bluuebunny/crossref_metadata_2025 huggingface dataset:
On Geometric Measures and Their Computation
Authors:   , Urhausen Jérôme Eric
Published: November 2023

In this thesis, we explore geometric measures and how to compute them. First, we use similarity measures to determine the quality of the output of a transformation. Second, we explore new algorithms and data structures that allow us to calculate these distance measures. Third, we present a new distance measure and investigate its computation. Last, we deal with diversity measures by researching how to subdivide a set into diverse subsets.
To be more precise, in Chapters 2 and 3, we transform a vector graphic into a raster image and measure the quality of the output using the Hausdorff distance. In Chapter 2, the vector graphic we transform is a set of regions. We investigate restrictions on the regions, like convexity or fatness, and prove worst case lower bounds of the Hausdorff distance between the regions and their corresponding grid polygons under these conditions. We finish by describing algorithms that match these bounds.
In Chapter 3, the regions we transform into a raster image are points. Even for this simple shape we were able to prove that determining pixels with the smallest possible Hausdorff distance to the input points is NP-hard. Nonetheless, we are able to find two polynomial-time algorithms that determine a set of pixels corresponding to the input points: first, we show an algorithm where the Hausdorff distance between the points and the pixels is at most a small constant factor larger than the optimal solution. Second, we show an algorithm where the Hausdorff distance between the points and the pixels is at most a small additive constant larger than the optimal solution.
In Chapter 4, we consider the computation of the Hausdorff distance. We present a data structure on a set of segments that allows queries of the following type: for a given segment, we can quickly determine the Hausdorff distance between the query segment and the set of segments the data structure is built on. We provided a mechanism to balance between space usage and preprocessing time for that data structure.
In Chapter 5, we explore a new similarity measure, the k-Fréchet distance. We define the two variants: the cover distance and the cut distance. Both bridge between the Hausdorff and the Fréchet distance and measure the similarity between two curves. Even though both the Fréchet distance and the Hausdorff distance are easy to compute, the k-Fréchet distances are NP-hard to compute. Still, we present efficient algorithms that compute the cover or cut distance with specific restrictions.
In Chapter 6, we focus on diversity measures instead of similarity measures like in the previous chapters. For sets of colored points we use the species richness measure or the Shannon index to determine its diversity. We investigate the problem of how to subdivide a set of colored points into subsets such that the subsets are diverse. We present results for multiple variants: we subdivide either into convex subsets or using a Voronoi diagram, and investigate the problem both in 1D and in 2D.
Precision Medicine in Diabetes
Authors: Meunier-McVey Natasha
Published: November 2023

THE 59th Annual Meeting of the European Association for the Study of
Diabetes (EASD) took place in Hamburg, Germany, as well as virtually. With
exciting new developments in diabetes treatment in the forefront of our
minds, as described by the EASD President, Chantal Mathieu, presenter Paul Franks
from Lund University, Sweden, took to the stage to deliver ‘ADA/EASD Precision
Medicine in Diabetes Initiative: Executive Summary of the Second Consensus
Report’. Franks provided the key updates to the consensus, published on 5th October
2023, only hours before the presentation.
A Retrospective Study in Patients With Varying Prescription Coverage With Ursodeoxycholic Acid and Association With Incidence of COVID-19 Diagnosis in Primary Care
Authors: Ming Simon Wan Yau Ming , Smith Mike , Zhou Yi
Published: November 2023

Background: The 2019 novel coronavirus (COVID-19) pandemic resulted in significant mortality and morbidity. Ursodeoxycholic acid (UDCA) is reportedly widely in demand in some countries, such as China, to protect individuals from the effects of infection, as there is evidence that it is effective in preventing viral replication in some in vitro studies. UDCA is commonly prescribed in patients with primary biliary cirrhosis and gallbladder calculi. By evaluating a set of patients prescribed UDCA, whether or not the risk of COVID-19 infection is attenuated by adherence to UDCA can be determined.

Method: This is a retrospective database study using the Clinical Practice Research Datalink (CPRD Aurum). Patients who received a prescription of UDCA in the study timeframe of March 1, 2020–May 30, 2021 were characterized, and their primary care electronic medical records analyzed for presence of COVID-19 infection. The proportion of days covered for each patient was used as a proxy for adherence. A comparison was made between categorized high- and low-adherence, and adherence as a continuous variable. Inverse probability weighting was used to adjust for confounding.

Results: Higher categorized adherence (≥80%) to UDCA was associated with a statistically significant lower incidence of COVID-19 (odds ratio [OR]: 0.864; 95% confidence interval [CI]: 0.759–0.984; p=0.027). This contrasted to adherence as a continuous variable, which was not statistically significant. Obesity and hematological malignancy were also associated with a higher incidence of COVID-19 infection.

Conclusion: There is evidence to suggest that the regular use of UDCA is associated with a lower risk of COVID-19 infection when compared to irregular or sporadic usage.
SINERGITAS PELAKSANAAN VAKSINASI COVID-19 BAGI PENYANDANG DISABILITAS DI KABUPATEN SLEMAN PROVINSI DAERAH ISTIMEWA YOGYAKARTA
Authors: Faiza Bunga Fata
Published: November 2023

Peningkatan penyebaran dan lahirnya varian baru virus COVID-19 serta dampaknya yang luas dan meliputi seluruh sektor kehidupan masyarakat menjadi dasar dari penelitian ini. Kemampuan kekebalan tubuh masyarakat dalam melawan virus menular (imunitas) perlu ditingkatkan, terlebih bagi penyandang disabilitas. Sejauh ini pelaksanaan vaksinasi masih menemui kendala meski telah dikeluarkan surat edaran oleh Kementerian Kesehatan RI. Para stakeholders di Kabupaten Sleman mencoba mengatasinya. Penelitian ini bertujuan untuk menganalisis sinergitas pelaksanaan vaksinasi COVID-19 pada Penyandang Disabilitas di Kabupaten Sleman. Metode penelitian yang digunakan ialah kualitatif deskriptif dengan pendekatan induktif. Pengumpulan data dilakukan dengan teknik wawancara, observasi, dan dokumentasi. Teknik analisa data menggunakan tahapan reduksi data, penyajian data, dan verifikasi. Hasil penelitian dan analisis menunjukkan bahwa sinergi yang terjadi antara akademisi, bisnis, komuitas, pemerintah, dan media sudah berhasil mewujudkan giat percepatan vaksinasi bagi penyandang disabilitas. Sinergi yang dibangun terbukti melahirkan kekuatan yang lebih besar. Walau demikian masih terdapat kendala yang perlu dipecahkan solusinya, sehingga kedepan hasil yang didapat meningkat. Stakeholders yang terlibat dalam pelaksanaan pecepatan vaksinasi disabilitas di Kabupaten Sleman seharusnya membuat komitmen secara tertulis agar dapat dipertanggungjawabkan dan legal di hadapan hukum. Kemudian, kegiatan vaksinasi sebaiknya disusun perencanaannya secara matang dari jauh-jauh hari agar kegiatan di waktu mendatang dapat berjalan lebih baik.  Sinergi yang dilakukan seluruh aktor dalam pelaksanaan vaksinasi COVID-19 bagi penyandang disabilitas di Kabupaten Sleman dalam upaya mewujudkan imunitas dapat dikatakan berhasil. Hal ini dapat diketahui, sebab penyandang disabilitas menyampaikan bahwa mereka merasa terbantu oelh kemudahan yang disediakan para stakeholders
FORMULASI SEDIAAN SPRAY GEL EKSTRAK DAUN BANDOTAN (Ageratum conyzoides.L) SEBAGAI ANTINYAMUK
Authors: Mangalik Anastasia Reni , Helmidanora Rusdiati , Sa'adah Hayatus
Published: November 2023

There are many types of mosquitoes that cause disease in humans, one of which is the Anopheles mosquito that spreads malaria. Bandotan plants are used to treat colic, flu, fever, antidiarrheal, diarrhoea. The purpose of this study was to determine the concentration of bandotan (Ageratum conyzoides.L) leaf extract that provides the best physical properties and anti-mosquito activity in spray gel preparations. The research method conducted was experimental. The object studied was the formulation of bandotan leaf preparation as an antinyamite. The research stages include plant determination, sample collection, simplisia preparation, extraction using maceration method with 70% ethanol solvent, identification of secondary metabolite compounds, preparation of spray gel formula, and preparation evaluation. Bandotan leaf extract was formulated into anti-mosquito spray gel preparations with concentration variants of 10%, 15%, 20%, and using positive control of X brand anti-mosquito spray as a comparison. The preparation testing included organoleptic test, homogeneity test, pH test, viscosity test, and mosquito repellency test. The results of data collection were analysed statistically. A good preparation formula is found in the negative control formula because it has a stable consistency and pH.  The results showed that the ethanol extract of bandotan leaves was not significantly different from the organoleptic test, homogeneity test, viscosity test, and pH test. The greatest mosquito repellency was at a concentration of 20% which was 66.33%, at concentrations of 10% and 15% had an average anti-mosquito activity of 22.83% and 57.83% respectively for the positive control with brand X of 99.30%.
RENDEMEN EKSTRAK ETANOL HERBA RUMPUT AKAR WANGI (Polygala paniculata L) PADA PERBANDINGAN KONSENTRASI PELARUT
Authors: Pradana Anugerah Riska , Wahyudi Hendra , Lestari Dwi
Published: November 2023

Rumput akar wangi (Polygala paniculata (L)) belongs to the Polygalaceae family. One of the extract yields is influenced by solvent concentration. The aim of the research is to determine the effect of variations in concentration on the yield of Polygala paniculata extract and the groups of compounds in the extract. This research includes determination, collection, and plant preparation, processing of Polygala paniculata simplicia, extraction, screening, and determination of yield. In this study, 50 grams of Polygala paniculata powder were extracted with different solvent concentrations, namely 70% and 95% ethanol using the maceration method. Replication was carried out on each solvent three times. Data were analyzed using descriptive methods and processed using SPSS (Statistical Product and Service Solutions) tools. The results of phytochemical screening showed that the extract contained flavonoids, tannins, saponins, and terpenoids. The calculation results of the ethanol extract of Polygala paniculata were 70% ethanol (17.77% ± 1.34) and 95% ethanol (12.59% ± 0.86). The SPSS test results on the Independent Samples Test show that there is a significant difference (p < 0.05). The highest yield of Polygala paniculata extract was obtained using 70% ethanol for filtration.
The Atomic and Quantum Mechanics Achievements of the Theory of Solar System Wave Packet
Authors: Soltani Abolfazl
Published: November 2023

In the previous article we discussed about Solar System Wave Packet (SSWP). It makes sense if we want to generalize our theory to the subatomic world. So, based on the theory of SSWP, we will enter into the atomic physics and arrive to a new atomic model with considerable results.
The Role of Low-Emission Hydrogen in Developing Countries: A Techno-Economic Assessment of Hydrogen Pathways in Colombia
Authors: Plazas-Niño Fernando , Yeganyan Rudolf , Cannone Carla , Howells Mark , Borba Bruno , Quirós-Tortós Jairo
Published: November 2023

Climate change is driving the need for new approaches to energy production and utilization globally, contributing to the mitigation of greenhouse gas (GHG) emissions. Low-emission hydrogen is recognized as a key energy vector for decarbonization, and numerous countries are currently evaluating strategies and roadmaps for its integration. Colombia, with its abundant renewable resources, is poised as a potential player in hydrogen production. The study presents an integrated techno-economic assessment of hydrogen’s role within Colombian energy mix. By employing an open energy system optimization model (OSeMOSYS), we analyzed a series of hydrogen scenarios from 2021 to 2050, including a sensitivity analysis. Our results show that hydrogen pathways will require 2-6.4 Mt/year in hydrogen production, 8-27 GW in installed capacity, and US$50-80 billion in investments, with favorable impacts in GHG mitigation, energy imports, and socioeconomic benefits. We use these findings to formulate an update to the targets of the current National Hydrogen Roadmap focused on a higher ambition to deploy a full hydrogen economy. Our open methodology provides a valuable tool for conducting further assessments in countries interested in defining hydrogen roadmaps.
On Nicolas Criterion for the Riemann Hypothesis
Authors: Vega Frank
Published: November 2023

The Riemann hypothesis is the assertion that all non-trivial zeros are complex numbers with real part $\frac{1}{2}$. It is considered by many to be the most important unsolved problem in pure mathematics. There are several statements equivalent to the famous Riemann hypothesis. For $x \geq 2$, the function $f$ was introduced by Nicolas in his seminal paper as $f(x) = e^{\gamma} \cdot \log\theta(x) \cdot \prod_{q \leq x} \left(1 - \frac{1}{q} \right)$, where $\theta(x)$ is the Chebyshev function, $\gamma \approx 0.57721$ is the Euler-Mascheroni constant and $\log$ is the natural logarithm. In 1983, Nicolas stated that if the Riemann hypothesis is false then there exists a real number $b$ with $0 < b < \frac{1}{2}$ such that, as $x\to \infty$, $\log f(x)=\Omega_{\pm }(x^{-b})$. In this note, using the Nicolas criterion, we prove that the Riemann hypothesis is true.
Pembuktian Rumus Jarak Dalam Bangun Ruang Dimensi Tiga Ditinjau Dari Ruang Lingkup Geometri Matematika Sekolah
Authors: Fahlevi Mahfudz Reza
Published: November 2023

Tulisan ini ditujukan sebagai bentuk penyajian tentang beragam pembuktian pada suatu rumus cepat (rumus jarak) dalam materi bangun ruang dimensi tiga. Dalam pembelajaran matematika sekolah, rumus cepat dalam materi bangun ruang dimensi tiga sering digunakan, namun jarang dilengkapi dengan penanaman konsep yang kuat sehingga dapat memberi dampak buruk bagi budaya belajar matematika. Dengan metode penelitian kualitatif melalui kajian kepustakaan, peneliti berupaya untuk berkontribusi memberikan bukti matematis suatu rumus cepat agar dapat menjadi referensi bagi pendidik. Pembuktian rumus cepat dijelaskan dari beragam sudut pandang menggunakan berbagai materi yang masih dalam ruang lingkup geometri. Adapun materi-materi yang dilibatkan meliputi konsep kesebangunan, konsep luas segitiga, konsep bangun ruang dimensi tiga, geometri analitis (dengan sistem koordinat Kartesius), serta dengan pendekatan analisis vektor (vektor ruang).
Conceptual Understanding and Reasoning of Students with Dyscalculia: A Literature Review
Authors: Salisa Resminati Dinda , Rahaya Wardani
Published: November 2023

Dyscalculia is a specific learning condition that affects one’s understanding and manipulation of numerical concepts. Conceptual understanding is one of the components of mathematics proficiency that can be developed through reasoning skills. However, neither the conceptual understanding nor the reasoning abilities of students with dyscalculia have been thoroughly described. The objective of this systematic review of the relevant scientific literature is to identify and analyse existing evidence regarding the conceptual understanding and reasoning skills of students with dyscalculia by using the following procedures: (1) developing a research question; (2) selection criteria; (3) developing the search strategy; (4) study selection process; (5) appraising the quality of studies; and (6) synthesis result. Twenty articles were selected and analysed in total. It was discovered that students with dyscalculia lacked conceptual understanding and reasoning skills, which could present them with a variety of difficulties, such as processing mathematical facts and further developing their mathematical skills.
Pembelajaran Melalui Pendekatan Pendidikan Matematika Realistik Untuk Meningkatkan Kemampuan Pemecahan Masalah Matematika Siswa SMP
Authors: Destiana Mali Maria , Loka Son Aloisius
Published: November 2023

This study was conducted with the aim of determining the comparison of achievement and improvement in the problem-solving ability of students who learn through realistic mathematics education and a conventional approach. The study used quantitative methods in the form of a quasi-experiment. The design of this study used a pretest-posttest control group design. The participants in this study were students in grade VIII from one of the junior high schools in the Belu district. The sample in this study consisted of 22 students from class VIIIA as the experimental group, and 22 students from class VIIIB as the control group. The research instruments used were a problem-solving ability test and observation sheets. The results showed that the achievement and improvement in the mathematics problem-solving ability of students who learned through the realistic mathematics education approach were better than those of students who learned with a conventional approach. Learning with a realistic mathematics education approach can facilitate the problem-solving skills of junior high school students. It is recommended that future researchers apply the realistic mathematics education approach to other mathematical abilities.
Dual-function transaminases with hybrid nanoflower for the production of value-added chemicals from biobased levulinic acid
Authors: Khobragade Taresh P. , Giri Pritam , Pagar Amol D. , Patil Mahesh D. , Sarak Sharad , Joo Sangwoo , Goh Younghwan , Jung Seohee , Yoon Hyunseok , Yun Subin , Kwon Youkyoung , Yun Hyungdon
Published: November 2023

The U.S. Department of Energy has listed levulinic acid (LA) as one of the top 12 compounds derived from biomass. LA has gained much attention owing to its conversion into enantiopure 4-aminopentanoic acid through an amination reaction. Herein, we developed a coupled-enzyme recyclable cascade employing two transaminases (TAs) for the synthesis of (S)-4-aminopentanoic acid. TAs were first utilized to convert LA into (S)-4-aminopentanoic acid using (S)-α-Methylbenzylamine [(S)-α-MBA] as an amino donor. The deaminated (S)-α-MBA i.e., acetophenone was recycled back using a second TAs while using isopropyl amine (IPA) amino donor to generate easily removable acetone. Enzymatic reactions were carried out using different systems, with conversions ranging from 30% to 80%. Furthermore, the hybrid nanoflowers (HNF) of the fusion protein were constructed which afforded complete biocatalytic conversion of LA to the desired (S)-4-aminopentanoic acid. The created HNF demonstrated storage stability for over a month and can be reused for up to 7 sequential cycles. A preparative scale reaction (100 mL) achieved the complete conversion with an isolated yield of 62%. Furthermore, the applicability of this recycling system was tested with different β-keto ester substrates, wherein 18%–48% of corresponding β-amino acids were synthesized. Finally, this recycling system was applied for the biosynthesis of pharmaceutical important drug sitagliptin intermediate ((R)-3-amino-4-(2,4,5-triflurophenyl) butanoic acid) with an excellent conversion 82%.
Beta-blocker management in patients admitted for acute heart failure and reduced ejection fraction: a review and expert consensus opinion
Authors: Schurtz Guillaume , Mewton Nathan , Lemesle Gilles , Delmas Clément , Levy Bruno , Puymirat Etienne , Aissaoui Nadia , Bauer Fabrice , Gerbaud Edouard , Henry Patrick , Bonello Laurent , Bochaton Thomas , Bonnefoy Eric , Roubille François , Lamblin Nicolas
Published: November 2023

The role of the beta-adrenergic signaling pathway in heart failure (HF) is pivotal. Early blockade of this pathway with beta-blocker (BB) therapy is recommended as the first-line medication for patients with HF and reduced ejection fraction (HFrEF). Conversely, in patients with severe acute HF (AHF), including those with resolved cardiogenic shock (CS), BB initiation can be hazardous. There are very few data on the management of BB in these situations. The present expert consensus aims to review all published data on the use of BB in patients with severe decompensated AHF, with or without hemodynamic compromise, and proposes an expert-recommended practical algorithm for the prescription and monitoring of BB therapy in critical settings.
Consistency and inconsistency in learning experiences across the early grades
Authors: Christopher Caroline , Nesbitt Kimberly
Published: November 2023

Introduction

The personal and societal benefits of providing quality early education experiences are well supported by research. While there is growing evidence as to the specific features and experiences that define quality and effective early education classrooms, there remain open questions as to whether these features and experiences differ as a function of grade level.

Methods

Using a behavioral-based observation system, researchers conducted day-long classroom observations in 98 prekindergarten through 2nd grade U.S. classrooms. Key features of these classrooms were examined to determine the extent to which features vary (or remain consistent) across grade levels.

Results

This study found that across the early school years, instruction tends to focus on basic skills provided in whole-class groupings that were related to passive participation from students. Across all grades, there was a predominant focus on language arts.

Discussion

These findings highlight the need to consider the appropriateness of pushing down the academic demands typical in 1st grade into prekindergarten and kindergarten classrooms in the U.S.
Clinical characterization and proteomic profiling of lean nonalcoholic fatty liver disease
Authors: Jiang Yuanye , Zhuang Xiaoyu , Zhang Jiaqi , Li Meng , Du Shengnan , Tian Jiyun , Yuan Yifu , Ji Guang , Hu Cheng
Published: November 2023

Introduction

Obesity has been historically associated with nonalcoholic fatty liver disease (NAFLD), but it can also occur in lean individuals. However, limited data is available on this special group. To investigate the clinical and proteomic characteristics of lean subjects with NAFLD, and to identify potential clinical variables and plasma proteins for diagnosing NAFLD in lean individuals, we collected clinical data from a large cohort of 2,236 subjects.

Methods

Diagnosis of NAFLD relied on detecting pronounced hepatic steatosis through abdominal ultrasonography. Participants were categorized into four groups based on body mass index: overweight NAFLD, overweight control, lean NAFLD, and lean control. Plasma proteomic profiling was performed on samples from 20 subjects in each group. The lean NAFLD group was compared to both lean healthy and obese NAFLD groups across all data.

Results and discussion

The results indicated that the lean NAFLD group exhibited intermediate metabolic profiles, falling between those of the lean healthy and overweight NAFLD groups. Proteomic profiling of plasma in lean subjects with or without NAFLD revealed 45 statistically significant changes in proteins, of which 37 showed high diagnostic value (AUC > 0.7) for lean NAFLD. These potential biomarkers primarily involved lipid metabolism, the immune and complement systems, and platelet degranulation. Furthermore, AFM, GSN, CFH, HGFAC, MMP2, and MMP9 have been previously associated with NAFLD or NAFLD-related factors such as liver damage, insulin resistance, metabolic syndromes, and extracellular homeostasis. Overall, lean individuals with NAFLD exhibit distinct clinical profiles compared to overweight individuals with NAFLD. Despite having worse metabolic profiles than their healthy counterparts, lean NAFLD patients generally experience milder systemic metabolic disturbances compared to obese NAFLD patients. Additionally, the plasma proteomic profile is significantly altered in lean NAFLD, highlighting the potential of differentially expressed proteins as valuable biomarkers or therapeutic targets for diagnosing and treating NAFLD in this population.
Cardiovascular outcomes and safety of SGLT2 inhibitors in chronic kidney disease patients
Authors: Chen Xiutian , Wang Jiali , Lin Yongda , Yao Kaijin , Xie Yina , Zhou Tianbiao
Published: November 2023

Background

Sodium–glucose co-transporter 2 (SGLT2) inhibitors provide cardiovascular protection for patients with heart failure (HF) and type 2 diabetes mellitus (T2DM). However, there is little evidence of their application in patients with chronic kidney disease (CKD). Furthermore, there are inconsistent results from studies on their uses. Therefore, to explore the cardiovascular protective effect of SGLT2 inhibitors in the CKD patient population, we conducted a systematic review and meta-analysis to evaluate the cardiovascular effectiveness and safety of SGLT2 inhibitors in this patient population.

Method

We searched the PubMed® (National Library of Medicine, Bethesda, MD, USA) and Web of Science™ (Clarivate™, Philadelphia, PA, USA) databases for randomized controlled trials (RCTs) of SGLT2 inhibitors in CKD patients and built the database starting in January 2023. In accordance with our inclusion and exclusion criteria, the literature was screened, the quality of the literature was evaluated, and the data were extracted. RevMan 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata® 17.0 (StataCorp LP, College Station, TX, USA) were used for the statistical analyses. Hazard ratios (HRs), odds ratios (ORs), and corresponding 95% confidence intervals (CIs) were used for the analysis of the outcome indicators.

Results

Thirteen RCTs were included. In CKD patients, SGLT2 inhibitors reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HHF) by 28%, CVD by 16%. and HHF by 35%. They also reduced the risk of all-cause death by 14% without increasing the risk of serious adverse effects (SAEs) and urinary tract infections (UTIs). However, they increased the risk of reproductive tract infections (RTIs).

Conclusion

SGLT2 inhibitors have a cardiovascular protective effect on patients with CKD, which in turn can significantly reduce the risk of CVD, HHF, and all-cause death without increasing the risk of SAEs and UTIs but increasing the risk of RTIs.
Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism
Authors: Lee Cheng-Ting , Tsai Wen-Hao , Chang Chien-Ching , Chen Pei-Chun , Fann Cathy Shen-Jang , Chang Hsueh-Kai , Liu Shih-Yao , Wu Mu-Zon , Chiu Pao-Chin , Hsu Wen-Ming , Yang Wei-Shiung , Lai Ling-Ping , Tsai Wen-Yu , Yang Shi-Bing , Chen Pei-Lung
Published: November 2023

Objective

Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.

Methods

We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot.

Results

Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient.

Conclusion

Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.
X-linked adrenoleukodystrophy and primary adrenal insufficiency
Authors: Cappa Marco , Todisco Tommaso , Bizzarri Carla
Published: November 2023

X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
Impact of agro-geotextiles on soil aggregation and organic carbon sequestration under a conservation-tilled maize-based cropping system in the Indian Himalayas
Authors: Roy Plabani , Bhattacharyya Ranjan , Singh Raman Jeet , Sharma N. K. , Kumar Gopal , Madhu M. , Biswas D. R. , Ghosh Avijit , Das Shrila , Joseph Ann Maria , Das T. K. , Kumar Soora Naresh , Jat S. L. , Saharawat Y. S. , Jha Pramod
Published: November 2023

Although agro-geotextile (AGT) emplacement shows potential to mitigate soil loss and, thus, increase carbon sequestration, comprehensive information is scanty on the impact of using agro-geotextiles on soil organic carbon (SOC) sequestration, aggregate-associated C, and soil loss in the foothills of the Indian Himalayan Region. We evaluated the impacts of Arundo donax AGT in different configurations on SOC sequestration, aggregate stability, and carbon management index (CMI) since 2017 under maize-based cropping systems on a 4% land slope, where eight treatment procedures were adopted. The results revealed that A. donax placement at 0.5-m vertical-interval pea–wheat (M + AD10G0.5-P-W) treatment had ∼23% increase in SOC stock (27.87 Mg·ha−1) compared to the maize–wheat (M-W) system in the 0–30-cm soil layer. M + AD10G0.5-P-W and maize–pea–wheat treatments under bench terracing (M-P-W)BT had similar impacts on SOC stocks in that layer after 5 years of cropping. The total SOC values in bulk soils, macroaggregates, and microaggregates were ∼24, 20, and 31% higher, respectively, in plots under M + AD10G0.5-P-W treatment than M-W in the topsoil (0–5 cm). The inclusion of post-rainy season vegetable pea in the maize–wheat cropping system, along with AGT application and crop residue management, generated additional biomass and enhanced CMI by ∼60% in the plots under M + AD10G0.5-P-W treatment over M-W, although M + AD10G0.5-P-W and (M-P-W)BT had similar effects in the topsoil. In the 5–15-cm layer, there was no significant effect of soil conservation practices on CMI values. Under the M + AD10G0.5-P-W treatment, the annual mean soil loss decreased by ∼92% over M-W treatment. We observed that CMI, proportion of macroaggregates, aggregate-associated C, labile C, total SOC concentration (thus, SOC accumulation rate), and mean annual C input were strongly correlated with the mean annual soil loss from 2017 to 2021. The study revealed that the emplacement of an A. donax mat and incorporation of a legume in a cropping system (M-W), conservation tillage, and crop residue retention not only prevented soil loss but also enhanced C sequestration compared to farmers’ practice (M-W) in the Indian Himalayas. The significance of this study is soil conservation, recycling of residues and weeds, and climate change adaptation and mitigation, as well as increasing farmers’ income.
High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis
Authors: De Luca Geraldine , Lev Paola R. , Camacho Maria F. , Goette Nora P. , Sackmann Federico , Castro Ríos Miguel A. , Moiraghi Beatriz , Cortes Guerrieri Veronica , Bendek Georgina , Carricondo Emiliano , Enrico Alicia , Vallejo Veronica , Varela Ana , Khoury Marina , Gutierrez Marina , Larripa Irene B. , Marta Rosana F. , Glembotsky Ana C. , Heller Paula G.
Published: November 2023

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1β and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.
Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation
Authors: Wellems Dianne , Hu Yawen , Jennings Scott , Wang Guoshun
Published: November 2023

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood. Here, we report that loss of CFTR function in macrophages causes extended lung inflammation. After intratracheal inoculation with Pseudomonas aeruginosa, mice with a macrophage-specific Cftr-knockout (Mac-CF) were able to mount an effective host defense to clear the bacterial infection. However, three days post-inoculation, Mac-CF lungs demonstrated significantly more neutrophil infiltration and higher levels of inflammatory cytokines, suggesting that Mac-CF mice had a slower resolution of inflammation. Single-cell RNA sequencing revealed that absence of CFTR in the macrophages altered the cell transcriptional program, affecting the cell inflammatory and immune responses, antioxidant system, and mitochondrial respiration. Thus, loss of CFTR function in macrophages influences cell homeostasis, leading to a dysregulated cellular response to infection that may exacerbate CF lung disease.
Oncostatin M suppresses IL31RA expression in dorsal root ganglia and interleukin-31-induced itching
Authors: Suehiro Masataka , Numata Tomofumi , Saito Ryo , Yanagida Nozomi , Ishikawa Chie , Uchida Kazue , Kawaguchi Tomoko , Yanase Yuhki , Ishiuji Yozo , McGrath John , Tanaka Akio
Published: November 2023

Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRβ and IL31RA subunits, and OSMRβ can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients.

Objective

The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression.

Methods

The expression levels of the OSM gene (OSM) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes.

Results

We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG.

Conclusion

These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch.
Circulating inflammatory cytokines and hypertensive disorders of pregnancy: a two-sample Mendelian randomization study
Authors: Guan Siqi , Bai Xiaoxu , Ding Jincheng , Zhuang Rujin
Published: November 2023

Background

Hypertensive disorders of pregnancy (HDP) pose a significant risk to maternal and fetal well-being; however, the etiology and pathogenesis of HDP remain ambiguous. It is now widely acknowledged that inflammatory response and the immune system are closely related to HDP. Previous research has identified several inflammatory cytokines are associated with HDP. This study applied Mendelian randomization (MR) analysis to further assess causality.

Methods

Patients with HDP who participated in the MR analysis presented with four types of HDP: pre-eclampsia or eclampsia (PE); gestational hypertension (GH); pre-existing hypertension complicating pregnancy, childbirth and the puerperium (EH); and pre-eclampsia or poor fetal growth (PF). A two-sample MR analysis was used to analyze the data in the study. The causal relationship between exposure and outcome was analyzed with inverse variance weighting (IVW), MR Egger, weighted median, weighted mode, and simple mode methods, where IVW was the primary method employed.

Results

Our MR analysis demonstrated a reliable causative effect of Interleukin-9 (IL-9) and macrophage migration inhibitory factor (MIF) on reducing HDP risk, while macrophage inflammatory protein 1-beta (MIP1b), Interleukin-13 (IL-13), and Interleukin-16 (IL-16) were associated with promoting HDP risk.

Conclusions

This study demonstrated that IL-9, MIF, MIP1b, IL-13, and IL-16 may be cytokines associated with the etiology of HDP, and that a number of inflammatory cytokines are probably involved in the progression of HDP. Additionally, our study revealed that these inflammatory cytokines have causal associations with HDP and may likely be potential therapeutic targets for HDP.
Bioinspired building materials—lessons from nature
Authors: Sandak Anna , Butina Ogorelec Karen
Published: November 2023

Systems found in nature are a valuable source of inspiration for several applications. Scientists and researchers from different fields (structural engineering, robotics, medicine, and materials science) use the concepts of biomimicking, biomimetics, and bioinspiration. More recently the possibility to benefit from solutions developed by nature has become of interest for sustainable architecture. Living organisms use smart, optimised, and elegant solutions to survive, thanks to continuous selection and mutation processes. For over 460 million years plants have been evolving in a constantly changing environment and have become well-adapted to different climatic conditions. Faced with several challenges (water loss, extreme temperatures, UV radiation, etc.) plants, for example, developed tissues with barrier properties. Furthermore, due to their immobility, plants are excellent biological materials for detecting climate phenomena. While animals, being mobile, developed other creative survival strategies through a long evolutionary process. Being exposed to various environments, they not only developed multifunctional surfaces, but also movements and a broad portfolio of sensing methods that increased their survival efficiency. Comprehensive analysis and evaluation of the adaptation strategies of plants (both static strategies and dynamic mechanisms) and animals to their environment in different climate zones are indispensable for transferring concepts from biology to architecture. Consequently, specific adaptation solutions might be implemented in new materials that will be used for building envelopes erected in the same climatic zones. Integrating length scales and mixing biological, chemical, and physical concepts for tailoring the properties of materials during preparation should allow for better designing of future smart materials. The process should lead to the development of active biomaterials that perform as interfaces between outdoor conditions and internal comfort. In that they should be able to regulate humidity, temperature, CO2, and light as well as capture and filter pollutants; in addition, they should have self-assembling, self-cleaning, grafting, and self-healing properties. This contribution provides an analysis of several examples that represent the adaptation of organisms to various environments and are presented with the aim to inspire future researchers in the development of new building materials.
Optical coherence tomography findings of the peripheral retina in patients with congenital X-linked retinoschisis
Authors: Nakajima Ayaka , Kuniyoshi Kazuki , Iwahashi Chiharu , Mano Fukutaro , Hayashi Takaaki , Kondo Hiroyuki , Mizobuchi Kei , Matsushita Itsuka , Suga Akiko , Yoshitake Kazutoshi , Nakano Tadashi , Iwata Takeshi , Matsumoto Chota , Kusaka Shunji
Published: November 2023

Introduction

Congenital X-linked retinoschisis (XLRS) presents as macular retinoschisis/degeneration in almost all patients and as peripheral retinoschisis in half the patients. Although the optical coherence tomography (OCT) findings of macular retinoschisis have been well investigated, those of peripheral retinoschisis have rarely been reported. This study aimed to report the ultra-widefield OCT findings of the peripheral retina in patients with XLRS.

Methods

Medical records of 10 Japanese patients (19 eyes) with clinically and/or genetically diagnosed XLRS were retrospectively reviewed. Funduscopic, electroretinographic, and OCT findings were reviewed and evaluated. Some were also genetically evaluated for the RS1 gene.

Results

OCT of the macula revealed schises and/or cystoid changes in the inner nuclear layer (INL) and outer nuclear layer. In contrast, OCT of the peripheral retina revealed schises and/or cystoid changes in the INL in eight eyes (44%), and/or splitting in the ganglion cell layer (GCL) in 10 (56%) of the 18 eyes with clear OCT images. No schisis or cystoid changes were found in the peripheral OCT images of eight eyes (44%). A 16-year-old boy presented with retinal splitting of the GCL and INL of the inferior retina, although he had no ophthalmoscopic peripheral retinoschisis. Genetic examinations were performed on three patients, all of whom had reported missense mutations in the RS1 gene.

Conclusion

In XLRS, peripheral bullous retinoschisis results from GCL splitting in the retina. One of the 10 patients with XLRS showed intraretinal retinoschisis in the GCL in the inferior periphery, which was unremarkable on ophthalmoscopy (occult retinoschisis). Although both peripheral bullous retinoschisis and occult retinoschisis showed splitting/cystic changes in the GCL, further studies are needed to determine whether occult retinoschisis progresses to bullous retinoschisis.