bluuebunny/crossref_metadata_2025 huggingface dataset:
Lord Macartney’s Duelling Fates: Writing, Reading and Revising the Macartney Embassy, 1792–1804
Authors: Bellamy Andrew
Published: March 2022

Recent scholarship on early Sino-British relations has begun challenging the longstanding projection of inevitability upon the First Anglo-Chinese War (1839–1842) by illuminating diverse opinions within each side rather than highlighting an inherent tension between “modern” Britain and “traditional” China. However, the assumption that the Macartney Embassy (1792–1794) served as the first major step toward war has gone largely unchallenged because its diplomatic drama and economic disputes appear to affirm the British and Qing Empires’ supposedly irreconcilable differences. This article examines Britons’ reactions to the Macartney Embassy through travelogues, periodicals, and diplomatic documents to reconstruct the Embassy free from the hindsight of war and the imposition of free trade upon the Qing in the Treaty of Nanjing (1842). It argues that late eighteenth-century Britons variably conceived of the Embassy as a success, dismissed it as inconsequential, or weaponized it for domestic political criticisms. They accordingly supported both optimism in the future of Sino-British relations and a deferent stance toward Britain’s Qing counterparts. The idea that the Embassy exemplified hostility between Britain and China only came about through John Barrow’s reactionary writings during the early nineteenth century that sought to defend Macartney’s conduct by foregrounding the Qing’s apparently impolite behavior. Barrow’s views took root after accounts of the Qing’s treatment of the Amherst Embassy (1816–1817) depicted this behavior as a pattern. In this way, Britons’ initial reactions to the Macartney Embassy complicate clear notions of a linear, causal relationship between the Embassy and the war. They rather suggest that these notions were invented through a misuse of hindsight by early nineteenth-century Britons and solidified by later historians.
Pembuatan Sistem Kontrol Otomatis pada Mesin Press Plastik Berbasis PLC di PT. Laksana Teknik Makmur
Authors: Prasetyani Lin
Published: March 2022

Laksana Tekhnik Makmur Tbk. is a manufacturing company that produces marine interiors and automotive accessories. The company usually uses a continuous sealer machine for plastic production processes. The continuous sealer machine is a plastic press machine that can automatically glue plastic packaging and aluminum foil. The plastic press process on this continuous sealer machine requires three persons as the operator and four work steps, namely, pressing the bottom plastic, installing the iron clip on the top, pressing the plastic on the top, and removing the iron clip. In these work steps, the plastic sealer press process is carried out twice in a product. These steps waste time and operator cause the plastic press process is inefficient. The problem from a continuous sealer machine was replaced by making an automatic control system on the plastic hot press machine. This machine will reduce the number of working steps from four working steps to two working steps. So that it can reduce the cycle time by 75% and increase the production of plastic presses by 24,000 pcs a day.
Consolidated Reading Strategies Used in Comprehending Text from Various Studies: A Systematic Literature Review
Authors: Pelila John Rey Osben , Palangyos Amabel C.
Published: March 2022

A number of studies about reading strategies conducted before 2020 have mostly identified respondents' strategies and the significant relationship of such reading strategies with different factors or variables. However, only a few tried to gather and list the plethora of reading strategies of different studies. Hence, the present study aimed to identify the most focused studies in reading strategies and consolidate all the most mentioned reading strategies from various studies. A systematic literature review was employed in the present study. Also, the researchers generated literature in Ebscohost and ERIC databases. Through inclusion-exclusion criteria, 41 articles (27- Quantitative; 5 Qualitative; 9-Mixed-method) were included for synthesis. It was found out that most research in 2020 and beyond still focused on identifying the reading strategies of their respondents and looking for the relationship of reading strategies in different factors. On the other hand, 71 reading strategies (13- before-reading, 44- while reading, 14- postreading) were consolidated based on the computed frequency and percentage. As suggested, these reading strategies can aid the reading activities of readers, especially that most learnings are in the online phase.
THE INFLUENCE OF ECONOMIC GROWTH AND MINIMUM WAGES ON POVERTY IN SOUTHEAST SULAWESI PROVINCE
Authors: Saputri Widya Eba , Aedy Hasan , Asizah Nur
Published: March 2022

This study aims to examine and analyze the effect of economic growth and the minimum wage on poverty in Southeast Sulawesi Province. The sampling technique used purposive sampling. The type of data used in this study is secondary data from 12 regencies/cities of Southeast Sulawesi Province which is accessed through the website sultra.bps.go.id in the form of time series for the period 2010 to 2019. The analysis tool used is panel data regression with the help of software Eviews 10. The results show the coefficient of determination (R2) is 0.90, meaning that the independent variables of economic growth and the minimum wage affect 90% of the dependent variable of poverty. During the study period, economic growth had a significant positive effect on poverty. The minimum wage has a significant negative effect on poverty.
Substrate Stiffness Determines the Establishment of Apical-Basal Polarization in Renal Epithelial Cells but Not in Tubuloid-Derived Cells
Authors: Hagelaars Maria J. , Yousef Yengej Fjodor A. , Verhaar Marianne C. , Rookmaaker Maarten B. , Loerakker Sandra , Bouten Carlijn V. C.
Published: March 2022

Mechanical guidance of tissue morphogenesis is an emerging method of regenerative medicine that can be employed to steer functional kidney architecture for the purpose of bioartificial kidney design or renal tissue engineering strategies. In kidney morphogenesis, apical-basal polarization of renal epithelial cells is paramount for tubule formation and subsequent tissue functions like excretion and resorption. In kidney epithelium, polarization is initiated by integrin-mediated cell-matrix adhesion at the cell membrane. Cellular mechanobiology research has indicated that this integrin-mediated adhesion is responsive to matrix stiffness, raising the possibility to use matrix stiffness as a handle to steer cell polarization. Herein, we evaluate apical-basal polarization in response to 2D substates of different stiffness (1, 10, 50 kPa and glass) in Madin Darby Canine Kidney cells (MDCKs), a classic canine-derived cell model of epithelial polarization, and in tubuloid-derived cells, established from human primary cells derived from adult kidney tissue. Our results show that sub-physiological (1 kPa) substrate stiffness with low integrin-based adhesion induces polarization in MDCKs, while MDCKs on supraphysiological (>10 kPa) stiffness remain unpolarized. Inhibition of integrin, indeed, allows for polarization on the supraphysiological substrates, suggesting that increased cellular adhesion on stiff substrates opposes polarization. In contrast, tubuloid-derived cells do not establish apical-basal polarization on 2D substrates, irrespective of substrate stiffness, despite their ability to polarize in 3D environments. Further analysis implies that the 2D cultured tubuloid-derived cells have a diminished mechanosensitive capacity when presented with different substrate stiffnesses due to immature focal adhesions and the absence of a connection between focal adhesions and the cytoskeleton. Overall, this study demonstrates that apical-basal polarization is a complex process, where cell type, the extracellular environment, and both the mechanical and chemical aspects in cell-matrix interactions performed by integrins play a role.
Recent Advances in Bioengineered Scaffolds for Cutaneous Wound Healing
Authors: Qin Jianghui , Chen Fang , Wu Pingli , Sun Guoming
Published: March 2022

Wound healing is an evolved dynamic biological process. Though many research and clinical approaches have been explored to restore damaged or diseased skin, the current treatment for deep cutaneous injuries is far from being perfect, and the ideal regenerative therapy remains a significant challenge. Of all treatments, bioengineered scaffolds play a key role and represent great progress in wound repair and skin regeneration. In this review, we focus on the latest advancement in biomaterial scaffolds for wound healing. We discuss the emerging philosophy of designing biomaterial scaffolds, followed by precursor development. We pay particular attention to the therapeutic interventions of bioengineered scaffolds for cutaneous wound healing, and their dual effects while conjugating with bioactive molecules, stem cells, and even immunomodulation. As we review the advancement and the challenges of the current strategies, we also discuss the prospects of scaffold development for wound healing.
Behavior of Magnetically-Driven Concrete (MDC) Filled Double-Skin GFRP Tubes (CFDGT) Under Axial Compression
Authors: Xie Xian-Song , Chen Ju , Wang Jun , Liu Cheng-Bin
Published: March 2022

In order to study the axial compression behavior of magnetically-driven concrete (MDC) filled double-skin GFRP tubes (CFDGT), the axial compression test was conducted on eight columns (the length of columns ranged from 1,000 mm to 3,000 mm). For the MDC, a magnetic vibration device was established to vibrate the MDC, and two series of MDC (concrete with and without vibration) were adopted to investigate the vibration effect, research results showed that the concrete between two circular GFRP tubes could be effectively vibrated by the magnetic force. For the CFDGT columns with MDC, the load-displacement curves, load-strain curves, failure modes and ultimate loads of tested columns were obtained. After the axial compression test, a finite element model was proposed to predict the axial compression behavior and carry out parametric analysis. The design equations for the ultimate load of CFDGTs were derived from the finite element results, comparison results showed that the design equations can predict the ultimate load of CFDGT columns accurately and conservatively, and the maximum calculation error was controlled within 10%.
Rapamycin and Resveratrol Modulate the Gliotic and Pro-Angiogenic Response in Müller Glial Cells Under Hypoxia
Authors: Subirada Paula V. , Vaglienti María V. , Joray Mariana B. , Paz María C. , Barcelona Pablo F. , Sánchez María C.
Published: March 2022

Hypoxia and hypoxia-reoxygenation are frequently developed through the course of many retinal diseases of different etiologies. Müller glial cells (MGCs), together with microglia and astrocytes, participate firstly in response to the injury and later in the repair of tissue damage. New pharmacological strategies tend to modulate MGCs ability to induce angiogenesis and gliosis in order to accelerate the recovery stage. In this article, we investigated the variation in autophagy flux under hypoxia during 4 h, employing both gas culture chamber (1% O2) and chemical (CoCl2) hypoxia, and also in hypoxia-reoxygenation. Then, we delineated a strategy to induce autophagy with Rapamycin and Resveratrol and analysed the gliotic and pro-angiogenic response of MGCs under hypoxic conditions. Our results showed an increase in LC3B II and p62 protein levels after both hypoxic exposure respect to normoxia. Moreover, 1 h of reoxygenation after gas hypoxia upregulated LC3B II levels respect to hypoxia although a decreased cell survival was observed. Exposure to low oxygen levels increased the protein expression of the glial fibrillary acid protein (GFAP) in MGCs, whereas Vimentin levels remained constant. In our experimental conditions, Rapamycin but not Resveratrol decreased GFAP protein levels in hypoxia. Finally, supernatants of MGCs incubated in hypoxic conditions and in presence of the autophagy inductors inhibited endothelial cells (ECs) tubulogenesis. In agreement with these results, reduced expression of vascular endothelial growth factor (VEGF) mRNA was observed in MGCs with Rapamycin, whereas pigment epithelium-derived factor (PEDF) mRNA levels significantly increased in MGCs incubated with Resveratrol. In conclusion, this research provides evidence about the variation of autophagy flux under hypoxia and hypoxia-reoxygenation as a protective mechanism activated in response to the injury. In addition, beneficial effects were observed with Rapamycin treatment as it decreased the gliotic response and prevented the development of newly formed blood vessels.
Relative Populations and IR Spectra of Cu38 Cluster at Finite Temperature Based on DFT and Statistical Thermodynamics Calculations
Authors: Buelna-García Carlos Emiliano , Castillo-Quevedo Cesar , Quiroz-Castillo Jesus Manuel , Paredes-Sotelo Edgar , Cortez-Valadez Manuel , Martin-del-Campo-Solis Martha Fabiola , López-Luke Tzarara , Utrilla-Vázquez Marycarmen , Mendoza-Wilson Ana Maria , Rodríguez-Kessler Peter L. , Vazquez-Espinal Alejandro , Pan Sudip , de Leon-Flores Aned , Mis-May Jhonny Robert , Rodríguez-Domínguez Adán R. , Martínez-Guajardo Gerardo , Cabellos Jose Luis
Published: March 2022

The relative populations of Cu38 isomers depend to a great extent on the temperature. Density functional theory and nanothermodynamics can be combined to compute the geometrical optimization of isomers and their spectroscopic properties in an approximate manner. In this article, we investigate entropy-driven isomer distributions of Cu38 clusters and the effect of temperature on their IR spectra. An extensive, systematic global search is performed on the potential and free energy surfaces of Cu38 using a two-stage strategy to identify the lowest-energy structure and its low-energy neighbors. The effects of temperature on the populations and IR spectra are considered via Boltzmann factors. The computed IR spectrum of each isomer is multiplied by its corresponding Boltzmann weight at finite temperature. Then, they are summed together to produce a final temperature-dependent, Boltzmann-weighted spectrum. Our results show that the disordered structure dominates at high temperatures and the overall Boltzmann-weighted spectrum is composed of a mixture of spectra from several individual isomers.
Thiophene Derivatives as Ligands for Highly Luminescent and Stable Manganese-Doped CsPbCl3 Nanocrystals
Authors: Wang Qian , Gao Long , Yu Chenxi , Wang Meng , Gou Lijie , Zhang Jiaqi
Published: March 2022

Ligands on the surface of perovskite nanocrystals are important to stabilize the nanocrystal structure. However, the research of ligands on Mn2+ ion-doped CsPbCl3 nanocrystals (Mn: CsPbCl3 NCs), a promising candidate family for the lightning community, is relatively rare. Here, we demonstrate a new ligand modification strategy for preparing high-quality Mn: CsPbCl3 NCs by a simple hot-injection method. Thiophene derivative, for the first time, is applied as ligands for perovskite nanocrystals. The new ligands of thiophene derivatives passivate defects on the surface of NCs and enhance optical properties, originating from the sulfur in thiophene additives binding to the uncoordinated lead ions. The photoluminescence quantum yield of the modified Mn: CsPbCl3 NCs is 93% in comparison with 46% of the pristine counterparts, whose value is the highest to date for ligand-modified Mn: CsPbCl3 NCs. Meanwhile, the thermal, storage, and purification stability are also significantly improved. The performance of related LEDs is also investigated.
Nitrite Triggers Reprogramming of the Oral Polymicrobial Metabolome by a Commensal Streptococcus
Authors: Huffines Joshua T. , Stoner Sara N. , Baty Joshua J. , Scoffield Jessica A.
Published: March 2022

Commensal streptococci regulate health and homeostasis within oral polymicrobial communities. Remarkably, high salivary nitrite concentrations have also been associated with improved health in the oral cavity. We previously demonstrated that nitrite assists hydrogen peroxide-producing oral commensal streptococci in regulating homeostasis via the generation of reactive nitrogen species (RNS), which have antimicrobial activity on oral pathogens. However, it is unknown how nitrite and commensal streptococci work in concert to influence the metabolome of oral polymicrobial communities. In this study, we report that nitrite aids commensal streptococci in the inhibition of multi-kingdom pathogens that reside in distinct oral niches, which supports commensal dominance. More importantly, we show that commensal streptococci utilize nitrite to drive the metabolic signature of multispecies biofilms in a manner that supports commensal metabolism and resistance to RNS, and restricts metabolic processes that are required for pathogen virulence. Taken together, our study provides insight into how commensal streptococci use nitrite to trigger shifts in the oral polymicrobial metabolome to support health and homeostasis.
Arterial Stiffness in a Cohort of Young People Living With Perinatal HIV and HIV Negative Young People in England
Authors: Mellin J. , Le Prevost M. , Kenny J. , Sturgeon K. , Thompson L. C. , Foster C. , Kessler H. H. , Goswami Nandu , Klein N. , Judd A. , Castro H.
Published: March 2022

Background

Antiretroviral therapy (ART) has increased life expectancy and consequently the risk of cardiovascular disease (CVD) in adults living with HIV. We investigated the levels and predictors of arterial stiffness in young people (YP) living with perinatal HIV (PHIV) and HIV negative YP in the Adolescents and Adults Living with Perinatal HIV (AALPHI) study.

Methods

AALPHI was a prospective study evaluating the impact of HIV infection and exposure to ART on YP living with PHIV (aged 13–21 years) who had known their HIV status for at least 6 months, and HIV negative YP (aged 13–23 years) who either had a sibling, friend or parent living with HIV. Participants were enrolled from HIV clinics and community services in England. Two hundred and thirteen PHIV and 65 HIV negative YP (42% siblings of PHIV) had pulse wave velocity (PWV) measurements taken (Vicorder software) from the supra-sternal notch to the middle of the thigh cuff, at their second interview in the study between 2015 and 2017. Average PWV was calculated from the three closest readings (≥3 and ≤ 12 m/s) within 0.6 m/s of each other. Linear regression examined predictors of higher (worse) PWV, including age, sex, HIV status and height as a priori, ethnicity, born outside UK/Ireland, alcohol/nicotine/drug use, weight, waist-to-hip-ratio, mean arterial pressure (MAP), caffeine 2 h before PWV and nicotine on day of PWV. A separate PHIV model included CD4, viral load, years taking ART and ART regimen.

Findings

One hundred and twenty eight (60%) PHIV and 45 (69%) HIV negative YP were female (p = 0.18), with median (IQR) age 18 (16, 20) and 18 (16, 21) years (p = 0.48) respectively. Most PHIV were taking a combination of three ART drugs from two classes. There was a trend toward higher (worse) mean PWV in the PHIV group than the HIV negative group [unvariable analysis 6.15 (SD 0.83) m/s vs. 5.93 (0.70) m/s, respectively, unadjusted p = 0.058], which was statistically significant in the multivariable analysis [adjusted p (ap) = 0.020]. In multivariable analysis being male (ap = 0.002), older age (ap < 0.001), higher MAP (ap < 0.001) and nicotine use on day of measurement (ap = 0.001) were also predictors of higher PWV. The predictors were the same in the PHIV model.

Interpretation

By late adolescence PHIV had worse PWV in comparison to HIV negative peers, and traditional risk factors for CVD (higher arterial pressure, being male and older age) were associated with higher PWV values. Regular detailed monitoring of cardiovascular risk factors should become standard of care for every young person with PHIV worldwide.
Earthquake Forecast as a Machine Learning Problem for Imbalanced Datasets: Example of Georgia, Caucasus
Authors: Chelidze Tamaz , Kiria Tengiz , Melikadze George , Jimsheladze Tamar , Kobzev Gennady
Published: March 2022

In this article, we considered the problem of M≥3 earthquake (EQ) forecasting (hindcasting) using a machine learning (ML) approach, using experimental (training) time series on monitoring water-level variations in deep wells as well as geomagnetic and tidal time series in Georgia (Caucasus). For such magnitudes’, the number of “seismic” to “aseismic” days in Georgia is approximately 1:5 and the dataset is close to the balanced one. However, the problem of forecast is practically important for stronger events—say, events of M≥3.5—which means that the learning dataset of Georgia became more imbalanced: the ratio of seismic to aseismic days for in Georgia reaches the values of the order of 1:20 and more. In this case, some accepted ML classification measures, such as accuracy leads to wrong predictions due to a large number of true negative cases. As a result, the minority class, here—seismically active periods—is ignored at all. We applied specific measures to avoid the imbalance effect and exclude the overfitting possibility. After regularization (balancing) of the training data, we build the confusion matrix and performed receiver operating classification in order to forecast the next day probability of M≥3.5  earthquake occurrence. We found that the Matthews’ correlation coefficient (MCC) is the measure, which gives good results even if the negative and positive classes are of very different sizes. Application of MCC to observed geophysical data gives a good forecast of the next day M≥3.5 seismic event probability of the order of 0.8. After randomization of EQ dates in the training dataset, the Matthews’ coefficient efficiency decreases to 0.17.
How Do Undergraduate Biology Instructors Engage With the Open Educational Resource Life Cycle?
Authors: Senn Lillian G. , Heim Ashley B. , Vinson Erin , Smith Michelle K.
Published: March 2022

Open Educational Resources (OER) are widely used instructional materials that are freely available and promote equitable access. OER research at the undergraduate level largely focuses on measuring student experiences with using the low cost resources, and instructor awareness of resources and perceived barriers to use. Little is known about how instructors work with materials based on their unique teaching context. To explore how instructors engage with OER, we surveyed users of CourseSource, an open-access, peer-reviewed journal that publishes lessons primarily for undergraduate biology courses. We asked questions aligned with the OER life cycle, which is a framework that includes the phases: Search, Evaluation, Adaptation, Use, and Share. The results show that OER users come from a variety of institution types and positions, generally have positions that focus more on teaching than research, and use scientific teaching practices. To determine how instructors engage throughout the OER life cycle, we examined the frequency of survey responses. Notable trends include that instructors search and evaluate OER based on alignment to course needs, quality of the materials, and ease of implementation. In addition, instructors frequently modify the published materials for their classroom context and use them in a variety of course environments. The results of this work can help developers design current and future OER repositories to better coincide with undergraduate instructor needs and aid content producers in creating materials that encourage implementation by their colleagues.
Self-Regulated Writing of English Learners: Intervention Development
Authors: Akhmedjanova Diana , Moeyaert Mariola
Published: March 2022

The goal of this study was to develop and test an intervention in order to improve academic writing and SRL skills of English learners (ELs). ELs are well-represented across university and college campuses in the United States. While most of them thrive academically and receive their undergraduate and graduate degrees, a majority of ELs experience difficulties with academic writing such as limited English proficiency levels and opportunities to practice academic writing. Therefore, there is a need to develop and examine evidence-based interventions to promote the development of academic writing skills of ELs. One promising line of research involves adding instruction in self-regulated learning (SRL) to writing courses. In this study, the SRL writing intervention was delivered as a one-credit semester-long course taught at a medium research university. A mixed-methods research design, combining single case quasi-experimental design to collect quantitative data and focus group interviews to collect qualitative data, was used with undergraduate ELs (n = 8) from Southeast Asia. The results of this study revealed that the SRL writing intervention had a small positive effect on the quality of students’ persuasive writing skills, but no effect on students’ SRL skills. Focus group interviews suggested that students appreciated learning about SRL skills, but found the SRL journal confusing and frequent. These findings suggest that both writing and SRL skills are teachable, but may require more time and adjustments to the teaching and learning methods employed in the study. Recommendations for the development of the improved intervention are also provided.
Adjuvant Probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in Patients With Type 1 Diabetes Mellitus
Authors: Wang Chung-Hsing , Yen Hung-Rong , Lu Wen-Li , Ho Hsieh-Hsun , Lin Wen-Yang , Kuo Yi-Wei , Huang Yen-Yu , Tsai Shin-Yu , Lin Hung-Chih
Published: March 2022

Introduction

Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic β cells. Previous study has discovered that probiotic strains residing in the gut play essential roles in host immune regulation. However, few clinical results demonstrated probiotic would actually benefit in attenuating glycated hemoglobin (HbA1c) along with inflammatory cytokine levels of the T1DM patients and analyzed their gut microbiota profile at the same time. In this clinical trial, we evaluated the therapeutic efficacy of probiotics on HbA1c along with inflammatory cytokine levels of T1DM patients to determine an alternative administration mode for T1DM medication. The probiotics changed T1DM gut microbiota profile will be measured by next-generation sequencing (NGS).

Research Design and Methods

A randomized, double-blind, placebo-controlled trial was performed at China Medical University Hospital. T1DM patients between 6 and 18 years of age were enrolled. 27 patients were administered regular insulin therapy plus capsules containing probiotic strainsLactobacillus salivariussubsp.saliciniusAP-32,L. johnsoniiMH-68, andBifidobacterium animalissubsp.lactisCP-9 daily for 6 months, and 29 patients were administered insulin therapy without extra probiotic supplement as placebo group. The variations of fasting blood glucose and HbA1c in these patients were analyzed. In addition, serum levels of inflammatory cytokines and anti-inflammatory cytokine were assessed using enzyme-linked immunosorbent assay. Patients’ stool microbiota were all subjects to NGS analysis.

Results

NGS data showed elevated populations ofBifidobacterium animalis, Akkermansia muciniphilaandLactobacillus salivariusin the gut of patients with T1DM who were taking probiotics. Patients with T1DM who were administered probiotics showed significantly reduced fasting blood glucose levels compared with the before-intervention levels. The HbA1c levels of the patients also improved after administration of probiotics. The concentrations of IL-8, IL-17, MIP-1β, RANTES, and TNF-α were significantly reduced and were associated with an increased TGF-β1 expression after probiotic intervention. The persistence effect of glycemic control and immunomodulation were observed even 3 months after discontinuation of the probiotics.

Conclusions

Here, we found that conventional insulin therapy plus probiotics supplementation attenuated T1DM symptoms than receiving insulin treatment only. Probiotics supplementation with insulin treatment changed gut microbiota and revealed better outcome in stabilizing glycemic levels and reducing HbA1c levels in patients with T1DM through beneficial regulation of immune cytokines.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03880760.
Genetic Variants Relate to Fasting Plasma Glucose, 2-Hour Postprandial Glucose, Glycosylated Hemoglobin, and BMI in Prediabetes
Authors: Lin Leweihua , Fang Tuanyu , Lin Lu , Ou Qianying , Zhang Huachuan , Chen Kaining , Quan Huibiao
Published: March 2022

Diabetes mellitus (DM) is a chronic disease that seriously threatens human health. Prediabetes is a stage in the progression of DM. The level of clinical indicators including fasting plasma glucose (FPG), 2-h postprandial glucose (2hPG), and glycosylated hemoglobin (HbA1C) are the diagnostic markers of diabetes. In this genome-wide association study (GWAS), we aimed to investigate the association of genetic variants with these phenotypes in Hainan prediabetes. In this study, we recruited 451 prediabetes patients from the residents aged ≥18 years who participated in the National Diabetes Prevalence Survey of the Chinese Medical Association in 2017. The GWAS of FPG, 2hPG, HbA1C, and body mass index (BMI) in prediabetes was analyzed with a linear model using an additive genetic model with adjustment for age and sex. We identified that rs13052524 inMRPS6and rs62212118 inSLC5A3were associated with 2hPG in Hainan prediabetes (p= 4.35 × 10-6,p= 4.05 × 10-6, respectively). Another six variants in the four genes (LINC01648,MATN1,CRAT37, andSLCO3A1) were related to HbA1C. Moreover, rs11142842, rs1891298, rs1891299, and rs11142843 inTRPM3/TMEM2and rs78432036 inMLYCD/OSGIN1were correlated to BMI (allp< 5 × 10-6). This study is the first to determine the genome-wide association of FPG, 2hPG, and HbA1C, which emphasizes the importance of in-depth understanding of the phenotypes of high-value susceptibility gene markers in the diagnosis of prediabetes.
Peptide Model of the Mutant Proinsulin Syndrome. I. Design and Clinical Correlation
Authors: Dhayalan Balamurugan , Glidden Michael D. , Zaykov Alexander N. , Chen Yen-Shan , Yang Yanwu , Phillips Nelson B. , Ismail-Beigi Faramarz , Jarosinski Mark A. , DiMarchi Richard D. , Weiss Michael A.
Published: March 2022

The mutant proinsulin syndrome is a monogenic cause of diabetes mellitus due to toxic misfolding of insulin’s biosynthetic precursor. Also designatedmutant INS-gene induced diabetes of the young(MIDY), this syndrome defines molecular determinants of foldability in the endoplasmic reticulum (ER) of β-cells. Here, we describe a peptide model of a key proinsulin folding intermediate and variants containing representative clinical mutations; the latter perturb invariant core sites in native proinsulin (LeuB15→Pro, LeuA16→Pro, and PheB24→Ser). The studies exploited a 49-residue single-chain synthetic precursor (designated DesDi), previously shown to optimizein vitroefficiency of disulfide pairing. Parent and variant peptides contain a single disulfide bridge (cystine B19-A20) to provide a model of proinsulin’s first oxidative folding intermediate. The peptides were characterized by circular dichroism and redox stability in relation to effects of the mutations on (a)in vitrofoldability of the corresponding insulin analogs and (b) ER stress induced in cell culture on expression of the corresponding variant proinsulins. Striking correlations were observed between peptide biophysical properties, degree of ER stress and age of diabetes onset (neonatal or adolescent). Our findings suggest that age of onset reflects the extent to which nascent structure is destabilized in proinsulin’s putative folding nucleus. We envisage that such peptide models will enable high-resolution structural studies of key folding determinants and in turn permit molecular dissection of phenotype-genotype relationships in this monogenic diabetes syndrome. Our companion study (next article in this issue) employs two-dimensional heteronuclear NMR spectroscopy to define site-specific perturbations in the variant peptides.
Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes
Authors: Tan Qiming , Akindehin Seun E. , Orsso Camila E. , Waldner Richelle C. , DiMarchi Richard D. , Müller Timo D. , Haqq Andrea M.
Published: March 2022

The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2–3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.
Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
Authors: Pillay Nikita Simone , Ross Owen A. , Christoffels Alan , Bardien Soraya
Published: March 2022

Parkinson’s disease is a neurodegenerative disorder with a heterogeneous genetic etiology. The advent of next-generation sequencing (NGS) technologies has aided novel gene discovery in several complex diseases, including PD. This Perspective article aimed to explore the use of NGS approaches to identify novel loci in familial PD, and to consider their current relevance. A total of 17 studies, spanning various populations (including Asian, Middle Eastern and European ancestry), were identified. All the studies used whole-exome sequencing (WES), with only one study incorporating both WES and whole-genome sequencing. It is worth noting how additional genetic analyses (including linkage analysis, haplotyping and homozygosity mapping) were incorporated to enhance the efficacy of some studies. Also, the use of consanguineous families and the specific search for de novo mutations appeared to facilitate the finding of causal mutations. Across the studies, similarities and differences in downstream analysis methods and the types of bioinformatic tools used, were observed. Although these studies serve as a practical guide for novel gene discovery in familial PD, these approaches have not significantly resolved the “missing heritability” of PD. We speculate that what is needed is the use of third-generation sequencing technologies to identify complex genomic rearrangements and new sequence variation, missed with existing methods. Additionally, the study of ancestrally diverse populations (in particular those of Black African ancestry), with the concomitant optimization and tailoring of sequencing and analytic workflows to these populations, are critical. Only then, will this pave the way for exciting new discoveries in the field.
Therapies for Membranous Nephropathy: A Tale From the Old and New Millennia
Authors: Scolari Francesco , Alberici Federico , Mescia Federica , Delbarba Elisa , Trujillo Hernando , Praga Manuel , Ponticelli Claudio
Published: March 2022

Primary Membranous Nephropathy (PMN) is the most frequent cause of nephrotic syndrome in adults. If untreated, PMN can lead to end-stage renal disease; moreover, affected patients are at increased risk of complications typical of nephrotic syndrome such as fluid overload, deep vein thrombosis and infection. The association of PMN with HLA-DQA1 and the identification in around 70% of cases of circulating autoantibodies, mainly directed towards the phospholipase A2 receptor, supports the autoimmune nature of the disease. In patients not achieving spontaneous remission or in the ones with deteriorating kidney function and severe nephrotic syndrome, immunosuppression is required to increase the chances of achieving remission. The aim of this review is to discuss the evidence base for the different immunosuppressive regimens used for PMN in studies published so far; the manuscript also includes a section where the authors propose, based upon current evidence, their recommendations regarding immunosuppression in the disease, while highlighting the still significant knowledge gaps and uncertainties.
Regulation of Inflammatory Cell Death by Phosphorylation
Authors: Xu Wen , Huang Yi
Published: March 2022

Cell death is a necessary event in multi-cellular organisms to maintain homeostasis by eliminating unrequired or damaged cells. Currently, there are many forms of cell death, and several of them, such as necroptosis, pyroptosis and ferroptosis, even apoptosis trigger an inflammatory response by releasing damage-associated molecular patterns (DAMPs), which are involved in the pathogenesis of a variety of human inflammatory diseases, including autoimmunity disease, diabetes, Alzheimer’s disease and cancer. Therefore, the occurrence of inflammatory cell death must be strictly regulated. Recently, increasing studies suggest that phosphorylation plays a critical role in inflammatory cell death. In this review, we will summarize current knowledge of the regulatory role of phosphorylation in inflammatory cell death and also discuss the promising treatment strategy for inflammatory diseases by targeting related protein kinases that mediate phosphorylation or phosphatases that mediate dephosphorylation.
pH-Responsive Amphoteric p (APTMACl-co-AMPS) Hydrogel as Effective Multiple Dye Sponge Network From Aqueous Media
Authors: Demirci Sahin , Ari Betul , Aktas Nahit , Sahiner Nurettin
Published: March 2022

Here, the cationic poly (3-acrylamidepropyl trimethyl ammonium chloride) [p (APTMACl)], anionic poly (2-acrylamido-2methylpropane sulfonic acid) [p (AMPS)], and amphoteric poly (APTMACl-co-AMPS) hydrogels were prepared via free-radical polymerization techniques as pH-sensitive hydrogels. The prepared systems were used in methylene blue (MB), and Eosin Y (EY) removal from aqueous media. HCl-treated p (APTMACl-co-AMPS) hydrogels prepared in 1:3 mol ratio adsorbed higher amount of MB and EY from their corresponding 50 ml 50 ppm aqueous solutions that are 47.5 ± 0.9, and 10.7 ± 0.1 mg/g, respectively. Also, the adsorbed amount of MB and EY by HCl-treated p (APTMACl-co-AMPS) hydrogels decreased with the increase in the medium pH from 3.0 to 9.0. It was also observed that HCl-treated p (APTMACl-co-AMPS)-3 hydrogels removed 39.2 ± 0.2, and 28.1 ± 1.0 mg/g MB and EY dyes simultaneously from their corresponding 50 ml 50 ppm aqueous mixture solutions. MB and EY adsorption by HCl-treated p (APTMACl-co-AMPS)-3 hydrogels were found to abide by pseudo-first-order adsorption kinetics. Moreover, MB adsorption by HCl-treated p (APTMACl-co-AMPS) hydrogels were found to fit with Freundlich, EY adsorption fit with Langmuir isotherms. The distribution coefficient values of HCl-treated p (APTMACl-co-AMPS) hydrogels were calculated as 3.7 ± 0.1 and 1.3 ± 0.1 for MB and EY, respectively. The calculated selectivity coefficient value showed that HCl-treated p (APTMACl-co-AMPS) hydrogels are at least 3-fold higher selective to MB than EY.
Frequency and Factors Associated With Adverse Events Among Multi-Drug Resistant Tuberculosis Patients in Pakistan: A Retrospective Study
Authors: Atif Muhammad , Ahmed Waqar , Nouman Iqbal Muhammad , Ahmad Nafees , Ahmad Wajiha , Malik Iram , Al-Worafi Yaser Mohammed
Published: March 2022

Background

Treatment of multi-drug resistant tuberculosis (MDR-TB) for a prolonged period with comparatively less effective and more toxic second-line anti-TB drugs is associated with greater incidence of adverse events.

Study aim

This study aimed to evaluate the frequency and factors associated with occurrence of adverse events among patients with MDR-TB attending the Bahawal Victoria Hospital, Bahawalpur, Pakistan.

Study design

This retrospective study included all patients with MDR-TB who were registered and treated at the study site between June 2014 and December 2016 and had their treatment outcomes available at the time of data collection (i.e., November 2018).

Measures and outcomes

The Electronic Nominal Record System (ERNS) records, medical charts of patients, and laboratory reports were reviewed to obtain the data. Adverse events were reported as per the standard criteria recommended by the WHO. Multivariate binary logistic regression was used to find the independent factors associated with the occurrence of adverse events.

Results

A total of 179 patients with MDR-TB were included in the final analysis. Out of these, 114 (63.7%) patients experienced at least one adverse event during the course of their treatment. Depression was the most common adverse events (33%), followed by nausea and vomiting (27.4%) and arthralgia (27.4%). The factors associated with the occurrence of adverse events included presence of comorbidity (adjusted odds ratio [AOR] 2.951; 95% CI 1.423, 6.118) and being employed (AOR 3.445; 95% CI 1.188, 9.993).

Conclusion

Adverse events were prevalent in this cohort, however, resolved with the effective management approaches. Patients with identified factors for occurrence of adverse events need special attention and enhanced clinical management.
Clinical Outcomes in Maximum Tolerated Medical Therapy in Penetrating Keratoplasty for Bullous Keratopathy
Authors: Wy Seoyoung , Kim Young Kook , Jeoung Jin Wook , Kim Mee Kum
Published: March 2022

Purpose

To compare the clinical outcomes of maximum tolerated medical therapy (MTMT) in patients with penetrating keratoplasty (PKP) with those of Ahmed glaucoma valve (AGV) implantation.

Methods

The medical records were retrospectively reviewed in patients who had undergone PKP for bullous keratopathy and were treated with MTMT or AGV implantation for the management of glaucoma. A total of 18 bullous keratopathic patients were investigated between January 2010 and February 2017: 9 patients treated with MTMT and 9 patients treated with AGV implantation. Non-corrected visual acuity (NCVA), intraocular pressure (IOP), endothelial cell density (ECD), hexagonality, coefficient of variation (CV), central corneal thickness (CCT), median survival time of the graft, and the presence of epithelial keratopathy were compared between the groups at each time point or between baseline and after treatment of glaucoma in each group.

Results

There were no significant differences in the visual acuity and corneal thickness between the two groups or within each group over time. Both groups showed a significant reduction in IOP compared with the baseline IOP, and IOP reductions were greater in the AGV group than in the MTMT group (p = 0.040). Significant ECD reductions were found in each group between the baseline and 6 months (p = 0.008 in the MTMT group, p = 0.015 in the AGV group); however, no differences were found between the two groups until 12 months. The significant hexagonality reduction was found in the AGV group between the baseline and 12 months (p = 0.018). The median survival time showed no significant difference in the survival analysis.

Conclusions

Maximum tolerated medical therapy in penetrating keratoplasty for bullous keratopathy seems to similarly affect the endothelial cell density or graft survival when compared with at least 12 month-followed Ahmed glaucoma valve implantation.
Metatranscriptomic Analyses Unravel Dynamic Changes in the Microbial and Metabolic Transcriptional Profiles in Artisanal Austrian Hard-Cheeses During Ripening
Authors: Quijada Narciso Martín , Dzieciol Monika , Schmitz-Esser Stephan , Wagner Martin , Selberherr Evelyne
Published: March 2022

Vorarlberger Bergkäse (VB) is an artisanal Austrian washed-rind hard cheese produced from alpine cows’ raw milk without the addition of ripening cultures. Ripening time is a key factor in VB, as it strongly influences the microbial communities present in the cheeses and the organoleptic properties of the product. In this study, the microbial and metabolic transcriptional profiles in VB rinds at different ripening times were investigated. VB products before (30 days of ripening) and after (90 days of ripening) selling were selected, RNA was extracted and subjected to shotgun metatranscriptomic sequencing. The analysis revealed some of the previously described abundant bacterial taxa of Brevibacterium, Corynebacterium, Halomonas, Psychrobacter, and Staphylococcus to be highly active in VB rinds. Additionally, the investigation of most important metabolic pathways in cheese ripening clearly showed differences in the gene transcription profiles and the active microbiota between the two ripening points investigated. At 30 days of ripening, metabolic events related with the degradation of residual lactose, lactate, citrate, proteolysis, and lipolysis were significantly more transcribed and mainly associated with Staphylococcus. On the other hand, genes involved in the degradation of smaller compounds derived from previous metabolism (i.e., metabolism of free amino acids and fatty acids) were significantly more expressed in VB rinds with 90 of ripening, and mainly associated with Brevibacterium and Corynebacterium. These latter metabolic activities are responsible of the generation of compounds, such as methanethiol and 2,3-butanediol, that are very important for the flavor and aroma characteristics of cheeses. This study shows the dynamic changes in the gene transcriptional profiles associated with energy substrates metabolism and the generation of organoleptic compounds during VB ripening and uncovers bacterial taxa as key drivers of the ripening process. These taxa might be the target for future studies toward an accelerated cheese ripening and the enhancement of its organoleptic properties.
Application Potential of CTHRC1 as a Diagnostic and Prognostic Indicator for Colon Adenocarcinoma
Authors: Pang Chen , Wang Hongwei , Shen Chengcheng , Liang Houjie
Published: March 2022

Colon adenocarcinoma (COAD), ranking third in incidence and second in mortality, is one of the most common cancer types in the world. The initial stages of COAD usually show no obvious clinical symptoms; moreover, effective screening or diagnostic indicators with high sensitivity and specificity are lacking, which often leads to missed treatment opportunities. Collagen triple helix repeat containing 1 (CTHRC1) is a glycosylated protein secreted during tissue repair, which reduces collagen matrix deposition and promotes cell migration. Under physiological conditions, the expression of CTHRC1 is conducive to wound healing; however, the pathological overexpression of CTHRC1 promotes tumour growth and proliferation. In this study, we evaluated the application potential of CTHRC1 as an early diagnosis and prognostic survival monitoring biomarker for COAD in addition to unravelling its molecular mechanism in the development of COAD and exploring new therapeutic targets. Therefore, various tumour databases were used to investigate the expression of CTHRC1 in COAD at the mRNA and protein levels. CTHRC1 expression was found to be significantly increased in COAD, regardless of clinical cancer stage, age, sex or race. Moreover, CTHRC1 expression was significantly correlated with poor prognosis and positively correlated with CD8+ T cell, CD4+ T cell, neutrophil, macrophage and dendritic cell infiltration. The relevant function pathways and neighbouring proteins to CTHRC1 in COAD were identified as ROR2, VAPA, LY6E and several collagen family proteins. Therefore, this study suggests that CTHRC1 is a potential diagnostic and prognostic biomarker for patients with COAD.