Fibrosing colonopathy is a unique pathology characterized by long segment stricture, usually of the ileocecal region. Historically, it is most commonly described in patients with cystic fibrosis (CF). Fibrosing colonopathy is felt to be secondary to excessive doses of exogenous lipase medication. This condition is rarely seen in the last decade. In this case presentation, fibrosing colonopathy was identified in a patient with the lysosomal storage disorder of cystinosis. Fibrosing colonopathy has not previously been described in patients with cystinosis. The patient was found to have fibrosing colonopathy after perforation of the colon during a colonoscopy for bloody diarrhea. This case report aims to draw attention to a noteworthy case of fibrosing colonopathy in a patient who does not have cystic fibrosis, but rather cystinosis.
Backgrounds: Adenoidectomy is widely used to cure sleep-disordered breathing symptoms in children, torus tubarius hypertrophy (TTH) after adenoidectomy causing recurred snoring, sleep apnea, nasal obstruction, or mouth breathing was rarely reported, and the causes of TTH are still unclear. Objectives: To report a rare complication TTH after adenoidectomy, and the features of TTH. Material and Methods: A total of 36 pediatric patients with TTH diagnosed by our hospital from January 2017 to 2023 were included in this study. All children were treated conservatively for a month at first, and 13 patients underwent partial resection of TTH. The influencing factors (sex, age, allergic rhinitis [AR], and first operation way) were analyzed. Results: There were 36 patients with TTH: 27 boys and 9 girls. The age of the first operation ranged from 20 to 63 months, and the interval time of TTH after operation ranged from 3 to 55 months. Thirteen patients underwent partial resection of TTH. Thirteen children had definite symptoms and signs of AR. Conclusions and Significance: TTH is a rare complication after adenoidectomy, which is common in male children (75.0%) and in patients who took adenoidectomy before the age of 5 years (94.4%). TTH can occur as early as 3 months after adenoidectomy. AR and the operation way might have relationships with TTH.
This study focuses on maternal antibody transfer following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before or during early pregnancy and its potential protective effects on infants, providing scientific evidence for vaccination strategies. This prospective study tested the samples for SARS-CoV-2 IgG antibody titers and neutralizing capacity and tracked the infections after birth. Perform multivariate analysis of factors influencing antibody transfer rate, newborn antibody titers, and infant infection. Total 87.1% (122/140) women received coronavirus disease 2019 (COVID-19) vaccine before or during early pregnancy, and 28 of them had breakthrough infection. The maternal and neonatal IgG positive rates at delivery were 60.7% (85/140) and 60.8% (87/143), respectively. A positive correlation was found between neonatal and maternal IgG antibody titers. Compared with the median IgG antibody transfer rate of infected pregnant women, that of vaccinated but not infected pregnant women was higher (1.21 versus: 1.53 [two doses], 1.71 [three doses]). However, neonatal IgG antibodies were relatively low (174.91 versus: 0.99 [two doses], 8.18 [three doses]), and their neutralizing capacity was weak. The overall effectiveness of maternal vaccination in preventing infant infection was 27.0%, and three doses had higher effectiveness than two doses (64.3% vs. 19.6%). Multivariate analysises showed that in vaccination group women receiving three doses or in infection group women with longer interval between infection and delivery had a higher antibody transfer rate and neonatal IgG antibody titer. More than half of women vaccinated before or during early pregnancy can achieve effective antibody transfer to newborns. However, the neonatal IgG antibody titer is low and has a weak neutralizing capacity, providing limited protection to infants.
Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient.
Ohm, Daniel T; Rhodes, Emma; Bahena, Alejandra; Capp, Noah; Lowe, MaKayla; Sabatini, Philip; Trotman, Winifred; Olm, Christopher A; Phillips, Jeffrey; Prabhakaran, Karthik; Rascovsky, Katya; Massimo, Lauren; McMillan, Corey; Gee, James; Tisdall, M Dylan; Yushkevich, Paul A; Lee, Edward B; Grossman, Murray; Irwin, David J;
ABSTRACT
Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.
SCOPE Vitamin D deficiency (VDD) is becoming a global issue and low 25-hydroxyvitamin D (25(OH)D) plasma levels have been linked to hepatic steatosis in adulthood. Nevertheless, the impact of maternal VDD on lipid metabolism and hepatic steatosis remains poorly documented, especially under obesogenic condition. The goal of this study is to assess the effects of maternal VDD on hepatic lipid accumulation in adult offspring fed a normal or obesogenic diet.METHODS AND RESULTS Several approaches are implemented including histology and lipidomics on the liver in both males and females. No major impact of high-fat (HF) or VDD is observed at histological level in both males and females. Nevertheless, in males born from VDD mice and fed an HF diet, an increase of total lipids and modulation of the relative lipid species distribution characterized by a decrease of triglycerides and increase of phospholipids is observed. In female no major lipid profile is noticed.CONCLUSION Maternal VDD combined with a HF diet in male may predispose to hepatic hypertrophia, with a specific lipid profile. Such observations reinforce our knowledge of the impact of maternal VDD on hepatic programming in the offspring.
Journal of digestive diseases, 2023 5 21, 24(3): 213-223
AMPK activation alleviated dextran sulfate sodium-induced colitis by inhibiting ferroptosis.
Sun, Shao Peng; Lu, Yi Fan; Li, Heng; Weng, Chun Yan; Chen, Jia Jia; Lou, Yi Jie; Lyu, Dong; Lyu, Bin;
ABSTRACT
OBJECTIVES Ferroptosis is a newly discovered cell death mode that has been confirmed to occur in the intestinal epithelial cells in ulcerative colitis (UC). In this study we aimed to elucidate the mechanism of ferroptosis and its association with adenosine monophosphate-activated protein kinase (AMPK) in UC.METHODS Gene expression profiles of colonic mucosa (GSE87473) were downloaded. Both human colonic samples and dextran sodium sulfate (DSS)-induced colitis murine model were used. The molecular markers of ferroptosis were detected using western blot and immunohistochemistry. Symptoms, iron abundance, and lipid peroxidation level of the mouse model were measured to evaluate the role of AMPK activation in ferroptosis.RESULTS Both gene and protein expressions of GPX4 and FTH1 were decreased in UC patients compared with the healthy controls. An increased iron abundance and lipid peroxidation level in colon tissues and damaged mitochondria were found in DSS-induced colitis. AMPK expression was decreased in UC patients and correlated with FTH1 and GPX4. Activation of AMPK with metformin inhibited ferroptosis in the colon, improved symptoms, and prolonged the lifespan in DSS-induced colitis mice.CONCLUSIONS Ferroptosis can be observed in colonic tissues in UC. AMPK activation inhibits ferroptosis in murine colitis model, which may act as a potential target for the treatment of colitis.
PURPOSE Prefrail and frail geriatric patients are at high risk of falling. Perturbation-based balance training on a treadmill appears to be highly effective, but there are no studies in prefrail and frail geriatric hospital patients. The aim of the work is to characterize the study population in whom reactive balance training on a perturbation treadmill was feasible.METHODS The study is recruiting patients with at least one fall event in the past year (age ? 70). The patients complete a minimum of 60-min treadmill training with/without perturbations on at least 4 occasions.RESULTS Until now, 80 patients (mean age 80 ? 5) took part in the study. More than half of the participants had some cognitive impairment with < 24 pts. (median MoCA 21 pts.), 35% were prefrail and 61% were frail. The drop-out rate was initially 31% and was reduced to 12% after adding a short pre-test on the treadmill.CONCLUSION Reactive balance training on a perturbation treadmill is feasible for prefrail and frail geriatric patients. Its effectiveness in fall prevention in this population needs to be proven.TRIAL REGISTRATION German Clinical trial register (DRKS-ID: DRKS00024637 on 24.02.2021).
PURPOSE Fetal growth restriction (FGR) is a common complication characterized by impaired placental function and unfavorable pregnancy outcomes. This study aims to elucidate the expression pattern of miR-181d-5p in FGR placentas and explore its effects on trophoblast fusion.METHODS The expression pattern of miR-181d-5p in human FGR placentas were evaluated using qRT-PCR. Western blot, qRT-PCR, and Immunofluorescence analysis were performed in a Forskolin (FSK)-induced BeWo cell fusion model following the transfection of miR-181d-5p mimic or inhibitor. Potential target genes for miR-181d-5p were identified by screening miRNA databases. The interaction between miR-181d-5p and Luman/CREB3 Recruitment Factor (CREBRF) was determined through a luciferase assay. Moreover, the effect of CREBRF on BeWo cell fusion was examined under hypoxic conditions.RESULTS Aberrant up-regulation of miR-181d-5p and altered expression of trophoblast fusion makers, including glial cell missing 1 (GCM1), Syncytin1 (Syn1), and E-cadherin (ECAD), were found in human FGR placentas. A down-regulation of miR-181d-5p expression was observed in the FSK-induced BeWo cell fusion model. Transfection of the miR-181d-5p mimic resulted in the inhibition of BeWo cell fusion, characterized by a down-regulation of GCM1 and Syn1, accompanied by an up-regulation of ECAD. Conversely, the miR-181d-5p inhibitor promoted BeWo cell fusion. Furthermore, miR-181d-5p exhibited negative regulation of CREBRF, which was significantly down-regulated in the hypoxia-induced BeWo cell model. The overexpression of CREBRF was effectively ameliorated the impaired BeWo cell fusion induced by hypoxia.CONCLUSIONS Our study demonstrated that miR-181d-5p, which is elevated in FGR placenta, inhibited the BeWo cell fusion through negatively regulating the expression of CREBRF.
The loss of chalcogenide microstructured optical fibers (ChG-MOFs) is generally higher than that of step fibers, mainly due to the immature fiber preform preparation method and strong waveguide defect scattering. Chemical polishing is used to polish mechanically drilled preforms to prepare ChG-MOFs with low defect scattering. Firstly, the scattering loss caused by the defective layer of ChG-MOFs is studied theoretically and experimentally. Then, a single-mode photonic crystal fiber (PCF) was prepared to verify the effect of chemical polishing on reducing fiber loss. The experimental results show that the PCF average loss is reduced from more than 8 dB/m to less than 2 dB/m, and the minimum loss reaches 0.8 dB/m @ 2.7 ?m. At the same time, the bending strength of the PCF after chemical polishing is also significantly improved.
AMBA CUP: Ensuring Accuracy in Measurement of Volume of Water for Salt Sugar Solution or Oral Rehydration Solution Preparation in Diarrhea Management.
Etokidem, Aniekan Jumbo;
ABSTRACT
Diarrhea remains a major cause of under-five mortality globally. In 2016, it accounted for 8% of under-five mortality worldwide. Most of these deaths occur in developing countries. Fluid replacement using Oral Rehydration Solution (ORS) or Salt Sugar Solution (SSS), has been the mainstay of diarrhea management. Gaps in knowledge and practice regarding the preparation of these solutions have been identified by various researchers. One challenge encountered by healthcare providers and caregivers of under-five children has been lack of a standard, easy to clean cup for measurement of accurate volume of water for ORS or SSS preparation. Soft drink bottles, which are currently being used, are difficult to clean because of their narrow necks. More so, the size and volume of these bottles change so often that non-numerate caregivers get easily confused. The aim of this paper is to introduce the AMBA CUP, an easy-to-clean cup that can be used to accurately measure one litre of water for SSS or ORS preparation.
Hybrid FSK-FDM Scheme for Data Rate Enhancement in Dual-Function Radar and Communication.
Munir, Muhammad Fahad; Basit, Abdul; Khan, Wasim; Wasim, Athar; Khan, Muhammad Mohsin; Saleem, Ahmed; AlQahtani, Salman A; Daraz, Amil; Pathak, Pranavkumar;
ABSTRACT
In this paper, we present a hybrid frequency shift keying and frequency division multiplexing (i.e., FSK-FDM) approach for information embedding in dual-function radar and communication (DFRC) design to achieve an improved communication data rate. Since most of the existing works focus on merely two-bit transmission in each pulse repetition interval (PRI) using different amplitude modulation (AM)- and phased modulation (PM)-based techniques, this paper proposes a new technique that doubles the data rate by using a hybrid FSK-FDM technique. Note that the AM-based techniques are used when the communication receiver resides in the side lobe region of the radar. In contrast, the PM-based techniques perform better if the communication receiver is in the main lobe region. However, the proposed design facilitates the delivery of information bits to the communication receivers with an improved bit rate (BR) and bit error rate (BER) regardless of their locations in the radar's main lobe or side lobe regions. That is, the proposed scheme enables information encoding according to the transmitted waveforms and frequencies using FSK modulation. Next, the modulated symbols are added together to achieve a double data rate using the FDM technique. Finally, each transmitted composite symbol contains multiple FSK-modulated symbols, resulting in an increased data rate for the communication receiver. Numerous simulation results are presented to validate the effectiveness of the proposed technique.
The Saudi dental journal, 2023 7 31, 35(5): 498-507
A study to estimate tooth size discrepancy values specific to Saudi orthodontic patients: A systematic review and
meta
-analysis.
Alqahtani, Hamad;
ABSTRACT
OBJECTIVE This study aimed to establish intermaxillary tooth size ratios (overall index (OI) and anterior index (AI)) for normal occlusion and different Angle's malocclusions specific to the Saudi population and compare them to Bolton's values, which were specific to Americans.METHODS The Saudi Digital Library, PubMed, Web of Science, Cochrane Library, Scopus, and Embase were searched systematically to acquire articles which reported OI and AI for Saudi patients; inclusion and exclusion criteria were applied. Data, including author's name, publication year, city, measurement technique, number of subjects, type of occlusion, means, and standard deviations, were extracted and sorted. To assess the methodological quality of the included studies, The National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was utilized.RESULTS Of the 1473 articles, eight met the inclusion criteria and were included in the meta -analysis. Values for normal occlusion and Bolton's values were not significantly different. All malocclusion classes showed significant differences in the overall OI and AI values compared with Bolton's original values and values for normal occlusion, but they did not differ from each other. Gender showed an effect only on the OI ratio for Class III malocclusion.CONCLUSIONS Bolton's original values can be used in Saudi patients only with normal occlusion. For cases with any Angle's malocclusion, we recommend using an AI value of 79.08 (?3.4) for both genders. Classes I and II, regardless of gender, have the same OI value of 92.51 (?2.82). For Class III, values of 91.97 (?2.4) for females and 93.13 (?2.6) for males can be used.
13. PMID: 37620607
Journal Article
Review
Research Support, N.I.H., Extramural
NCBI pageFree PMC ArticleP F D C
RGD annotations:
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology, 2023 8 24, 31(3): 24
Consequences of gaining an extra chromosome.
Torres, Eduardo M;
ABSTRACT
Mistakes in chromosome segregation leading to aneuploidy are the primary cause of miscarriages in humans. Excluding sex chromosomes, viable aneuploidies in humans include trisomies of chromosomes 21, 18, or 13, which cause Down, Edwards, or Patau syndromes, respectively. While individuals with trisomy 18 or 13 die soon after birth, people with Down syndrome live to adulthood but have intellectual disabilities and are prone to multiple diseases. At the cellular level, mistakes in the segregation of a single chromosome leading to a cell losing a chromosome are lethal. In contrast, the cell that gains a chromosome can survive. Several studies support the hypothesis that gaining an extra copy of a chromosome causes gene-specific phenotypes and phenotypes independent of the identity of the genes encoded within that chromosome. The latter, referred to as aneuploidy-associated phenotypes, are the focus of this review. Among the conserved aneuploidy-associated phenotypes observed in yeast and human cells are lower viability, increased gene expression, increased protein synthesis and turnover, abnormal nuclear morphology, and altered metabolism. Notably, abnormal nuclear morphology of aneuploid cells is associated with increased metabolic demand for de novo synthesis of sphingolipids. These findings reveal important insights into the possible pathological role of aneuploidy in Down syndrome. Despite the adverse effects on cell physiology, aneuploidy is a hallmark of cancer cells. Understanding how aneuploidy affects cell physiology can reveal insights into the selective pressure that aneuploid cancer cells must overcome to support unlimited proliferation.
MeSH Terms: Humans; Down Syndrome; Sex Chromosomes; Aneuploidy; Trisomy; Chromosome Segregation;
BACKGROUND/AIM For predicting esophagogastric varices (EGV), the Virtual Baveno VII Consensus Workshop has proposed a combination of liver stiffness determination and platelet count measurement using a FibroScan?. However, that is not available at all institutions. The present study aimed to develop a simple method to predict development of EGV using only general blood examination results.MATERIALS/METHODS A total of 1090 hepatocellular carcinoma (HCC) patients were enrolled, after excluding 956 with major portal vein tumor thrombus (Vp3/Vp4) or without upper gastrointestinal endoscopy examination results available. Those with EGV (?grade F2) or a history of treatment for the condition were defined as positive for significant EGV, then clinical factors were retrospectively evaluated to determine indicators of occurrence.RESULTS Logistic multivariate analysis showed platelet count (?12 x104/?L) [odds ratio (OR) 3.79, P<0.001], mALBI grade 2a (OR 1.52, P=0.036), and mALBI 2b or 3 (OR 3.46, P<0.001) as significant predictive factors. Based on the OR values, platelet count (?12 x104/?L) and mALBI grade 2b/3 were each assigned 2 points and mALBI 2a was given 1 point, with the result termed Recommendation for EGV Screening (REGS) score. EGV occurrence was noted in 2.9% (9/311) of the patients with a REGS score 0, 11.0% (13/118) with a score 1, 19.3% (53/274) with a score 2, 29.5% (39/132) with a score 3, and 38.0% (97/255) with a score 4 (P<0.001).CONCLUSION The findings indicate that REGS score can provide useful predictive information for development of significant EGV without the need for special equipment such as a FibroScan?.
STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals.
INTRODUCTION Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the 'Statins for Reducing Events in the Elderly' (STAREE) primary prevention trial.METHODS Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure.ETHICS AND DISSEMINATION Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206.TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT05586750.
The impact of genetic risk for schizophrenia on eating disorder clinical presentations.
Zhang, Ruyue; Kuja-Halkola, Ralf; Borg, Stina; Lepp?, Virpi; Thornton, Laura M; Birgeg?rd, Andreas; Bulik, Cynthia M; Bergen, Sarah E;
ABSTRACT
A growing body of literature recognizes associations between eating disorders (EDs) and schizophrenia and suggests that familial liability to schizophrenia in individuals with anorexia nervosa (AN) reveals distinct patterns of clinical outcomes. To further investigate the influence of schizophrenia genetic liability among individuals with EDs, we evaluated the associations between schizophrenia polygenic risk scores (PRS) and clinical presentations of individuals with EDs including their overall health condition and ED-related symptoms. Using data from two previous studies of the genetics of EDs comprising 3,573 Anorexia Nervosa Genetics Initiative (ANGI) cases and 696 Binge Eating Genetics Initiative (BEGIN) cases born after 1973 and linked to the Swedish National Patient Register, we examined the association of schizophrenia PRS on ED clinical features, psychiatric comorbidities, and somatic and mental health burden. Among ANGI cases, higher schizophrenia PRS was statistically significantly associated with higher risk of major depressive disorder (MDD) measured by hazard ratio (HR) with 95% confidence interval (CI) (HR [95% CI]: 1.07 [1.02, 1.13]) and substance abuse disorder (SUD) (HR [95% CI]: 1.14 [1.03, 1.25]) after applying multiple testing correction. Additionally, higher schizophrenia PRS was associated with decreased clinical impairment assessment scores (-0.56, 95% CI: [-1.04, -0.08]) at the conventional significance level (p < 0.05). Further, in BEGIN cases, higher schizophrenia PRS was statistically significantly associated with earlier age at first ED symptom (-0.35 year, 95% CI: [-0.64, -0.06]), higher ED symptom scores (0.16, 95% CI: [0.04, 0.29]), higher risk of MDD (HR [95% CI]: 1.18 [1.04, 1.34]) and SUD (HR [95% CI]: 1.36 [1.07, 1.73]). Similar, but attenuated, patterns held in the subgroup of exclusively AN vs other eating disorder (OED) cases. These results suggest a similar pattern of influence of schizophrenia PRS for AN and OED cases in terms of psychiatric comorbidities, but a different pattern in terms of ED-related clinical features. The disparity of the effect of schizophrenia PRS on AN vs OED merits further investigation.
This paper sets out to discover more about the name 'Tarrant' whose ophthalmic paintings have regularly featured in ophthalmic textbooks over the past 50 years. Through a series of telephone calls, I have spoken to Tarrant about his life and work while I research the origins of ophthalmic illustrations charting the story behind this art movement. The paper also explores the eventual decline of retinal painting and the emergence of photography, concluding that due to the continuing advance of technology the ophthalmic photographer may eventually succumb to the same fate as the artist.
To overcome the influence of the daytime skylight background on long-distance optical detection, a new type of shearing interference detection system was proposed to improve the detection performance of the traditional detection system for finding dark objects such as dim stars during the daytime. This article focuses on the basic principle and mathematical model as well as the simulation and experimental research of the new type of shearing interference detection system. The comparison of the detection performance between this new-type detection system and the traditional system is also carried out in this article. The experimental results show that the detection performance of the new type of shearing interference detection system is significantly better than that of the traditional system, and the image signal-to-noise ratio of this new-type system (about 13.2) is much higher than that of the best result of the traditional detection system (about 5.1).
What's so hard about hierarchical control? Pinpointing processing constraints within cue-based and serial-order control structures.
Moss, Melissa E; Mayr, Ulrich;
ABSTRACT
Most task spaces require a hierarchical structure, where decisions on one level are contingent on previous decisions made on one or more higher levels. While it is a truism that increasing the number of hierarchical levels makes it harder to solve a given task, the exact nature of this "number-of-levels" effect is not clear. On the one hand, processing costs might be strictly "local," incurred only when higher-level settings need to be updated, while otherwise lower-level decisions are insulated from the presence of higher-level settings (local updating costs with ballistic control). On the other hand, maintaining and integrating more complex hierarchical structures could require overall greater representational resources, negatively affecting each individual decision within the represented task space (global integration/maintenance costs). Further, navigation through hierarchical structures can be guided either through prompts in the environment (cue-based), or through sequential plans (serial-order based), with potentially distinct maintenance and updating demands. In two experiments, we assessed performance as a function of hierarchical level and format (serial-order vs. cue-based). Model comparisons showed that the pattern of costs in the serial-order format was consistent with a global maintenance/integration account. In contrast, in the cue-based format, costs arose at updating points and when one additional relevant level beyond the current decision was relevant, while additional levels produced no further costs. This overall constellation of costs can be explained by assuming that each decision requires checking the immediately relevant higher-level context for that decision. For cue-based control, this context involves the "next-level-up" rule, whereas in the serial-order format, each trial requires updating of the current position within the sequence, which in turn requires integration across all relevant hierarchical levels.
Peroxisome proliferator-activated receptor ? (PPAR?) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPAR? agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPAR? agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPAR? activity and subtype selectivity. This led to the discovery of 21 having strong PPAR? agonist activity (EC 50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.