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Kristina S Chen,1 Jipan Xie,2 Wenxi Tang,3 Jing Zhao,4 Palle B Jeppesen,5 James E Signorovitch4 1Outcomes Research and Epidemiology, Shire Human Genetic Therapies, Inc., Cambridge, MA, USA; 2Analysis Group, Inc., Los Angeles, CA, USA; 3Analysis Group, Inc., New York, NY, USA; 4Analysis Group, Inc., Boston, MA, USA; 5Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark Purpose: Teduglutide, a glucagon-like peptide-2 analog, has demonstrated efficacy in reducing parenteral support (PS) among patients with short bowel syndrome with intestinal failure (SBS–IF). This study aims to identify a subpopulation of SBS–IF patients for whom teduglutide has an especially pronounced effect. Patients and methods: Data were from a 24-week, Phase III trial (Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent SBS Subjects; NCT00798967) that randomized SBS–IF patients with PS dependency to receive teduglutide (n=43) or placebo (n=43). Two prediction models (1 for each arm) were developed for response, defined as 20% reduction in weekly PS at Weeks 20 and 24. Potential predictors included demographics, disease characteristics, and concomitant medications. Patients were then ranked based on the effect score, an individualized predicted response rate difference with teduglutide versus placebo. A subpopulation of patients with a pronounced benefit from teduglutide versus placebo was identified. Baseline characteristics and clinical outcomes were compared between patients included versus those not included in the subpopulation. Results: Six predictors of response to teduglutide were selected: older age, volvulus as the cause of major intestinal resection, baseline PS volume >6 L per week, longer time since start of PS dependency, absence of ileocecal valve, and lower percentage of colon remaining. Higher percentage of colon remaining and volvulus were the selected predictors for response to placebo. A subpopulation of patients more likely to respond to teduglutide was identified as those with the top 60% effect scores. The difference in response rate between teduglutide and placebo was 62% in the subpopulation, which was substantially higher than the difference of 33% in the overall population. Mean PS day reduction was also significantly higher for teduglutide compared to placebo in the subpopulation. Conclusion: Pretreatment characteristics as predictors of response to teduglutide versus placebo within 24 weeks were identifiable in the clinical trial population of SBS–IF patients. Keywords: SBS, intestinal failure, teduglutide, subpopulation

Moshe Fridman,1 Tobias Banaschewski,2 Vanja Sikirica,3 Javier Quintero,4 Kristina S Chen5 1AMF Consulting, Inc., Los Angeles, CA, USA; 2Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; 3Global Health Economics Outcomes Research and Epidemiology, Shire, Wayne, PA, USA; 4Psychiatry Department, Hospital Universitario Infanta Leonor, Complutense University, Madrid, Spain; 5Global Health Economics Outcomes Research and Epidemiology, Shire, Lexington, MA, USA Background: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders and negatively impacts caregivers’ lives. Factors including barriers to accessing care, dissatisfaction with support services, and lack of caregiver resources may contribute to this.Objectives: To report caregivers’ experiences of ADHD diagnosis, behavioral therapy (BT), and supportive care for children/adolescents with ADHD.Methods: The Caregiver Perspective on Pediatric ADHD (CAPPA) survey included caregivers of children/adolescents (6–17 years) from ten European countries who were currently receiving/had received ADHD pharmacotherapy in the previous 6 months. Caregivers reported experiences of obtaining an ADHD diagnosis, access to BT, availability of caregiver resources, and level of health care/school support. Pan-EU and country-specific descriptive statistics are reported; responses were compared across countries.Results: Of 3,616 caregivers, 66% were female. Mean age of children/adolescents was 11.5 years; 80% were male. Mean time from the first doctor visit to diagnosis was 10.8 (95% confidence interval 10.2, 11.3) months; 31% of caregivers reported the greatest degrees of difficulty in obtaining an ADHD diagnosis; 44% of children/adolescents did not receive BT. Forty-seven percent of caregivers reported that sufficient resources were available, 44% were “very satisfied”/“satisfied” with medical care, and 50% found health care providers “very supportive”/“somewhat supportive”. Mainstream schools were attended by 82% of children/adolescents. Of those, 67% of caregivers thought schools could help more with the child/adolescent’s ADHD and 48% received extra help/special arrangement. Results varied significantly between countries (P

Moshe Fridman,1 Tobias Banaschewski,2 Vanja Sikirica,3 Javier Quintero,4 M Haim Erder,3 Kristina S Chen5 1AMF Consulting, Inc., Los Angeles, CA, USA; 2Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; 3Global Health Economics Outcomes Research and Epidemiology, Shire, Wayne, PA, USA; 4Psychiatry Department, Hospital Universitario Infanta Leonor, Complutense University, Madrid, Spain; 5Global Health Economics Outcomes Research and Epidemiology, Shire, Lexington, MA, USA Background: Burden on caregivers of children/adolescents with attention-deficit/hyperactivity disorder (ADHD) is multidimensional, but incompletely understood. Objective: To analyze caregiver burden across the concepts of work, social/family life, and parental worry/stress, in relation to selected contributing factors. Methods: The online Caregiver Perspective on Pediatric ADHD survey was fielded in ten European countries. Analysis included children/adolescents (6–17 years) who were receiving/had received ADHD pharmacotherapy in the previous 6 months. Caregivers recorded their child’s/adolescent’s symptoms “on”/“off” medication (ie, when the caregiver reported that the child/adolescent forgot/chose not to take medication, before the onset of medication effect, or medication worn off). Effects of ADHD severity, comorbidities, and medication adherence on each burden outcome were assessed (multiple regression models). Results: In total, 2,326 caregivers were included (children/adolescents’ mean age: 11.5 years, 80% male). Caregivers reported missed/altered work, avoiding social activity, increased parental worry/stress, and strain on family life, despite using ADHD pharmacotherapy. Child/adolescent comorbidities and ADHD severity were significantly related to all burden concepts measured; the strongest comorbidity associations were with altered work (odds ratios [ORs] =1.68 [95% confidence interval {CI} 1.33, 2.12], 1.87 [1.37, 2.54], 3.47 [2.51, 4.78] for 1, 2, 3+ comorbidities, respectively) and planning the day around the child/adolescent (OR =1.42 [95% CI 1.17, 1.72], 1.73 [1.33, 2.15], 2.65 [1.99, 3.53]); the strongest severity associations were: quitting a job (OR =1.41 [95% CI 1.26, 1.59]) and planning a day around the child/adolescent (OR =1.26 [95% CI 1.20, 1.32]). Increased medication adherence was most associated with reducing the caregiver burden for altered work (OR =0.57 [95% CI 0.45, 0.72]), worrying about how they are being perceived as a parent (OR =0.68 [0.56, 0.83]), and avoiding social activity (OR =0.56 [0.45, 0.68]), but not family or stress burden. Conclusion: Burdens related to work, social activity, family life, and parental worry/stress were experienced by the caregivers of children/adolescents with ADHD, despite using ADHD pharmacotherapy. Better understanding of clinical/treatment characteristics most associated with the components of caregiver burden may help improve ADHD management and may ease caregiver burden. Keywords: attention-deficit/hyperactivity disorder, treatment, caregivers, burden of illness

Moshe Fridman,1 Tobias Banaschewski,2 Vanja Sikirica,3 Javier Quintero,4 M Haim Erder,3 Kristina S Chen5 1AMF Consulting, Inc., Los Angeles, CA, USA; 2Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; 3Global Health Economics Outcomes Research and Epidemiology, Shire, Wayne, PA, USA; 4Psychiatry Department, Hospital Universitario Infanta Leonor, Complutense University, Madrid, Spain; 5Global Health Economics Outcomes Research and Epidemiology, Shire, Lexington, MA, USA Abstract: The caregiver perspective on pediatric attention-deficit/hyperactivity disorder (ADHD) study (CAPPA) was a web-based, cross-sectional survey of caregivers of children and adolescents (6–17 years of age) with ADHD and was conducted in 10 European countries. CAPPA included caregiver assessments of global medication satisfaction, global symptom control, and satisfaction with ADHD medication attributes. Overall, 2,326 caregiver responses indicated that their child or adolescent was currently receiving ADHD medication and completed the “off medication” assessment required for inclusion in the present analyses. Responses to the single-item global medication satisfaction question indicated that 88% were satisfied (moderately satisfied to very satisfied) with current medication and 18% were “very satisfied” on the single-item question. Responses to the single-item global symptom control question indicated that 47% and 19% of caregivers considered their child or adolescent’s symptoms to be “controlled” or “very well controlled”, respectively. Significant variations in response to the questions of medication satisfaction and symptom control were observed between countries. The correlation between the global medication satisfaction and global symptom control questions was 0.677 (P

In the present work, a three-dimension (3-D) model of polymer electrolyte fuel cells (PEFCs) is employed to investigate the complex, non-isothermal, two-phase flow in the gas diffusion layer (GDL). Phase change in gas flow channels is explained, and a simplified approach accounting for phase change is incorporated into the fuel cell model. It is found that the liquid water contours in the GDL are similar along flow channels when the channels are subject to two-phase flow. Analysis is performed on a dimensionless parameter Da0 introduced in our previous paper [Y. Wang and K. S. Chen, Chemical Engineering Science 66 (2011) 3557–3567] and the parameter is further evaluated in a realistic fuel cell. We found that the GDL's liquid water (or liquid-free) region is determined by the Da0 number which lumps several parameters, including the thermal conductivity and operating temperature. By adjusting these factors, a liquid-free GDL zone can be created even though the channel stream is two-phase flow. Such a liquid-free zone is adjacent to the two-phase region, benefiting local water management, namely avoiding both severe flooding and dryness.

This paper explores the through-/in-plane characteristics of water transport in the cathode gas diffusion layer (GDL) of a polymer electrolyte fuel cell (PEFC). Theoretical analysis is performed on the non-isothermal two-phase flow under flow channels. A dimensionless group Da (Damkohler number for PEFC operation), defined as the ratio of water generation rate to water vapor-phase removal rate, is formulated to characterize the flow regimes in a PEFC. This group, lumping geometrical parameters and physical properties, compares the water vapor-phase removal capability (via water diffusion and holding capacity) with the rate of water production by the oxygen reduction reaction. We find that this dimensionless group can be used to characterize the non-isothermal, two-phase phenomena: when Da→0, the fuel cell is subjected to single-phase operation; while as Da→ we have full two-phase operation. A more precise expression is explored for the dimensionless group at the channel central line, i.e. Da0: when Da0>1 the entire cathode GDL-CL (catalyst layer) interface is in two-phase region, whereas part of the interface is free of liquid water for Da0

A multidimensional mathematical model is presented for simulating the coupled phenomena of gaseous fuel/reactant flows, species (including liquid water) transport, heat transfer, hydrogen oxidation, and oxygen reduction reactions in a polymer electrolyte fuel cell (PEFC). The present work focuses on elucidating water distribution in the through-plane direction, in particular across the membrane electrode assembly (MEA) and gas diffusion layer (GDL). Two-dimensional model predictions are computed numerically and compared with available experimental data from neutron radiography or imaging. Using the same set of model parameters, reasonably good agreements are obtained quantitatively between the computed water profile in the MEA-GDL component and the neutron-imaging data reported by two separate research groups, and qualitatively between model prediction and the data from another (third) group. Case-study simulations are carried out for PEFC operation at various temperatures, relative humidities, and current densities. It is found that liquid-water content is lower at higher cell temperatures due to greater water evaporation and stronger water diffusion in the vapor phase, as expected. Without strong water diffusion in the vapor phase, the liquid-water profiles are found to increase with current density in the cathode GDL but indicate a complex trend in the anode. Effect of varying GDL thermal conductivity on water distribution is also examined. © 2010 The Electrochemical Society.

Choong SS, Latiff ZA, Mohamed M, Lim LLW, Chen KS, Vengidasan L, Razali H, Abdul Rahman EJ, Ariffin H for Malaysian Society of Paediatric Haematology-Oncology. Childhood adrenal cortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations. Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant disorder where affected individuals carry a 50% risk of developing cancer before 30 years of age. It is most commonly associated with mutations in the tumour suppressor gene, TP53. Adrenocortical carcinoma (ACC) is a very rare paediatric cancer, and up to 80% of affected children are found to carry germline TP53 mutations. Hence, we propose using childhood ACC incidence as selection criteria for referral for TP53 mutation testing, independent of familial cancer history. Under the auspices of the Malaysian Society of Paediatric Haematology-Oncology, four eligible children diagnosed with ACC over a 30-month study period were referred for mutation testing. Three had a germline TP53 mutation. Subsequent TP53 testing in relatives showed two inherited mutations and one de novo mutation. These findings strongly support paediatric ACC as a useful sentinel cancer for initiating a germline TP53/LFS detection programme, particularly in countries where the lack of structured oncogenetic practice precludes the identification of families with LFS features. [ABSTRACT FROM AUTHOR]

Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. Conversely, we observed that overexpression of VEGF reduced microglial response to excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses widely throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Mutations in the microRNA processing genes DICER1 and DROSHA drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2 , which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation., Competing Interests: The authors have no competing interests to declare.

Cultivated strawberry (Fragaria × ananassa) is a popular, economically important fruit. The ripening of the receptacle (pseudocarp), the main edible part, depends on endogenously produced abscisic acid (ABA) and is suppressed by the high level of auxin produced from achenes (true fruit) during early development. However, the mechanism whereby auxin regulates receptacle ripening through inhibiting ABA biosynthesis remains unclear. Here, we identified AUXIN RESPONSE FACTOR 2 (FaARF2), which showed decreased expression with reduced auxin content in the receptacle, leading to increased ABA levels and accelerated ripening. Dual-luciferase, yeast one-hybrid, and electrophoretic mobility shift assays demonstrated that FaARF2 could bind to the AuxRE element in the promoter of 9-CIS-EPOXYCAROT-ENOID DIOXYGENASE 1 (FaNCED1), a key ABA biosynthetic gene, to suppress its transcriptional activity. Transiently overexpressing FaARF2 in the receptacles decreased FaNCED1 expression and ABA levels, resulting in inhibition of receptacle ripening and of development of quality attributes, such as pigmentation, aroma, and sweetness. This inhibition caused by overexpressing FaARF2 was partially recovered by the injection of exogenous ABA; conversely, transient silencing of FaARF2 using RNA interference produced the opposite results. The negative targeting of FaNCED1 by FaARF2 is a key link between auxin-ABA interactions and regulation of strawberry ripening., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the Registry's goals is to continue to refine these guidelines as additional data becomes available., Experimental Design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the National Cancer Institute Natural History of DICER1 Syndrome study., Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor (SLCT) at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed under age 8 years, the current age of onset of pelvic surveillance. Additionally, 4% of SLCTs were diagnosed before the age of 4 years., Conclusion: Ongoing data collection highlights the role of lung surveillance in the detection of early PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before age 8 years, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

Information on the clinical outcomes of feline azotemia using ultrasound examinations is limited. This study aimed to understand the correlation between cortical anisotropy backscattering artifact (CABA) and serum creatinine (sCr) changes in feline azotemia after hospitalization and to investigate whether CABA is useful for predicting the clinical outcome of feline azotemia. Sixty-five hospitalized cats with azotemia, including 49 cats with moderate or severe azotemia (severe group) and 16 cats with mild azotemia (mild group). This retrospective study reviewed the CABA using ultrasound images of cats hospitalized with azotemia between 2016 and 2021. The correlation between CABA and the clinical outcomes of cats with azotemia was investigated using the chi-squared or Fisher's exact test, and the intra- and inter-observer agreements in CABA were assessed using McNemar's and Cohen's kappa tests. The presence of CABA was significantly positively correlated with the clinical outcomes of cats with azotemia only in the severe group ( p  = 0.0034, odds ratio = 8.57). There was no association between CABA and clinical outcomes in cats with mild azotemia ( p  = 0.75). CABA can be used for clinical outcome prediction in moderate and severe feline azotemia, with a sensitivity of 80.8% and a specificity of 73.9%. Also, satisfactory intra- and inter-observer agreements were revealed in the detection of CABA during ultrasound image review. Our study demonstrated that cats with moderate and severe azotemia with CABA observed during ultrasonography might have better clinical outcomes. These findings provide additional information on the prognosis and treatment of feline azotemia.

Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4, the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor., (©2024 American Association for Cancer Research.)

This study examines diatom assemblages in the Matsu Archipelago, an area influenced by Minjiang River runoff. It focuses on harmful algal blooms (HABs) that occurred between August 2021 and July 2022. Utilizing 18S rRNA metabarcoding and microscopic analysis, we observed a significant diatom bloom during early summer runoff, peaking at 5 × 10 5 cells L -1 . The research reveals dynamic community changes during the runoff season, with dominant genera including Pseudo-nitzschia, Chaetoceros, and Skeletonema. Skeletonema cell density correlated with NO 3 levels, Chaetoceros had a slight PO 4 affinity, and Pseudo-nitzschia showed a negative correlation with Skeletonema. Pseudo-nitzschia, which prefers high light and pH conditions, had notably high concentrations in the flood season and in the autumn. In both, it was dominated by potential toxin-producing species - P. multistriata and P. pungens during the flooding, and P. cuspidate in the autumn. These findings highlight the intricate relationship between diatom dynamics and environmental factors, providing essential insights for managing HABs, especially Pseudo-nitzschia species, amidst environmental changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear., Methods: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance., Results: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively., Conclusion: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors., (© 2024 Wiley Periodicals LLC.)

Auxin response transcription factors (ARFs) form a large gene family, many of whose members operate at the final step of the auxin signaling pathway. ARFs participate directly in many aspects of plant growth and development. Here we summarize recent advances in understanding the roles of ARFs in regulating aspects of fleshy fruit development and ripening. ARFs play a crucial role in regulating fruit size, color, nutrients, texture, yield, and other properties that ultimately influence the ripening and quality of important crops such as tomato, apple, strawberry, and peach. ARFs impact these processes acting as positive, negative, or bidirectional regulators via phytohormone-dependent or -independent mechanisms. In the phytohormone-dependent pathway, ARFs act as a central hub linking interactions with multiple phytohormones generating diverse effects. The three domains within ARFs, namely the DNA-binding domain, the middle region, and the carboxy-terminal dimerization domain, exhibit distinct yet overlapping functions, contributing to a range of mechanisms mediated by ARFs. These findings not only provide a profound understanding of ARF functions, but also raise new questions. Further exploration can lead to a more comprehensive understanding of the regulatory mechanisms of fleshy fruit development and ripening mediated by ARFs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Phosphorus (P) plays an important role in immobilizing heavy metals (HMs), thereby preventing their accumulation, especially in edible parts of crops. In this study, vermicompost (VM) and chemical fertilizers (CFs) were used as soil amendments to increase the available P concentration in soil contaminated with cadmium (Cd) and nickel (Ni), with the aim of reducing their bioavailability, uptake, and bioaccessibility. Using CF and VM as soil amendments substantially increased the available P and exchangeable potassium concentrations in the soil. Furthermore, VM addition led to an increase in OM content and in exchangeable calcium and magnesium, resulting in the improved growth of lettuce. It also reduced the uptake of Cd and Ni in the two lettuce cultivars tested in the study. However, CF addition boosted the accumulation of Cd and Ni by increasing the soil acidity. CF addition, and especially VM addition, altered the chemical forms of Cd and Ni from active to inactive. Overall, the results of this study underscore the positive impact of using VM as a soil amendment on lettuce growth and the prevention of HM accumulation in edible parts of lettuce. VM addition led to decreased bioavailability, uptake, and bioaccessibility of HMs in soil, which could improve food safety and reduce potential risks associated with HM contamination., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Vascular dementia (VaD) is a cognitive disorder characterized by a decline in cognitive function resulting from cerebrovascular disease. The hippocampus is particularly susceptible to ischemic insults, leading to memory deficits in VaD. Astaxanthin (AST) has shown potential therapeutic effects in neurodegenerative diseases. However, the mechanisms underlying its protective effects in VaD and against hippocampal neuronal death remain unclear. In this study, We used the bilateral common carotid artery occlusion (BCCAO) method to establish a chronic cerebral hypoperfusion (CCH) rat model of VaD and administered a gastric infusion of AST at 25 mg/kg per day for 4 weeks to explore its therapeutic effects. Memory impairments were assessed using Y-maze and Morris water maze tests. We also performed biochemical analyses to evaluate levels of hippocampal neuronal death and apoptosis-related proteins, as well as the impact of astaxanthin on the PI3K/Akt/mTOR pathway and oxidative stress. Our results demonstrated that AST significantly rescued memory impairments in VaD rats. Furthermore, astaxanthin treatment protected against hippocampal neuronal death and attenuated apoptosis. We also observed that AST modulated the PI3K/Akt/mTOR pathway, suggesting its involvement in promoting neuronal survival and synaptic plasticity. Additionally, AST exhibited antioxidant properties, mitigating oxidative stress in the hippocampus. These findings provide valuable insights into the potential therapeutic effects of AST in VaD. By elucidating the mechanisms underlying the actions of AST, this study highlights the importance of protecting hippocampal neurons and suggests potential targets for intervention in VaD. There are still some unanswered questions include long-term effects and optimal dosage of the use in human. Further research is warranted to fully understand the therapeutic potential of AST and its application in the clinical treatment of VaD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)