bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Involvement of a Subset of Spinal Dorsal Horn Neurons Operated by a Prodynorphin Promoter in Aβ Fiber-Mediated Neuropathic Allodynia-Like Behavioral Responses in Rats
Authors: Ishibashi Tadayuki , Yoshikawa Yu , Sueto Daichi , Tashima Ryoichi , Tozaki-Saitoh Hidetoshi , Koga Keisuke , Yamaura Ken , Tsuda Makoto
Published: June 2022

Mechanical allodynia (pain produced by innocuous stimuli such as touch) is the main symptom of neuropathic pain. Its underlying mechanism remains to be elucidated, but peripheral nerve injury (PNI)-induced malfunction of neuronal circuits in the central nervous system, including the spinal dorsal horn (SDH), is thought to be involved in touch-pain conversion. Here, we found that intra-SDH injection of adeno-associated viral vectors including a prodynorphin promoter (AAV-PdynP) captured a subset of neurons that were mainly located in the superficial laminae, including lamina I, and exhibited mostly inhibitory characteristics. Using transgenic rats that enable optogenetic stimulation of touch-sensing Aβ fibers, we found that the light-evoked paw withdrawal behavior and aversive responses after PNI were attenuated by selective ablation of AAV-PdynP-captured SDH neurons. Notably, the ablation had no effect on withdrawal behavior from von Frey filaments. Furthermore, Aβ fiber stimulation did not excite AAV-PdynP+ SDH neurons under normal conditions, but after PNI, this induced excitation, possibly due to enhanced Aβ fiber-evoked excitatory synaptic inputs and elevated resting membrane potentials of these neurons. Moreover, the chemogenetic silencing of AAV-PdynP+ neurons of PNI rats attenuated the Aβ fiber-evoked paw withdrawal behavior and c-FOS expression in superficial SDH neurons. Our findings suggest that PNI renders AAV-PdynP-captured neurons excitable to Aβ fiber stimulation, which selectively contributes to the conversion of Aβ fiber-mediated touch signal to nociceptive. Thus, reducing the excitability of AAV-PdynP-captured neurons may be a new option for the treatment of neuropathic allodynia.
Brain Synchronization and Multivariate Autoregressive (MVAR) Modeling in Cognitive Neurodynamics
Authors: Bressler Steven L. , Kumar Ashvin , Singer Isaac
Published: June 2022

This paper is a review of cognitive neurodynamics research as it pertains to recent advances in Multivariate Autoregressive (MVAR) modeling. Long-range synchronization between the frontoparietal network (FPN) and forebrain subcortical systems occurs when multiple neuronal actions are coordinated across time (Chafee and Goldman-Rakic, 1998), resulting in large-scale measurable activity in the EEG. This paper reviews the power and advantages of the MVAR method to analyze long-range synchronization between brain regions (Kaminski et al., 2016; Kaminski and Blinowska, 2017). It explores the synchronization expressed in neurocognitive networks that is observable in the local field potential (LFP), an EEG-like signal, and in fMRI time series. In recent years, the surge in MVAR modeling in cognitive neurodynamics experiments has highlighted the effectiveness of the method, particularly in analyzing continuous neural signals such as EEG and fMRI (Pereda et al., 2005). MVAR modeling has been particularly useful in identifying causality, a multichannel time-series measure that can only be consistently computed with multivariate processes. Due to the multivariate nature of neuronal communication, multiple non-linear multivariate-analysis models are successful, presenting results with much greater accuracy and speed than non-linear univariate-analysis methods. Granger’s framework provides causal information about neuronal flow using neural time and frequency analysis, comprising the basis of the MVAR model. Recent advancements in MVAR modeling have included Directed Transfer Function (DTF) and Partial Directed Coherence (PDC), multivariate methods based on MVAR modeling that are capable of determining causal influences and directed propagation of EEG activity. The related Granger causality is an increasingly popular tool for measuring directed functional interactions from time series data.
Association of Coffee, Tea, and Caffeine Consumption With All-Cause Risk and Specific Mortality for Cardiovascular Disease Patients
Authors: Zheng Haotian , Lin Fan , Xin Ning , Yang Linxin , Zhu Pengli
Published: June 2022

Aim

The aim of the study was to examine the relationship between coffee, tea, caffeine consumption and risk of all-cause death and cardiovascular disease (CVD) death in CVD population.

Methods

This cohort study included 626 CVD participants aged ≥18 years old who derived from the National Health and Nutrition Examination Surveys (NHANES) database 2003–2006. The end time of follow-up was 2015, and with a median follow-up time of 113.5 (63, 133) months. CVD death was defined as a death caused by congestive heart failure (CHF), coronary heart disease (CHD), angina pectoris, heart attack or stroke. Cox model and competitive-risk model were used to explore the relationship of coffee, tea, caffeine, decaffeinated coffee/tea on the risk of the all-cause death and CVD death for CVD population, respectively. Additionally, we explored the effect of urinary caffeine and caffeine metabolites on all-cause death.

Results

All patients were divided into survival group (n = 304), non-CVD death group (n = 223), and CVD death group (n = 99). The incidence of all-cause death and CVD death was ~51.44 and 15.81% in the study. After adjusting age, body mass index (BMI), cancer, estimated glomerular filtration rate (eGFR), energy, the history of CVD medications, carbohydrate and family income to poverty ratio (PIR), the results suggested coffee, caffeine, iced tea and hot tea consumption (≥4 cups per day) were associated with an increased risk of the all-cause death in CVD patients; while hot tea (1–3 cups per day), decaffeinated coffee/iced tea/hot tea could reduce the risk of the all-cause death. Likewise, coffee, caffeine, iced tea (≥4 cups per day), hot tea, decaffeinated iced tea/ hot tea (Always) could enhance the risk of the CVD death in CVD population. We also found that 1-methylxanthine showed a significant positive association on the risk of all-cause death in CVD population.

Conclusion

Our study indicated that higher consumption of coffee, tea and caffeine could increase the risk of all-cause and CVD death for CVD patients.
Royal Jelly Plus Coenzyme Q10 Supplementation Enhances High-Intensity Interval Exercise Performance via Alterations in Cardiac Autonomic Regulation and Blood Lactate Concentration in Runners
Authors: Ovchinnikov Aleksandr N. , Deryugina Anna V. , Paoli Antonio
Published: June 2022

Purpose

This study aimed to examine whether oral royal jelly (RJ) and coenzyme Q10 (CoQ10) co-supplementation could improve high-intensity interval exercise (HIIE) performance in runners, reducing exercise-induced lactic acidosis and decreasing elevated sympathetic tone following exercise.

Methods

Thirty regional-level runners (age: 19 ± 1 years; height: 173 ± 2 cm; body mass: 68.9 ± 2 kg; body mass index: 23.1 ± 1 kg/m2) were randomly allocated to receive either 400 mg of RJ and 60 mg of CoQ10 (RJQ) or matching placebo (PLA) once daily for 10 days. Exercise performance expressed as time taken to complete HIIE was evaluated at baseline, and then reassessed at day 10 of intervention. HIIE protocol applied to the runners included three repetitions of 100 m distance at maximum possible speed interspersed with 45 s of recovery periods. Indices of heart rate variability and blood lactate concentration were also measured before and immediately after HIIE in each group.

Results

HIIE performance significantly improved in RJQ group (p = 0.005) compared to PLA group. Blood lactate levels and sympathetic influence on the heart were significantly lower both before and after the HIIE in athletes who received RJQ (p < 0.05) compared to PLA. Regression analysis showed that oral RJQ administration for 10 days was significantly associated with reductions in HIIE-induced increases in blood lactate concentration and enhanced cardiac parasympathetic modulation following exercise compared to PLA. Principal component analysis revealed that runners treated with RJQ are grouped by the first two principal components into a separate cluster compared to PLA. Correlation analysis demonstrated that the improvements in runners’ HIIE performance were due in significant part to RJQ-induced reduction of increment in blood lactate levels in response to exercise in combination with a more rapid shift in autonomic activity toward increased parasympathetic control early at post-exercise.

Conclusion

These findings suggest that RJQ supplementation for 10 days is potentially effective for enhancing HIIE performance and alleviating adverse effects of increased intramuscular acidity and prolonged sympathetic dominance following intense exercise.
Betacyanins and Anthocyanins in Pulp and Peel of Red Pitaya (Hylocereus polyrhizus cv. Jindu), Inhibition of Oxidative Stress, Lipid Reducing, and Cytotoxic Effects
Authors: Khoo Hock Eng , He Xuemei , Tang Yayuan , Li Zhichun , Li Changbao , Zeng Yuan , Tang Jie , Sun Jian
Published: June 2022

This study aimed to promote red pitaya fruit parts as alternate sources of nutraceuticals. The red pitaya of Chinese origin was determined for its in vitro efficacy, where the fruit extracts were evaluated based on the selected antioxidative properties, lipid-reducing capacity, and cytotoxicity. The betanin, total betacyanins, total anthocyanins, and DPPH radical scavenging activity of the red pitaya pulp and peel extracts were determined by spectrophotometric analyses. Cell culture assays were used to examine in vitro efficacy and cytotoxicity of the pitaya extracts. The result showed that red pitaya peel extract had a higher total betacyanins and total anthocyanins content than the pulp extract, but the peel extract had a lower DPPH radical scavenging effect than the pulp extract. The red pitaya extracts also had a protective effect in reducing oxidative stress, especially the peel extract. All fruit samples had a low anticancer potential except for betanin and anthocyanin standards. The protective effect of pitaya peel could be attributed to betacyanins and anthocyanins. Both pulp and peel extracts had a weak anticancer effect because these extracts contained polysaccharides and other phytochemicals that were not cytotoxic. As the peel extract of red pitaya was not cytotoxic, it is a potent source of betacyanins for reducing oxidative stress.
Identification and Characterization of the Stability of Hydrophobic Cyclolinopeptides From Flaxseed Oil
Authors: Fojnica Adnan , Leis Hans-Jörg , Murkovic Michael
Published: June 2022

Flaxseed (linseed) is a cultivar of the spring flowering annual plant flax (Linum usitatissimum) from the Linaceae family. Derivatives of this plant are widely used as food and as health products. In recent years, cyclic peptides isolated from flaxseed and flaxseed oil, better known as cyclolinopeptides (CLPs), have attracted the attention of the scientific community due to their roles in the inhibition of osteoclast differentiation or their antimalarial, immunosuppressive, and antitumor activities, as well as their prospects in nanotechnology and in the biomedical sector. This study describes the detection, identification, and measurement of CLPs in samples obtained from nine different flaxseed oil manufacturers. For the first time, Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer was used for CLP identification together with RP-HPLC. The routine analyses were performed using RP chromatography, measuring the absorption spectra and fluorescence detection for identifying tryptophan-containing peptides using the native fluorescence of tryptophan. In addition, existing protocols used for CLP extraction were optimized and improved in a fast and cost-efficient way. For the first time, 12 CLPs were separated using methanol/water as the eluent with RP-HPLC. Finally, the stability and degradation of individual CLPs in the respective flaxseed oil were examined over a period of 60 days at different temperatures. The higher temperature was chosen since this might reflect the cooking practices, as flaxseed oil is not used for high-temperature cooking. Using HPLC–MS, 15 CLPs were identified in total in the different flaxseed oils. The characterization of the peptides via HPLC–MS highlighted two types of CLP profiles with a substantial variation in the concentration and composition of CLPs per manufacturer, probably related to the plant cultivar. Among the observed CLPs, CLP-O, CLP-N, and CLP-B were the least stable, while CLP-C and CLP-A were the most stable peptides. However, it is important to highlight the gradual degradation of most of the examined CLPs over time, even at room temperature.
Brain Responses to Food Choices and Decisions Depend on Individual Hedonic Profiles and Eating Habits in Healthy Young Women
Authors: Coquery Nicolas , Gautier Yentl , Serrand Yann , Meurice Paul , Bannier Elise , Thibault Ronan , Constant Aymery , Moirand Romain , Val-Laillet David
Published: June 2022

The way different food consumption habits in healthy normal-weight individuals can shape their emotional and cognitive relationship with food and further disease susceptibility has been poorly investigated. Documenting the individual consumption of Western-type foods (i.e., high-calorie, sweet, fatty, and/or salty) in relation to psychological traits and brain responses to food-related situations can shed light on the early neurocognitive susceptibility to further diseases and disorders. We aimed to explore the relationship between eating habits, psychological components of eating, and brain responses as measured by blood oxygen level-dependent functional magnetic resonance imaging (fMRI) during a cognitive food choice task and using functional connectivity (FC) during resting-state fMRI (rsfMRI) in a population of 50 healthy normal-weight young women. A Food Consumption Frequency Questionnaire (FCFQ) was used to classify them on the basis of their eating habits and preferences by principal component analysis (PCA). Based on the PCA, we defined two eating habit profiles, namely, prudent-type consumers (PTc, N = 25) and Western-type consumers (WTc, N = 25), i.e., low and high consumers of western diet (WD) foods, respectively. The first two PCA dimensions, PCA1 and PCA2, were associated with different psychological components of eating and brain responses in regions involved in reward and motivation (striatum), hedonic evaluation (orbitofrontal cortex, OFC), decision conflict (anterior cingulate cortex, ACC), and cognitive control of eating (prefrontal cortex). PCA1 was inversely correlated with the FC between the right nucleus accumbens and the left lateral OFC, while PCA2 was inversely correlated with the FC between the right insula and the ACC. Our results suggest that, among a healthy population, distinct eating profiles can be detected, with specific correlates in the psychological components of eating behavior, which are also related to a modulation in the reward and motivation system during food choices. We could detect different patterns in brain functioning at rest, with reduced connectivity between the reward system and the frontal brain region in Western-type food consumers, which might be considered as an initial change toward ongoing modified cortico-striatal control.
Differential Private Deep Learning Models for Analyzing Breast Cancer Omics Data
Authors: Islam Md. Mohaiminul , Mohammed Noman , Wang Yang , Hu Pingzhao
Published: June 2022

Proper analysis of high-dimensional human genomic data is necessary to increase human knowledge about fundamental biological questions such as disease associations and drug sensitivity. However, such data contain sensitive private information about individuals and can be used to identify an individual (i.e., privacy violation) uniquely. Therefore, raw genomic datasets cannot be publicly published or shared with researchers. The recent success of deep learning (DL) in diverse problems proved its suitability for analyzing the high volume of high-dimensional genomic data. Still, DL-based models leak information about the training samples. To overcome this challenge, we can incorporate differential privacy mechanisms into the DL analysis framework as differential privacy can protect individuals’ privacy. We proposed a differential privacy based DL framework to solve two biological problems: breast cancer status (BCS) and cancer type (CT) classification, and drug sensitivity prediction. To predict BCS and CT using genomic data, we built a differential private (DP) deep autoencoder (dpAE) using private gene expression datasets that performs low-dimensional data representation learning. We used dpAE features to build multiple DP binary classifiers to predict BCS and CT in any individual. To predict drug sensitivity, we used the Genomics of Drug Sensitivity in Cancer (GDSC) dataset. We extracted GDSC’s dpAE features to build our DP drug sensitivity prediction model for 265 drugs. Evaluation of our proposed DP framework shows that it achieves improved prediction performance in predicting BCS, CT, and drug sensitivity than the previously published DP work.
Regulation of Gamma-Aminobutyric Acid Transaminase Expression and Its Clinical Significance in Hepatocellular Carcinoma
Authors: Gao Xiaoqiang , Jia Xiaodong , Xu Moyan , Xiang Jiao , Lei Jin , Li Yinyin , Lu Yinying , Zuo Shi
Published: June 2022

Background

Gamma-aminobutyric acid transaminase (ABAT) catalyzes the conversion of gamma-aminobutyric acid (GABA) into succinic semialdehyde. Although some evidence supports a key role of ABAT in the progression of hepatocellular carcinoma (HCC), no systematic analysis is available. Thus, this study aimed to investigate the possible mechanisms related to low ABAT expression and the prognostic value and potential functions of ABAT in HCC.

Methods

We obtained relevant datasets from the Encyclopedia of RNA Interactomes, MethSurv, cBioPortal, TISIDB and The Cancer Genome Atlas and used bioinformatic methods to analyze DNA methylation, copy number variation, gene mutation, and upstream microRNAs (miRNAs) of ABAT, exploring the potential relationship between ABAT expression and the prognosis, glycolysis, and immune infiltration in HCC.

Results

The results indicated that ABAT expression was lower in HCC tumor tissues than in normal tissues or adjacent tissues. Low ABAT expression was related to patient age, T stage classification, pathologic stage, histological grade, and alpha-fetoprotein level of HCC. Kaplan-Meier survival analyses indicated that low ABAT expression was correlated with poor HCC prognosis. ABAT was also verified as an independent risk factor in HCC via Cox multivariate analysis. Gene set enrichment analysis showed enrichment in various signaling pathways. Furthermore, DNA methylation, copy number variation, and gene mutation potentially induced low ABAT expression; miR-135a-5p was a potential upstream miRNA of ABAT. Additionally, ABAT expression was associated with glycolysis-related genes, infiltrated immune cells, immunoinhibitors, and immunostimulators in HCC.

Conclusions

Our study reveals that deficient ABAT expression is correlated with disease progression and poor prognosis in HCC because of its role in tumorigenesis and tumor immunity.
NAMPT Inhibition Induces Neuroblastoma Cell Death and Blocks Tumor Growth
Authors: Vallejo Frederic A. , Sanchez Anthony , Cuglievan Branko , Walters Winston M. , De Angulo Guillermo , Vanni Steven , Graham Regina M.
Published: June 2022

High-risk neuroblastoma (NB) portends very poor prognoses in children. Targeting tumor metabolism has emerged as a novel therapeutic strategy. High levels of nicotinamide-adenine-dinucleotide (NAD+) are required for rapid cell proliferation. Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme for NAD+ salvage and is overexpressed in several cancers. Here, we determine the potential of NAMPT as a therapeutic target for NB treatment. NAMPT inhibition cytotoxicity was determined by trypan blue exclusion and LDH assays. Neuroblastoma stem cell self-renewal was evaluated by neurosphere assay. Protein expression was evaluated via Western blot. The effect of targeting NAMPT in vivo was determined using an NB1691-xenografted mouse model. Robust NAMPT expression was demonstrated in multiple N-MYC amplified, high-risk neuroblastoma cell lines. NAMPT inhibition with STF-118804 (STF) decreased ATP, induced apoptosis, and reduced NB stem cell neurosphere formation. STF treatment down-regulated N-MYC levels and abrogated AKT activation. AKT and glycolytic pathway inhibitors in combination with NAMPT inhibition induced robust, greater-than-additive neuroblastoma cell death. Lastly, STF treatment blocked neuroblastoma tumor growth in mouse xenograft models. NAMPT is a valid therapeutic target as inhibition promoted neuroblastoma cell death in vitro and prevented tumor growth in vivo. Further investigation is warranted to establish this therapy’s role as an adjunctive modality.
Drug Repurposing by Tumor Tissue Editing
Authors: Lüke Florian , Harrer Dennis Christoph , Pantziarka Pan , Pukrop Tobias , Ghibelli Lina , Gerner Christopher , Reichle Albrecht , Heudobler Daniel
Published: June 2022

The combinatory use of drugs for systemic cancer therapy commonly aims at the direct elimination of tumor cells through induction of apoptosis. An alternative approach becomes the focus of attention if biological changes in tumor tissues following combinatory administration of regulatorily active drugs are considered as a therapeutic aim, e.g., differentiation, transdifferentiation induction, reconstitution of immunosurveillance, the use of alternative cell death mechanisms. Editing of the tumor tissue establishes new biological ‘hallmarks’ as a ‘pressure point’ to attenuate tumor growth. This may be achieved with repurposed, regulatorily active drug combinations, often simultaneously targeting different cell compartments of the tumor tissue. Moreover, tissue editing is paralleled by decisive functional changes in tumor tissues providing novel patterns of target sites for approved drugs. Thus, agents with poor activity in non-edited tissue may reveal new clinically meaningful outcomes. For tissue editing and targeting edited tissue novel requirements concerning drug selection and administration can be summarized according to available clinical and pre-clinical data. Monoactivity is no pre-requisite, but combinatory bio-regulatory activity. The regulatorily active dose may be far below the maximum tolerable dose, and besides inhibitory active drugs stimulatory drug activities may be integrated. Metronomic scheduling often seems to be of advantage. Novel preclinical approaches like functional assays testing drug combinations in tumor tissue are needed to select potential drugs for repurposing. The two-step drug repurposing procedure, namely establishing novel functional systems states in tumor tissues and consecutively providing novel target sites for approved drugs, facilitates the systematic identification of drug activities outside the scope of any original clinical drug approvals.
Surgical Treatment of Intraductal Papillary Neoplasm of the Bile Duct: A Report of Two Cases and Review of the Literature
Authors: Li Binjie , Liu Zhiqiang , Meng Zhuo , Li Mingyang , Tian Weijun , Liu Quanyan
Published: June 2022

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct tumor characterized by intraductal papillary or villous neoplasms covered by neoplastic epithelium with fine fibrovascular stalks in the dilated bile ducts (1). Its true etiology remains unknown. Herein, we report two cases of IPNB that underwent surgical resection. The first case was a 66-year-old male who complained of upper abdominal pain for three years. We found obstruction of the common bile duct and dilation of the intrahepatic and extrahepatic bile ducts after MRCP. Laparoscopic hepatic segmentectomy (S2, S3, S4), resection of the common bile duct, cholecystectomy, and hepaticojejunostomy were performed. The second case was a 67-year-old male with asymptomatic dilation of the intrahepatic duct. The patient underwent robot-assisted laparoscopic hepatic segmentectomy (S5, S6, S7, S8), resection of the common bile duct, hepaticojejunostomy and cholecystectomy.
Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm
Authors: Keller Alana L. , Sherbenou Daniel W. , Forsberg Peter A. , Mark Tomer M.
Published: June 2022

Multiple myeloma is an incurable hematologic malignancy. The typical disease course for myeloma patients is characterized by initial response to treatment followed by eventual development of resistance. Subsequent cycles of remission and relapse proceed as long as patients have new lines of therapy available to them. This reality has prompted development of many novel immunotherapeutics. Many of these drugs exploit the cytotoxic capabilities of the patients’ own T cells, effectively redirecting them to myeloma cells that are otherwise evading immune attack. Approaches including CAR T cell therapy and bispecific antibodies have displayed impressive efficacy in clinical trials for myeloma patients. This review examines the different approaches that utilize T cells in multiple myeloma therapy and investigates the benefits and risks of these exciting new strategies.
High-Throughput mRNA Sequencing Reveals Potential Therapeutic Targets of Febuxostat in Secondary Injury After Intracerebral Hemorrhage
Authors: Wang Xueyan , Zhang Chenyu , Li Yuwen , Xu Ting , Xiang Jin , Bai Yang , Zhang Ying , Wang Qi , Zhang Tiejun , Liao Linchuan
Published: June 2022

Febuxostat is a urate-lowering medication for the treatment of patients with gout. This study was performed to elucidate the effects and underlying mechanisms of febuxostat on neuronal injury induced by intracerebral hemorrhage (ICH) in mice. The results showed that the administration of febuxostat improved neurological severity scores and blood–brain barrier (BBB) permeability. Moreover, febuxostat attenuated neuronal cell death and cytokine levels compared with the ICH group. Next, we conducted a transcriptome analysis of the neuroprotective effects of febuxostat. The overlapping significant differentially expressed genes (DEGs) were identified. Gene ontology (GO) analysis revealed that the overlapping significant DEGs were most enriched in five items. The intersecting DEGs of the aforementioned five pathways were Wisp1, Wnt7b, Frzb, and Pitx2. In addition, GO terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that DEGs were mainly involved in the wnt signaling pathway. Furthermore, the expression of Wisp1 and Wnt7b in the perihematomal region at 72 h post-ICH was observed. The results showed that both Wisp1 and Wnt7b were increased in the ICH group and were decreased by the administration of febuxostat. Taken together, the study showed that febuxostat protected against secondary brain injury after ICH and the Wnt7b-Wisp1 pathway was closely related to neuroprotective effects.
L-GSH Supplementation in Conjunction With Rifampicin Augments the Treatment Response to Mycobacterium tuberculosis in a Diabetic Mouse Model
Authors: Beever Abrianna , Kachour Nala , Owens James , Sasaninia Kayvan , Kolloli Afsal , Kumar Ranjeet , Ramasamy Santhamani , Sisliyan Christina , Khamas Wael , Subbian Selvakumar , Venketaraman Vishwanath
Published: June 2022

Both active tuberculosis (TB) and asymptomatic latentMycobacterium tuberculosis(M. tb) infection (LTBI) cause significant health burdens to humans worldwide. Individuals with immunocompromising health conditions, such as Type 2 Diabetes Mellitus (T2DM), have a weakened ability to controlM. tbinfection and are more susceptible to reactivation of LTBI to active diseases. T2DM cases are known to have glutathione (GSH) deficiency and impaired immune cell function, including the granulomatous response toM. tbinfection. We have previously reported that liposomal glutathione (L-GSH) supplementation can restore the immune cell effector responses of T2DM cases. However, the effects of L-GSH supplementation on the bactericidal activities of first-line anti-TB drug rifampicin (RIF) againstM. tbinfection have yet to be explored. The aim of this study is to elucidate the effects of L-GSH supplementation in conjunction with RIF treatment during an activeM. tbinfection in a diabetic mouse model. In this study, we evaluated total and reduced levels of GSH, cytokine profiles, malondialdehyde (MDA) levels,M. tbburden, and granulomatous response in the lungs. We show that L-GSH supplementation caused a significant reduction inM. tbburden in the lungs, decreased oxidative stress, and increased the production of IFN-γ, TNF-α, IL-17, IL-10, and TGF-β1compared to the untreated mice. In addition, L-GSH supplementation in conjunction with RIF treatment achieved better control ofM. tbinfection in the lungs and significantly reduced the levels of oxidative stress compared to treatment with RIF alone. Moreover, L-GSH in conjunction with RIF significantly increased TGF-β1 levels compared to treatment with RIF alone. These findings suggest potential therapeutic benefits of L-GSH supplementation in conjunction with first-line antibiotic therapy againstM. tbinfection in individuals with T2DM.
Advanced in Vitro Safety Assessment of Herbal Medicines for the Treatment of Non-Psychotic Mental Disorders in Pregnancy
Authors: Spiess Deborah , Winker Moritz , Dolder Behna Alexandra , Gründemann Carsten , Simões-Wüst Ana Paula
Published: June 2022

When confronted with non-psychotic mental disorders, pregnant women often refrain from using synthetic drugs and resort to herbal medicines such as St. John’s wort, California poppy, valerian, lavender, and hops. Nevertheless, these herbal medicines have not yet been officially approved in pregnancy due to lack of safety data. Using a variety of in vitro methods (determination of cytotoxicity, apoptosis induction, genotoxicity, effects on metabolic properties, and inhibition/induction of differentiation) in a commonly used placental cell line (BeWo b30), we were previously able to show that extracts from these plants are likely to be safe at the usual clinical doses. In the present work, we wanted to extend our safety assessment of these herbal medicines by 1) looking for possible effects on gene expression and 2) using the same in vitro methods to characterize effects of selected phytochemicals that might conceivably lead to safety issues. Proteomics results were promising, as none of the five extracts significantly affected protein expression by up- or down-regulation. Protopine (contained in California poppy), valerenic acid (in valerian), and linalool (in lavender) were inconspicuous in all experiments and showed no adverse effects. Hyperforin and hypericin (two constituents of St. John’s wort) and valtrate (typical for valerian) were the most obvious phytochemicals with respect to cytotoxic and apoptotic effects. A decrease in cell viability was evident with hypericin (≥1 µM) and valtrate (≥10 µM), whereas hyperforin (≥3 µM), hypericin (30 µM) and valtrate (≥10 µM) induced cell apoptosis. None of the tested phytochemicals resulted in genotoxic effects at concentrations of 0.1 and 1 µM and thus are not DNA damaging. No decrease in glucose consumption or lactate production was observed under the influence of the phytochemicals, except for valtrate (at all concentrations). No compound affected cell differentiation, except for hyperforin (≥1 µM), which had an inhibitory effect. This study suggests that extracts from St. John’s wort, California poppy, valerian, lavender, and hops are likely to be safe during pregnancy. High plasma concentrations of some relevant compounds—hyperforin and hypericin from St. John’s wort and valtrate from valerian—deserve special attention, however.
D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats
Authors: Getsy Paulina M. , Baby Santhosh M. , May Walter J. , Young Alex P. , Gaston Benjamin , Hodges Matthew R. , Forster Hubert V. , Bates James N. , Wilson Christopher G. , Lewis Tristan H. J. , Hsieh Yee-Hee , Lewis Stephen J.
Published: June 2022

Cell-penetrant thiol esters including the disulfides, D-cystine diethyl ester and D-cystine dimethyl ester, and the monosulfide, L-glutathione ethyl ester, prevent and/or reverse the deleterious effects of opioids, such as morphine and fentanyl, on breathing and gas exchange within the lungs of unanesthetized/unrestrained rats without diminishing the antinociceptive or sedative effects of opioids. We describe here the effects of the monosulfide thiol ester, D-cysteine ethyl ester (D-CYSee), on intravenous morphine-induced changes in ventilatory parameters, arterial blood–gas chemistry, alveolar–arterial (A-a) gradient (i.e., index of gas exchange in the lungs), and sedation and antinociception in freely-moving rats. The bolus injection of morphine (10 mg/kg, IV) elicited deleterious effects on breathing, including depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive. Subsequent injections of D-CYSee (2 × 500 μmol/kg, IV, given 15 min apart) elicited an immediate and sustained reversal of these effects of morphine. Morphine (10 mg/kg, IV) also A-a gradient, which caused a mismatch in ventilation perfusion within the lungs, and elicited pronounced changes in arterial blood–gas chemistry, including pronounced decreases in arterial blood pH, pO2 and sO2, and equally pronounced increases in pCO2 (all responses indicative of decreased ventilatory drive). These deleterious effects of morphine were immediately reversed by the injection of a single dose of D-CYSee (500 μmol/kg, IV). Importantly, the sedation and antinociception elicited by morphine (10 mg/kg, IV) were minimally affected by D-CYSee (500 μmol/kg, IV). In contrast, none of the effects of morphine were affected by administration of the parent thiol, D-cysteine (1 or 2 doses of 500 μmol/kg, IV). Taken together, these data suggest that D-CYSee may exert its beneficial effects via entry into cells that mediate the deleterious effects of opioids on breathing and gas exchange. Whether D-CYSee acts as a respiratory stimulant or counteracts the inhibitory actions of µ-opioid receptor activation remains to be determined. In conclusion, D-CYSee and related thiol esters may have clinical potential for the reversal of the adverse effects of opioids on breathing and gas exchange, while largely sparing antinociception and sedation.
Toward Therapeutic Drug Monitoring of Lenalidomide in Hematological Malignancy? Results of an Observational Study of the Exposure-Safety Relationship
Authors: Song Zaiwei , Ma Lan , Bao Li , Ma Yi , Yang Ping , Jiang Dan , Liu Aijun , Zhang Lu , Li Yan , Cheng Yinchu , Dong Fei , Zhao Rongsheng , Jing Hongmei
Published: June 2022

Objective: Continuous lenalidomide (LEN) therapy is important to achieve a therapeutic effect in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). However, despite dose adjustment according to kidney function, many patients discontinue LEN therapy because of hematological toxicity. To date, therapeutic drug monitoring (TDM) of LEN has not been performed in oncology, and no target concentration level has been yet defined. The aim of this study was to evaluate the exposure-safety relationship of LEN and determine the target concentration for toxicity.

Materials and Methods: A prospective observational study was designed and implemented. Blood samples were collected at 0.5 h (trough concentration, Cmin) before oral administration and 1 h (C1h) thereafter on the day. Clinical data were gathered from patients’ medical records and laboratory reports. Outcome measures of hematological toxicity were defined by the Common Terminology Criteria for Adverse Events. The concentration values were dichotomized by receiver operating characteristic (ROC) curve analysis, and the association between exposure and outcome was determined using the logistic regression model.

Results: Out of the 61 patients enrolled in this study, 40 (65.57%) had MM, and 21 (34.43%) had NHL. Hematological toxicity was reported in 15 (24.59%) patients. The LEN Cmin showed remarkable differences (p = 0.031) among patients with or without hematological toxicity, while no association between C1h values and toxicity was noted (p>0.05). By ROC analysis, a Cmin threshold of 10.95 ng/mL was associated with the best sensitivity/specificity for toxicity events (AUC = 0.687; sensitivity = 0.40; specificity = 0.935). By multivariate logistic regression, an LEN Cmin below 10.95 ng/mL was associated with a markedly decreased risk of hematological toxicity (<10.95 ng/mL vs. >10.95 ng/mL: OR = 0.023, 95% CI = 0.002–0.269; p = 0.003).

Conclusions: We demonstrate that the LEN trough concentration correlates with hematological toxicity, and the Cmin threshold for hematological toxicity (10.95 ng/mL) is proposed. Altogether, LEN TDM appears to be a new approach to improve medication safety and achieve continuous treatment for patients with NHL or MM in routine clinical care.
An Ionization-Driven Air Plasma Jet
Authors: Jin Shaohui , Nie Lanlan , Zhou Rusen , Luo Jingyi , Lu Xinpei
Published: June 2022

Non-thermal atmospheric pressure plasma jets (NAPPJs) using ambient air as the inducer are of particular and desirable interest but with significant challenges. In this study, we report an air APPJ driven by ionization in the afterglow region, resembling noble gas APPJs. A pin-to-nozzle electrode is used for the air plasma jet with a nanosecond-pulsed DC high voltage as the power supply. Results show that the nozzle diameter plays an essential role in forming the air plasma jet. When the nozzle diameter is 3 mm, the air APPJ is driven by ionization in the afterglow region which is proved by the following three phenomena. First, with an exposure time of 0.1 s, an obvious shiny line (the narrow channel plasma) formed by electron accumulation is observed in the jet. The narrow channel becomes much brighter with a grounding pin approaching the nozzle vertically. In comparison, there is no such phenomenon with a 1-mm diameter nozzle. Second, the afterglow region discharge current of the ionization-driven processes is hundreds of mA distinguished from airflow-driven processes, the afterglow region current of which is typically zero. By using E-FISH to measure the electric field in the afterglow region, it can detect the electric field which has a maximum value of 10.5 kV/cm. Third, the intensity of the N2+ band is much stronger with a 3-mm diameter nozzle than with a 1-mm diameter nozzle, indicating that the local electric field plays an important role in the discharge. We expect this study can offer useful guidelines on the design and understanding of ionization-driven air plasma jets.
Investigating Fractal Analysis as a Diagnostic Tool That Probes the Connectivity of Hippocampal Neurons
Authors: Rowland Conor , Harland Bruce , Smith Julian H. , Moslehi Saba , Dalrymple-Alford John , Taylor Richard P.
Published: June 2022

Many of nature’s fractal objects benefit from the favorable functionality that results from their pattern repetition at multiple scales. Our recent research focused on the importance of fractal scaling in establishing connectivity between neurons. Fractal dimension DA of the neuron arbors was shown to relate to the optimization of competing functional constraints—the ability of dendrites to connect to other neurons versus the costs associated with building the dendrites. Here, we consider whether pathological states of neurons might affect this fractal optimization and if changes in DA might therefore be used as a diagnostic tool in parallel with traditional measures like Sholl analyses. We use confocal microscopy to obtain images of CA1 pyramidal neurons in the coronal plane of the dorsal rat hippocampus and construct 3-dimensional models of the dendritic arbors using Neurolucida software. We examine six rodent groups which vary in brain condition (whether they had lesions in the anterior thalamic nuclei, ATN) and experience (their housing environment and experience in a spatial task). Previously, we showed ATN lesions reduced spine density in hippocampal CA1 neurons, whereas enriched housing increased spine density in both ATN lesion and sham rats. Here, we investigate whether ATN lesions and experience also effect the complexity and connectivity of CA1 dendritic arbors. We show that sham rats exposed to enriched housing and spatial memory training exhibited higher complexity (as measured by DA) and connectivity compared to other groups. When we categorize the rodent groups into those with or without lesions, we find that both categories achieve an optimal balance of connectivity with respect to material cost. However, the DA value used to achieve this optimization does not change between these two categories, suggesting any morphological differences induced by the lesions are too small to influence the optimization process. Accordingly, we highlight considerations associated with applying our technique to publicly accessible repositories of neuron images with a broader range of pathological conditions.
Opportunities for Orphan Crops: Expected Economic Benefits From Biotechnology
Authors: Zambrano Patricia , Wood-Sichra Ulrike , Ruhinduka Remidius D. , Phillip Dayo , Nin Pratt Alejandro , Komen John , Kikulwe Enoch Mutebi , Falck Zepeda José , Dzanku Fred M. , Chambers Judith A.
Published: June 2022

An enabling, evidence-based decision-making framework is critical to support agricultural biotechnology innovation, and to ensure farmers’ access to genetically modified (GM) crops, including orphan crop varieties. A key element, and often a challenge in the decision-making process, involves the balancing of identified potential risks with expected economic benefits from GM crops. The latter is particularly challenging in the case of orphan crops, for which solid economic data is scarce. To address this challenge, the International Food Policy Research Institute (IFPRI) in collaboration with local economists analyzed the expected economic benefits to farmers and consumers from the adoption of GM crops in 5 sub-Saharan African countries. This paper focuses on case studies involving insect-resistant cowpea in Nigeria and Ghana; disease-resistant cassava in Uganda and Tanzania; and disease-resistant banana in Uganda. Estimations from these case studies show substantial economic benefits to farmers and consumers from the timely adoption and planting in farmers’ fields of GM orphan crops. Our analysis also shows how the benefits would significantly be reduced by regulatory or other delays that affect the timely release of these crops. These findings underscore the importance of having an enabling policy environment and regulatory system—covering, among other elements, biosafety and food/feed safety assessment, and varietal release registration—that is efficient, predictable, and transparent to ensure that the projected economic benefits are delivered and realized in a timely manner.
Comparative Transcriptome and Metabolome Analysis of Resistant and Susceptible Piper Species Upon Infection by the Oomycete Phytophthora Capsici
Authors: Fan Rui , Tao Xiao-yuan , Xia Zhi-qiang , Sim Soonliang , Hu Li-song , Wu Bao-duo , Wang Qing-huang , Hao Chao-yun
Published: June 2022

Phytophthora capsici is a destructive oomycete pathogen that causes devastating disease in black pepper, resulting in a significant decline in yield and economic losses. Piper nigrum (black pepper) is documented as susceptible to P. capsici, whereas its close relative Piper flaviflorum is known to be resistant. However, the molecular mechanism underlying the resistance of P. flaviflorum remains obscure. In this study, we conducted a comparative transcriptome and metabolome analysis between P. flaviflorum and P. nigrum upon P. capsici infection and found substantial differences in their gene expression profiles, with altered genes being significantly enriched in terms relating to plant-pathogen interaction, phytohormone signal transduction, and secondary metabolic pathways, including phenylpropanoid biosynthesis. Further metabolome analysis revealed the resistant P. flaviflorum to have a high background endogenous ABA reservoir and time-course-dependent accumulation of ABA and SA upon P. capsici inoculation, while the susceptible P. nigrum had a high background endogenous IAA reservoir and time-course-dependent accumulation of JA-Ile, the active form of JA. Investigation of the phenylpropanoid biosynthesis metabolome further indicated the resistant P. flaviflorum to have more accumulation of lignin precursors than the susceptible P. nigrum, resulting in a higher accumulation after inoculation. This study provides an overall characterization of biologically important pathways underlying the resistance of P. flaviflorum, which theoretically explains the advantage of using this species as rootstock for the management of oomycete pathogen in black pepper production.
Effects of Cadmium on Root Morpho-Physiology of Durum Wheat
Authors: Sabella Erika , Aprile Alessio , Tenuzzo Bernadetta Anna , Carata Elisabetta , Panzarini Elisa , Luvisi Andrea , De Bellis Luigi , Vergine Marzia
Published: June 2022

Durum wheat [Triticum turgidum L. subsp. durum (Desf.) Husn.] can accumulate a high level of Cd in grains with a significant variability depending on cultivars. Understanding how this toxic element is distributed in cereal tissues and grains is essential to improve the nutritional quality of cereal-based products. The main objective of this work was to investigate roots of durum wheat plants (cv. Iride) exposed to different Cd concentrations (0.5 and 5.0 μM) to identify the mechanisms involved in Cd management. Results showed that the root morphology was altered by Cd treatment both at macroscopic (increased number of tips and primary root length) and ultrastructural levels (cell membrane system damaged, cell walls thickened and enriched in suberin). On the other side, Cd was localized in vesicles and in cell walls, and the metal colocalized with the phytosiderophore nicotianamine (NA). Overall, data suggest that Cd is chelated by NA and then compartmentalized, through vesicular trafficking, in the root thickened walls reducing Cd translocation to the aerial organs of the plant.