bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficient Chaperone-Mediated Autophagy Promotes Inflammation and Atherosclerosis
Authors: Qiao Lei , Ma Jing , Zhang Zihao , Sui Wenhai , Zhai Chungang , Xu Dan , Wang Zunzhe , Lu Huixia , Zhang Meng , Zhang Cheng , Chen Wenqiang , Zhang Yun 
Published: October 2021

Rationale:
The NLRP3 (NLR [NOD-like receptor] family, pyrin domain containing 3) inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy (CMA), one of the main lysosomal degradative process, has a regulatory role in lipid metabolism of macrophages. However, whether the NLRP3 inflammasome is regulated by CMA, and the role of CMA in atherosclerosis remains unclear.

Objective:
To determine the role of CMA in the regulation of NLRP3 inflammasome and atherosclerosis.

Methods and Results:

The expression of CMA marker, LAMP-2A (lysosome-associated membrane protein type 2A), was first analyzed in ApoE
−/−
mouse aortas and human coronary atherosclerotic plaques, and a significant downregulation of LAMP-2A in advanced atherosclerosis in both mice and humans was observed. To selectively block CMA, we generated macrophage-specific conditional LAMP-2A knockout mouse strains in C57BL/6 mice and ApoE
−/−
mice. Deletion of macrophage LAMP-2A accelerated atherosclerotic lesion formation in the aortic root and the whole aorta in ApoE
−/−
mice. Mechanistically, LAMP-2A deficiency promoted NLRP3 inflammasome activation and subsequent release of mature IL (interleukin)-1β in macrophages and atherosclerotic plaques. Furthermore, gain-of-function studies verified that restoration of LAMP-2A levels in LAMP-2A–deficient macrophages greatly attenuated NLRP3 inflammasome activation. Importantly, we identified the NLRP3 protein as a CMA substrate and demonstrated that LAMP-2A deficiency did not affect the NLRP3 mRNA levels but hindered degradation of the NLRP3 protein through CMA pathway.

Conclusions:
CMA function becomes impaired during the progression of atherosclerosis, which increases NLRP3 inflammasome activation and secretion of IL-1β, promoting vascular inflammation and atherosclerosis progression. Our study unveils a new mechanism by which NLRP3 inflammasome is regulated in macrophages and atherosclerosis, thus providing a new insight into the role of autophagy-lysosomal pathway in atherosclerosis. Pharmacological activation of CMA may provide a novel therapeutic strategy for atherosclerosis and other NLRP3 inflammasome/IL-1β–driven diseases.
FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes
Authors: Jeong Kyuho , Murphy James M. , Kim Jung-Hyun , Campbell Pamela Moore , Park Hyeonsoo , Rodriguez Yelitza A.R. , Choi Chung-Sik , Kim Jun-Sub , Park Sangwon , Kim Hyun Joon , Scammell Jonathan G. , Weber David S. , Honkanen Richard E. , Schlaepfer David D. , Ahn Eun-Young Erin , Lim Ssang-Taek Steve 
Published: October 2021

Rationale:
Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions.

Objective:
Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated.

Methods and Results:
Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression.

Conclusions:
This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.
Parts and Wholes in Scene Processing
Authors: Kaiser Daniel , Cichy Radoslaw M. 
Published: October 2021

AbstractDuring natural vision, our brains are constantly exposed to complex, but regularly structured, environments. Real-world scenes are defined by typical part–whole relationships, where the meaning of the whole scene emerges from configurations of localized information present in individual parts of the scene. Such typical part–whole relationships suggest that information from individual scene parts is not processed independently, but that there are mutual influences between the parts and the whole during scene analysis. Here, we review recent research that used a straightforward, but effective approach to study such mutual influences: By dissecting scenes into multiple arbitrary pieces, these studies provide new insights into how the processing of whole scenes is shaped by their constituent parts and, conversely, how the processing of individual parts is determined by their role within the whole scene. We highlight three facets of this research: First, we discuss studies demonstrating that the spatial configuration of multiple scene parts has a profound impact on the neural processing of the whole scene. Second, we review work showing that cortical responses to individual scene parts are shaped by the context in which these parts typically appear within the environment. Third, we discuss studies demonstrating that missing scene parts are interpolated from the surrounding scene context. Bridging these findings, we argue that efficient scene processing relies on an active use of the scene's part–whole structure, where the visual brain matches scene inputs with internal models of what the world should look like.
Two new species, Ophiopogon dolichocaulis and O. trigonantherus (Asparagaceae), from northern Vietnam
Authors: NGUYEN KHANG SINH , TANAKA NORIYUKI , AVERYANOV LEONID V. , MAISAK TATIANA V. , NGUYEN PHUONG HANH , TRAN DUC BINH 
Published: October 2021

Two new species of Ophiopogon, O. dolichocaulis from Son La Province and O. trigonantherus from Cao Bang Province in northern Vietnam, are described and illustrated. The former is similar to O. chingii, while the latter is similar to O. rupestris and O. dracaenoides. This paper not only details their taxonomic features and relationships to similar species but also provides ecological data on their habitats and phenology.
Quantifying the Human Influence on the Intensity of Extreme 1- and 5-Day Precipitation Amounts at Global, Continental, and Regional Scales
Authors: Sun Qiaohong , Zwiers Francis , Zhang Xuebin , Yan Jun 
Published: October 2021

Abstract
This study provides a comprehensive analysis of the human contribution to the observed intensification of precipitation extremes at different spatial scales. We consider the annual maxima of the logarithm of 1-day (Rx1day) and 5-day (Rx5day) precipitation amounts for 1950–2014 over the global land area, four continents, and several regions, and compare observed changes with expected responses to external forcings as simulated by CanESM2 in a large-ensemble experiment and by multiple models from phase 6 of the Coupled Model Intercomparison Project (CMIP6). We use a novel detection and attribution analysis method that is applied directly to station data in the areas considered without prior processing such as gridding, spatial or temporal dimension reduction, or transformation to unitless indices and uses climate models only to obtain estimates of the space–time pattern of extreme precipitation response to external forcing. The influence of anthropogenic forcings on extreme precipitation is detected over the global land area, three continental regions (the western Northern Hemisphere, western Eurasia, and eastern Eurasia), and many smaller IPCC regions, including central North America, East Asia, east-central Asia, eastern Europe, eastern North America, northern Europe, and western Siberia for Rx1day, and central North America, eastern Europe, eastern North America, northern Europe, the Russian Arctic region, and western Siberia for Rx5day. Consistent results are obtained using forcing response estimates from either CanESM2 or CMIP6. Anthropogenic influence is estimated to have substantially decreased the approximate waiting time between extreme annual maximum events in regions where anthropogenic influence has been detected, which has important implications for infrastructure design and climate change adaptation policy.
Significance Statement
All previous detection and attribution studies of observed changes in extreme precipitation (i) use station data that has been heavily processed via gridding, transformation, and spatial and temporal averaging or other dimension reduction approaches, as well as using climate models to estimate the responses to external forcing, and (ii) also use models to estimate the unforced natural variability of extreme precipitation. Both aspects reduce user confidence in detection and attribution results. This study uses station data directly and avoids difficult to verify model-based estimates of the unforced variability of precipitation extremes. Results confirm findings from previous studies, and extend them to a number of subcontinental regions, thus substantially increasing confidence in detection and attribution findings precipitation.
Energy Transfers between Multidecadal and Turbulent Variability
Authors: Hochet Antoine , Huck Thierry , Arzel Olivier , Sévellec Florian , Verdière Alain Colin de 
Published: October 2021

Abstract
One of the proposed mechanisms to explain the multidecadal variability observed in sea surface temperature of the North Atlantic Ocean consists of a large-scale low-frequency internal mode spontaneously developing because of the large-scale baroclinic instability of the time-mean circulation. Even though this mode has been extensively studied in terms of the buoyancy variance budget, its energetic properties remain poorly known. Here we perform the full mechanical energy budget including available potential energy (APE) and kinetic energy (KE) of this internal mode and decompose the budget into three frequency bands: mean, low frequency (LF) associated with the large-scale mode, and high frequency (HF) associated with mesoscale eddy turbulence. This decomposition allows us to diagnose the energy fluxes between the different reservoirs and to understand the sources and sinks. Because of the large scale of the mode, most of its energy is contained in the APE. In our configuration, the only source of LF APE is the transfer from mean APE to LF APE that is attributed to the large-scale baroclinic instability. In return the sinks of LF APE are the parameterized diffusion, the flux toward HF APE, and, to a much lesser extent, the flux toward LF KE. The presence of an additional wind stress component weakens multidecadal oscillations and modifies the energy fluxes between the different energy reservoirs. The KE transfer appears to only have a minor influence on the multidecadal mode relative to the other energy sources involving APE, in all experiments. These results highlight the utility of the full APE–KE budget.
Dignity as a Constitutional Value: Abortion, Political Communication and Proportionality
Authors: Henckels Caroline , Sifris Ronli , Penovic Tania 
Published: October 2021

AbstractThis article examines the High Court of Australia’s treatment of the concept of dignity as both a value animating the implied freedom of political communication and as a legitimate reason to limit the exercise of that freedom. It does so through the lens of Clubb v Edwards, Preston v Avery, where the Court found that laws establishing safe access zones around abortion clinics were compatible with the implied freedom. The use of dignity as a prism through which to view the interests at stake in both abortion and speech cases is a familiar feature of developments abroad, and the Court has laid the foundations for recognition of dignity as one of the axiological bases of the implied freedom in a manner that generally emphasises individual autonomy over other conceptions of dignity that might be described as operating as a constraint on behaviour to protect other interests. Yet, while the Court has used dignity as the common measure with which to commensurate competing claims, it has yet to convincingly address concerns regarding incommensurability that attend the balancing stage of proportionality review, not to mention the potential objection that its reliance on dignity is not properly grounded in the text and structure of the Constitution. In light of these issues, the role of dignity ought to be tethered to its central role in facilitating political participation so as to more clearly link the concept to the text and structure of the Constitution, and to identify what is at stake when women’s ability to access reproductive health care is impaired or denied.
Distribution Characteristics of Juvenile-Onset Recurrent Respiratory Papillomatosis at First-Time Surgery
Authors: Qu Xiaoli , Xiao Yang , Ma Lijing , Wang Jun 
Published: October 2021

Objectives The lesion distribution of juvenile-onset recurrent respiratory papillomatosis (JORRP) during first-time surgery has been rarely reported. The purpose of this study was to describe the anatomical distribution of papilloma across 25 Derkay sites during initial surgery and to assess the impact of the lesion distribution on disease severity. Methods Surgical videos and medical records of 106 patients with JORRP (27 aggressive and 79 nonaggressive cases) were retrospectively reviewed. Lesion locations were recorded using Derkay anatomical sites. Logistic regression was used to analyze the effect of the lesion distribution on disease severity. Results Among the 106 patients, the true vocal cords (90.6% left, 84.0% right) were the most frequently involved site, followed by the false vocal cords (39.6% left, 35.8% right) and the anterior commissure (26.4%). Two patients (1.9%) had tracheal involvement. Patients with false vocal cord involvement (odds ratio [OR] = 3.425, 95% confidence interval [CI] [1.285, 9.132], P = .014) and a younger age at diagnosis (OR = .698, 95% CI [.539, .905], P = .007) were more likely to require more than 4 procedures in the year following first-time surgery. Conclusions Lesions were most common on the true vocal cords. False vocal cord involvement and a younger age at diagnosis were risk factors for disease severity.
Scientific and Regulatory Policy Committee Points to Consider: Biological Sample Retention From Nonclinical Toxicity Studies
Authors: Harbison Carole E. , Aulbach Adam D. , Bennet Bindu M. , Boyle Molly H. , Carsillo Mary E. , Crabbs Torrie A. , Keirstead Natalie D. , La Perle Krista M. D. , Pandiri Arun R. , Shoieb Ahmed M. , Siska William D. 
Published: October 2021

Samples of biologic specimens and their derivatives (eg, wet tissues, paraffin-embedded tissue blocks, histology slides, frozen tissues, whole blood, serum/plasma, and urine) are routinely collected during the course of nonclinical toxicity studies. Good Laboratory Practice regulations and/or guidance specify minimum requirements for specimen retention duration, with the caveat that retention of biologic specimens need not extend beyond the duration of sample stability. However, limited availability of published data regarding stability for various purposes following storage of each specimen type has resulted in confusion, uncertainty, and inconsistency as to the appropriate duration for storage of these specimens. To address these issues, a working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee was formed to review published information, regulations, and guidance pertinent to this topic and to summarize the current practices and rationales for retention duration through a survey-based approach. Information regarding experiences reaccessing biologic specimens and performing sample stability investigations was also collected. Based on this combined information, the working group developed several points to consider that may be referenced when developing or revising sample retention practices. [Box: see text]
Effects of 31 recombinant CYP2C19 variants on clomipramine metabolism in vitro
Authors: Lan Tian , Ma Ya-Qing , Dang Ya-Min , Wang Chen-Chen , Xu Ren-Ai , Cai Jian-Ping , Hu Guo-Xin 
Published: October 2021

Background: CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31CYP2C19 alleles in the Han Chinese population; studying the effects of CYP2C19 on drug metabolism can help reduce adverse drug reactions and therapeutic failure. Aim: The aim of this study was to assess the catalytic activities of 31 allelic isoforms and their effects on the metabolism of clomipramine in vitro. Methods: The wild-type and 30 CYP2C19 variants were expressed in insect cells, and each variant was characterized using clomipramine as the substrate. Reactions were performed at 37°C with 5–150 μmol/L substrate for 30 min. By using ultra-high-performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl clomipramine were determined. Results: Among the CYP2C19 variants tested, CYP2C19*29, L16F, and T130M showed extremely increased intrinsic clearance of clomipramine, CYP2C19*3C, and N277K showed similar intrinsic clearance (Vmax/Km) values with CYP2C19*1, while the intrinsic clearance values of other variants were significantly decreased (from 0.65% to 63.28%). In addition, CYP2C19*3 and 35FS could not be detected because they have no detectable enzyme activity. Conclusions: As the first report of 31 CYP2C19 alleles for clomipramine metabolism, our study could provide corresponding reference for clomipramine for further studies in vivo and offer valuable information relevant to the personalized medicine for CYP2C19-metabolized drug.
Functional improvement of bilateral frozen shoulder by unilateral intra-articular corticosteroid injection: a retrospective study
Authors: Kim Minchul , Kim Ki-Yong , Huh Yool-Gang , Ma Sang Hyeok , Jeong Kil-Yong , Yoon Seung-Hyun 
Published: October 2021

Objective Bilateral frozen shoulder (FS) is often treated with intra-articular corticosteroid injection (IACI). No studies have been performed to establish whether IACI must be administered in both shoulders or in only one shoulder to improve function. This study was therefore performed to determine whether unilateral IACI improves shoulder pain and passive range of motion (pROM) in bilateral FS. Methods The medical records of 165 patients with bilateral primary FS who underwent ultrasonography-guided IACI (2 mL of 10-mg/mL triamcinolone acetonide mixed with 5 mL of 1% lidocaine) in one shoulder were retrospectively reviewed. The outcome measures, namely the numeric rating scale (NRS) scores and pROM values (abduction, external rotation, flexion, hyperextension, and internal rotation), were evaluated pre- and post-injection. Results The patients’ mean age was 54.0 ± 8.0 years. The mean symptom duration was 6.5 ± 2.8 months. The mean follow-up period after injection was 6.7 ± 0.8 weeks. The NRS scores and pROM values significantly improved in both the injected and non-injected shoulders. Conclusions This study showed that unilateral IACI in patients with bilateral FS improves the clinical outcome of the non-injected shoulder. We suggest that physicians observe the non-injected shoulder after unilateral injection rather than performing bilateral injections.
Experimental infection of cats with Cryptosporidium felis
Authors: Scorza Andrea V , Tyrrell Phyllis , Wennogle Sara , Chandrashekar Ramaswamy , Lappin Michael R 
Published: October 2021

Objectives The aims of this study were to experimentally inoculate cats with Cryptosporidium felis oocysts and compare fecal detection by fluorescent antibody assay (FA) and quantitative PCR (qPCR), and document clinical signs associated with infection. Methods Cryptosporidium felis oocysts were concentrated from the feces of a naturally infected cat and orally inoculated into six cats that tested negative for C felis by an FA and fecal flotation (FF). Cats were observed daily for the presence of clinical signs consistent with infection. Fecal samples from all cats on days 0 and 9, and one sample per cat (days 18–21), were evaluated by all assays. On day 31, two cats negative for C felis by FF and FA were administered methylprednisolone acetate and all assays were repeated on days 34, 36 and 38. Samples from all cats were tested by FF and FA on days 41, 43, 45 and 48. Results A total of 41 samples were tested, 25 of which were compared by FA and qPCR. Cryptosporidium felis was detected in 2/25 (8%) and in 19/25 (76%) samples by FA and by qPCR, respectively; the other 16 samples were tested by FF and FA. None of the cats was positive for C felis by FF or FA in samples collected on days 0, 9 or 18–21. One, five and six samples tested positive by qPCR on days 0, 9 and 18–21, respectively. The cats administered methylprednisolone acetate tested positive for C felis by FA on day 36 and by qPCR on days 31, 34, 36 and 38. None of the cats showed clinical signs of disease. Conclusions and relevance Clinical signs were not recognized in any of the cats for the duration of the study. FA was insensitive compared with qPCR for detecting cats with subclinical C felis infection.