bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut Microbiota Characteristics Are Associated With Severity of Acute Radiation-Induced Esophagitis
Authors: Lin Ming-qiang , Wu Ya-hua , Yang Jun , Lin Han-cui , Liu Ling-yun , Yu Yi-lin , Yao Qi-wei , Li Jian-cheng
Published: June 2022

Background

Acute radiation-induced esophagitis (ARIE) is one of the most debilitating complications in patients who receive thoracic radiotherapy, especially those with esophageal cancer (EC). There is little known about the impact of the characteristics of gut microbiota on the initiation and severity of ARIE.

Materials and Methods

Gut microbiota samples of EC patients undergoing radiotherapy (n = 7) or concurrent chemoradiotherapy (n = 42) were collected at the start, middle, and end of the radiotherapy regimen. Assessment of patient-reported ARIE was also performed. Based on 16S rRNA gene sequencing, changes of the gut microbial community during the treatment regimen and correlations of the gut microbiota characteristics with the severity of ARIE were investigated.

Results

There were significant associations of several properties of the gut microbiota with the severity of ARIE. The relative abundance of several genera in the phylum Proteobacteria increased significantly as mucositis severity increased. The predominant genera had characteristic changes during the treatment regimen, such as an increase of opportunistic pathogenic bacteria including Streptococcus. Patients with severe ARIE had significantly lower alpha diversity and a higher abundance of Fusobacterium before radiotherapy, but patients with mild ARIE were enriched in Klebsiella, Roseburia, Veillonella, Prevotella_9, Megasphaera, and Ruminococcus_2. A model combining these genera had the best performance in prediction of severe ARIE (area under the curve: 0.907).

Conclusion

The characteristics of gut microbiota before radiotherapy were associated with subsequent ARIE severity. Microbiota-based strategies have potential use for the early prediction of subsequent ARIE and for the selection of interventions that may prevent severe ARIE.
SARS-CoV-2 RNA in Wastewater Was Highly Correlated With the Number of COVID-19 Cases During the Fourth and Fifth Pandemic Wave in Kobe City, Japan
Authors: Tanimoto Yoshihiko , Ito Erika , Miyamoto Sonoko , Mori Ai , Nomoto Ryohei , Nakanishi Noriko , Oka Naohiro , Morimoto Takao , Iwamoto Tomotada
Published: June 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the current coronavirus disease 2019 (COVID-19) pandemic and associated respiratory infections, has been detected in the feces of patients. Therefore, determining SARS-CoV-2 RNA levels in sewage may help to predict the number of infected people within the area. In this study, we quantified SARS-CoV-2 RNA copy number using reverse transcription quantitative real-time PCR with primers and probes targeting the N gene, which allows the detection of both wild-type and variant strain of SARS-CoV-2 in sewage samples from two wastewater treatment plants (WWTPs) in Kobe City, Japan, during the fourth and fifth pandemic waves of COVID-19 between February 2021 and October 2021. The wastewater samples were concentrated via centrifugation, yielding a pelleted solid fraction and a supernatant, which was subjected to polyethylene glycol (PEG) precipitation. The SARS-CoV-2 RNA was significantly and frequently detected in the solid fraction than in the PEG-precipitated fraction. In addition, the copy number in the solid fraction was highly correlated with the number of COVID-19 cases in the WWTP basin (WWTP-A: r = 0.8205, p < 0.001; WWTP-B: r = 0.8482, p < 0.001). The limit of capturing COVID-19 cases per 100,000 people was 0.75 cases in WWTP-A and 1.20 cases in WWTP-B, respectively. Quantitative studies of RNA in sewage can be useful for administrative purposes related to public health, including issuing warnings and implementing preventive measures within sewage basins.
Conventional vs. Organic Agriculture–Which One Promotes Better Yields and Microbial Resilience in Rapidly Changing Climates?
Authors: Azarbad Hamed
Published: June 2022

In recent years, agricultural productivity has been affected dramatically by climate-related events such as drought. On the other hand, agricultural intensification is expected to increase to satisfy the need for increased global food production. Microbes associated with soil and plants produce a range of bioactive natural products that significantly contribute to crop stress tolerance. Therefore, a better understanding of the parallel effects of agricultural management (conventional and organic croplands) and climate conditions on soil-microbe-plant interactions is crucial to maximizing the effort in engineering a plant microbiome that can better support productivity in agroecosystems. This paper provides a general overview of the major current debates on conventional and organic farming performance regarding yields, particularly under ambient and future climate conditions. With the main focus on cropland, the effect of agricultural management on soil and plant microbiomes is discussed. In addition, the advantage of incorporating microbiome-based approaches into current farming practices to ensure agricultural productivity with less adverse environmental impacts is highlighted. To enhance crop production under organic farming without massive land-use changes and expansion of farmland, the microbial-based approach can be used to ensure higher productivity, particularly under a rapidly changing climate.
Effects of Conventional and Organic Agriculture on Soil Arbuscular Mycorrhizal Fungal Community in Low-Quality Farmland
Authors: Chen Jiawei , Li Jianwei , Yang Yurong , Wang Yimei , Zhang Yifei , Wang Ping
Published: June 2022

Arbuscular mycorrhizal (AM) fungi have promising applications in low-quality farmlands all over the world, but research on their responses to conventional and organic farming systems in low-quality soil is limited. We hypothesized that the colonization activity and community diversity of AM fungi in conventional farming systems may not be lower than in organic farming on low-quality farmlands where beneficial symbiosis is required. We collected soil and maize root samples from medium to low fertility farmlands with conventional or organic farming systems in western Jilin Province, China. The colonization percentage and intensity, taxonomic and phylogenetic diversity, community composition of soil AM fungi, and soil factors were detected and compared between the two farming systems. The colonization intensity and operational taxonomic unit (OTU) taxonomic diversity on conventional farms were higher than on organic farms. Glomus was the most common genus on conventional farms, whereas Paraglomus and Glomus were the most common on organic farms. We also found a simpler AM fungal network structure with lower OTU phylogenetic diversity on conventional farms. Our findings suggested that though the conventional farming system resulted in different compositions and simpler structures of soil AM fungal community, there are potential diverse OTU resources currently present on conventional farms. This work has potential impacts on understanding the influence of different farming systems on soil AM fungi in low-quality farmlands and the development of efficient mycorrhizal inoculant production.
How Honey Bee Vitellogenin Holds Lipid Cargo: A Role for the C-Terminal
Authors: Leipart Vilde , Halskau Øyvind , Amdam Gro V.
Published: June 2022

Vitellogenin (Vg) is a phylogenetically broad glycolipophosphoprotein. A major function of this protein is holding lipid cargo for storage and transportation. Vg has been extensively studied in honey bees (Apis mellifera) due to additional functions in social traits. Using AlphaFold and EM contour mapping, we recently described the protein structure of honey bee Vg. The full-length protein structure reveals a large hydrophobic lipid binding site and a well-defined fold at the C-terminal region. Now, we outline a shielding mechanism that allows the C-terminal region of Vg to cover a large hydrophobic area exposed in the all-atom model. We propose that this C-terminal movement influences lipid molecules’ uptake, transport, and delivery. The mechanism requires elasticity in the Vg lipid core as described for homologous proteins in the large lipid transfer protein (LLTP) superfamily to which Vg belongs. Honey bee Vg has, additionally, several structural arrangements that we interpret as beneficial for the functional flexibility of the C-terminal region. The mechanism proposed here may be relevant for the Vg molecules of many species.
Case Report: Diagnosis of Petrous Apex IgG4-Related Disease by Middle Cranial Fossa Craniotomy and Temporal Bone Biopsy
Authors: Hofmeyr Louis , Herbst Gerrida , Pretorius Elias , Sarembock Brian , Taylor Kathryn , Roytowski David
Published: June 2022

Introduction

Primary IgG4-related disease (IgG4-RD) of the temporal bone is a rare condition. Unlike typical petrous apicitis or Gradenigo syndrome, our patient presented exclusively with unilateral cranial nerve VI palsy and symptoms of diplopia. Skull base imaging demonstrated a destructive bony lesion in the petrous apex. Imaging and systemic investigations were insufficient to support a diagnosis. The diagnosis was achieved histologically after acquiring the specimen by middle cranial fossa craniotomy and temporal bone biopsy. This case report is thought to be the first published description of a diagnosis of IgG4-RD proven with the middle cranial fossa approach.

Case Report

We describe a 29-year-old female with primary IgG4-RD of the petrous apex of the temporal bone. This patient presented with a few-month history of left-sided headache and recent-onset diplopia due to paralysis of cranial nerve VI. Imaging demonstrated a petrous apex lesion, and comprehensive systemic investigations could not reach a diagnosis. A middle cranial fossa craniotomy and a biopsy of the temporal bone lesion were undertaken to establish the diagnosis. Histological confirmation of IgG4-RD was proven. Following treatment with corticosteroids, the patient experienced complete recovery and resolution of her symptoms.

Conclusion

This study describes a case of primary IgG4-RD of the petrous apex of the temporal bone that presented with diplopia and was diagnosed by middle fossa craniotomy and temporal bone biopsy. To the best of our knowledge, this is the first case description where primary diagnosis was made based on middle cranial fossa craniotomy and temporal bone biopsy.
A Wearable Mixed Reality Platform to Augment Overground Walking: A Feasibility Study
Authors: Evans Emily , Dass Megan , Muter William M. , Tuthill Christopher , Tan Andrew Q. , Trumbower Randy D.
Published: June 2022

Humans routinely modify their walking speed to adapt to functional goals and physical demands. However, damage to the central nervous system (CNS) often results in abnormal modulation of walking speed and increased risk of falls. There is considerable interest in treatment modalities that can provide safe and salient training opportunities, feedback about walking performance, and that may augment less reliable sensory feedback within the CNS after injury or disease. Fully immersive virtual reality technologies show benefits in boosting training-related gains in walking performance; however, they lack views of the real world that may limit functional carryover. Augmented reality and mixed reality head-mount displays (MR-HMD) provide partially immersive environments to extend the virtual reality benefits of interacting with virtual objects but within an unobstructed view of the real world. Despite this potential advantage, the feasibility of using MR-HMD visual feedback to promote goal-directed changes in overground walking speed remains unclear. Thus, we developed and evaluated a novel mixed reality application using the Microsoft HoloLens MR-HMD that provided real-time walking speed targets and augmented visual feedback during overground walking. We tested the application in a group of adults not living with disability and examined if they could use the targets and visual feedback to walk at 85%, 100%, and 115% of each individual’s self-selected speed. We examined whether individuals were able to meet each target gait speed and explored differences in accuracy across repeated trials and at the different speeds. Additionally, given the importance of task-specificity to therapeutic interventions, we examined if walking speed adjustment strategies were consistent with those observed during usual overground walking, and if walking with the MR-HMD resulted in increased variability in gait parameters. Overall, participants matched their overground walking speed to the target speed of the MR-HMD visual feedback conditions (all p-values > 0.05). The percent inaccuracy was approximately 5% across all speed matching conditions and remained consistent across walking trials after the first overall walking trial. Walking with the MR-HMD did not result in more variability in walking speed, however, we observed more variability in stride length and time when walking with feedback from the MR-HMD compared to walking without feedback. The findings offer support for mixed reality-based visual feedback as a method to provoke goal-specific changes in overground walking behavior. Further studies are necessary to determine the clinical safety and efficacy of this MR-HMD technology to provide extrinsic sensory feedback in combination with traditional treatments in rehabilitation.
Vulnerability of Human Cerebellar Neurons to Degeneration in Ataxia-Causing Channelopathies
Authors: Bushart David D. , Shakkottai Vikram G.
Published: June 2022

Mutations in ion channel genes underlie a number of human neurological diseases. Historically, human mutations in ion channel genes, the so-called channelopathies, have been identified to cause episodic disorders. In the last decade, however, mutations in ion channel genes have been demonstrated to result in progressive neurodegenerative and neurodevelopmental disorders in humans, particularly with ion channels that are enriched in the cerebellum. This was unexpected given prior rodent ion channel knock-out models that almost never display neurodegeneration. Human ataxia-causing channelopathies that result in even haploinsufficiency can result in cerebellar atrophy and cerebellar Purkinje neuron loss. Rodent neurons with ion channel loss-of-function appear to, therefore, be significantly more resistant to neurodegeneration compared to human neurons. Fundamental differences in susceptibility of human and rodent cerebellar neurons in ataxia-causing channelopathies must therefore be present. In this review, we explore the properties of human neurons that may contribute to their vulnerability to cerebellar degeneration secondary to ion channel loss-of-function mutations. We present a model taking into account the known allometric scaling of neuronal ion channel density in humans and other mammals that may explain the preferential vulnerability of human cerebellar neurons to degeneration in ataxia-causing channelopathies. We also speculate on the vulnerability of cerebellar neurons to degeneration in mouse models of spinocerebellar ataxia (SCA) where ion channel transcript dysregulation has recently been implicated in disease pathogenesis.
HPN Standard of Care and Long-Term Outcomes of CIF Pediatric Patients: Twenty-Eight Years' Experience in a Reference Center
Authors: Lezo Antonella , D'Eusebio Chiara , Riboldi Lorenzo , Baldini Letizia , Spada Marco
Published: June 2022

Background and Aims

Chronic intestinal failure (CIF) therapy changed significantly in recent decades, and both survival and complication rates improved over time. International guidelines claim that early referral of long-term home parenteral nutrition (HPN) patients to an expert center with specific standards of care may positively affect long-term outcomes. Herein, we retrospectively analyse the long-term outcomes of a cohort of pediatric patients with CIF followed-up since our Pediatric Intestinal Failure Unit foundation, in 1989.

Methods

Data of the 120 children followed up at Pediatric Intestinal Failure Unit during the last 28 years were retrospectively collected. Patients' and HPN characteristics, as well as dependence, survival, and complication rates, were described.

Results

Incidence and prevalence of CIF increased during the study period particularly due to the increase of HPN for non-digestive disease (NDD) CIF (47.5% of the study sample). Catheter-related bloodstream infection (CRBSI) rate decreased over the study period: 0.33 episodes/1,000 catheters days before 2011 and 0.19 episodes/1,000 catheters days afterwards. Only 1 patient out of 12 died because of HPN complications. The survival rate of patients with PDD was 98.4% at 1 year from the beginning of HPN, 96.5% at 2 years, and 93.8% from the fifth year onwards. Concerning the dependence rate, 70.6% of patients were still on HPN 1 year after the start of HPN, 63.7% at 2 years, 52.4% at 5 years, and 40.8% from the 9th year onwards, with no significant difference according to the underlying intestinal pathology. The survival rate of NDD patients was 91.2% at 1 year from the beginning of HPN, 87.4% at 2 years, and 81.9% from the third year onwards. For what concerns the enteral autonomy, it was regained by 56.7% 1 year after the start of HPN, 74.5% at 2 years, and 95.0% in the 5th year.

Conclusions

Our data confirmed the importance of appropriate standards of care and suggest that applying a specific set of standards and protocols may further improve patients' outcomes and survival. Indeed, both primary and non-digestive diseases HPN showed good outcomes.
The Effect of Rye-Based Foods on Postprandial Plasma Insulin Concentration: The Rye Factor
Authors: Iversen Kia Nøhr , Jonsson Karin , Landberg Rikard
Published: June 2022

Consumption of whole grain has been associated with lower incidence of type-2 diabetes, cardiovascular disease and their risk factors including improved glycemic control. In comparison with other whole grain products, rye bread has been shown to induce lower insulin response in the postprandial phase, without affecting the glucose response. This phenomenon has been referred to as the “rye factor” and is being explored in this review where we summarize the findings from meal and extended meal studies including rye-based foods. Overall, results from intervention studies showed that rye-based foods vs. (wheat) control foods had positive effect on both insulin and glucose responses in the postprandial phase, rather than on insulin alone. Mechanistic studies have shown that the rye factor phenomenon might be due to slowing of the glucose uptake in the intestine. However, this has also been shown for wheat-based bread and is likely an effect of structural properties of the investigated foods rather than the rye per se. More carefully controlled studies where standardized structural properties of different cereals are linked to the postprandial response are needed to further elucidate the underlying mechanisms and determinants for the effect of specific cereals and product traits on postprandial glycemic control.
Diet as a Risk Factor for Early-Onset Colorectal Adenoma and Carcinoma: A Systematic Review
Authors: Carroll Kaitlin L. , Frugé Andrew D. , Heslin Martin J. , Lipke Elizabeth A. , Greene Michael W.
Published: June 2022

Background

Colorectal cancer in adults 50 years old and younger is increasing in incidence worldwide. Diet may be a modifiable risk factor. The objective of this study was to examine evidence regarding the association between diet and the risk of developing early-onset colorectal cancer (EOCRC) and early-onset colorectal adenomas in young adults.

Methods

PUBMED, Web of Science, and Embase were systematically searched for studies examining dietary intake as a risk factor for EOCRC and early-onset colorectal adenomas. Results were synthesized narratively due to the heterogeneity of the studies.

Results

Of the 415 studies identified, ten met the inclusion criteria. Of these ten studies, four provided data on dietary risk factors for early-onset colorectal adenomas and six provided data on dietary risk factors for EOCRC. The four studies that measured colorectal adenoma occurrence reported an increased incidence with high sugar sweetened beverage intake, a higher pro-inflammatory diet, a higher Western diet score and higher sulfur microbial diet score. A protective effect against early-onset colorectal adenomas was observed in those who had a higher Prudent diet score or higher adherence to other health dietary approaches (Dietary Approaches to Stop Hypertension, Alternative Healthy Eating Index-2010, or the alternative Mediterranean diet). Those who consumed large amounts of deep-fried foods, refined foods, followed a high fat diet, consumed large amounts of sugary drinks and desserts, and had low folate and fiber consumption had a significantly higher occurrence of EOCRC. A protective effect against EOCRC was observed for those who consumed more fruits and vegetables, high amounts of micronutrients and those who adhered to a vegetarian diet.

Conclusions

The results of this study reveal various dietary habits may be risk factors or protective against early-onset colorectal cancer and adenomas. Future research should focus on large prospective cohort studies with long-term follow-up to confirm published results and further examine whether differences in diet quality are associated with EOCRC risk.
Immunoglobulin M Monoclonal Gammopathies of Clinical Significance
Authors: Girard Louis-Pierre , Soekojo Cinnie Yentia , Ooi Melissa , Chng Wee Joo , de Mel Sanjay
Published: June 2022

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler’s syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.
Hypercalcemia and Osteolytic Lesions as Presenting Symptoms of Acute Lymphoblastic Leukemia in Children: Case Report and Literature Review
Authors: Chen Min , Ni Jiaqi , Lu Xiaoxi
Published: June 2022

Acute lymphoblastic leukemia (ALL) presenting with hypercalcemia and osteolytic lesions is rare and unusual in childhood. We report a case of a 13-year-old boy with ALL who presented with intermittent fever, nausea, vomiting, and increasing lower limb pain. Skeletal X-rays and CT scan showed severe osteolytic lesions of the skull and extremities. Physical examination revealed multiple inguinal lymph nodes. Laboratory tests demonstrated severe hypercalcemia (Ca > 3.49 mmol/L), decreased parathyroid hormone (PTH), and vitamin D level. Despite a normal complete blood count and the absence of circulating blasts, bone marrow biopsy revealed B-precursor ALL. Hypercalcemia was initially treated with intravenous isotonic sodium chloride and furosemide but the serum calcium level was not normalized. It was successfully managed with calcitonin and pamidronate afterward. Later, the child responded well to chemotherapy and continued with consolidation treatment. The clinical condition was stable, and the bone marrow revealed complete remission. This case indicated that hypercalcemia alone or combined with osteolytic lesions can be the only presenting symptom of ALL in children. Diagnostic errors may occur especially when combined with the absence of circulating blasts in the peripheral blood smear. Bone marrow aspiration should be considered to confirm the diagnosis.
Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc)
Authors: Schulte Dominik M. , Waetzig Georg H. , Schuett Harald , Marx Marlies , Schulte Berenice , Garbers Christoph , Lokau Juliane , Vlacil Ann-Kathrin , Schulz Juliane , Seoudy Anna K. , Schieffer Bernhard , Rosenstiel Philip , Seeger Marcus , Laudes Matthias , Rose-John Stefan , Lützen Ulf , Grote Karsten , Schreiber Stefan
Published: June 2022

Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr−/−) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr−/− mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.
Renoprotection of Microcystin-RR in Unilateral Ureteral Obstruction-Induced Renal Fibrosis: Targeting the PKM2-HIF-1α Pathway
Authors: Ren Yan , Wang Jie , Guo Wenwen , Chen Jingwen , Wu Xin , Gu Shubo , Xu Lizhi , Wu Zhiwei , Wang Yaping
Published: June 2022

Renal fibrosis is a pathological characteristic of the endpoint of chronic kidney disease (CKD), which remains a major public health problem. None of the current therapies is effective in stopping kidney fibrosis progression. In light of our novel detection of a potential antifibrosis of microcystins (MCs), we investigate the renoprotection effect of MCs with UUO-induced renal fibrosis. The treatment of MCs was initiated in model animals in advance of UUO operation. After determining that the antifibrotic effect of MCs was independent of its toxicity, our study focused on the renoprotection of microcystin-RR (MC-RR), a lower toxic congener of MCs, in UUO mice and the cell models in vitro. The co-immunoprecipitation assay and recombination plasmid transfection were used in the investigation of the mechanism of antifibrosis of MC-RR. The data show that MC-RR substantially exerts an effect on renoprotection with suppression of the expression of TGF-β1/Smad signaling molecules and a blockage in epithelial dedifferentiation and myofibroblast activation in UUO model animals. MC-RR shows a binding directly to pyruvate kinase M2 (PKM2), downregulates PKM2-HIF-1α signaling, restores the inhibited expression of MMP-7 and MMP-13, and reduces the upregulated expression of MMP-9 in UUO renal tissues. The current study demonstrates a novel effect of MC-RR on renoprotection in kidney damage, which could be conducted in therapeutics for chronic kidney disease.
Molecular Mechanism of Naringenin Against High-Glucose-Induced Vascular Smooth Muscle Cells Proliferation and Migration Based on Network Pharmacology and Transcriptomic Analyses
Authors: He Wenjun , Wang Yanming , Yang Rui , Ma Huihui , Qin Xuqing , Yan Meijuan , Rong Yi , Xie Yufang , Li Li , Si Junqiang , Li Xinzhi , Ma Ketao
Published: June 2022

Although the protective effects of naringenin (Nar) on vascular smooth muscle cells (VSMCs) have been confirmed, whether it has anti-proliferation and anti-migration effects in high-glucose-induced VSMCs has remained unclear. This study aimed to clarify the potential targets and molecular mechanism of Nar when used to treat high-glucose-induced vasculopathy based on transcriptomics, network pharmacology, molecular docking, and in vivo and in vitro assays. We found that Nar has visible anti-proliferation and anti-migration effects both in vitro (high-glucose-induced VSMC proliferation and migration model) and in vivo (type 1 diabetes mouse model). Based on the results of network pharmacology and molecular docking, vascular endothelial growth factor A (VEGFA), the proto-oncogene tyrosine-protein kinase Src (Src) and the kinase insert domain receptor (KDR) are the core targets of Nar when used to treat diabetic angiopathies, according to the degree value and the docking score of the three core genes. Interestingly, not only the Biological Process (BP), Molecular Function (MF), and KEGG enrichment results from network pharmacology analysis but also transcriptomics showed that phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) is the most likely downstream pathway involved in the protective effects of Nar on VSMCs. Notably, according to the differentially expressed genes (DEGs) in the transcriptomic analysis, we found that cAMP-responsive element binding protein 5 (CREB5) is a downstream protein of the PI3K/Akt pathway that participates in VSMCs proliferation and migration. Furthermore, the results of molecular experiments in vitro were consistent with the bioinformatic analysis. Nar significantly inhibited the protein expression of the core targets (VEGFA, Src and KDR) and downregulated the PI3K/Akt/CREB5 pathway. Our results indicated that Nar exerted anti-proliferation and anti-migration effects on high-glucose-induced VSMCs through decreasing expression of the target protein VEGFA, and then downregulating the PI3K/Akt/CREB5 pathway, suggesting its potential for treating diabetic angiopathies.
Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors
Authors: Zeng Yue , Zheng Yueming , Zhang Tongtong , Ye Fei , Zhan Li , Kou Zengwei , Zhu Shujia , Gao Zhaobing
Published: June 2022

N-methyl-D-aspartate receptors (NMDARs) are Ca2+-permeable ionotropic glutamate receptors (iGluRs) in the central nervous system and play important roles in neuronal development and synaptic plasticity. Conventional NMDARs, which typically comprise GluN1 and GluN2 subunits, have different biophysical properties than GluN3-containing NMDARs: GluN3-containing NMDARs have smaller unitary conductance, less Ca2+-permeability and lower Mg2+-sensitivity than those of conventional NMDARs. However, there are very few specific modulators for GluN3-containing NMDARs. Here, we developed a cell-based high-throughput calcium assay and identified 3-fluoro-1,2-phenylene bis (3-hydroxybenzoate) (WZB117) as a relatively selective inhibitor of GluN1/GluN3 receptors. The IC50 value of WZB117 on GluN1/GluN3A receptors expressed in HEK-293 cells was 1.15 ± 0.34 μM. Consistently, WZB117 exhibited strong inhibitory activity against glycine-induced currents in the presence of CGP-78608 but only slightly affected the NMDA-, KA- and AMPA-induced currents in the acutely isolated rat hippocampal neurons. Among the four types of endogenous currents, only the first one is primarily mediated by GluN1/GluN3 receptors. Mechanistic studies showed that WZB117 inhibited the GluN1/GluN3A receptors in a glycine-, voltage- and pH-independent manner, suggesting it is an allosteric modulator. Site-directed mutagenesis and chimera construction further revealed that WZB117 may act on the GluN3A pre-M1 region with key determinants different from those of previously identified modulators. Together, our study developed an efficient method to discover modulators of GluN3-containing NMDARs and characterized WZB117 as a novel allosteric inhibitor of GluN1/GluN3 receptors.
A Qualitative Study of Stakeholders’ Views on Pharmacovigilance System, Policy, and Coordination in Pakistan
Authors: Khan Muhammad Akhtar Abbas , Hamid Saima , Khan Shahzad Ali , Sarfraz Mariyam , Babar Zaheer-Ud-Din
Published: June 2022

Objectives:Due to the absence of necessary rules, poor coordination, and various challenges, the pharmacovigilance system of Pakistan is not optimally functional at all levels of the health system. The objective of the study was to assess the stakeholders’ perceptions of the current ADR reporting system and to identify the pharmacovigilance policy issues and problems of effective coordination.

Methodology:Stakeholders from a broad range of disciplines, academia, regulatory authorities, the pharmaceutical industry, international health organizations, as well as pharmacovigilance experts, and healthcare professionals were included in the study. A total of 25 stakeholders throughout Pakistan were interviewed during exploratory semi-structured interviews. The interviews were recorded digitally, transcribed, coded, compared, and grouped according to their similarity of themes. Participants provided insights into gaps, limitations, and challenges of Pakistan’s current ADR reporting system, issues with proposed pharmacovigilance rules, and coordination difficulties.

Results:The majority of the participants considered the ADR reporting system in Pakistan to be improving but in a nascent phase. The identified gaps, challenges, limitations of the system, and barriers to reporting were labeled as reasons for limited functioning. Almost all stakeholders were aware of the existence of draft pharmacovigilance rules; however, participants in the industry were familiar with the contents and context of draft pharmacovigilance rules. Bureaucratic red tape and lack of political will appeared to be the top reasons for delaying the approval of the pharmacovigilance rules. Wider consultation, advocacy, and awareness sessions of policymakers and HCPs were suggested for early approval of rules. Participants unanimously agreed that the approval of rules shall improve the quality of life and reduce the economic burden along with morbidity and mortality rates. The need for greater and collaborative coordination among the stakeholders in promoting medicines’ safety was highlighted. All participants suggested the use of media and celebrities to disseminate the safety information.

Conclusion:Participants showed partial satisfaction with the way pharmacovigilance in Pakistan is moving forward. However, stakeholders believed that engagement of multi-stakeholders, approval of pharmacovigilance rules, and the establishment of pharmacovigilance centers in provinces, hospitals, and public health programs (PHPs) shall support in achieving the desired results.
Recommendations on Off-Label Drug Use in Pediatric Guidelines
Authors: Meng Min , Zhou Qi , Lei Wenjuan , Tian Min , Wang Ping , Liu Yunlan , Sun Yajia , Chen Yaolong , Li Qiu
Published: June 2022

Objective: To systematically analyze the supporting evidence, drug information, and the type of off-label drug use in recommendations on off-label drug use in pediatric guidelines.

Methods: A cross-sectional study was performed by systematic search through MEDLINE (via PubMed) and Embase databases to identify literature published from 1 January 2018, to 31 December 2020. Only pediatric clinical practice guidelines that included recommendations on off-label use of drugs were included. We present descriptive information on the sources of the included guidelines, country, publication year, evidence grading system used, details on the types of off-label drug use, and the types of studies used as references to support the recommendations.

Results: A total of 66 pediatric guidelines with 605 recommendations were included. Eighty-seven (14.4%) recommendations did not cite any references; and the remaining 518 recommendations were supported by 2,240 references (mean 4.3 references/recommendation). The most common types of studies cited were pediatric RCTs (n = 314, 14.0%), pediatric case series studies (n = 260, 11.6%), and reviews (n = 255, 11.4%). Twenty-one percent (n = 470) of the references were studies on adults. One hundred and forty (23.1%) recommendations were graded using the Grading of Recommendations, Assessments, Development, and Evaluations (GRADE) system, of which 37 (26.4%) were graded as strong but supported with only C or D level of evidence. The most commonly reported type of information in the recommendations was indication (n = 499, 82.5%). The most commonly addressed type of off-label drug use in the 523 positive recommendations was unapproved population (n = 255, 48.8%). Sixty-nine (11.4%) recommendations explicitly reported the drug use as off-label.

Conclusion: Children may be exposed to medical risks due to gaps in reporting and evidence of off-label drug use recommendations in pediatric guidelines.
Adenosine-A2A Receptor Signaling Plays a Crucial Role in Sudden Unexpected Death in Epilepsy
Authors: Shen Hai-Ying , Baer Sadie B. , Gesese Raey , Cook John M. , Weltha Landen , Coffman Shayla Q. , Wu Jie , Chen Jiang-Fan , Gao Ming , Ji Teng
Published: June 2022

Adenosinergic activities are suggested to participate in SUDEP pathophysiology; this study aimed to evaluate the adenosine hypothesis of SUDEP and specifically the role of adenosine A2A receptor (A2AR) in the development of a SUDEP mouse model with relevant clinical features. Using a combined paradigm of intrahippocampal and intraperitoneal administration of kainic acid (KA), we developed a boosted-KA model of SUDEP in genetically modified adenosine kinase (ADK) knockdown (Adk+/-) mice, which has reduced ADK in the brain. Seizure activity was monitored using video-EEG methods, and in vivo recording of local field potential (LFP) was used to evaluate neuronal activity within the nucleus tractus solitarius (NTS). Our boosted-KA model of SUDEP was characterized by a delayed, postictal sudden death in epileptic mice. We demonstrated a higher incidence of SUDEP in Adk+/- mice (34.8%) vs. WTs (8.0%), and the ADK inhibitor, 5-Iodotubercidin, further increased SUDEP in Adk+/- mice (46.7%). We revealed that the NTS level of ADK was significantly increased in epileptic WTs, but not in epileptic Adk+/- mutants, while the A2AR level in NTS was increased in epileptic (WT and Adk+/-) mice vs. non-epileptic controls. The A2AR antagonist, SCH58261, significantly reduced SUDEP events in Adk+/- mice. LFP data showed that SCH58261 partially restored KA injection-induced suppression of gamma oscillation in the NTS of epileptic WT mice, whereas SCH58261 increased theta and beta oscillations in Adk+/- mutants after KA injection, albeit with no change in gamma oscillations. These LFP findings suggest that SCH58261 and KA induced changes in local neuronal activities in the NTS of epileptic mice. We revealed a crucial role for NTS A2AR in SUDEP pathophysiology suggesting A2AR as a potential therapeutic target for SUDEP risk prevention.
A Fractal Theory of Urban Growth
Authors: Molinero C.
Published: June 2022

This paper presents an analytical framework for the physical environment of cities using fractal theory. The strength of the approach lies in its simplicity and precision. The equations presented in this article comprise: the number of occupied sites in an area; the population and the length of roads of a city; its fractal dimension; its number of average and maximum levels (floors per building); the average density of population and roads; what are the limits to growth as well as an analysis on some of the city’s scaling laws. These equations describe to a high level of precision the real values measured in the system of the United Kingdom, for every city above 5,000 people, which amounts to a sample size of 1,031 cities. This work will allow further research into the nature of cities, since it enables the creation of synthetic cities, and further analytical derivations that can arise from these building blocks. The paper shows as well how the same set of equations can be used to characterise the internal distribution of cities from the perspective of its growth as a possible example of an application of the framework.
Microbial Adhesion on Circular Obstacles: An Optimization Study
Authors: Faúndez Tamara , Espinoza Bastián , Soto Rodrigo , Guzmán-Lastra Francisca
Published: June 2022

Microbial filtration is an important process with applications in environmental, mining, and sanitary engineering. Here, we study the interplay between the motility of microswimmers and the imposed flow to determine the adhesion of bacteria at the surface of the solid obstacle. For that, we perform numerical simulations of active Brownian particles interacting with a single cylindrical obstacle when an imposed laminar flow is present. Highly and weakly persistent swimmers are studied, representing extreme cases of bacteria used in experiments and we vary the swimmers’ velocity u0, the imposed flow velocity U∞, and the obstacle radius R. Starting with no swimmers close to the cylinder, we inject them steadily until a constant number of swimmers are adhered to the obstacle surface. The deposition/erosion process is characterized by the number of bacteria in contact with the obstacle, quantified by the average coverage of the cylinder surface λtrap, and the relaxation time to reach the steady state τtrap. Two regimes are found. The Brownian deposition is attained when swimmer velocities are smaller than the imposed flow. In this case, the particles can diffuse across the streamlines and settle around the obstacle covering the whole perimeter, forming multiple layers. The direct interception is obtained when the particle’s velocities are larger, reaching the obstacle by direct swimming, in which case they form approximately one layer on the obstacle surface. It is found that λtrap decreases with u0 and R, but the dependence with the imposed flow U∞ is non-monotonic, with and optimum coverage for intermediate flows, given by the crossover of the two regimes. The relaxation rate τtrap decreases with u0 and increases with R. The dependence of τtrap with U∞ is more complex, depending on the persistence of the swimmers. The existence of an optimum value of the flow velocity to reach maximum values of the number of deposited swimmers is an important design information for different applications that use microbial filtration. Finally, in general, it is found that optimal adhesion that has larger values of λtrap and smaller values of τtrap is obtained for more-persistent swimmers moving at small velocities interacting with small obstacles.
Design and Analysis of Field-of-View Independent k-Space Trajectories for Magnetic Resonance Imaging
Authors: Speidel Tobias , Metze Patrick , Stumpf Kilian , Hüfken Thomas , Rasche Volker
Published: June 2022

This manuscript describes a method of three-dimensional k-space sampling that is based on a generalised form of the previously introduced “Seiffert Spirals,” which exploits the equality between undersampling and the reconstruction of a field of view which is larger than what is represented by the primary sampling density, leading to an imaging approach that does not require any prior commitment to an imaging field of view. The concept of reconstructing arbitrary FOVs based on a low-coherently sampled k-space is demonstrated analytically by simulations of the corresponding point spread functions and by an analysis of the noise power spectrum of undersampled datasets. In-vivo images highlight the feasibility of the presented approach by reconstructing white noise governed images from an undersampled datasets with a smaller encoded FOV. Beneficial properties are especially given by an artefact behaviour, which is widely comparable to the introduction of white noise in the image domain. Furthermore, these aliasing properties provide a promising precondition for the combination with non-linear reconstruction techniques such as Compressed Sensing. All presented results show dominant low-coherent aliasing properties, leading to a noise-like aliasing behaviour, which enables parameterization of the imaging sequence according to a given resolution and scan-time, without the need for FOV considerations.
Stray-Light Suppression of the Internally Occulted Reflecting Solar Corona Imager
Authors: Zhang Guang , Wang Yunqi , He Lingping , Wang Xiaodong , Ren Shuai , Xuan Yubo , Liu Fei , Chen Bo
Published: June 2022

In order to achieve a clear observation of the ultra-low brightness solar corona and provide a physical basis for forecasting space weather that seriously affects the human living environment, the stray-light suppression level becomes the key factor affecting the development of the coronagraph. In this study, a stray-light suppression method is adopted for Solar Corona Imager (SCI) which is a dual-waveband internally occulted reflecting coronagraph simultaneously and independently observing the inner corona in the HI Lyman-alpha (121.6 ± 10 nm) line and white-light (700.0 ± 40 nm) wavebands with a field-of-view (FOV) from 1.1 to 2.5 R⊙ (R⊙ stands for the mean solar radius). The scattered stray-light from the primary mirror, including the surface errors, cosmetic defects, and particulate contamination, is analyzed and suppressed, and the corresponding scattering models are established for simulation based on the laboratory testing. The stray-light measurement results for SCI in the laboratory show that the stray-light level can be suppressed to the order of 10−8 B⊙ at 2.5 R⊙ (B⊙ is the mean brightness of the solar disk) in the white-light (WL) band, which is consistent with the stray-light level obtained by simulation and verifies the modeling and simulation.