of amyloid-negative (Am−) subjects were MTA+. The combination of amyloid PET and MTA data was additive, with an overall correct classification rate for aMCI of 86%, when a liberal cut point (standard uptake value ratio = 1.4) was used for amyloid positivity. Interpretation: 18F-flutemetamol PET and structural MRI provided additive information in the diagnostic classification of aMCI subjects, suggesting an amyloid-independent neurodegenerative component among aMCI subjects in this sample. [Copyright &y& Elsevier]

Abstract: Background: The segmentation of brain structures on magnetic resonance imaging scans for calculating regional brain volumes, using automated anatomic labeling, requires the use of both brain atlases and templates (template sets). This study aims to improve the accuracy of volumetric analysis of hippocampus (HP) and amygdala (AMG) in the assessment of early Alzheimer’s disease (AD) by developing template sets that correspond more closely to the brains of elderly individuals. Methods: Total intracranial volume and HP and AMG volumes were calculated for elderly subjects with no cognitive impairment (n = 103), with amnestic mild cognitive impairment (n = 68), or with probable AD (n = 46) using the following: (1) a template set consisting of a standard atlas (atlas S), drawn on a young adult male brain, and the widely used Montreal Neurological Institute template (MNI template set); (2) a template set (template S set) in which the template is based on smoothing the image from which atlas S is derived; and (3) a new template set (template E set) in which the template is based on an atlas (atlas E) created from the brain of an elderly individual. Results: Correspondence to HP and AMG volumes derived from manual segmentation was highest with automated segmentation by template E set, intermediate with template S set, and lowest with the MNI template set. The areas under the receiver operating curve for distinguishing elderly subjects with no cognitive impairment from elderly subjects with amnestic mild cognitive impairment or probable AD and the correlations between HP and AMG volumes and cognitive and functional scores were highest for template E set, intermediate for template S set, and lowest for the MNI template set. Conclusions: The accuracy of automated anatomic labeling and the diagnostic value of the derived volumes are improved with template sets based on brain atlases closely resembling the anatomy of the to-be-segmented brain magnetic resonance imaging scans. [Copyright &y& Elsevier]

Abstract: Objective: To assess medial temporal atrophy (MTA) and atrophy adjacent to the third ventricle (Peri-IIIVent) on brain magnetic resonance images as biomarkers for the diagnosis of Alzheimer’s disease (AD) and Lewy body dementia (LBD), and to assess the relationship between biomarkers and clinical and functional measures. Methods: Subjects diagnosed with no cognitive impairment (n = 30), AD (n = 30), or LBD (n = 31) were evaluated with the Mini-Mental State Examination, Multiple Delayed Recall Test, Category Fluency Test, Clinical Dementia Rating Sum of Boxes score, Functional Assessment Questionnaire, and the Unified Parkinson’s Disease Rating Scale. A validated visual rating system was used to rate MTA, and volumetric studies were performed to measure total intracranial and hippocampal volumes. Additionally, linear measurements of third ventricle width, Peri-IIIVent height, and Peri-IIIVent width were performed. Results: Subjects with AD and those with LBD were equivalent with respect to age and levels of cognitive impairment. Atrophy in medial temporal and Peri-IIIVent regions was greater among both patients with AD and those with LBD compared with subjects with no cognitive impairment. The best discriminators of AD from LBD were the severity of MTA, using visual rating, and the severity of memory impairment. Only subjects with LBD showed significant correlations between Unified Parkinson’s Disease Rating Scale scores and Peri-IIIVent atrophy measures. Conclusions: Mild AD could be distinguished from mild LBD by the severity of MTA and memory impairment. The severity of parkinsonism was associated with the severity of atrophy in the third ventricular region, but was not a good discriminator between AD and LBD. [Copyright &y& Elsevier]

Abstract: Background/Aims: To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI). Methods: We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination. Results: The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression. Conclusion: Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits. [Copyright &y& Elsevier]

A transgenic mouse model expressing Simian virus 40 T-antigen (SV40Tag) under the control of a tetracycline system was generated. In this model, a cerebellar tumor was developed after doxycycline hydrochloride treatment. Real time-polymerase chain reaction and immunohistochemistry results indicated that the SV40Tag gene was expressed in the tumor. Pathological analysis showed that the tumor belonged to medulloblastoma. Further molecular characterization of the tumor demonstrated that the insulin-like growth factor (IGF) signaling pathway was activated. We also found that the SV40Tag could bind and translocate insulin receptor substrate 1 into the nucleus in primary cultured tumor cells. The interaction between the IGF pathway and SV40Tag may contribute to the process of malignant transformation in medulloblastoma. This transgenic animal model provides an important tool for studies on the signal pathways involved in the preneoplastic process in medulloblastoma and could help to identify therapeutic targets for brain tumors. ( Cancer Sci 2008; 99: 234–240) [ABSTRACT FROM AUTHOR]

Abstract: Background: In the diagnosis of Alzheimer’s disease (AD), structural magnetic resonance imaging (MRI) scans have been used primarily to exclude non-Alzheimer’s causes of dementia. However, the pattern and the extent of medial temporal atrophy on structural MRI scans, which correlate strongly with the pathological severity of AD, can be used to support the diagnosis of a degenerative dementia, especially AD, even in its early predementia stage. Methods: Elderly subjects (n = 224) were diagnosed with either no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), or AD. Hippocampal and hemispheric gray matter volumes were measured on structural MRI scans, and a new visual rating system was used to score the severity of medial temporal atrophy (VRS-MTA) of the hippocampus (HPC), entorhinal cortex, and perirhinal cortex on a coronal image intersecting the mammillary bodies. Results: Although both VRS-MTA scores and HPC volumes distinguished between subjects with NCI, aMCI, and AD, subjects with aMCI and NCI could be better distinguished using right VRS-MTA scores, in comparison with right HPC volumes. VRS-MTA scores were more highly correlated with episodic memory and Clinical Dementia Rating scores. A combination of left sided VRS-MTA scores and left sided hippocampal volume was the most predictive measure of diagnostic classification. Conclusion: VRS-MTA is a clinically convenient method or distinguishing aMCI or AD from NCI. As compared with volumetric measures, it provides better discriminatory power and correlates more strongly with memory and functional scores. [Copyright &y& Elsevier]