bluuebunny/crossref_metadata_2025 huggingface dataset:
Analisis Kemampuan Komunikasi Matematis Pada Soal Cerita Aritmetika Sosial
Authors: Dewanti Sintha Sih , Muna Khozainul
Published: August 2023

Abstrak. Kemampuan komunikasi matematis memiliki peranan penting dalam kehidupan. Penelitian dilakukan guna mengetahui kemampuan komunikasi matematis siswa kelas VII dalam menyelesaikan soal cerita materi aritmetika sosial. Metode yang digunakan pada penelitian adalah deskriptif kualitatif. Sampel penelitian merupakan 82 siswa kelas VII SMPN 5 Ngawi dan 72 siswa dari kelas VII MTs Al Istiqomah Madiun. Teknik pengambilan data dengan memberikan instrumen tes. Terdapat beberapa indikator kemampuan komunikasi matematis, 1) Menyajikan kejadian sehari-hari ke istilah matematika, 2) Menjelaskan atau merumuskan pertanyaan matematika yang relevan dengan pernyataan atau cerita, 3) Menghubungkan benda nyata, gambar, tabel, dan diagram dengan konsep matematika, 4) Menjelaskan konsep, situasi, dan hubungan matematis dengan benda nyata, gambar, grafik, dan tabel. Hasil penelitian menyebutkan bahwa kemampuan komunikasi matematis dari kedua sekolah masih cukup rendah. Dimana siswa kelompok tinggi memenuhi indikator pertama, kedua, ketiga dan keempat. Siswa kelompok sedang cukup memenuhi indikator pertama, tetapi belum memenuhi indikator kedua, ketiga, dan keempat. Siswa kelompok rendah belum memenuhi keempat indikator, sehingga memerlukan upaya peningkatan kemampuan komunikasi matematis siswa. Kata Kunci: Komunikasi Matematis, Soal Cerita, Aritmetika Sosial.
ELECTROLYTIC CATALYSTS BASED ON TUNGSTEN AND CARBON COMPOUNDS FOR THE HYDROGEN EVOLUTION REACTION
Authors: Kuleshov Serhii , Novoselova Inessa , Medvezhynska Olha
Published: August 2023

The hydrogen evolution reaction (HER) is one of the most promising methods of obtaining high-purity hydrogen. However, the high cost and limited resources of materials with low cathodic hydrogen evolution overvoltage values, such as platinum group metals, are the main obstacles to the use HER for obtaining hydrogen on an industrial scale. Therefore, it is necessary to develop new alternative materials and methods of their production. One of the promising materials are catalysts based on refractory metals, in particular tungsten carbides. Metal tungsten can also be used for these purposes. In our opinion, high-temperature electrochemical synthesis (HTES) in molten salts can be a promising method of obtaining materials with properties that meet the requirements for effective catalysts, namely: ultra-dispersity, high specific surface area, mesoporosity and defective structure, high chemical and electrochemical stability. Therefore, the purpose of this work is to evaluate the electrocatalytic activity of a group of materials for HER, which are obtained by HTES in melts. Four samples of electrolytic materials were chosen for the study: tungsten, carbon, tungsten mono- and semi-carbides (WC and W2С). All samples were characterized in detail using X-ray diffraction (phase composition), SEM (morphology), Raman spectroscopy (structure of carbon phases), DTG (free carbon content).
Based on the analysis of the obtained data, it was established that all samples can be used as catalysts: crystallites have a nanometer size and a large number of structural defects; morpho­logy provides increased surface area; tungsten carbide particles are covered with a layer of free carbon, which prevents oxidation of carbide to WO3, which has a lower catalytic acti­vity; carbon particles are nanosized (20–30 nm) and contain a large number of structural defects; tungsten carbide-based samples contain free carbon, which increases the specific surface area, but does not cause clogging of pores.
Polarization measurements were carried out at room temperature at a polarization rate of 5 mV/s in a standard three-electrode cell with an Ag|AgCl reference electrode. 1N H2SO4 was used as a base solution, which was bubbled with high-purity argon. Onset potentials for all samples are -0.05 – -0.25 V (in order WC/C – W2C/WC/C – C – W). The overvoltage and Tafel slope were calculated and WC/C composite was shown to have the lowest values of -0.2 V and -75 mV, respectively.
Electrolytic composite of tungsten carbide/carbon have demonstrated the best characteristics, so we plan to continue the development of synthesis method of carbide compounds, which will allow us to reveal even greater potential of carbide catalysts and pave the way for their wide application in catalytic processes.
Horizontal and Vertical Differentiation: Approaching Endogenous Measurement in Intra-industry Trade
Authors: Dutta Sourish
Published: August 2023

Studying intra-industry trade involves theoretical explanations and empirical methods to measure the phenomenon. Indicators have been developed to measure the intensity of intra-industry trade, leading to theoretical models explaining its determinants. It is essential to distinguish between horizontal and vertical differentiation in empirical analyses. The determinants and consequences of intra-industry trade depend on whether the traded products differ in quality. A method for distinguishing between vertical and horizontal differentiation involves comparing exports' unit value to imports for each industry's intra-industry trade. This approach has limitations, leading to the need for an alternative method.
Determination of the Relationship Between Family and Social Support and Anxiety-Depression Levels in Liver Transplant Patients
Authors: KORAŞ SÖZEN Kezban , KARABULUT Neziha
Published: August 2023

Objective: The present study was conducted to determine of the relationship between family and social support and anxiety-depression levels in liver transplant patients.

Methods: The Introductory Characteristics Determination Form, Hospital Anxiety and Depression Scale (HADS), Multidimensional Perceived Social Support Scale (MPSSS) and Perceived Family Support Scale (PFSS) were used to question the socio-demographic characteristics of the patients.

Results: When the distribution of the mean anxiety and depression scores according to their introductory characteristics of the patients was examined, it was determined that the mean score of HADS was found to be high (HAD-A=19.71±3.29, HAD-D=15.90±1.99). The mean MPSSS of the patients was found to be at moderate level as 54.56±17.40; and the mean total score of the PFSS of the patients was found to be at high level as 35.77± 7.16. It was determined that family and social support was effective in reducing the depression levels after liver transplantation.

Conclusions: It was found that family and social support was influential in reducing the depression levels after liver transplantation.
Ultrafast laser processing of glass waveguide substrates for multi-fiber connectivity in co-packaged optics
Authors: Grenier Jason R. , Brusberg Lars , Wieland Kristopher A. , Matthies Juergen , Terwilliger Chad C.
Published: August 2023

High bandwidth demanding applications such as high-performance computing and hyperscale datacenters are drivers for co-packaged optics, which aims to bring optical signals as close as possible to the electrical computing chips by integrating the electro-optic transceivers and ASICs on the same package substrate. These next-generation switches require advanced fiber-to-chip connectivity and novel packaging concepts to enable sufficient power and cost savings. As such, low-loss, high bandwidth, and high fiber-counts are required at the photonic chip interface. In this work, these challenges are addressed by enabling the multi-fiber push-on (MPO) interface at the edge of integrated glass waveguide substrates and thus leverages the existing fiber connector eco-system. An ultrafast laser process is used to singulate glass wafers into individual photonic chips leaving optical-quality end-facets with <1 μm flatness over the 6.5 mm wide connector region thereby directly enabling low-loss fiber-to-chip edge-coupling. To overcome the high-costs and complex photonic packaging associated with active alignment of the fiber connectors to the glass waveguide interfaces, ultrafast laser-ablated features are accurately positioned on the glass substrate to enable self-alignment of the MPO connector guide-pins resulting in a passive alignment approach. Subsequent mating and de-mating of the MPO connector to the glass waveguide interface yields on average a 0.19 dB increase in the coupling loss compared to using active alignment.
Proliferation and migration of ML1 follicular thyroid cancer cells are inhibited by IU1 targeting USP14: role of proteasome and autophagy flux
Authors: Srinivasan Vignesh , Asghar Muhammad Yasir , Zafar Sadia , Törnquist Kid , Lindholm Dan
Published: August 2023

USP14 is a deubiquitinating enzyme involved in protein degradation by interacting with the proteasome and removal of poly-ubiquitin chains on target proteins. USP14 can influence cellular processes such as cell survival, DNA repair, ER stress, endocytosis, and the inflammatory response. USP14 further plays a role in tumor growth, and the inhibition of USP14 by compounds such as IU1 may affect cancer cell migration and invasion. Here we have studied the mechanisms for the action of IU1 in ML1 follicular thyroid cancer cells, comparing them with control, primary thyroid cells. Treatment with IU1 reduced proliferation of ML1 cells in a concentration-dependent manner, and more prominently than in control cells. IU1 decreased basal migration of ML1 cells, and after stimulation of cells with the bioactive compound, sphingosine-1-phosphate. The sphingosine-1-phosphate receptor 3 was increased in ML1 cells as compared with control thyroid cells, but this was not influenced by IU1. Further studies on the mechanism, revealed that IU1 enhanced the proteasome activity as well as LC3B-dependent autophagy flux in ML1 cells with an opposite effect on control thyroid cells. This indicates that IU1 elicits a cell-type dependent autophagy response, increasing it in ML1 cancer cells. The IU1-mediated stimulation of autophagy and proteasomes can likely contribute to the reduced cell proliferation and migration observed in ML1 cells. The precise set of proteins affected by IU1 in ML1 thyroid and other cancer cells warrant further investigations.
Within-host acquisition of colistin-resistance of an NDM-producing Klebsiella quasipneumoniae subsp. similipneumoniae strain through the insertion sequence-903B-mediated inactivation of mgrB gene in a lung transplant child in China
Authors: Wu Yongli , Zhao Jiankang , Li Ziyao , Liu Xinmeng , Hu Yanning , Zhang Feilong , Zhang Yulin , Pu Danni , Li Chen , Zhuo Xianxia , Shi Huihui , Lu Binghuai
Published: August 2023

Background

Colistin, as the antibiotic of “last resort” for carbapenem-resistant Klebsiella, develop resistance during administration of this antimicrobial agent. We identified an NDM-1-producing Klebsiella quasipneumonuae subsp. similipneumoniae (KQSS) strain KQ20605 recovered from a child, which developed resistance to colistin (KQ20786) through acquiring an IS903B element between the -27th and -26th bp of mgrB promoter region after 6-day colistin usage.

Objectives

The aim of this study is to explore the source of IS903B in the disruptive mgrB gene and its underlying mechanisms.

Materials and methods

Antibiotics susceptibility testing was conducted via microbroth dilution method. The in vitro colistin-induced experiment of KQ20605 was performed to mimic the in vivo transition from colistin-sensitive to resistant. Whole-genome sequencing was used to molecular identification of colistin resistance mechanism.

Results

The IS903B element integrated into mgrB gene of KQ20786 had a 100% nucleotide identity and coverage match with one IS903B on plasmid IncR, and only 95.1% (1005/1057) identity to those on chromosome. In vitro, upon the pressure of colistin, KQ20605 could also switch its phenotype from colistin-sensitive to resistant with IS elements (e.g., IS903B and IS26) frequently inserted into mgrB gene at “hotspots”, with the insertion site of IS903B nearly identical to that of KQ20786. Furthermore, IS26 elements in this isolate were only encoded by plasmids, including IncR and conjugative plasmid IncN harboring blaNDM.

Conclusion

Mobilizable IS elements on plasmids tend to be activated and integrated into mgrB gene at “hotspots” in this KQSS, thereby causing the colistin resistance emergence and further dissemination.
Elucidating the role of dsRNA sensing and Toll6 in antiviral responses of Culex quinquefasciatus cells
Authors: Prince Brian C. , Chan Kalvin , Rückert Claudia
Published: August 2023

The first step of any immune response is the recognition of foreign molecular structures inside the host organism. An important molecule that is generally foreign to eukaryotic cells is long double-stranded RNA (dsRNA), which can be generated during virus replication. The mechanisms of sensing viral dsRNA are well-studied in mammalian systems but are only poorly understood in insects, including disease vectors such as Culex quinquefasciatus mosquitoes. These mosquitoes are vectors for important arboviruses, such as West Nile virus, and Culex species mosquitoes are distributed across the globe in many temperate and tropical regions. The major antiviral response triggered by dsRNA in mosquitoes is RNA interference – a sequence-specific response which targets complementary viral RNA for degradation. However, here, we aimed to identify whether sequence-independent dsRNA sensing, mimicked by poly(I:C), can elicit an antiviral response. We observed a significant reduction in replication of La Crosse virus (LACV) in Cx. quinquefasciatus mosquito cells following poly(I:C) priming. We identified a number of antimicrobial peptides and Toll receptors that were upregulated at the transcript level by poly(I:C) stimulation. Notably, Toll6 was upregulated and we determined that a knockdown of Toll6 expression resulted also in increased LACV replication. Future efforts require genetic tools to validate whether the observed Toll6 antiviral activity is indeed linked to dsRNA sensing. However, large-scale functional genomic and proteomic approaches are also required to determine which downstream responses are part of the poly(I:C) elicited antiviral response.
Amodal completion of coincidentally occluded angles: a matter of visual approximation
Authors: Dissegna Andrea , Gerbino Walter , Fantoni Carlo
Published: August 2023

In the Gerbino illusion a regular but coincidentally occluded polygon appears distorted. Such a display represents a critical condition for amodal completion (AC), in which the smooth continuations of contour fragments—however small—conflict with their possible monotonic interpolation. Smoothness and monotonicity are considered the fundamental constraints of AC at the contour level. To account for the Gerbino illusion we contrasted two models derived from alternative AC frameworks: visual interpolation, based on the literal representation of contour fragments, vs. visual approximation, which tolerates a small misorientation of contour fragments, compatible with smoothness and monotonicity constraints. To measure the perceived misorientation of sides of coincidentally occluded angles we introduced a novel technique for analyzing data from a multiple probe adjustment task. An unsupervised cluster analysis of errors in extrapolation and tilt adjustments revealed that the distortion observed in the Gerbino illusion is consistent with visual approximation and, in particular, with the concatenation of misoriented and locally shrinked amodally completed angles. Implications of our technique and obtained results shed new light on visual completion processes.
Association of gender with cardiovascular and autonomic responses to central hypovolemia
Authors: Shankhwar Vishwajeet , Urvec Janez , Steuber Bianca , Schmid Zalaudek Karin , Bergauer Andrej , Alsuwaidi Hanan , Du Plessis Stefan , Alsheikh-Ali Alawi , Kellett Catherine , Bayoumi Riad , Blaber Andrew Phillip , Goswami Nandu
Published: August 2023

Introduction

Lower body negative pressure (LBNP) eliminates the impact of weight-bearing muscles on venous return, as well as the vestibular component of cardiovascular and autonomic responses. We evaluated the hemodynamic and autonomic responses to central hypovolemia, induced by LBNP in both males and females.

Methodology

A total of 44 participants recruited in the study. However, 9 participants did not complete the study protocol. Data from the remaining 35 participants were analysed, 18 males (25.28 ± 3.61 years, 181.50 ± 7.43 cm height, 74.22 ± 9.16 kg weight) and 17 females (22.41 ± 2.73 years, 167.41 ± 6.29 cm height, 59.06 ± 6.91 kg weight). During the experimental protocol, participants underwent three phases, which included 30 min of supine rest, four 4 min intervals of stepwise increases in LBNP from −10 mmHg to −40 mmHg, and 5 min of supine recovery. Throughout the protocol, hemodynamic variables such as blood pressure, heart rate, stroke index, cardiac index, and total peripheral resistance index were continuously monitored. Autonomic variables were calculated from heart rate variability measures, using low and high-frequency spectra, as indicators of sympathetic and parasympathetic activity, respectively.

Results

At rest, males exhibited higher systolic (118.56 ± 9.59 mmHg and 110.03 ± 10.88 mmHg, p < 0.05) and mean arterial (89.70 ± 6.86 and 82.65 ± 9.78, p < 0.05) blood pressure as compared to females. Different levels of LBNP altered hemodynamic variables in both males and females: heart rate [F(1,16) = 677.46, p < 0.001], [F(1,16) = 550.87, p < 0.001]; systolic blood pressures [F(1,14) = 3,186.77, p < 0.001], [F(1,17) = 1,345.61, p < 0.001]; diastolic blood pressure [F(1,16) = 1,669.458, p < 0.001], [F(1,16) = 1,127.656, p < 0.001]; mean arterial pressures [F(1,16) = 2,330.44, p < 0.001], [F(1,16) = 1,815.68, p < 0.001], respectively. The increment in heart rates during LBNP was significantly different between both males and females (p = 0.025). The low and high-frequency powers were significantly different for males and females (p = 0.002 and p = 0.001, respectively), with the females having a higher increase in low-frequency spectral power.

Conclusions and future directions

Cardiovascular activity and autonomic function at rest are influenced by gender. During LBNP application, hemodynamic and autonomic responses differed between genders. These gender-based differences in responses during central hypovolemia could potentially be attributed to the lower sympathetic activity in females. With an increasing number of female crew members in space missions, it is important to understand the role sex-steroid hormones play in the regulation of cardiovascular and autonomic activity, at rest and during LBNP.
Global eligibility and cost effectiveness of icosapent ethyl in primary and secondary cardiovascular prevention
Authors: Toth Peter P. , Ferrières Jean , Waters Max , Mortensen Martin Bødtker , Lan Nick S. R. , Wong Nathan D.
Published: August 2023

Icosapent ethyl (IPE) is a purified eicosapentaenoic acid–only omega-3 fatty acid that significantly reduced cardiovascular (CV) events in patients receiving statins with established cardiovascular disease (CVD) and those with diabetes and additional risk factors in the pivotal REDUCE-IT trial. Since the publication of REDUCE-IT, there has been global interest in determining IPE eligibility in different patient populations, the proportion of patients who may benefit from IPE, and cost effectiveness of IPE in primary and secondary prevention settings. The aim of this review is to summarize information from eligibility and cost effectiveness studies of IPE to date. A total of sixteen studies were reviewed, involving 2,068,111 patients in the primary or secondary prevention settings worldwide. Up to forty-five percent of patients were eligible for IPE, depending on the selection criteria used (ie, REDUCE-IT criteria, US Food and Drug Administration label, Health Canada label, practice guidelines) and the population studied. Overall, eight cost-effectiveness studies across the United States, Canada, Germany, Israel, and Australia were included in this review and findings indicated that IPE is particularly cost effective in patients with established CVD.
Intermediate pressure-normalized principal wall strain values are associated with increased abdominal aortic aneurysmal growth rates
Authors: Zottola Zachary R. , Kong Daniel S. , Medhekar Ankit N. , Frye Lauren E. , Hao Scarlett B. , Gonring Dakota W. , Hirad Adnan A. , Stoner Michael C. , Richards Michael S. , Mix Doran S.
Published: August 2023

Introduction

Current abdominal aortic aneurysm (AAA) assessment relies on analysis of AAA diameter and growth rate. However, evidence demonstrates that AAA pathology varies among patients and morphometric analysis alone is insufficient to precisely predict individual rupture risk. Biomechanical parameters, such as pressure-normalized AAA principal wall strain (ερ+¯/PP, %/mmHg), can provide useful information for AAA assessment. Therefore, this study utilized a previously validated ultrasound elastography (USE) technique to correlate ερ+¯/PP with the current AAA assessment methods of maximal diameter and growth rate.

Methods

Our USE algorithm utilizes a finite element mesh, overlaid a 2D cross-sectional view of the user-defined AAA wall, at the location of maximum diameter, to track two-dimensional, frame-to-frame displacements over a full cardiac cycle, using a custom image registration algorithm to produce ερ+¯/PP. This metric was compared between patients with healthy aortas and AAAs (≥3 cm) and compared between small and large AAAs (≥5 cm). AAAs were then separated into terciles based on ερ+¯/PP values to further assess differences in our metric across maximal diameter and prospective growth rate. Non-parametric tests of hypotheses were used to assess statistical significance as appropriate.

Results

USE analysis was conducted on 129 patients, 16 healthy aortas and 113 AAAs, of which 86 were classified as small AAAs and 27 as large. Non-aneurysmal aortas showed higher ερ+¯/PP compared to AAAs (0.044 ± 0.015 vs. 0.034 ± 0.017%/mmHg, p = 0.01) indicating AAA walls to be stiffer. Small and large AAAs showed no difference in ερ+¯/PP. When divided into terciles based on ερ+¯/PP cutoffs of 0.0251 and 0.038%/mmHg, there was no difference in AAA diameter. There was a statistically significant difference in prospective growth rate between the intermediate tercile and the outer two terciles (1.46 ± 2.48 vs. 3.59 ± 3.83 vs. 1.78 ± 1.64 mm/yr, p = 0.014).

Discussion

There was no correlation between AAA diameter and ερ+¯/PP, indicating biomechanical markers of AAA pathology are likely independent of diameter. AAAs in the intermediate tercile of ερ+¯/PP values were found to have nearly double the growth rates than the highest or lowest tercile, indicating an intermediate range of ερ+¯/PP values for which patients are at risk for increased AAA expansion, likely necessitating more frequent imaging follow-up.
Analysis of an “international teaching practicum” as a program for achieving “teacher agency” and strengthening “technological pedagogical content knowledge”
Authors: Kim Youn Ock , Yun Soyoung , Sol Yang Hwan
Published: August 2023

Introduction

This research aimed to study the achievement of teacher agency of Korean pre-service teachers through their experiences in an international teaching practicum (ITP). This study also diagnosed the domestic pre-orientation (DPO) program of G University to seek the possibilities of developing a TPACK strengthening program. The participants of this study were five female Korean pre-service teachers who were in the ITP from 2015-2016.

Methods

The data were collected in two different time slots: the teaching diaries and ITP reports from the Korean pre-service teachers, DPO teaching materials, and program instructor's field notes were collected in 2016, and then, the interview was conducted in 2018.

Results and discussion

To study their teacher agency achievement, the three chordal triads of agency, the iterational dimension, the practical-evaluative dimension, and the projective dimension, were spotlighted and used as the lens to analyze the data. In addition, the DPO program was analyzed based on the elements of TPACK competencies. The research shows that the ITP was a trigger experience for the Korean pre-service teachers in terms of the achievement of teacher agency. The participants could project their aspirations and then decide and execute what they had learned from the ITP in their actual Korean classrooms. Also, the need to reconstruct the DPO program to be able to assist the pre-service teachers' TPACK achievement has been raised.
Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies
Authors: Cha Jeeyeon , Aguayo-Mazzucato Cristina , Thompson Peter J.
Published: August 2023

Cellular senescence is a response to a wide variety of stressors, including DNA damage, oncogene activation and physiologic aging, and pathologically accelerated senescence contributes to human disease, including diabetes mellitus. Indeed, recent work in this field has demonstrated a role for pancreatic β-cell senescence in the pathogenesis of Type 1 Diabetes, Type 2 Diabetes and monogenic diabetes. Small molecule or genetic targeting of senescent β-cells has shown promise as a novel therapeutic approach for preventing and treating diabetes. Despite these advances, major questions remain around the molecular mechanisms driving senescence in the β-cell, identification of molecular markers that distinguish senescent from non-senescent β-cell subpopulations, and translation of proof-of-concept therapies into novel treatments for diabetes in humans. Here, we summarize the current state of the field of β-cell senescence, highlighting insights from mouse models as well as studies on human islets and β-cells. We identify markers that have been used to detect β-cell senescence to unify future research efforts in this field. We discuss emerging concepts of the natural history of senescence in β-cells, heterogeneity of senescent β-cells subpopulations, role of sex differences in senescent responses, and the consequences of senescence on integrated islet function and microenvironment. As a young and developing field, there remain many open research questions which need to be addressed to move senescence-targeted approaches towards clinical investigation.
Case report: identification of one frameshift variant and two in cis non-canonical splice variants of NEB gene in prenatal arthrogryposis
Authors: Liu Yuefang , Xu Juan , Lv Qiaoyi , Liang Zhe , Li Lingling , Pan Qiong
Published: August 2023

NEB mutation is associated with congenital nemaline myopathies. Here, we report a family with recurrent prenatal arthrogryposis. Trio whole exome sequencing (WES) disclosed three novel NEB (NM_001271208.2) variants including one paternal frameshift c.19049_19050delCA (p.Thr6350Argfs*14) and two double maternal variants in cis c. [24871G>T;24871-10C>G] (p. [Val8291Phe;?]). They are evaluated as “likely pathogenic (LP)”, “variant of uncertain of significance (VUS)”, and “VUS”, respectively. After further prediction, the c.24871G>T, c.24871-10C>G, and c.[24871G>T;24871-10C>G] were respectively genetically engineered into the three plasmids. Compared with their wild-type counterparts, the three plasmids all produced truncated transcripts, and also a significant proportion of the full-length transcripts, which allowed us to reclassify NEB c.24871G>T and c.24871-10C>G variants as LP. As far as we know, this is the first case carrying NEB allele-specific function of partial loss. This result helped the couple make informed reproductive choices and opt for assisted reproduction for future pregnancies. This study also increased awareness to the phenotype of prenatal nemaline myopathy and expanded the variant spectrum of NEB.
LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition
Authors: Buchta Rosean Claire , Leyder Erica C. , Hamilton Jeneice , Carter Joseph J. , Galloway Denise A. , Koelle David M. , Nghiem Paul , Heiland Teri
Published: August 2023

Introduction

Most cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine.

Methods

We designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LTS220A, encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform.

Results

Vaccination with LTS220A-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LTS220A. This effect was dependent on the CD4 T cells’ ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival.

Conclusions

These findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).
Effects of different grassland use patterns on soil bacterial communities in the karst desertification areas
Authors: Chi Yongkuan , Song Shuzhen , Xiong Kangning
Published: August 2023

Soil bacteria are closely related to soil environmental factors, and their community structure is an important indicator of ecosystem health and sustainability. A large number of artificial grasslands have been established to control rocky desertification in the karst areas of southern China, but the influence of different use patterns on the soil bacterial community in artificial grasslands is not clear. In this study, three grassland use patterns [i.e., grazing (GG), mowing (MG), and enclosure (EG)] were used to investigate the effects of different use patterns on the soil bacterial community in artificial grassland by using 16S rDNA Illumina sequencing and 12 soil environmental indicators. It was found that, compared with EG, GG significantly changed soil pH, increased alkaline hydrolyzable nitrogen (AN) content (P < 0.05), and decreased soil total phosphorus (TP) content (P < 0.05). However, MG significantly decreased the contents of soil organic carbon (SOC), total phosphorus (TP), available nitrogen (AN), ammonium nitrogen (NH4+-N), β-1,4-glucosidase (BG), and N-acetyl-β-D-glucamosonidase (NAG) (P < 0.05). The relative abundance of chemoheterotrophy was significantly decreased by GG and MG (P < 0.05). GG significantly increased the relative abundance of Acidobacteria and Gemmatimonadota (P < 0.05) and significantly decreased the relative abundance of Proteobacteria (P < 0.05), but the richness index (Chao 1) and diversity index (Shannon) of the bacterial community in GG, MG, and EG were not significantly different (P > 0.05). The pH (R2 = 0.79, P = 0.029) was the main factor affecting the bacterial community structure. This finding can provide a scientific reference for ecological restoration and sustainable utilization of grasslands in the karst desertification areas.
Sigma-1 receptor knockout disturbs gut microbiota, remodels serum metabolome, and exacerbates isoprenaline-induced heart failure
Authors: Yang Jian-Zheng , Zhang Kai-Kai , Shen Hong-Wu , Liu Yi , Li Xiu-Wen , Chen Li-Jian , Liu Jia-Li , Li Jia-Hao , Zhao Dong , Wang Qi , Zhou Chu-Song
Published: August 2023

Introduction

Heart failure (HF) is usually the end stage of the continuum of various cardiovascular diseases. However, the mechanism underlying the progression and development of HF remains poorly understood. The sigma-1 receptor (Sigmar1) is a non-opioid transmembrane receptor implicated in many diseases, including HF. However, the role of Sigmar1 in HF has not been fully elucidated.

Methods

In this study, we used isoproterenol (ISO) to induce HF in wild-type (WT) and Sigmar1 knockout (Sigmar1−/−) mice. Multi-omic analysis, including microbiomics, metabolomics and transcriptomics, was employed to comprehensively evaluate the role of Sigmar1 in HF.

Results

Compared with the WT-ISO group, Sigmar1−/− aggravated ISO-induced HF, including left ventricular systolic dysfunction and ventricular remodeling. Moreover, Sigmar1−/− exacerbated ISO-induced gut microbiota dysbiosis, which was demonstrated by the lower abundance of probiotics g_Akkermansia and g_norank_f_Muribaculaceae, and higher abundance of pathogenic g_norank_f_Oscillospiraceae and Allobaculum. Furthermore, differential metabolites among WT-Control, WT-ISO and Sigmar−/−-ISO groups were mainly enriched in bile secretion, tryptophan metabolism and phenylalanine metabolism, which presented a close association with microbial dysbiosis. Corresponding with the exacerbation of the microbiome, the inflammation-related NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway were activated in the heart tissues.

Conclusion

Taken together, this study provides evidence that a Sigmar1 knockout disturbs the gut microbiota and remodels the serum metabolome, which may exacerbate HF by stimulating heart inflammation.
CSF metabolites associated with biomarkers of Alzheimer’s disease pathology
Authors: Dong Ruocheng , Lu Qiongshi , Kang Hyunseung , Suridjan Ivonne , Kollmorgen Gwendlyn , Wild Norbert , Deming Yuetiva , Van Hulle Carol A. , Anderson Rozalyn M. , Zetterberg Henrik , Blennow Kaj , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Engelman Corinne D.
Published: August 2023

Introduction

Metabolomics technology facilitates studying associations between small molecules and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with Alzheimer’s disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease.

Methods

The relative abundance of untargeted metabolites was assessed in 161 individuals from the Wisconsin Registry for Alzheimer’s Prevention. A metabolome-wide association study (MWAS) was conducted between 269 CSF metabolites and protein biomarkers reflecting brain amyloidosis, tau pathology, neuronal and synaptic degeneration, and astrocyte or microglial activation and neuroinflammation. Linear mixed-effects regression analyses were performed with random intercepts for sample relatedness and repeated measurements and fixed effects for age, sex, and years of education. The metabolome-wide significance was determined by a false discovery rate threshold of 0.05. The significant metabolites were replicated in 154 independent individuals from then Wisconsin Alzheimer’s Disease Research Center. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study.

Results

Metabolome-wide association study results showed several significantly associated metabolites for all the biomarkers except Aβ42/40 and IL-6. Genetic variants associated with metabolites and Mendelian randomization analysis provided evidence for a causal association of metabolites for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid β (Aβ40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aβ40 and α-synuclein.

Discussion

This study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.
Mortality and causes of death in patients with Parkinson's disease: a nationwide population-based cohort study
Authors: Ryu Dong-Woo , Han Kyungdo , Cho A-Hyun
Published: August 2023

Objective

Parkinson's disease (PD) is a neurodegenerative disease involving multiple systems that can affect mortality. This study aimed to compare all-cause and cause-specific mortality between people with PD and without PD.

Methods

This population-based prospective cohort study is based on Korean National Health Insurance Service data. The primary outcome was the hazard ratio (HR) of all-cause and cause-specific mortality for PD from 2010 to 2019. Cox proportional hazards regression was applied to calculate HRs under crude and three adjusted models with epidemiologic variables.

Results

A total of 8,220 PD patients and 41,100 age- and sex-matched controls without PD were registered. Ten-year mortality was 47.9% in PD patients and 20.3% in non-PD controls. The mortality rate was higher among older and male participants. The leading cause of death in PD was nervous system diseases (38.73%), and 97.1% of those were extrapyramidal and movement disorders, followed by circulatory diseases (15.33%), respiratory diseases (12.56%), and neoplasms (9.7%). PD contributed to an increased risk of all-cause death with an HR of 2.96 (95% CI = 2.84–3.08). HRs of death for PD were 3.07 (95% CI = 2.74–3.45) from respiratory diseases, 1.93 (95% CI = 1.75–2.13) from circulatory diseases, 2.35 (95% CI = 2.00–2.77) from external causes, and 2.69 (95% CI = 2.10–3.43) from infectious diseases.

Conclusion

These results showed that PD was related to a higher risk of mortality in all ages and sexes. The leading causes of death in PD were nervous, circulatory, respiratory, infectious diseases, and external causes.
A toxin-based approach to neuropeptide and peptide hormone discovery
Authors: Koch Thomas Lund , Torres Joshua P. , Baskin Robert P. , Salcedo Paula Flórez , Chase Kevin , Olivera Baldomero M. , Safavi-Hemami Helena
Published: August 2023

Peptide hormones and neuropeptides form a diverse class of bioactive secreted molecules that control essential processes in animals. Despite breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the use of somatostatin-mimicking toxins from cone snails to identify the invertebrate ortholog of somatostatin. Here, we show that this toxin-based approach can be systematically applied to discover other unknown secretory peptides that are likely to have signaling function. Using large sequencing datasets, we searched for homologies between cone snail toxins and secreted proteins from the snails’ prey. We identified and confirmed expression of five toxin families that share strong similarities with unknown secretory peptides from mollusks and annelids and in one case also from ecdysozoans. Based on several lines of evidence we propose that these peptides likely act as signaling peptides that serve important physiological functions. Indeed, we confirmed that one of the identified peptides belongs to the family of crustacean hyperglycemic hormone, a peptide not previously observed in Spiralia. We propose that this discovery pipeline can be broadly applied to other systems in which one organism has evolved molecules to manipulate the physiology of another.
Comparative transcriptomic and plastid development analysis sheds light on the differential carotenoid accumulation in kiwifruit flesh
Authors: Bhargava Nitisha , Ampomah-Dwamena Charles , Voogd Charlotte , Allan Andrew C.
Published: August 2023

Carotenoids are colorful lipophilic isoprenoids synthesized in all photosynthetic organisms which play roles in plant growth and development and provide numerous health benefits in the human diet (precursor of Vitamin A). The commercially popular kiwifruits are golden yellow-fleshed (Actinidia chinensis) and green fleshed (A. deliciosa) cultivars which have a high carotenoid concentration. Understanding the molecular mechanisms controlling the synthesis and sequestration of carotenoids in Actinidia species is key to increasing nutritional value of this crop via breeding. In this study we analyzed fruit with varying flesh color from three Actinidia species; orange-fleshed A. valvata (OF), yellow-fleshed A. polygama (YF) and green-fleshed A. arguta (GF). Microscopic analysis revealed that carotenoids accumulated in a crystalline form in YF and OF chromoplasts, with the size of crystals being bigger in OF compared to YF, which also contained globular substructures in the chromoplast. Metabolic profiles were investigated using ultra-performance liquid chromatography (UPLC), which showed that β-carotene was the predominant carotenoid in the OF and YF species, while lutein was the dominant carotenoid in the GF species. Global changes in gene expression were studied between OF and GF (both tetraploid) species using RNA-sequencing which showed higher expression levels of upstream carotenoid biosynthesis-related genes such as DXS, PSY, GGPPS, PDS, ZISO, and ZDS in OF species compared to GF. However, low expression of downstream pathway genes was observed in both species. Pathway regulatory genes (OR and OR-L), plastid morphology related genes (FIBRILLIN), chlorophyll degradation genes (SGR, SGR-L, RCCR, and NYC1) were upregulated in OF species compared to GF. This suggests chlorophyll degradation (primarily in the initial ripening stages) is accompanied by increased carotenoid production and localization in orange flesh tissue, a contrast from green flesh tissue. These results suggest a coordinated change in the carotenoid pathway, as well as changes in plastid type, are responsible for an orange phenotype in certain kiwifruit species.
Strategic use of observer-perspective questions in couples therapy
Authors: Muntigl Peter , Horvath Adam O.
Published: August 2023

Questions are one of the most frequently used strategies in therapy. There is a body of theoretical work on the kinds of questions that are preferred in specific treatment approaches. However, research on the use of questions in general, how they are formed and what specific therapeutic work they do, is relatively scarce in the literature. In this study, we use the conceptual framework and methods of conversation analysis (CA) to examine how systemic questions soliciting clients' perspective on the partners' thoughts and intents (Observer-Perspective Questions; OPQs) are realized interactively in actual clinical practice and the range of therapeutic work they perform in couples therapy. We identified 78 OPQs from archival data of videotaped time-limited couples therapies, a clinical population working with a professional therapist. From this set of 78 OPQs, five excerpts representing diverse use of OPQs were selected. These excerpts were transcribed in detail capturing not only the textual content but also the prosodic, gestural, and non-verbal aspects of these episodes. Using CA methodology, we identified four specific kinds of changes these questions can promote: progress toward relational optimism, support of positive aspects of the couple's relationship, promoting the concept that the couples' experiences and emotions are interlinked, and introducing new creative relational options. Detailed CA analyses of these clinical excerpts allowed us to identify how the OPQ sequences were built to realize these therapeutically useful moves using various conversational resources progressively and interactively. The conversational analysis of these sequences facilitated the exploration of relationships between the ways the questions are formed, timed, and delivered and the specific functions they perform to move the therapy forward. In conclusion, we make the general argument that examining important therapy events through a CA perspective provides a significant complementary vector to quantitative research on the therapy process.
Is there a processing advantage for verb-noun collocations in Chinese reading? Evidence from eye movements during reading
Authors: Li Hui , Wang Xiaolu , Paterson Kevin B. , Zhang Hua , Li Degao
Published: August 2023

A growing number of studies show a processing advantage for collocations, which are commonly-used juxtapositions of words, such as “joint effort” or “shake hands,” suggesting that skilled readers are keenly perceptive to the occurrence of two words in phrases. With the current research, we report two experiments that used eye movement measures during sentence reading to explore the processing of four-character verb-noun collocations in Chinese, such as 修改文章 (“revise the article”). Experiment 1 compared the processing of these collocations relative to similar four-character expressions that are not collocations (e.g., 修改结尾, “revise the ending”) in neutral contexts and contexts in which the collocation was predictable from the preceding sentence context. Experiment 2 further examined the processing of these four-character collocations, by comparing eye movements for commonly-used “strong” collocations, such as 保护环境 (“protect the environment”), as compared to less commonly-used “weak” collocations, such as 保护自然 (“protect nature”), again in neutral contexts and contexts in which the collocations were highly predictable. The results reveal a processing advantage for both collocations relative to novel expressions, and for “strong” collocations relative to “weak” collocations, which was independent of effects of contextual predictability. We interpret these findings as providing further evidence that readers are highly sensitive to the frequency that words co-occur as a phrase in written language, and that a processing advantage for collocations occurs independently of contextual expectations.