Iz Liburnije i Kastavštine potekli su brojni vrijedni ljudi koje je životni put odveo daleko od rodnog kraja da bi u nekim novim sredinama stvarali uspješne karijere o kojima se u njihovu zavičaju ...gotovo ništa ne zna. O dvjema takvim osobama, liječnicima istog imena i prezimena, autor je proveo detaljna rodoslovna istraživanja i prikupio mnoštvo podataka koji su rezultirali ovdje prikazanim biografijama kako bi se s njima upoznala šira javnost u njihovu rodnom kraju.
Many hardworking people came from the area of Kastav and Liburnia, whose life journey took them far from their native land and who created successful careers in some new environments, about which almost nothing is known in their homeland. Autor has conducted detailed genealogical research about two such people, two doctors with the same first and last name, and collected a lot of data presented in the biographies so that the public in their native region could get to know them.
The low ability of students to understand and transform the concept of reflection to solve everyday problems is the main problem with learning mathematics because the implementation of learning ...mathematics is mechanical. Mathematics is taught by conveying formulas practically without linking them to students' daily activities. For this reason, this study aims to design a reflection learning trajectory in the context of the Lipa Sabbe Bunga Caramming motif as a starting point in learning to help students understand reflection material for solving everyday problems. The method used in this study is design research, which consists of three stages: preliminary design, design trials, and retrospective analysis. The subjects of this study were 23 students in class VIII-A of SMP Negeri 1 Tanasitolo. The instruments used in this study were student activity sheets (LAS), learning achievement tests, and interview guidelines. Student activity data during learning were analyzed retrospectively, and learning outcomes data were analyzed descriptively. The results of this study found that the learning trajectory of transformation geometry using the context of the lipa sabbe bunga caramming motif has four learning stages: (1) informal; (2) modes of; (3) modes of; and (4) formal. The learning stages can easily increase students' understanding of the concept of reflection. In the learning process, mathematical concepts are connected with daily habits, so students are enthusiastic and active in the learning process. This learning trajectory can assist teachers in optimizing learning so that students can easily understand the concept of reflection, equip them with critical thinking skills, and shape their character (cooperation, empathy, respect for others, awareness of social problems, a social spirit, and responsibility).
The lysosome is an acid organelle that contains a variety of hydrolytic enzymes and plays a significant role in intracellular degradation to maintain cellular homeostasis. Genetic variants in ...lysosome-related genes can lead to severe congenital diseases, such as lysosomal storage diseases. In the present study, we investigated the impact of depleting lysosomal acid lipase A (LIPA), a lysosomal esterase that metabolizes esterified cholesterol or triglyceride, on lysosomal function. Under nutrient-rich conditions, LIPA gene KO (LIPAKO) cells exhibited impaired autophagy, whereas, under starved conditions, they showed normal autophagy. The cause underlying the differential autophagic activity was increased sensitivity of LIPAKO cells to ammonia, which was produced from l-glutamine in the medium. Further investigation revealed that ammonia did not affect upstream signals involved in autophagy induction, autophagosome–lysosome fusion, and hydrolytic enzyme activities in LIPAKO cells. On the other hand, LIPAKO cells showed defective lysosomal acidity upon ammonia loading. Microscopic analyses revealed that lysosomes of LIPAKO cells enlarged, whereas the amount of lysosomal proton pump V-ATPase did not proportionally increase. Since the enlargement of lysosomes in LIPAKO cells was not normalized under starved conditions, this is the primary change that occurred in the LIPAKO cells, and autophagy was affected by impaired lysosomal function under the specific conditions. These findings expand our comprehension of the pathogenesis of Wolman's disease, which is caused by a defect in the LIPA gene, and suggest that conditions, such as hyperlipidemia, may easily disrupt lysosomal functions.
This paper proposes a novel optimisation approach for laser induced phased-arrays for detection purposes in large area inspection. The optimisation aims to maximise the detection capability of a ...phased-array while minimising the inspection time. This is done by using a simulation ray-tracing model that evaluates multiple candidate configurations. The metrics that measure the detection performance for a target defect are the receiver operating characteristic curve and the signal-to-noise ratio. The inspection time is indirectly computed through the number of measurement points per unit length in a continuous inspection. This depends on the physical aperture and pitch of the phased-array and they are the quantities optimised. The optimisation and modelling approach are validated in an experimental case study for a side-drilled hole as target defect. Further recommendations about directional defects (e.g. cracks at different angles) are provided.
•Optimisation approach for Laser-Induced Phased-Array configurations in continuous inspections.•Optimal balance between detectability of target defect and acquisition time.•Signal-to-Noise Ratio proves to be a valid proxy of Area Under the Curve.•The method is experimentally validated for 1 mm side-drilled holes.•Recommended configurations given for side-drilled holes and embedded cracks.
•LiPA assays 1.0 and 2.0 exhibit similar concordance profiles.•LiPA is inaccurate on complex samples such as recombinants and mixed infections.•NGS on full genomes has significant advantages in ...genotyping over LiPA.•High rate of failure in patients with HCV1b treated with Zepatier.•High frequency of RAS was observed in responders and non-responders.
Although most currently used regimens for Hepatitis C virus (HCV) infections can be initiated without prior knowledge of genotype and subtype, genotyping is still useful to identify patients who might benefit from a personalized treatment due to resistance to direct-acting antivirals (DAA).
To assess the utility of full-genome next-generation sequencing (FG-NGS) for HCV genotyping.
138 HCV plasma samples previously genotyped by VERSANT HCV Genotype Assay (LiPA) were subjected to FG-NGS and phylogenetically genotyped Genome Detective. Consensuses were analysed by HCV-GLUE for resistance-associated substitutions (RASs) and their impact on treatment response was investigated.
102/138 (73.9%) samples were sequenced to a genome coverage and depth of >90% of the HCV open reading frame covered by >100 reads/site. Concordant genotype and subtype results were assigned in 97.1% and 79.4% of samples, respectively. FG-NGS resolved the subtype of 13.7% samples that had ambiguous calls by LiPA and identified one dual infection and one recombinant strain. At least one RAS was found for the HCV genes NS3, NS5A, and NS5B in 2.91%, 36.98% and 27.3% samples, respectively. Irrespective of the observed RAS, all patients responded well to DAA treatment, except for HCV1b-infected patients treated with Zepatier (33.3% failure rate (5/15)).
While LiPA and FG-NGS showed overall good concordance, FG-NGS improved specificity for subtypes, recombinant and mixed infections. FG-NGS enabled the detection of RAS, but its predictive value for treatment outcome in DAA-naïve patients remains uncertain. With additional refinements, FG-NGS may be the way forward for HCV genotyping.
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RATIONALE:Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the ...endocytic compartment.
OBJECTIVE:Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo.
METHODS AND RESULTS:We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress–induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1–dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor–mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia.
CONCLUSIONS:Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.
Background
Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) ...activity due to
LIPA
gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations.
Methods
Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected
LIPA
mRNA expression.
Results
Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on
LIPA
, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity.
Conclusions
Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a
LIPA
gene mutation.
Low‐cost, accurate high‐risk human papillomavirus (HR‐HPV) tests are needed for cervical cancer screening in limited‐resource settings. More than 200 cervical cytological specimens from hospital ...patients were collected and analyzed for a real‐world study. We evaluated the analytical and clinical performance of four widely used HR‐HPV test (Tellgen, Hybribio, Liferiver, and Sansure) based on real‐time polymerase chain reaction technology platforms, compared with the cobas test. Cervical intraepithelial neoplasia grade 2 or worse lesions (CIN2+) were set as the disease endpoint, and all the five HPV tests were performed with equal sensitivity (McNemar's test; P = 0.971) and specificity (McNemar's test; P = 0.953). All genotyping using the INNO‐LiPA HPV test showed that HPV‐16, ‐52, and ‐54 were the most common types among CIN2+ cases. Overall, the four HR‐HPV tests analyzed appear to be as effective as the cobas HPV test in both agreement and clinical performance. Therefore, each of these low‐cost HPV test kits could be implemented in limited‐resource settings to accelerate the control of cervical cancer. However, we suggest that there is a need to further standardize and optimize testing around clinical sensitivity and specificity.
Highlights
This study compared the analytical and clinical performances of four HR‐HPV tests against the cobas test for low‐resource settings.
The four HR‐HPV tests analyzed appear to be as effective as the cobas HPV test in both analytical and clinical performance.
HPV 16, 52, and 54 were the most prevalent types among CIN2+ cases.
There is a need to further standardize and optimize testing around clinical sensitivity and specificity.
Introduction
The association of light‐intensity physical activity (LPA) with mortality is poorly understood. This meta‐analysis of cohort studies aimed to examine the dose‐response relationships ...between daily device‐measured LPA and mortality in adults aged 18 or older and to explore whether the associations were independent of moderate‐to‐vigorous physical activity (MVPA).
Methods
Searches for prospective cohort studies providing effect estimates of daily LPA (exposure) on all‐cause mortality (outcome) were systematically undertaken in electronic databases up to April 30, 2019. Subgroup analyses and meta‐regression analyses with random‐effects models were performed to quantify the dose‐response relationships between daily LPA and mortality. Sensitivity analyses were also conducted to assess the stability of the results.
Results
A total of 11 studies were included in the meta‐analysis. Analyses contained 49 239 individuals (mean age 60.7, SD = 13.6) who were followed up for a mean 6.2 years (2.3‐14.2 years), during which 3669 (7.5%) died. In comparison with the reference group (<3 h/d), the pooled HRs (and 95% CIs) of mortality were 0.71 (0.62‐0.82), 0.68 (0.59‐0.79), 0.56 (0.44‐0.71) for groups 3 to <5 h/d, 5 to <7 h/d, and more than 7 hours a day LPA, respectively. Meta‐regression models indicated that there was a log‐cubic dose‐response relationship between daily LPA and mortality in adults and older people, independent of MVPA.
Conclusions
Time spent in daily LPA was associated with reduced risks of mortality in adults and older people. These data support the inclusion of LPA in the future physical activity guidelines.
This article investigates 21st century disco and its nostalgic influences from 1970s and 1980s dance culture. First, it outlines the article's argument that contemporary disco music, whilst being ...influenced by its musical past, has different meanings in the present, and that artists are combining past influences with their own innovations. Second, it explores academic interpretations of nostalgia, and how these relate to popular culture. Third, it analyses three albums that consciously incorporate 1970s and 1980s disco aesthetics: Daft Punk's Random Access Memories (2013), Nile Rodgers and Chic's It's About Time (2018) and Dua Lipa's Future Nostalgia (2020). It does this through a combination of analysing different media including artists' stated intentions in interviews, lyrics and sounds. This opens a discussion of nostalgia in these albums, exploring what nostalgic feelings, specifically for 1970s and 1980s disco culture, can tell us about our present. Finally, it contextualises disco culture's historical journey to the present.
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