bluuebunny/crossref_metadata_2025 huggingface dataset:
An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases
Authors: Liu Peipei , Pan Zhongzong , Gu Chunyin , Cao Xiaodan , Liu Xiaowu , Zhang Jianjian , Xiao Zheng , Wang Xueping , Guo Haibing , Ju Dianwen , Deng Su-Jun
Published: November 2020

The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate’s stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potencyin vitro, prolonged half-life in human FcRn transgenic mouse, and enhancedin vivoefficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.
Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory
Authors: Miao Runfeng , Lim Vivian Y. , Kothapalli Neeharika , Ma Yifan , Fossati Julia , Zehentmeier Sandra , Sun Ruifeng , Pereira João P.
Published: November 2020

Studies over the last couple of decades have shown that hematopoietic stem cells (HSCs) are critically dependent on cytokines such as Stem Cell Factor and other signals provided by bone marrow niches comprising of mesenchymal stem and progenitor cells (MSPCs) and endothelial cells (ECs). Because of their critical roles in HSC maintenance the niches formed by MSPCs and ECs are commonly referred to as HSC niches. For the most part, the signals required for HSC maintenance act in a short-range manner, which imposes the necessity for directional and positional cues in order for HSCs to localize and be retained properly in stem cell niches. The chemokine CXCL12 and its Gαi protein coupled receptor CXCR4, besides promoting HSC quiescence directly, also play instrumental roles in enabling HSCs to access bone marrow stem cell niches. Recent studies have revealed, however, that HSC niches also provide a constellation of hematopoietic cytokines that are critical for the production of most, if not all, blood cell types. Some hematopoietic cytokines, namely IL-7 and IL-15 produced by HSC niches, are not only required for lymphopoiesis but are also essential for memory T cell maintenance. Consequently, hematopoietic progenitors and differentiated immune cells, such as memory T cell subsets, also depend on the CXCL12/CXCR4 axis for migration into bone marrow and interactions with MSPCs and ECs. Similarly, subsets of antibody-secreting plasma cells also reside in close association with CXCL12-producing MSPCs in the bone marrow and require the CXCR4/CXCL12 axis for survival and long-term maintenance. Collectively, these studies demonstrate a broad range of key physiological roles, spanning blood cell production and maintenance of immunological memory, that are orchestrated by stem cell niches through a common and simple mechanism: CXCL12/CXCR4-mediated cell recruitment followed by receipt of a maintenance and/or instructive signal. A fundamental flaw of this type of cellular organization is revealed by myeloid and lymphoid leukemias, which target stem cell niches and induce profound transcriptomic changes that result in reduced hematopoietic activity and altered mesenchymal cell differentiation.
Exploring the Trophic Spectrum: Placing Mixoplankton Into Marine Protist Communities of the Southern North Sea
Authors: Schneider Lisa K. , Flynn Kevin J. , Herman Peter M. J. , Troost Tineke A. , Stolte Willem
Published: November 2020

While traditional microplankton community assessments focus primarily on phytoplankton and protozooplankton, the last decade has witnessed a growing recognition of photo-phago mixotrophy (performed by mixoplankton) as an important nutritional route among plankton. However, the trophic classification of plankton and subsequent analysis of the trophic composition of plankton communities is often subjected to the historical dichotomy. We circumvented this historical dichotomy by employing a 24 year-long time series on abiotic and protist data to explore the trophic composition of protist communities in the Southern North Sea. In total, we studied three different classifications. Classification A employed our current knowledge by labeling only taxa documented to be mixoplankton as such. In a first trophic proposal (classification B), documented mixoplankton and all phototrophic taxa (except for diatoms, cyanobacteria, and colonial Phaeocystis) were classified as mixoplankton. In a second trophic proposal (classification C), documented mixoplankton as well as motile, phototrophic taxa associated in a principle component analysis with documented mixoplankton were classified as mixoplankton. In all three classifications, mixoplankton occurred most in the inorganic nutrient-depleted, seasonally stratified environments. While classification A was still subjected to the traditional dichotomy and underestimated the amount of mixoplankton, our results indicate that classification B overestimated the amount of mixoplankton. Classification C combined knowledge gained from the other two classifications and resulted in a plausible trophic composition of the protist community. Using results of classification C, our study provides a list of potential unrecognized mixoplankton in the Southern North Sea. Furthermore, our study suggests that low turbidity and the maturity of an ecosystem, quantified using a newly proposed index of ecosystem maturity (ratio of organic to total nitrogen), provide an indication on the relevance of mixoplankton in marine protist communities.
Plasma Soluble CD146 as a Potential Diagnostic Marker of Acute Rejection in Kidney Transplantation
Authors: Liao Jun , Fu Qian , Chen Wenfang , Li Jun , Zhang Wenhui , Zhang Huanxi , Gao Yifang , Yang Shicong , Xu Bowen , Huang Huiting , Wang Jiali , Li Xirui , Liu Longshan , Wang Changxi
Published: November 2020

Previous studies have implicated the role of CD146 and its soluble form (sCD146) in the pathogenesis of inflammatory diseases. However, the association between CD146 and acute rejection in kidney transplant patients remains unexplored. In this study, fifty-six patients with biopsy-proved rejection or non-rejection and 11 stable allograft function patients were retrospectively analyzed. Soluble CD146 in plasma was detected in peripheral blood by enzyme linked immunosorbent assay (ELISA), and local CD146 expression in graft biopsy was detected by immunohistochemistry. We found that plasma soluble CD146 in acute rejection recipients was significantly higher than in stable patients without rejection, and the biopsy CD146 staining in the rejection group was higher than that of the non-rejection group. Multivariate analysis demonstrated soluble CD146 as an independent risk factor of acute rejection. The area under the receiver operating characteristic curve (AUC) of sCD146 for AR diagnosis was 0.895, and the optimal cut-off value was 75.64 ng/ml, with a sensitivity of 87.8% and a specificity of 80.8%, which was better than eGFR alone (P = 0.02496). Immunohistochemistry showed CD146 expression in glomeruli was positively correlated with the Banff-g score, and its expression in tubules also had a positive relationship with the Banff-t score. Therefore, soluble CD146 may be a potential biomarker of acute rejection. Increased CD146 expression in the endothelial or tubular epithelial cells may imply that endothelial/epithelial dysfunction is involved in the pathogenesis of immune injury.
Risk Factors and Outcomes of Treatment Delays in Lyme Disease: A Population-Based Retrospective Cohort Study
Authors: Hirsch Annemarie G. , Poulsen Melissa N. , Nordberg Cara , Moon Katherine A. , Rebman Alison W. , Aucott John N. , Heaney Christopher D. , Schwartz Brian S.
Published: November 2020

Background: Longer time between symptom onset and treatment of Lyme disease has been associated with poor outcomes. Reducing time-to-treatment requires knowledge of risks for treatment delays. We conducted a population-based study to evaluate factors associated with delayed treatment of Lyme disease and the relation between delayed treatment and post-treatment Lyme disease syndrome (PTLDS).

Methods: We mailed questionnaires to 5,314 individuals with a Lyme disease diagnosis or blood test followed by an antibiotic order in the medical record of a Pennsylvania health system from 2015 to 2017. Analyses were confined to 778 respondents who reported that they were treated for Lyme disease within the past 5 years and reported a rash and/or a positive blood test for Lyme disease. Time-to-treatment was calculated as the sum of two windows before and after seeking care for Lyme disease symptoms: time to first medical contact and time under care. We used logistic regression to evaluate factors associated with delayed time-to-treatment in each time window (>14 days vs. ≤14 days) and the association between total time-to-treatment (>30 days vs. ≤30 days) and PTLDS. We used inverse probability weighting to calculate estimates for the study's source population (5,314 individuals sent questionnaires).

Results: In the source population, 25% had time to first contact >14 days, 21% had time under care >14 days, and 31% had a total time-to-treatment >30 days. Being uninsured and attributing initial symptoms to something other than Lyme disease were positively associated with delayed time to first medical contact, while seeking care at an urgent care or emergency setting (vs. primary care) was negatively associated. Diagnoses between November and April, and the absence of rash were positively associated with delays. Individuals whose treatment was delayed, defined as time-to treatment >30 days had 2.26 (95% confidence interval: 1.25, 4.05) times the odds of PTLDS as those who were treated within 30 days of symptom onset.

Conclusions: In a population-based study in Pennsylvania, one-third of Lyme disease patients reported delayed treatment, which was associated with PTLDS. To improve Lyme disease outcomes, prevention efforts should aim to reduce the time before and after seeking care.
Divergent Effects of the N-Methyl-D-Aspartate Receptor Antagonist Kynurenic Acid and the Synthetic Analog SZR-72 on Microcirculatory and Mitochondrial Dysfunction in Experimental Sepsis
Authors: Juhász László , Rutai Attila , Fejes Roland , Tallósy Szabolcs P. , Poles Marietta Z. , Szabó Andrea , Szatmári István , Fülöp Ferenc , Vécsei László , Boros Mihály , Kaszaki József
Published: November 2020

Introduction: Sepsis is a dysregulated host response to infection with macro- and microhemodynamic deterioration. Kynurenic acid (KYNA) is a metabolite of the kynurenine pathway of tryptophan catabolism with pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenously administered KYNA or the synthetic analog SZR-72 affects the microcirculation and mitochondrial function in a clinically relevant rodent model of intraabdominal sepsis.

Methods: Male Sprague–Dawley rats (n = 8/group) were subjected to fecal peritonitis (0.6 g kg−1 feces ip) or a sham operation. Septic animals were treated with sterile saline or received ip KYNA or SZR-72 (160 μmol kg−1 each) 16 and 22 h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic dysfunctions (PaO2/FiO2 ratio, mean arterial pressure, urea, AST/ALT ratio and lactate levels, respectively) based on the Rat Organ Failure Assessment (ROFA) score. The ratio of perfused vessels (PPV) of the ileal serosa was quantified with the intravital imaging technique. Complex I- and II-linked (CI; CII) oxidative phosphorylation capacities (OXPHOS) and mitochondrial membrane potential (ΔΨmt) were evaluated by High-Resolution FluoRespirometry (O2k, Oroboros, Austria) in liver biopsies. Plasma endothelin-1 (ET-1), IL-6, intestinal nitrotyrosine (NT) and xanthine oxidoreductase (XOR) activities were measured as inflammatory markers.

Results: Sepsis was characterized by an increased ROFA score (5.3 ± 1.3 vs. 1.3 ± 0.7), increased ET-1, IL-6, NT and XOR levels, and decreased serosal PPV (65 ± 12% vs. 87 ± 7%), ΔΨmt and CI–CII-linked OXPHOS (73 ± 16 vs. 158 ± 14, and 189 ± 67 vs. 328 ± 81, respectively) as compared to controls. Both KYNA and SZR-72 reduced systemic inflammatory activation; KYNA treatment decreased serosal perfusion heterogeneity, restored PPV (85 ± 11%) and complex II-linked OXPHOS (307 ± 38), whereas SZR-72 improved both CI- and CII-linked OXPHOS (CI: 117 ± 18; CII: 445 ± 107) without effects on PPV 24 h after sepsis induction.

Conclusion: Treatment with SZR-72 directly modulates mitochondrial respiration, leading to improved conversion of ADP to ATP, while administration of KYNA restores microcirculatory dysfunction. The results suggest that microcirculatory and mitochondrial resuscitation with KYNA or the synthetic analog SZR-72 might be an appropriate supportive tool in sepsis therapy.
Controlled Human Malaria Infection Induces Long-Term Functional Changes in Monocytes
Authors: Walk Jona , Keramati Farid , de Bree L. Charlotte J. , Arts Rob J. W. , Blok Bas , Netea Mihai G. , Stunnenberg Hendrik G. , Sauerwein Robert W.
Published: November 2020

Innate immune memory responses (also termed “trained immunity”) have been described in monocytes after BCG vaccination and after stimulation in vitro with microbial and endogenous ligands such as LPS, β-glucan, oxidized LDL, and monosodium urate crystals. However, whether clinical infections are also capable of inducing a trained immunity phenotype remained uncertain. We evaluated whether Plasmodium falciparum infection can induce innate immune memory by measuring monocyte-derived cytokine production from five volunteers undergoing Controlled Human Malaria Infection. Monocyte responses followed a biphasic pattern: during acute infection, monocytes produced lower amounts of inflammatory cytokines upon secondary stimulation, but 36 days after malaria infection they produced significantly more IL-6 and TNF-α in response to various stimuli. Furthermore, transcriptomic and epigenomic data analysis revealed a clear reprogramming of monocytes at both timepoints, with long-term changes of H3K4me3 at the promoter regions of inflammatory genes that remain present for several weeks after parasite clearance. These findings demonstrate an epigenetic basis of trained immunity induced by human malaria in vivo.
Effects of Exosomes on Neurological Function Recovery for Ischemic Stroke in Pre-clinical Studies: A Meta-analysis
Authors: Huang Mudan , Hong Zhongqiu , Xiao Chongjun , Li Lili , Chen Lilin , Cheng Shimei , Lei Tingting , Zheng Haiqing
Published: November 2020

Background: Exosomes, especially stem cell-derived exosomes, have been widely studied in pre-clinical research of ischemic stroke. However, their pooled effects remain inconclusive.

Methods: Relevant literature concerning the effects of exosomes on neurological performance in a rodent model of ischemic stroke was identified via searching electronic databases, including PubMed, Embase, and Web of Science. The primary outcomes included neurological function scores (NFS) and infarct volume (IV), and the secondary outcomes were several pro-inflammatory factors and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells. Subgroup analyses regarding several factors potentially influencing the effects of exosomes on NFS and IV were also conducted.

Results: We identified 21 experiments from 18 studies in the meta-analysis. Pooled analyses showed the positive and significant effects of exosomes on NFS (standardized mean difference −2.79; 95% confidence interval −3.81 to −1.76) and IV (standardized mean difference −3.16; 95% confidence interval −4.18 to −2.15). Our data revealed that the effects of exosomes on neurological outcomes in rodent stroke models might be related to routes of administration and exosomes sources. In addition, there was significant attenuation in pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and interleukin-1β, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells when undergoing exosomes treatment.

Conclusion: Cell-derived exosomes treatment demonstrated statistically significant improvements in structural and neurological function recovery in animal models of ischemic stroke. Our results also provide relatively robust evidence supporting cell-derived exosomes as a promising therapy to promote neurological recovery in stroke individuals.
Rapamycin Alleviates the Symptoms of Multiple Sclerosis in Experimental Autoimmune Encephalomyelitis (EAE) Through Mediating the TAM-TLRs-SOCS Pathway
Authors: Li Xiao-ling , Zhang Bo , Liu Wei , Sun Meng-jiao , Zhang Ya-lan , Liu Hui , Wang Man-xia
Published: November 2020

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Our research aimed to find an immunomodulatory therapy for MS. An experimental autoimmune encephalomyelitis (EAE) mouse model of MS was established induced with the syntheticmyelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Fifty C57BL/6 mice were randomly divided into the Normal group, EAE group, and Rapamycin group (EAE mice treated with three different doses of rapamycin). Hematoxylin and eosin staining and Weil myelin staining were performed on the brain tissues of mice after 21 days post-immunization. The protein expression of Gas6, Tyro3, Axl, Mer in paraventricular tissues were analyzed by immunohistochemistry. The mRNA and protein expression of Gas6, Tyro3, Axl, Mer, SOCS1, SOCS3, Toll-like receptor (TLR) 3, and TLR4 were detected by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of the inflammatory factors IFN-γ and IL-17. Rapamycin treatment could ameliorate the behavior impairment in EAE mice induced by MOG35-55. The expression of Gas6, Tyro3, Axl, Mer, SOCS1, and SOCS3 were decreased in EAE mice at 21 days post-immunization, while the expression of Gas6, Tyro3, Axl, and Mer in rapamycin group was higher than that in EAE group. It was accompanied by an increase in anti-inflammatory proteins SOCS1 and SOCS3, a decrease in the inflammatory proteins TLR-3, TLR-4 and in the amount of IFN-γ, and IL-17. Rapamycin injection relieved the nerve function of and the loss of myelin sheath in the EAE mice, mainly through mediating the TAM-TLRs-SOCS signaling pathway to regulate natural immunity.
Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?
Authors: Chu Xujun , Meng Lingchao , Zhang Wei , Luo Jinjun , Wang Zhaoxia , Yuan Yun
Published: November 2020

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.

Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.

Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.

Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.
Association of Odor Identification Ability With Amyloid-β and Tau Burden: A Systematic Review and Meta-Analysis
Authors: Tu Lihui , Lv Xiaozhen , Fan Zili , Zhang Ming , Wang Huali , Yu Xin
Published: November 2020

Background: The associations between olfactory identification (OI) ability and the Alzheimer's disease biomarkers were not clear.

Objective: This meta-analysis aimed to examine the associations between OI and Aβ and tau burden.

Methods: Electronic databases (PubMed, Embase, PsycINFO, and Google Scholar) were searched until June 2019 to identify studies that reported correlation coefficients or regression coefficients between OI and Aβ or tau levels measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Pooled Pearson correlation coefficients were computed for the PET imaging and CSF biomarkers, with subgroup analysis for subjects classified into different groups.

Results: Nine studies met the inclusion criteria. Of these, five studies (N = 494) involved Aβ PET, one involved tau PET (N = 26), and four involved CSF Aβ or tau (N = 345). OI was negatively associated with Aβ PET in the mixed (r = −0.25, P = 0.008) and cognitively normal groups (r = −0.15, P = 0.004) but not in the mild cognitive impairment group. A similar association with CSF total tau in the mixed group was also observed. No association was found between OI and CSF phosphorylated tau or Aβ42 in the subgroup analysis of the CSF biomarkers. Due to a lack of data, no pooled r value could be computed for the association between the OI and tau PET.

Conclusion: The associations between OI ability and Aβ and CSF tau burden in older adults are negligible. While current evidence does not support the association, further studies using PET tau imaging are warranted.
Protein Kinase C Isozymes Associated With Relapse Free Survival in Non-Small Cell Lung Cancer Patients
Authors: Halvorsen Ann Rita , Haugen Mads Haugland , Öjlert Åsa Kristina , Lund-Iversen Marius , Jørgensen Lars , Solberg Steinar , Mælandsmo Gunhild M. , Brustugun Odd Terje , Helland Åslaug
Published: November 2020

Introduction

Protein expression is deregulated in cancer, and the proteomic changes observed in lung cancer may be a consequence of mutations in essential genes. The purpose of this study was to identify protein expression associated with prognosis in lung cancers stratified by smoking status, molecular subtypes, and EGFR-, TP53-, and KRAS-mutations.

Methods

We performed profiling of 295 cancer-relevant phosphorylated and non-phosphorylated proteins, using reverse phase protein arrays. Biopsies from 80 patients with operable lung adenocarcinomas were analyzed for protein expression and association with relapse free survival (RFS) were studied.

Results

Spearman’s rank correlation analysis identified 46 proteins with significant association to RFS (p<0.05). High expression of protein kinase C (PKC)-α and the phosporylated state of PKC-α, PKC-β, and PKC-δ, showed the strongest positive correlation to RFS, especially in the wild type samples. This was confirmed in gene expression data from 172 samples. Based on protein expression, unsupervised hierarchical clustering separated the samples into four subclusters enriched with the molecular subtypes terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI) (p=0.0001). Subcluster 2 contained a smaller cluster (2a) enriched with samples of the subtype PP, low expression of the PKC isozymes, and associated with poor RFS (p=0.003) compared to the other samples. Low expression of the PKC isozymes in the subtype PP and a reduced relapse free survival was confirmed with The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) samples.

Conclusion

This study identified different proteins associated with RFS depending on molecular subtype, smoking- and mutational-status, with PKC-α, PKC-β, and PKC-δ showing the strongest correlation.
Vaccine Interactions With the Infant Microbiome: Do They Define Health and Disease?
Authors: Ruck Candice E. , Odumade Oludare A. , Smolen Kinga K.
Published: November 2020

Over the past decade, there has been a growing awareness of the vital role of the microbiome in the function of the immune system. Recently, several studies have demonstrated a relationship between the composition of the microbiome and the vaccine-specific immune response. As a result of these findings, the administration of probiotics has been proposed as a means of boosting vaccine-specific immunity. Early results have so far been highly inconsistent, with little evidence of sustained benefit. To date, a precise determination of the aspects of the microbiome that impact immunity is still lacking, and the mechanisms of action are also unknown. Further investigations into these questions are necessary to effectively manipulate the microbiome for the purpose of boosting immunity and enhancing vaccine-specific responses in infants. In this review, we summarize recent studies aimed at altering the neonatal gut microbiome to enhance vaccine responses and highlight gaps in knowledge and understanding. We also discuss research strategies aimed at filling these gaps and developing potential therapeutic interventions.
Total Flavonoids of Rhizoma Drynariae Enhances Angiogenic-Osteogenic Coupling During Distraction Osteogenesis by Promoting Type H Vessel Formation Through PDGF-BB/PDGFR-β Instead of HIF-1α/ VEGF Axis
Authors: Shen Zhen , Chen Zehua , Li Zige , Zhang Yan , Jiang Tao , Lin Haixiong , Huang Minling , Chen Huamei , Feng Junjie , Jiang Ziwei
Published: November 2020

Background: Total flavonoids of Rhizoma Drynariae (TFRD), extracted from the kidney-tonifying traditional Chinese medicine Rhizoma Rrynariae, has been proved to be effective in treating osteoporosis, bone fractures and defects. However, pharmacological effects of TFRD on type H vessels, angiogenic-osteogenic coupling in distraction osteogenesis (DO) and the mechanism remain unclear. This study aims at investigating whether type H vessels exist in the DO model, effects of TFRD on angiogenic-osteogenic coupling and further elucidating the underlying mechanism.

Methods: Rats models of DO and bone fracture (FR) were established, and then were separately divided into TFRD and control subgroups. Imageological and histological analyses were performed to assess bone and vessel formation. Immunofluorescent staining of CD31 and endomucin (Emcn) was conducted to determine type H vessel formation. Matrigel tube formation, ALP and Alizarin Red S staining assays were performed to test the effects of TFRD on angiogenesis or osteogenesis of endothelial precursor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs). Additionally, expression levels of HIF-1α, VEGF, PDGF-BB, RUNX2 and OSX were determined by ELISA, qPCR or western blot, respectively.

Results: The in vivo results indicated more formed type H vessels in DO groups than in FR groups and TFRD obviously increased the abundance of type H vessels. Moreover, groups with higher abundance of type H vessels showed better angiogenesis and osteogenesis outcomes. Further in vitro experiments showed that TFRD significantly promoted while blocking PDGF-BB remarkably suppressed the angiogenic activity of EPCs under stress conditions. The levels of p-AKT and p-ERK1/2, downstream mediators of the PDGF-BB pathway, were up-regulated by TFRD but blocked by function blocking anti-PDGF-BB antibody. In contrast, the activated AKT and ERK1/2 and corresponding tube formation were not affected by the HIF-1α inhibitor. Besides, blocking PDGF-BB inhibited the osteogenic differentiation of the stretched BMSCs, but TFRD enhanced the osteogenic activity of BMSCs and ameliorated the inhibition, with more calcium nodes, higher ALP activity and mRNA and protein levels of RUNX2 and OSX.

Conclusion: Type H vessels exist in the DO model and TFRD enhances angiogenic-osteogenic coupling during DO by promoting type H vessel formation via PDGF-BB/PDGFR-β instead of HIF-1α/VEGF axis.
Assessing Child-to-Parent Violence With the Child-to-Parent Violence Questionnaire, Parents’ Version (CPV-Q-P): Factor Structure, Prevalence, and Reasons
Authors: Contreras Lourdes , León Samuel P. , Cano-Lozano M. Carmen
Published: November 2020

Child-to-parent violence has dramatically risen in the last decade, becoming a concerning issue in many countries, so research on this issue has also increased. However, most of the studies on this topic have been conducted with samples of adolescents, and very few with samples of parents. In addition, the variety of assessment instruments does not reflect the elements of this type of violence. Thus, the current study was aimed to examine the factor structure, reliability, and validity of the Child-to-parent Violence Questionnaire, parents’ version (CPV-Q-P), in a sample of Spanish parents of adolescents. Moreover, the prevalence rates of the different types of violence and the reasons for violence were also examined. A total of 1,012 Spanish parents of adolescents aged between 12 and 17 years old (55.1% mothers, 44.9% fathers) were assessed using the CPV-Q-P. Data indicated a matrix of four factors with 14 items, assessing psychological violence, physical violence, financial violence, and control/domain over parents, and two factors with 8 items capturing the reasons for child-to-parent violence (instrumental and reactive), with adequate psychometric properties. The more frequent type of violence was control and domain over parents, followed by psychological, financial, and physical violence, with no significant differences between mothers and fathers. Otherwise, instrumental reasons were more frequent than reactive types, with no differences between mothers and fathers. The CPV-Q-P is a useful instrument to assess child-to-parent violence from the parents’ perspective in both professional and research settings.
Moving Toward Telehealth Surveillance Services for Toddlers at Risk for Autism During the COVID-19 Pandemic
Authors: Conti Eugenia , Chericoni Natasha , Costanzo Valeria , Lasala Roberta , Mancini Alice , Prosperi Margherita , Tancredi Raffaella , Muratori Filippo , Calderoni Sara , Apicella Fabio
Published: November 2020

Since 2016, the project “Early Bird Diagnostic Protocol for Autism Spectrum Disorders (ASD)” funded by the Italian Ministry of Health has been operative at IRCCS Fondazione Stella Maris (FSM), Pisa (IT), with the main aim of developing early age-specific diagnostic protocols by longitudinally enrolling two different populations at risk for ASD: (i) toddlers with older siblings with ASD (FR) and (ii) toddlers referred by a child psychiatrist or pediatrician for suspected ASD (CR). On January 30, 2020, when the World Health Organization declared the outbreak of coronavirus disease 2019 (COVID-19), 136 patients (85 FR; 51 CR; 93 males; 43 females) had been enrolled in the project with 324 completed time points and 64 still missing. Considering both the huge psychological burden on families with toddlers at risk for ASD during the lockdown and the longitudinal studies reporting the positive “surveillance effect” in terms of a better outcome in at-risk toddlers, our priority has been to maintain regular contact and support to enrolled families. To do this, the research team, being authorized for smart-working research activities, has set up a detailed remote surveillance protocol (RSP). The RSP includes three online interviews and one online video registration of parent–child play. In the current community case study, the authors report the telehealth procedure and discuss possible future directions in developing remote assessment and new evaluation modalities for ecological parent–child play video recordings in at-risk populations. Hopefully, the surveillance protocol will further improve our ability to detect risk and activate early tailored intervention.
Developments in Drug Addiction During COVID-19—An Austrian Perspective Based on a Clinical Sample
Authors: Fuchs-Leitner Isabella , Yazdi Kurosch , Gerstgrasser Nikolas W. , Rosenleitner Jan
Published: November 2020

Concerns about the negative consequences of the COVID-19 pandemic on people with substance use disorder (SUD) were raised by experts in the field around the world. Here we provide an Austrian perspective, discussing the impact of the pandemic on help-seeking patient with drug use disorder during the initial stage of the pandemic. Our perspectives are based on the situation as perceived at our clinical facility, and supported by original data collected from a small clinical sample of patients with drug use disorder (N = 32). The viewpoints and related descriptive data include the perceived individual impact of COVID-19, as well as various aspects of drug use behavior and the Austrian drug market before and after the onset of the pandemic. The consequences for a subgroup of patients in opioid substitution treatment (N = 24) are discussed. Surprisingly and in contrast to anticipated developments, we had the impression of a rather stable situation in Austria, at least at this early stage of the pandemic. The immediate impact of COVID-19 on these help-seeking patients with high levels of drug dependency seemed less severe than anticipated so far. Importantly, this observation might be a short-term effect for this already fragile group and careful monitoring of further developments as well as preparation of long-term strategies are advised. In general, problematic drug use is associated with many health risk factors and finding appropriate long-term health care strategies has to remain a top priority facing the pandemic. Our perspectives are restricted to observations from help-seeking patients at our clinic, and no conclusions for the general population can be directly drawn.
Pathways to Enable Primary Healthcare Nurses in Providing Comprehensive Primary Healthcare to Rural, Tribal Communities in Rajasthan, India
Authors: Amin Arpita , Dutta Manisha , Brahmawar Mohan Sanjana , Mohan Pavitra
Published: November 2020

Background:Emerging health needs and uneven distribution of human resources of health have led to poor access to quality healthcare in rural areas. Rural pathways provide an approach to plan and evaluate strategies for ensuring availability, retention, motivation, and performance of human resources for health in rural areas. While effectiveness of primary healthcare (PHC) nurses to deliver primary health care is established, there is not enough evidence on ways to ensure their availability, retention, motivation, and performance. The paper draws on the program experience and evidence from a primary healthcare network (AMRIT Clinics), in which nurses play a central role in delivering primary healthcare in rural tribal areas of Rajasthan, India, to bridge this gap.

Methods:Rural, tribal areas of Rajasthan have limited access to functional healthcare facilities, despite having a high burden of diseases. We used the rural pathway approach to describe factors that contributed to the performance of the nurses in AMRIT Clinics. We analyzed information from the human resource information system and health management information system; and supplemented it with semi-structured interviews with nurses, conducted by an independent organization.

Results:Most nurses were sourced from rural and tribal communities that the clinics serve; nurses from these communities were likely to have a higher retention than those from urban areas. Sourcing from rural and tribal communities, on-going training in clinical and social skills, a non-hierarchical work environment, and individualized mentoring appear to be responsible for high motivation of the primary healthcare nurses in AMRIT Clinics. Task redistribution with due credentialing, intensive and on-going training, and access to tele-consultation helped in sustaining high performance. However, family expectations to perform gendered roles and pull of government jobs affect their retention.

Conclusion:Rural and remote areas with healthcare needs and scarcity of health provisions need to optimize the health workforce by adopting a multi-pronged pathway in its design and implementation. At the same time, there is a need to focus on structural factors that affect retention of workforce within the pathway. Our experience highlights a pathway of up-skilling PHC nurses in providing comprehensive primary healthcare in rural and remote communities in Low and Middle-Income Countries (LMICs).
Farmers' Soil Fertility Management in Niger and Opportunities for Improvements Through Mechanization, Microdosing, and Seed Coating
Authors: Nourou Abdourahamane Issa M. , Saidou Addam Kiari , Aune Jens B.
Published: November 2020

The objective of this study was to characterize pearl millet production in Niger and to assess the potential impact of a low-cost production package on land- and labor productivity. The survey showed that 62% of the farmers used manure, while 22% used mineral fertilizer. Of those who used mineral fertilizer only 18% practiced microdosing. High labor demand was given as the reason why 89% of the farmers did not practice microdosing. In field experiments, we tested at three sites and over 2 years a control (no fertilizer and manual sowing) against two improved production packages consisting of mechanized sowing, seed priming, seed treatment with fungicide and NPK fertilizer in treatment 1 (T1), or phosphate coating in treatment 2 (T2). In the production package T1, seed and NPK fertilizer were mixed in a 1:1 ratio and this mixture was thereafter applied by a planter giving a fertilizer rate of 0.3 g NPK hill−1. In treatment T2, the seeds were coated with rock phosphate, and were thereafter sown by a planter giving a rate of 0.35 g rock phosphate hill−1. Compared to the control, the T1 and T2 treatments increased yield by 70.9 and 42.7%, respectively. The two improved production packages reduced time to maturity by 10 days. The net benefit increased for the T1 and T2 treatments compared to the control by 111.8 and 72.8%, respectively. This increase was particularly due to the higher grain and stover yield as well as lower weeding costs. These technologies will also render pearl millet production more resistant to climate change due to timelier sowing and weeding, a better crop establishment, and a shortened growing season.
Case Report: Pathologic Complete Response to Pembrolizumab in Combination With Neoadjuvant Chemotherapy in a Patient With Stage IIB Squamous Lung Cancer
Authors: Zhang Lin , Mai Wuqian , Jiang Wenyang , Geng Qing
Published: November 2020

The emergence of PD-1 antibodies has radically changed the therapeutic profiles of lung cancer, which has the highest incidence and mortality rate among all cancers worldwide. Pembrolizumab, an anti-PD-1 antibody, has been proven to have strong anti-tumor activity in a variety of clinical studies. Here, we described a patient with stage IIB squamous lung cancer who has benefited from a preoperative pembrolizumab plus chemotherapy regimen. The addition of pembrolizumab to neoadjuvant chemotherapy before surgery led to a pathologic complete response and the avoidance of left pneumonectomy. This case highlights the effect of neoadjuvant pembrolizumab plus chemotherapy on non-small cell lung cancer patients and has provided a promising choice in future clinical practice.
Retrotransposons and the Evolution of Genome Size in Pisum
Authors: Ellis T. H. Noel , Vershinin Alexander V.
Published: November 2020

Here we investigate the plant population genetics of retrotransposon insertion sites in pea to find out whether genetic drift and the neutral theory of molecular evolution can account for their abundance in the pea genome. (1) We asked whether two contrasting types of pea LTR-containing retrotransposons have the frequency and age distributions consistent with the behavior of neutral alleles and whether these parameters can explain the rate of change of genome size in legumes. (2) We used the recently assembled v1a pea genome sequence to obtain data on LTR-LTR divergence from which their age can be estimated. We coupled these data to prior information on the distribution of insertion site alleles. (3) We found that the age and frequency distribution data are consistent with the neutral theory. (4) We concluded that demographic processes are the underlying cause of genome size variation in legumes.
Pan-RAF Inhibition Shows Anti-Leukemic Activity in RAS-Mutant Acute Myeloid Leukemia Cells and Potentiates the Effect of Sorafenib in Cells with FLT3 Mutation
Authors: Khoury Joseph D. , Tashakori Mehrnoosh , Yang Hong , Loghavi Sanam , Wang Ying , Wang Jing , Piya Sujan , Borthakur Gautam
Published: November 2020

RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using LY3009120 in AML cells harboring mutations upstream and downstream of RAF. LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably, LY3009120 potentiated the effect of Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect.
Does Phytogeography Change with Shifts in Geopolitics? The Curious Case of Cycads in the United States
Authors: Deloso Benjamin E. , Ferreras Ulysses F. , Marler Thomas E.
Published: November 2020

The United States is currently home to five native cycad species. We provide a discussion on these five cycad species to illuminate how evolutionary and geopolitical processes influence phytogeography and published checklists of threatened plants. The number of threatened species in need of protection within any given country is a product of speciation that is contingent with evolutionary processes. However, this number may change instantaneously along with shifting of geopolitical boundaries brought about by armed conflict between rival states and multilateral negotiations. There are five contemporary cycad species within the United States, and the various historical bilateral and multilateral agreements that have generated this list are reviewed. Three of these five cycad species are threatened and in need of urgent protection. A discussion on the history of United States cycads as a microcosm of worldwide conservation issues is presented, with a focus on how federal conservation endeavors of individual nations may influence the world’s biodiversity crisis.
Experimental Studies of the Influence of Dynamic Loading on the Elastic Properties of Sandstone
Authors: Guzev Mikhail , Kozhevnikov Evgenii , Turbakov Mikhail , Riabokon Evgenii , Poplygin Vladimir
Published: November 2020

Under dynamic loading, the geomechanical properties of porous clastic rocks differ from those in quasistatic loading. A small experimental rig was built to directly assess the influence of vibrations on the uniaxial compressive strength (UCS), Young modulus, and Poisson’s ratio. A piezoelectric actuator powered by a signal from an oscillator was used in the rig as a generator of vibrations. A laser sensor and eddy current probe measured the longitudinal and transverse deformation. Tinius Hounsfield and Instron Series 4483 installations were used to determine the geomechanical properties of new red sandstone in a quasistatic regime. The boundaries of elastic deformations determined in the quasistatic loading were implemented in the dynamic loading. To perform the experiments in the elastic zone (on the graph of stress (σ)–strain (ε)), small samples with diameters ranging between 7.5 and 24.7 mm were manufactured. The investigation demonstrated that the Young’s modulus of the sandstone increased with increasing values of the dynamic load and frequency.
Multicriterial Evaluation of Renewable Energy Expansion Projects at Municipal Level for the Available Biomass Potential
Authors: Blickwedel Lucas , Stößel Laura , Schelenz Ralf , Jacobs Georg
Published: November 2020

To reduce emissions in the energy sector and reach worldwide climate goals, further expansion of renewable energy sources (RES) is inevitable. Local opposition has increased in recent years, resulting in the need for more consideration of acceptance issues in the planning process of RES projects. To fill this gap, a method is introduced to consider the dimension of social acceptance in a holistic approach and at an early project stage. In a two-step procedure, a municipal interest profile is created, followed by an examination of possible expansion projects based on the municipal profile. Both hard and soft characteristics of a given project are assessed in combination. Using the example of two potential scenarios for biomass expansion in a given municipality in Germany, the methodology is put to the test. The results show that with the new method House of municipal Energy (HomE), the interest profile of a municipality can be quantified in a comprehensible and transparent way. It is further shown that, depending on the initial objective function of the municipality, different expansion scenarios can be advantageous. In the examined case, the larger biogas plant achieves a higher utility value, since a clearly higher local added value can be generated. A smaller plant, which is only operated with waste materials, is preferable with regard to the required area and lower environmental impact. However, the advantages of the larger plant outweigh those of the smaller plant for the investigated example.