bluuebunny/crossref_metadata_2025 huggingface dataset:
PENGARUH KUALITAS KEHIDUPAN KERJA (QUALITY OF WORK LIFE), KELELAHAN EMOSIONAL DAN KOMPETENSI TERHADAP KINERJA BIDAN PADA RUMAH SAKIT UMUM DAERAH KABUPATEN MUNA
Authors: Aifu Dewi Kurniati , Ansir Ansir , Aliddin Laode Asfahyadin , Sujono Sujono , Zaludin Zaludin
Published: February 2022

The purpose of this study was to examine and explain the effect of Quality of Work Life (Quality of Work Life), Emotional Fatigue and Competence on the Performance of Midwives at the Muna Regency General Hospital. This research approach is a survey with an Explanatory Research design. Data was collected using instruments in the form of data analysis, namely descriptive analysis and inferential statistics, namely Multivariate Regression Analysis. The results of this study state that (1) Quality of Work Life has a positive and significant effect on the performance of midwives, (2) Emotional exhaustion has a positive and insignificant effect on the performance of midwives, (3) Competence has a positive and significant effect on the performance of midwives, (4) Quality of Work Life, Emotional exhaustion and competence simultaneously affect the performance of midwives
PENGARUH PROMO GRATIS ONGKIR DAN CUSTOMER EXPERIENCE TERHADAP KEPUASAN PELANGGAN PENGGUNA APLIKASI SHOPEE
Authors: Lubis Rinanda Hamida , Ramadhan Zein , Yusuf Abdul
Published: February 2022

This study aims to determine the effect of free shipping promos and customer experience on customer satisfaction. The population in this study are customers who shop online through the Shopee application. The technique used in sampling is non-probability sampling with purposive sampling method. The sample in this study amounted to 100 respondents. Data collection was obtained from distributing questionnaires and literature studies. The data analysis method used in this research is multiple linear regression. The results showed that the free shipping promo and customer experience had a positive and significant effect on customer satisfaction. Based on the results of the coefficient of determination test, the R Square value of the customer experience variable is 0.384 or 38.4%, meaning that the customer experience variable has the most dominant influence on customer satisfaction.
MEMUASKAN PELANGGAN DENGAN KUALITAS LAYANAN
Authors: Yusuf Yusuf , Mustamin Hastuti , Taufik Muhammad
Published: February 2022

Kepuasan pelanggan penting bagi restorankarena merupakan syarat yang perlu dipenuhi agar pelanggan tidak meninggalkan rumah makan dan beralih ke rumah makan lain. Salah satu factor penting untuk memuaskan pelanggan adalah memberikan layanan yang berkualitas. Penelitian ini bertujuan untuk menganalisis peran kualitas layanan dalam memuaskan pelanggan rumah makan. Penelitian ini dilakukan pada 135 pelanggan rumah makan padang “Sederhana” di kota Kendari. Analisis data menggunakan regresi linier berganda. Hasil penelitian menemukan kualitas layanan yang terdiri dari tangible, emphaty, reliability, responsiveness dan assurance baik secara parsial maupun simultan memiliki peran yang signifikan dalam memuaskan pelanggan
IMPLEMENTASI SOFT SKILL DAN HARD SKILL DALAM MENINGKATKAN KINERJA PEGAWAI DINAS PEMUDA DAN OLAHRAGA PROVINSI ( BENGKULU
Authors: Markoni Markoni
Published: February 2022

The problem in this study is how to implement Soft Skills and Hard Skills in improving the performance of the Bengkulu Province Youth and Sports Service (Dispora) Employees. Primary data needed was obtained through a questionnaire. Considering that the research population is diverse, the sample is taken using a stratified sampling technique. Data analysis used multiple regression and correlation methods, while the hypothesis test with t test and F test with 0.05.The results of the analysis show that Soft Skill and Hard Skill have an effect on employee performance, respectively 0.318 and 0.539. By comparing the two, the influence of Hard Skills on employee performance is more dominant when compared to the influence of Soft Skill changes.Soft Skills and Hard Skills together have a very strong relationship with employee performance with a variation contribution of 60.4%. Considering the contribution of the two types of expertise, it is recommended that the relevant officials make efforts to improve these skills, by conducting internal training, involving their employees in various trainings organized by other parties, and motivating their employees to continue to develop their skills independently.
“Islands of Qualities in an Ocean of Quantification”: A Conversation with Wendy Espeland and Michael Sauder
Authors: Ossandón José , Espeland Wendy , Sauder Michael
Published: February 2022

In this interview, Wendy Espeland and Michael Sauder both reflect on their work on rankings, reactivity and commensuration, and think about the implication their sociological work could have on the practices of those dealing with rankings and their reactive effects.
CALCULATION OF GRADING OF COLD RECYCLED MIXTURES USING NEW AGGREGATES ACCORDING TO THE DESIGNED THICKNESS OF A REHABILITATED LAYER
Authors: Tereshchenko Tetyana , Illiash Serhiy
Published: February 2022

Technologies of cold recycling of asphalt concrete using various types of binders have been widely implemented in road building industry in Ukraine. Technologies of cold recycling allow to eliminate some types of deformations or destructions and also to enhance bearing capacity of flexible road pavements. If required, process of cold recycling assumes application of new aggregates to achieve standard grading of a recycled mixture. As the standard requirement does not state any restrictions on relative content of new aggregates, these can be applied to achieve the designed thickness of a rehabilitated layer. This article presents a method for calculation of grading of cold recycled mixtures according to the designed thickness of a rehabilitated layer assuming the amount of reclaimed asphalt pavement (RAP) equals to the amount of asphalt concrete in a milled layer. The proposed method is based on calculation of grading of a mixture of new aggregates that should be rather individual for each recycled mixture. The input data for calculation should be obtained from results of a field testing of “old” road pavement construction and also from laboratory investigation of “old” asphalt concrete cores.
The article gives also some examples of calculation which are performed on base of mean values of standard grading of recycled mixtures. Nevertheless, the proposed method of calculation could be applied on the base of any values selected within the standard limits. The proposed method assures precise modeling of composition and properties of a recycled mixture and could be implemented when planning projects on rehabilitation of flexible road pavements either by cold in-plant or cold in-place recycling.
Male Embryos Produced in vitro Deviate From Their in vivo Counterparts in Placental Gene Expression on Day 32 of Pregnancy
Authors: Drum Jéssica N. , Madureira Guilherme , Rosa Camila O. , Seneda Marcelo M. , Wiltbank Milo C. , Sartori Roberto , Ortega M. Sofia
Published: February 2022

This study compared the gene expression of extraembryonic membranes (EEM) from in vitro produced (IVP) and in vivo (AI) derived pregnancies. A piece of conceptus (day 18) or chorioallantois (day 32) was used for DNA and RNA isolation and sex determination. Male and female ratios were analyzed by Chi-square. A total of three samples per sex and group (AI and IVP, days 18 and 32) were used for transcriptome analysis. Differentially expressed genes (DEGs) were determined using edgeR-robust. A false discovery rate (FDR) <0.05 was used for statistical significance. Sex ratio was similar on day 18 for AI and IVP groups. On day 32, the IVP group had a greater number of females than males (75 vs. 25%, P = 0.004). When comparing AI and IVP males vs. females, in both groups, genes upregulated in females on day 18 were related to placental function such as PAGs and TKDPs. On males on day 18, IFNT-related genes were upregulated. Comparing the techniques within sex, on day 18 female conceptuses, 50 genes were upregulated in IVP, and 21 in AI. IGF2, which is involved in placenta development, and APOA2, APOB, and APOE, involved in lipid metabolism, were upregulated in IVP conceptuses. On day 18, males had 15 upregulated genes in AI and 7 in IVP. On day 32, females had 21 upregulated genes in AI and 53 in IVP. Genes involved in lipid synthesis and metabolism were increased in the IVP group. Males on day 32 presented 899 DEGs, 564 upregulated in AI and 335 in IVP. Embryos from IVP had decreased expression of genes related to lipid and carbohydrate metabolism. Interestingly, pregnancy-associated glycoproteins (PAG) 7, 9, 10, and 19, were downregulated in IVP male. In conclusion, IVP-derived male embryos were more susceptible to alterations in gene expression and these effects extend to the peri-implantation period including genes associated with placental development and markers of placental function.
Metallic Nanoparticles for the Modulation of Tumor Microenvironment; A New Horizon
Authors: Shariatzadeh Siavash , Moghimi Negin , Khalafi Farima , Shafiee Sepehr , Mehrabi Mohsen , Ilkhani Saba , Tosan Foad , Nakhaei Pooria , Alizadeh Ali , Varma Rajender S. , Taheri Mohammad
Published: February 2022

Cancer is one of the most critical human challenges which endangers many people’s lives every year with enormous direct and indirect costs worldwide. Unfortunately, despite many advanced treatments used in cancer clinics today, the treatments are deficiently encumbered with many side effects often encountered by clinicians while deploying general methods such as chemotherapy, radiotherapy, surgery, or a combination thereof. Due to their low clinical efficacy, numerous side effects, higher economic costs, and relatively poor acceptance by patients, researchers are striving to find better alternatives for treating this life-threatening complication. As a result, Metal nanoparticles (Metal NPs) have been developed for nearly 2 decades due to their important therapeutic properties. Nanoparticles are quite close in size to biological molecules and can easily penetrate into the cell, so one of the goals of nanotechnology is to mount molecules and drugs on nanoparticles and transfer them to the cell. These NPs are effective as multifunctional nanoplatforms for cancer treatment. They have an advantage over routine drugs in delivering anticancer drugs to a specific location. However, targeting cancer sites while performing anti-cancer treatment can be effective in improving the disease and reducing its complications. Among these, the usage of these nanoparticles (NPs) in photodynamic therapy and sonodynamic therapy are notable. Herein, this review is aimed at investigating the effect and appliances of Metal NPs in the modulation tumor microenvironment which bodes well for the utilization of vast and emerging nanomaterial resources.
Sa12b-Modified Functional Self-Assembling Peptide Hydrogel Enhances the Biological Activity of Nucleus Pulposus Mesenchymal Stem Cells by Inhibiting Acid-Sensing Ion Channels
Authors: Han Letian , Wang Ziyu , Chen Haoyu , Li Jie , Zhang Shengquan , Zhang Sumei , Shao Shanzhong , Zhang Yinshun , Shen Cailiang , Tao Hui
Published: February 2022

Various hydrogels have been studied for nucleus pulposus regeneration. However, they failed to overcome the changes in the acidic environment during intervertebral disc degeneration. Therefore, a new functionalized peptide RAD/SA1 was designed by conjugating Sa12b, an inhibitor of acid-sensing ion channels, onto the C-terminus of RADA16-I. Then, the material characteristics and biocompatibility of RAD/SA1, and the bioactivities and mechanisms of degenerated human nucleus pulposus mesenchymal stem cells (hNPMSCs) were evaluated. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) confirmed that RAD/SA1 self-assembling into three-dimensional (3D) nanofiber hydrogel scaffolds under acidic conditions. Analysis of the hNPMSCs cultured in the 3D scaffolds revealed that both RADA16-I and RAD/SA1 exhibited reliable attachment and extremely low cytotoxicity, which were verified by SEM and cytotoxicity assays, respectively. The results also showed that RAD/SA1 increased the proliferation of hNPMSCs compared to that in culture plates and pure RADA16-I. Quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting demonstrated that the expression of collagen I was downregulated, while collagen II, aggrecan, and SOX-9 were upregulated. Furthermore, Ca2+ concentration measurement and western blotting showed that RAD/SA1 inhibited the expression of p-ERK through Ca2+-dependent p-ERK signaling pathways. Therefore, the functional self-assembling peptide nanofiber hydrogel designed with the short motif of Sa12b could be used as an excellent scaffold for nucleus pulposus tissue engineering. Moreover, RAD/SA1 exhibits great potential applications in the regeneration of mildly degenerated nucleus pulposus.
Asymmetrical Flow Field-Flow Fractionation Methods for Quantitative Determination and Size Characterization of Thiols and for Mercury Size Speciation Analysis in Organic Matter-Rich Natural Waters
Authors: Worms Isabelle A. M. , Kavanagh Killian , Moulin Elodie , Regier Nicole , Slaveykova Vera I.
Published: February 2022

Asymmetrical flow field-flow fractionation (AF4) efficiently separates various macromolecules and nano-components of natural waters according to their hydrodynamic sizes. The online coupling of AF4 with fluorescence (Fluo) and UV absorbance (UV) detectors (FluoD and UVD, respectively) and inductively coupled plasma–mass spectrometry (ICP-MS) provides multidimensional information. This makes it a powerful tool to characterize and quantify the size distributions of organic and inorganic nano-sized components and their interaction with trace metals. In this study, we developed a method combining thiol labeling by monobromo(trimethylammonio)bimane bromide (qBBr) with AF4–FluoD to determine the size distribution and the quantities of thiols in the macromolecular dissolved organic matter (DOM) present in highly colored DOM-rich water sampled from Shuya River and Lake Onego, Russia. We found that the qBBr-labeled components of DOM (qB-DOM) were of humic type, characterized by a low hydrodynamic size (dh < 2 nm), and have concentrations <0.3 μM. After enrichment with mercury, the complexes formed between the nano-sized components and Hg were analyzed using AF4–ICP-MS. The elution profile of Hg followed the distribution of the UV-absorbing components of DOM, characterized by slightly higher sizes than qB-DOM. Only a small proportion of Hg was associated with the larger-sized components containing Fe and Mn, probably inorganic oxides that were identified in most of the samples from river to lake. The size distribution of the Hg–DOM complexes was enlarged when the concentration of added Hg increased (from 10 to 100 nM). This was explained by the presence of small iron oxides, overlapping the size distribution of Hg–DOM, on which Hg bound to a small proportion. In addition, to provide information on the dispersion of macromolecular thiols in colored DOM-rich natural water, our study also illustrated the potential of AF4–FluoD–UVD–ICP-MS to trace or quantify dynamic changes while Hg binds to the natural nano-colloidal components of surface water.
Hemoglobin-to-Red-Cell Distribution Width Ratio Is a Novel Predictor of Long-Term Patient Outcomes After Percutaneous Coronary Intervention: A Retrospective Cohort Study
Authors: Xiu Wen-Juan , Zheng Ying-Ying , Wu Ting-Ting , Hou Xian-Geng , Yang Yi , Ma Yi-Tong , Xie Xiang
Published: February 2022

Background

The hemoglobin level and red cell distribution width (RDW) have been linked to the prognosis of coronary atherosclerotic heart disease (CAHD). However, the relationship between the ratio of hemoglobin to the RDW (HRR) and clinical outcomes after percutaneous coronary intervention (PCI) is not known. Here, we explored the impact of the HRR on clinical outcomes after PCI.

Methods

In our study, we selected 6,046 CAHD patients with PCI hospitalized in the First Affiliated Hospital of Xinjiang Medical University from 2008 to 2016. The patients were grouped according to their HRR ratio: group A (HRR < 10.25, n = 2,344) and group B (HRR ≥ 10.25, n = 3,702). The difference in clinical outcomes between the two groups was compared. Patients were followed up for 35.9 ± 22.6 months.

Results

Three hundred nine patients died during follow-up. These included 166 patients (7.1%) in the HRR < 10.25 group and 143 patients (3.9%) in the HRR ≥ 10.25 group (P < 0.001). The incidences of cardiogenic death (5.7 vs. 3.2%) and major cardiovascular adverse events (16.5 vs. 12.9%) also differed significantly between the groups (both Ps < 0.001). Analysis using the multivariate Cox proportional hazard model found a significant association between a decreased HRR and post-PCI mortality (all-cause death, adjusted HR: 1.479, 95% CI: 1.156–1.893, p = 0.002; cardiac death, adjusted HR: 1.470, 95% CI: 1.116–1.936, p = 0.006).

Conclusion

The HRR is predictive of post-PCI mortality among CAHD patients.
Calculation Method for Optimizing the Bearing Capacity of Two-Layer Clay Foundation Based on Upper-Bound Limit Analysis
Authors: Lin Xing-Chao , Zhang Qiang , Wang Xianzhi , Feng Yelin , Zhu Guina
Published: February 2022

In this study, a foundation bearing capacity limit analysis upper-bound solution (FLU) was proposed under the theoretical framework of limit analysis. To be more specific, an optimized mathematical model based on a rigid block discrete system was first established, with the minimum bearing capacity as the objective function, block velocity as the main variable, and the satisfaction of velocity compatibility, associated flow rule, and functional equilibrium equations of adjacent blocks as main constraints. Then, using an optimization approach, the upper-bound value of the foundation’s bearing capacity was obtained. On this basis, the principle of establishing the value interval of the most dangerous slip depth of the two-layer clay foundation was developed by investigating the effects of varying depths on the bearing capacity of the two-layer clay foundation. Meanwhile, an approach for calculating the bearing capacity of the two-layer clay foundation was proposed to achieve the goal of reaching the foundation’s minimum bearing capacity. Furthermore, using a mathematical example, the proposed approach was proven to be rational.
Case Report: Plasmacytoma of External Urethral Meatus
Authors: Su Wen , Zeng Liang , Zhao Dongsheng , Fu Ying , Tang Jin
Published: February 2022

Rationale

Extramedullary plasmacytoma (EMP) can occur in various parts of the body. It is generally accepted that the highest site of occurrence is the head and neck region (80% to 90%), followed by the gastrointestinal tract and the skin. It is worth mentioning that the site of disease, in this case, was the urethral meatus, which is extremely rare in clinical practice.

Patient Concerns

A 50-year-old female complained of an episode of painless gross hematuria without symptoms of frequent urination, urgency, abdominal pain, abdominal distension, fever, or oliguria. The patient has no history of smoking or drinking and denied any family history of solid malignancy or hematological disease.

Diagnosis and Interventions

Urethrocystoscopy revealed urethral polypoid hyperplasia, which we initially thought could be a urethral caruncle. The patient was asked to undergo caruncle resection after 1 week of potassium permanganate sitz bath, and postoperative pathology revealed plasmacytoma. After that, a whole-body MRI showed no other lesions. She received postoperative radiotherapy.

Outcomes

During radiotherapy, the patient’s condition and appetite were fair, and the skin mucositis was I°. Pelvic contrast-enhanced MRI and whole-body PET-CT 6 months after urethral meatus lumpectomy and radiotherapy showed changes without obvious abnormal signs. No recurrence or metastasis was detected after one year of follow-up.

Lessons

Urinary EMP is a rare disease. It is not easy to diagnose due to its rare site of occurrence and non-specific symptoms. The diagnosis of EMP requires a combination of imaging studies and pathological findings. Currently, surgery combined with radiotherapy or radiotherapy alone is the mainstay treatment and usually results in an acceptable local control rate. At the same time, chemotherapy cannot be ignored.
Efficient Identification of Multiple Parameter Errors in Power Grids by Mixed-Effects Models and Generalized Least Squares
Authors: Liang Dong , Cheng Yawen , Su Suntao , Wang Xiaoxue , Zeng Lin
Published: February 2022

Accurate knowledge of static parameters forms the basis for nearly all applications in the energy management system. This paper proposes an efficient method for the simultaneous identification and correction of multiple network parameter errors based on a linear mixed-effects (LME) model and the generalized least squares (GLS) method. An LME model for parameter error identification is formulated using the residual equations of multiple-snapshot state estimation with equality constraints. The parameter errors are considered as the fixed effects and the measurement errors are considered as the random effects. Then, using the measurement error variances estimated by the LME model, the GLS method is used to estimate the parameter errors along with a hypothesis testing to infer whether each parameter error is zero. The semi-supervised adversarial autoencoder is used for bad data detection in the presence of erroneous parameters and limited labels such that only measurement snapshots that are free of any bad data are used. The proposed methodology is efficient in that the LME model is only used to estimate the variances of the measurement errors using a small number of measurement snapshots, therefore the huge computation burden needed to solve a large-scale LME model is avoided. In addition, the GLS only involves inversion of low-dimension matrices, which is very efficient even a large number of measurement snapshots are used. Thorough tests of the proposed methodology on a large number of scenarios are provided to show the effectiveness of the proposed methodology with promising results.
A Simplified SARS-CoV-2 Mouse Model Demonstrates Protection by an Oral Replicon-Based mRNA Vaccine
Authors: Jawalagatti Vijayakumar , Kirthika Perumalraja , Hewawaduge Chamith , Park Ji-Young , Yang Myeon-Sik , Oh Byungkwan , So Mi Young , Kim Bumseok , Lee John Hwa
Published: February 2022

A mouse model of SARS-CoV-2 that can be developed in any molecular biology lab with standard facilities will be valuable in evaluating drugs and vaccines. Here we present a simplified SARS-CoV-2 mouse model exploiting the rapid adenoviral purification method. Mice that are sensitive to SARS-CoV-2 infection were generated by transducing human angiotensin-converting enzyme 2 (hACE2) by an adenovirus. The expression kinetics of the hACE2 in transduced mice were assessed by immunohistochemistry, RT-PCR, and qPCR. Further, the ability of the hACE2 to support viral replication was determined in vitro and in vivo. The hACE2 expression in the lungs of mice was observed for at least nine days after transduction. The murine macrophages expressing hACE2 supported viral replication with detection of high viral titers. Next, in vivo studies were carried out to determine viral replication and lung disease following SARS-CoV-2 challenge. The model supported viral replication, and the challenged mouse developed lung disease characteristic of moderate interstitial pneumonia. Further, we illustrated the utility of the system by demonstrating protection using an oral mRNA vaccine. The multicistronic vaccine design enabled by the viral self-cleaving peptides targets receptor binding domain (RBD), heptad repeat domain (HR), membrane glycoprotein (M) and epitopes of nsp13 of parental SARS-CoV-2. Further, Salmonella and Semliki Forest virus replicon were exploited, respectively, for gene delivery and mRNA expression. We recorded potent cross-protective neutralizing antibodies in immunized mice against the SARS-CoV-2 delta variant. The vaccine protected the mice against viral replication and SARS-CoV-2-induced weight loss and lung pathology. The findings support the suitability of the model for preclinical evaluation of anti-SARS-CoV-2 therapies and vaccines. In addition, the findings provide novel insights into mRNA vaccine design against infectious diseases not limiting to SARS-CoV-2.
Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature
Authors: Leffler Jonatan , Trend Stephanie , Ward Natalie C. , Grau Georges E. , Hawke Simon , Byrne Scott N. , Kermode Allan G. , French Martyn A. , Hart Prue H.
Published: February 2022

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system that results in demyelination of axons, inefficient signal transmission and reduced muscular mobility. Recent findings suggest that B cells play a significant role in disease development and pathology. To further explore this, B cell profiles in peripheral blood from 28 treatment-naive patients with early MS were assessed using flow cytometry and compared to 17 healthy controls. Conventional and algorithm-based analysis revealed a significant increase in MS patients of IgA+ memory B cells (MBC) including CD27+, CD27- and Tbet+ subsets. Screening circulating B cells for markers associated with B cell function revealed a significantly decreased expression of the B cell activation factor receptor (BAFF-R) in MS patients compared to controls. In healthy controls, BAFF-R expression was inversely associated with abundance of differentiated MBC but this was not observed in MS. Instead in MS patients, decreased BAFF-R expression correlated with increased production of proinflammatory TNF following B cell stimulation. Finally, we demonstrated that reactivation of Epstein Barr Virus (EBV) in MS patients was associated with several phenotypic changes amongst MBCs, particularly increased expression of HLA-DR molecules and markers of a T-bet+ differentiation pathway in IgM+ MBCs. Together, these data suggest that the B cell compartment is dysregulated in MS regarding aberrant MBC homeostasis, driven by reduced BAFF-R expression and EBV reactivation. This study adds further insights into the contribution of B cells to the pathological mechanisms of MS, as well as the complex role of BAFF/BAFF-R signalling in MS.
Repolarization of Tumor-Infiltrating Myeloid Cells for Augmentation of CAR T Cell Therapies
Authors: Luo Weichuan , Napoleon John V. , Zhang Fenghua , Lee Yong Gu , Wang Bingbing , Putt Karson S. , Low Philip S.
Published: February 2022

Although CAR T cell therapies have proven to be effective in treating hematopoietic cancers, their abilities to regress solid tumors have been less encouraging. Mechanisms to explain these disparities have focused primarily on differences in cancer cell heterogeneity, barriers to CAR T cell penetration of solid tumors, and immunosuppressive microenvironments. To evaluate the contributions of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) on CAR T cell efficacies, we have exploited the ability of a folate-targeted Toll-like receptor 7 agonist (FA-TLR7-1A) to specifically reactivate TAMs and MDSCs from an immunosuppressive to pro-inflammatory phenotype without altering the properties of other immune cells. We report here that FA-TLR7-1A significantly augments standard CAR T cell therapies of 4T1 solid tumors in immune competent mice. We further show that co-administration of the FA-TLR7-1A with the CAR T cell therapy not only repolarizes TAMs and MDSCs from an M2-like anti-inflammatory to M1-like pro-inflammatory phenotype, but also enhances both CAR T cell and endogenous T cell accumulation in solid tumors while concurrently increasing their states of activation. Because analogous myeloid cells in healthy tissues ar not altered by administration of FA-TLR7-1A, no systemic activation of the immune system nor accompanying weight loss is observed. These data argue that immunosuppressive myeloid cells contribute prominently to the failure of CAR T cells to eradicate solid tumors and suggest that methods to reprogram tumor associated myeloid cells to a more inflammatory phenotype could significantly augment the potencies of CAR T cell therapies.
Chemokine-Driven Migration of Pro-Inflammatory CD4+ T Cells in CNS Autoimmune Disease
Authors: Heng Aaron H. S. , Han Caleb W. , Abbott Caitlin , McColl Shaun R. , Comerford Iain
Published: February 2022

Pro-inflammatory CD4+ T helper (Th) cells drive the pathogenesis of many autoimmune conditions. Recent advances have modified views of the phenotype of pro-inflammatory Th cells in autoimmunity, extending the breadth of known Th cell subsets that operate as drivers of these responses. Heterogeneity and plasticity within Th1 and Th17 cells, and the discovery of subsets of Th cells dedicated to production of other pro-inflammatory cytokines such as GM-CSF have led to these advances. Here, we review recent progress in this area and focus specifically upon evidence for chemokine receptors that drive recruitment of these various pro-inflammatory Th cell subsets to sites of autoimmune inflammation in the CNS. We discuss expression of specific chemokine receptors by subsets of pro-inflammatory Th cells and highlight which receptors may be tractable targets of therapeutic interventions to limit pathogenic Th cell recruitment in autoimmunity.
Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity
Authors: Laghmouchi Aicha , Kester Michel G. D. , Hoogstraten Conny , Hageman Lois , de Klerk Wendy , Huisman Wesley , Koster Eva A. S. , de Ru Arnoud H. , van Balen Peter , Klobuch Sebastian , van Veelen Peter A. , Falkenburg J. H. Frederik , Jedema Inge
Published: February 2022

In the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire leading to graft-versus-leukemia effect and/or graft-versus-host disease in the patient. The magnitude of allo-HLA-DP-specific immune responses has been shown to depend on the specific HLA-DP disparity between donor and patient and the immunogenicity of the mismatched HLA-DP allele(s). HLA-DP peptidome clustering (DPC) was developed to classify the HLA-DP molecules based on similarities and differences in their peptide-binding motifs. To investigate a possible categorization of HLA-DP molecules based on overlap of presented peptides, we identified and compared the peptidomes of the thirteen most frequently expressed HLA-DP molecules. Our categorization based on shared peptides was in line with the DPC classification. We found that the HLA-DP molecules within the previously defined groups DPC-1 or DPC-3 shared the largest numbers of presented peptides. However, the HLA-DP molecules in DPC-2 segregated into two subgroups based on the overlap in presented peptides. Besides overlap in presented peptides within the DPC groups, a substantial number of peptides was also found to be shared between HLA-DP molecules from different DPC groups, especially for groups DPC-1 and -2. The functional relevance of these findings was illustrated by demonstration of cross-reactivity of allo-HLA-DP-reactive T-cell clones not only against HLA-DP molecules within one DPC group, but also across different DPC groups. The promiscuity of peptides presented in various HLA-DP molecules and the cross-reactivity against different HLA-DP molecules demonstrate that these molecules cannot be strictly categorized in immunogenicity groups.
Effects of High Salinity Stress on the Survival, Gill Tissue, Enzyme Activity and Free Amino Acid Content in Razor Clam Sinonovacula constricta
Authors: Cao Wei , Bi Siqi , Chi Changfeng , Dong Yinghui , Xia Sudong , Liu Zhihong , Zhou Liqing , Sun Xiujun , Geng Yusong , Wu Biao
Published: February 2022

Salinity can affect the physiological and productive characteristics of bivalves. The razor clam Sinonovacula constricta naturally distributing in intertidal zones and estuarine waters is extensively cultured in China. High-salinity is a serious threat to its culture, especially in pond culture model. Here, we investigated the effects of high-salinity on the survival, gill tissue, enzyme activity and free amino acid content of S. constricta. Individuals were randomly divided into six groups treated with different salinities of 20, 25, 30, 35, 40, and 45 ppt. The median lethal salinity calculated by linear regression and probit analysis methods were similar, with 46.61, 43.17, 36.99, 35.99, and 34.99 ppt by linear regression, while 44.63, 42.87, 38.45, 37.32, and 36.17 ppt by probit analysis at 72, 96, 120, 144, and 168 h, respectively. Furthermore, paraffin section revealed that the gill of razor clam shrunk quickly under high-salinity and dissolved at 48 h under salinity of 40 ppt, but not under 30 ppt. In addition, the activities of three enzymes including Na+-K+-ATPase, acid phosphatase and alkaline phosphatase changed significantly under high-salinity. Besides, the contents of total free amino acids (TFAAs) in the gill tissues were 61.25 ± 1.58, 89.36 ± 4.18, and 111.98 ± 1.46 mg⋅g–1 at salinity of 20, 30, and 40 ppt, respectively, indicating increasing TFAA contents with salinity. Notably, several amino acid species including taurine, alanine, proline, glycine and glutamic showed significantly changed contents in response to salinity variation, suggesting these amino acids might play an important role in razor clam’s adaptation to salinity stress. Combining all these results, it was referred that razor clams may adapt to moderately high-salinity of 30 ppt in a short time through osmotic adjustment. Although a small proportion of individuals could survive under the salinity of 35 ppt, the death of most individuals still suggested it can hardly be accepted in aquacultural production. Notably, living under a salinity of 40 ppt for more than 48 h could cause great damage to razor clams. Therefore, the seawater salinity is recommended to be lower than 30 ppt for S. constricta aquaculture. Overall, this study provides guidance for the culture and breeding of high-salinity tolerant razor clams.
A Comparison of Face-Down Positioning and Adjustable Positioning After Pars Plana Vitrectomy for Macular Hole Retinal Detachment in High Myopia
Authors: Gao Yan , Ruan Ting , Chen Nan , Yu Bin , Xing Xiaoli , Du Qing , Qi Yan , Li Jun
Published: February 2022

Purpose

To compare the anatomical and functional outcomes of macular hole retinal detachment (MHRD) in high myopia after pars plana vitrectomy (PPV) with face-down positioning and adjustable positioning.

Methods

Fifty-three eyes from 53 patients with MHRD were analyzed in this study. All patients received PPV with silicon oil for tamponade and then subdivided into 2 groups: 28 were included in a face-down positioning group and 25 were included in the adjustable positioning group. Patients were followed up for at least 6 months. The main outcome was the rate of anatomical macular hole (MH) closure and retinal reattachment. Secondary outcome measures were the best-corrected visual acuity and postoperative complications.

Results

There was no significant difference in the rate of MH closure (53.6 vs. 72.0%, p = 0.167) and retinal reattachment (100 vs. 96%, p = 0.472) between the face-down group and adjustable group. Compared with the mean preoperative best-corrected visual acuity (BCVA), the mean postoperative BCVA at the 6-month follow-up improved significantly in both groups (p = 0, both). But there was no significant difference in the mean postoperative BCVA (p = 0.102) and mean BCVA improvement (p = 0.554) at 6 months after surgery between the two groups. There was no significant difference in the high intraocular pressure (IOP) after surgery between the two groups (53.6 vs. 44%, p = 0.487). There were no other complications that occurred during the follow-up.

Conclusion

Adjustable positioning after PPV with silicon oil tamponade for MHRD repair is effective and safe. Face-down positioning does not seem to be necessary for all patients with MHRD.
Intensive Systolic Blood Pressure Lowering and Kidney Disease Progression in IgA Nephropathy: A Cohort Study
Authors: Yu Guizhen , Cheng Jun , Jiang Yan , Li Heng , Li Xiayu , Chen Jianghua
Published: February 2022

Background

Hypertension has been shown to be an important risk factor in IgA nephropathy (IgAN). The 2021 the Kidney Disease Improving Global Outcomes (KDIGO) Guideline proposes a target systolic blood pressure (SBP) of less than 120 mmHg in patients with Chronic Kidney Disease (CKD) not receiving dialysis. However, whether lowering SBP from <140– <120 mm Hg is renoprotective is unknown. This study aims to evaluate the association of SBP and the progression of IgAN, then explore whether lowering SBP from <140– <120 mm Hg is renoprotective.

Methods

Overall, 2,240 patients with IgAN were enrolled in this study. Cox proportional hazards models and restricted cubic splines were used to estimate the associations between SBP and kidney failure events which are defined as 50% estimated glomerular filtration rate (eGFR) decline or kidney failure.

Results

After a median follow-up of 30.05 months, 217 (9.69%) patients reached composite kidney failure events. The association of SBP and kidney failure events showed a linear relationship. The risk of kidney failure events was greater with higher SBP. Compared with SBP <120 mm Hg, the hazard ratio was 1.85 (1.16–2.97, p = 0.010) for SBP <140 mm Hg after adjustment for traditional risk factors. The renoprotective benefits of therapy targeting SBP <120 mm Hg from SBP <140 mm Hg was detectable within the subgroup with proteinuria >1.0 g/d, CKD 1-3a stage, but not those with proteinuria ≤ 1.0 g/d and CKD 3b-4 stage.

Conclusions

In patients with IgAN, SBP was independently associated with composite kidney failure events. Lowering SBP from <140– <120 mm Hg was renoprotective.
Effectiveness of Proton-Pump Inhibitors in Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Randomized Controlled Trials
Authors: Yu Fei , Huang Qihui , Ye Yousheng , Zhang Lin
Published: February 2022

Background

Although several randomized controlled trials (RCTs) have been published in recent years, the role of proton-pump inhibitors (PPI) in patients with chronic obstructive pulmonary disease (COPD) remains controversial. This preliminary meta-analysis was conducted to evaluate the clinical efficacy of PPI in patients with COPD.

Methods

RCTs related to PPI in the treatment of patients with a definite diagnosis of COPD were enrolled in this meta-analysis. PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP databases were retrieved to identify eligible studies from database establishment to September 22, 2021. Two researchers independently screened the articles, extracted the data and evaluated the risk of bias in the included studies independently. The study complied with PRISMA 2020 guideline for this study. The meta-analysis was performed using RevMan 5.3. Heterogeneity among studies was tested using the I2 test. The results were presented as risk ratios (RRs) with 95% confidence intervals (CIs).

Results

A total of 15 RCTs, including 1,684 patients, were enrolled. The meta-analysis revealed that PPI plus conventional treatment was superior to conventional treatment with respect to the case fatality rate (RR = 0.30; 95% CI, 0.18–0.52; P < 0.001), the incidence of gastrointestinal bleeding (RR = 0.23; 95% CI, 0.14–0.38; P < 0.001), the incidence of other adverse reactions (RR = 0.33; 95% CI, 0.28–0.39; P < 0.001) and the number of acute exacerbations [mean difference (MD) = −1.17; 95% CI, 1.75 to −0.60: P < 0.001] in patients with COPD. No significant differences were found in clinical efficacy (RR = 1.08; 95% CI, 0.95–1.22; P = 0.25), FEV1/FVC (MD = 3.94; 95% CI, −8.70 to 16.58; P = 0.54) and nosocomial infection rate (RR = 1.31; 95% CI, 0.57–3.00; P = 0.52) between the two groups.

Discussion

This comprehensive meta-analysis suggested that PPI treatment for COPD may reduce the case fatality rate, incidence of gastrointestinal bleeding and other adverse reactions and number of acute exacerbations. However, the present meta-analysis also has some limitations of the evidence, such as the high risk of bias of the included studies, and predominance of included studies from China, which may result in publication bias. Therefore, further large-scale RCTs are needed to confirm our findings.

Systematic Trial Registration

Identifier: CRD42022301304.
A Novel Coagulation Classification and Postoperative Bleeding in Severe Spontaneous Intracerebral Hemorrhage Patients on Antiplatelet Therapy
Authors: Liu Qingyuan , Li Xiong , Wang Nuochuan , Yang Junhua , Wang Kaiwen , Chen Shanwen , Li Jiangan , Wu Jun , Zhang Yanan , Wang Shuo
Published: February 2022

Background and Purpose

For patients with severe spontaneous intracerebral hemorrhage on antiplatelet therapy (patients with APT-SICH), postoperative rebleeding (PR) is an important cause of poor outcomes after surgery. As impacted by coagulation disorder caused by APT, patients with APT-SICH are likely to suffer from PR. This study aimed to assess the risk of PR in patients with APT-SICH receiving emergency surgery using a novel coagulation classification.

Methods

This prospective, multicenter cohort study consecutively selected patients with APT-SICH between September 2019 and March 2021. The preoperative coagulation factor function was recorded, and the platelet function was assessed using thrombelastography. Based on platelet and coagulation factor function, a novel four-type coagulation classification, i.e., Type I (severe coagulation disorder), Type IIa (low platelet reserve capacity), Type IIb (normal coagulation), and Type III (hypercoagulation), was presented. The primary outcome was PR, defined as the rebleeding in the operative region or new intracerebral hemorrhage correlated with the operation.

Results

Of the included 197 patients with APT-SICH, PR occurred in 40 patients (20.3%). The novel coagulation classification categorized 28, 32, 122, and 15 patients into Type I, Type IIa, Type IIb, and Type III, respectively. The Type I patients had the highest incident rate of PR (39.3 per 100 persons), followed by the Type IIa patients (31.3 per 100 persons). In the PR-related analysis, the large hematoma volume (hazard ratio (HR): 1.02; 95% CI: 1.02–1.03; p < 0.001), Type I (HR: 9.72; 95% CI: 1.19–79.67; p = 0.034), and Type IIa (HR: 8.70; 95% CI: 1.09–69.61; p = 0.041) were correlated with the highest risk of PR. The coagulation classification could discriminate the PR patients from no PR (NPR) patients (p < 0.001), and it outperformed the conventional coagulation assessment (only considering platelet count and coagulation factor function) (c-statistic, 0.72 vs. 0.55).

Conclusion

The novel coagulation classification could discriminate the patients with APT-SICH with the highest risk of PR preoperatively. For the Type I and Type IIa patients, emergency surgery should be performed carefully.
Long-Term Motor Cortical Electrical Stimulation Ameliorates 6-Hydroxydopamine-Induced Motor Dysfunctions and Exerts Neuroprotective Effects in a Rat Model of Parkinson’s Disease
Authors: Kuo Chi-Wei , Chang Ming-Yuan , Chou Ming-Yi , Pan Chien-Yuan , Peng Chih-Wei , Tseng Hui-Chiun , Jen Tsu-Yi , He Xiao-Kuo , Liu Hui-Hua , Nguyen Thi Xuan Dieu , Chang Pi-Kai , Hsieh Tsung-Hsun
Published: February 2022

Objective

Cortical electrical stimulation (CES) can modulate cortical excitability through a plasticity-like mechanism and is considered to have therapeutic potentials in Parkinson’s disease (PD). However, the precise therapeutic value of such approach for PD remains unclear. Accordingly, we adopted a PD rat model to determine the therapeutic effects of CES. The current study was thus designed to identify the therapeutic potential of CES in PD rats.

Methods

A hemiparkinsonian rat model, in which lesions were induced using unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to identify the therapeutic effects of long-term (4-week) CES with intermittent theta-burst stimulation (iTBS) protocol (starting 24 h after PD lesion observation, 1 session/day, 5 days/week) on motor function and neuroprotection. After the CES intervention, detailed functional behavioral tests including gait analysis, akinesia, open-field locomotor activity, apomorphine-induced rotation as well as degeneration level of dopaminergic neurons were performed weekly up to postlesion week 4.

Results

After the CES treatment, we found that the 4-week CES intervention ameliorated the motor deficits in gait pattern, akinesia, locomotor activity, and apomorphine-induced rotation. Immunohistochemistry and tyrosine hydroxylase staining analysis demonstrated that the number of dopamine neurons was significantly greater in the CES intervention group than in the sham treatment group.

Conclusion

This study suggests that early and long-term CES intervention could reduce the aggravation of motor dysfunction and exert neuroprotective effects in a rat model of PD. Further, this preclinical model of CES may increase the scope for the potential use of CES and serve as a link between animal and PD human studies to further identify the therapeutic mechanism of CES for PD or other neurological disorders.
Dynamic Temporal Relationship Between Autonomic Function and Cerebrovascular Reactivity in Moderate/Severe Traumatic Brain Injury
Authors: Froese Logan , Gomez Alwyn , Sainbhi Amanjyot Singh , Batson Carleen , Stein Kevin , Alizadeh Arsalan , Zeiler Frederick A.
Published: February 2022

There has been little change in morbidity and mortality in traumatic brain injury (TBI) in the last 25 years. However, literature has emerged linking impaired cerebrovascular reactivity (a surrogate of cerebral autoregulation) with poor outcomes post-injury. Thus, cerebrovascular reactivity (derived through the pressure reactivity index; PRx) is emerging as an important continuous measure. Furthermore, recent literature indicates that autonomic dysfunction may drive impaired cerebrovascular reactivity in moderate/severe TBI. Thus, to improve our understanding of this association, we assessed the physiological relationship between PRx and the autonomic variables of heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) using time-series statistical methodologies. These methodologies include vector autoregressive integrative moving average (VARIMA) impulse response function analysis, Granger causality, and hierarchical clustering. Granger causality testing displayed inconclusive results, where PRx and the autonomic variables had varying bidirectional relationships. Evaluating the temporal profile of the impulse response function plots demonstrated that the autonomic variables of BRS, ratio of low/high frequency of HRV and very low frequency HRV all had a strong relation to PRx, indicating that the sympathetic autonomic response may be more closely linked to cerebrovascular reactivity, then other variables. Finally, BRS was consistently associated with PRx, possibly demonstrating a deeper relationship to PRx than other autonomic measures. Taken together, cerebrovascular reactivity and autonomic response are interlinked, with a bidirectional impact between cerebrovascular reactivity and circulatory autonomics. However, this work is exploratory and preliminary, with further study required to extract and confirm any underlying relationships.