bluuebunny/crossref_metadata_2025 huggingface dataset:
Mass Cytometry Identifies Expansion of T-bet+ B Cells and CD206+ Monocytes in Early Multiple Sclerosis
Authors: Couloume Laura , Ferrant Juliette , Le Gallou Simon , Mandon Marion , Jean Rachel , Bescher Nadège , Zephir Helene , Edan Gilles , Thouvenot Eric , Ruet Aurelie , Debouverie Marc , Tarte Karin , Amé Patricia , Roussel Mikael , Michel Laure
Published: May 2021

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206+classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation.
Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy
Authors: Wiendl Maximilian , Becker Emily , Müller Tanja M. , Voskens Caroline J. , Neurath Markus F. , Zundler Sebastian
Published: May 2021

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC)are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.
Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV
Authors: Zhao Juan , Schank Madison , Wang Ling , Li Zhengke , Nguyen Lam Nhat , Dang Xindi , Cao Dechao , Khanal Sushant , Nguyen Lam Ngoc Thao , Thakuri Bal Krishna Chand , Ogbu Stella C. , Lu Zeyuan , Wu Xiao Y. , Morrison Zheng D. , Gazzar Mohamed El , Liu Ying , Zhang Jinyu , Ning Shunbin , Moorman Jonathan P. , Yao Zhi Q.
Published: May 2021

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.
An Integrative Transcriptomic and Metabolomic Study Revealed That Melatonin Plays a Protective Role in Chronic Lung Inflammation by Reducing Necroptosis
Authors: Mao Kaimin , Luo Ping , Geng Wei , Xu Juanjuan , Liao Yuhan , Zhong Hua , Ma Pei , Tan Qi , Xia Hui , Duan Limin , Song Siwei , Long Danling , Liu Yuqi , Yang Tinglin , Wu Yali , Jin Yang
Published: May 2021

It has been reported that melatonin can relieve the symptoms of chronic obstructive pulmonary disease (COPD) by improving sleep quality, that is to say, the pineal secreted hormone melatonin has a protective effect in the pathogenesis of COPD, but its underlying mechanism remains unclear. In this study, we recruited 73 people into control (n = 22), stable COPD (n = 20), and acute exacerbation of COPD (n = 31) groups to detect the serum melatonin levels. Then, through the mouse model, we employed a systematic study based on the metabolomic and transcriptomic analyses to investigate the molecular mechanisms involved in the progression of the disease. Circulating melatonin in acute exacerbation of COPD patients was decreased compared with that in healthy donors and stable COPD patients. The serum melatonin level was positively correlated with lung function parameters, such as FEV1, FEV1/FVC, and FEV1% predicted in acute exacerbation of COPD patients. Animal experiments showed that melatonin can not only alleviate chronic lipopolysaccharide (LPS)-induced mouse lung destruction and chronic lung inflammation but also reduce necroptosis (RIP1/RIP3/MLKL), a programmed cell death process in bronchial epithelial cells. The protective effect of melatonin on chronic lung inflammation was further suggested to be dependent on targeting its membrane receptor MT1/MT2. In addition, transcriptomic and metabolomic profiling in the lungs of mice indicated that LPS can induce perturbations of the mainstream metabolites associated with amino acid and energy metabolism. Melatonin may reduce the necroptosis by modifying the disordered pathways of alanine, aspartate, and glutamate metabolism caused by LPS. This study suggests that melatonin may act as a potential therapeutic agent for alleviating the chronic inflammation associated with COPD.
Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites
Authors: Cortés-Vieyra Ricarda , Silva-García Octavio , Gómez-García Anel , Gutiérrez-Castellanos Sergio , Álvarez-Aguilar Cleto , Baizabal-Aguirre Víctor M.
Published: May 2021

Knowledge of glycogen synthase kinase 3β (GSK3β) activity and the molecules identified that regulate its function in infections caused by pathogenic microorganisms is crucial to understanding how the intensity of the inflammatory response can be controlled in the course of infections. In recent years many reports have described small molecular weight synthetic and natural compounds, proteins, and interference RNA with the potential to regulate the GSK3β activity and reduce the deleterious effects of the inflammatory response. Our goal in this review is to summarize the most recent advances on the role of GSK3β in the inflammatory response caused by bacteria, bacterial virulence factors (i.e. LPS and others), viruses, and parasites and how the regulation of its activity, mainly its inhibition by different type of molecules, modulates the inflammation.
Intracellular and Extracellular Roles of Granzyme K
Authors: Bouwman Annemieke C. , van Daalen Kim R. , Crnko Sandra , ten Broeke Toine , Bovenschen Niels
Published: May 2021

Granzymes are a family of serine proteases stored in granules inside cytotoxic cells of the immune system. Granzyme K (GrK) has been only limitedly characterized and knowledge on its molecular functions is emerging. Traditionally GrK is described as a granule-secreted, pro-apoptotic serine protease. However, accumulating evidence is redefining the functions of GrK by the discovery of novel intracellular (e.g. cytotoxicity, inhibition of viral replication) and extracellular roles (e.g. endothelial activation and modulation of a pro-inflammatory immune cytokine response). Moreover, elevated GrK levels are associated with disease, including viral and bacterial infections, airway inflammation and thermal injury. This review aims to summarize and discuss the current knowledge of i) intracellular and extracellular GrK activity, ii) cytotoxic and non-cytotoxic GrK functioning, iii) the role of GrK in disease, and iv) GrK as a potential therapeutic target.
Prediction of COVID-19 Hospital Length of Stay and Risk of Death Using Artificial Intelligence-Based Modeling
Authors: Mahboub Bassam , Bataineh Mohammad T. Al , Alshraideh Hussam , Hamoudi Rifat , Salameh Laila , Shamayleh Abdulrahim
Published: May 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious virus with overwhelming demand on healthcare systems, which require advanced predictive analytics to strategize COVID-19 management in a more effective and efficient manner. We analyzed clinical data of 2017 COVID-19 cases reported in the Dubai health authority and developed predictive models to predict the patient's length of hospital stay and risk of death. A decision tree (DT) model to predict COVID-19 length of stay was developed based on patient clinical information. The model showed very good performance with a coefficient of determination R2 of 49.8% and a median absolute deviation of 2.85 days. Furthermore, another DT-based model was constructed to predict COVID-19 risk of death. The model showed excellent performance with sensitivity and specificity of 96.5 and 87.8%, respectively, and overall prediction accuracy of 96%. Further validation using unsupervised learning methods showed similar separation patterns, and a receiver operator characteristic approach suggested stable and robust DT model performance. The results show that a high risk of death of 78.2% is indicated for intubated COVID-19 patients who have not used anticoagulant medications. Fortunately, intubated patients who are using anticoagulant and dexamethasone medications with an international normalized ratio of <1.69 have zero risk of death from COVID-19. In conclusion, we constructed artificial intelligence–based models to accurately predict the length of hospital stay and risk of death in COVID-19 cases. These smart models will arm physicians on the front line to enhance management strategies to save lives.
Vasopressin Loading for Refractory Septic Shock: A Preliminary Analysis of a Case Series
Authors: Nakamura Kensuke , Nakano Hidehiko , Naraba Hiromu , Mochizuki Masaki , Takahashi Yuji , Sonoo Tomohiro , Hashimoto Hideki , Abe Toshikazu , Hayakawa Mineji , Yamakawa Kazuma
Published: May 2021

Background: Vasopressin is one of the strong vasopressor agents associated with ischemic events. Responses to the administration of vasopressin differ among patients with septic shock. Although the administration of a high dose of vasopressin needs to be avoided, the effects of bolus loading have not yet been examined. Since the half-life of vasopressin is longer than that of catecholamines, we hypothesized that vasopressin loading may be effective for predicting responses to its continuous administration.

Methods: We retrospectively analyzed consecutive cases of septic shock for which vasopressin was introduced with loading under noradrenaline at >0.2 μg/kg/min during the study period. Vasopressin was administered in a 1 U bolus followed by its continuous administration at 1 U/h. The proportion of patients with a negative catecholamine index (CAI) change 6 h after the introduction of vasopressin was set as the primary outcome. We defined non-responders for exploration as those with a mean arterial pressure change <18 mmHg 1 min after vasopressin loading, among whom none had a change in CAI <0.

Results: Twenty-one consecutive cases were examined in the present study, and included 14 responders and 7 non-responders. The primary outcome accounted for 71.4% of responders and 0% of non-responders, with a significant difference (p = 0.0039). Median CAI changes 2, 4, and 6 h after the administration of vasopressin were 0, −5, and −10 in responders and +20, +10, and +10 in non-responders, respectively. CAI was not reduced in any non-responder. Outcomes including mortality were not significantly different between responders and non-responders. Digital ischemia (1/21) and mesenteric ischemia (1/21) were observed.

Conclusions: Vasopressin loading may predict responses to its continuous administration in septic shock patients. Further investigations involving a safety analysis are needed.
Genomics, Exometabolomics, and Metabolic Probing Reveal Conserved Proteolytic Metabolism of Thermoflexus hugenholtzii and Three Candidate Species From China and Japan
Authors: Thomas Scott C. , Payne Devon , Tamadonfar Kevin O. , Seymour Cale O. , Jiao Jian-Yu , Murugapiran Senthil K. , Lai Dengxun , Lau Rebecca , Bowen Benjamin P. , Silva Leslie P. , Louie Katherine B. , Huntemann Marcel , Clum Alicia , Spunde Alex , Pillay Manoj , Palaniappan Krishnaveni , Varghese Neha , Mikhailova Natalia , Chen I-Min , Stamatis Dimitrios , Reddy T. B. K. , O’Malley Ronan , Daum Chris , Shapiro Nicole , Ivanova Natalia , Kyrpides Nikos C. , Woyke Tanja , Eloe-Fadrosh Emiley , Hamilton Trinity L. , Dijkstra Paul , Dodsworth Jeremy A. , Northen Trent R. , Li Wen-Jun , Hedlund Brian P.
Published: May 2021

Thermoflexus hugenholtzii JAD2T, the only cultured representative of the Chloroflexota order Thermoflexales, is abundant in Great Boiling Spring (GBS), NV, United States, and close relatives inhabit geothermal systems globally. However, no defined medium exists for T. hugenholtzii JAD2T and no single carbon source is known to support its growth, leaving key knowledge gaps in its metabolism and nutritional needs. Here, we report comparative genomic analysis of the draft genome of T. hugenholtzii JAD2T and eight closely related metagenome-assembled genomes (MAGs) from geothermal sites in China, Japan, and the United States, representing “Candidatus Thermoflexus japonica,” “Candidatus Thermoflexus tengchongensis,” and “Candidatus Thermoflexus sinensis.” Genomics was integrated with targeted exometabolomics and 13C metabolic probing of T. hugenholtzii. The Thermoflexus genomes each code for complete central carbon metabolic pathways and an unusually high abundance and diversity of peptidases, particularly Metallo- and Serine peptidase families, along with ABC transporters for peptides and some amino acids. The T. hugenholtzii JAD2T exometabolome provided evidence of extracellular proteolytic activity based on the accumulation of free amino acids. However, several neutral and polar amino acids appear not to be utilized, based on their accumulation in the medium and the lack of annotated transporters. Adenine and adenosine were scavenged, and thymine and nicotinic acid were released, suggesting interdependency with other organisms in situ. Metabolic probing of T. hugenholtzii JAD2T using 13C-labeled compounds provided evidence of oxidation of glucose, pyruvate, cysteine, and citrate, and functioning glycolytic, tricarboxylic acid (TCA), and oxidative pentose-phosphate pathways (PPPs). However, differential use of position-specific 13C-labeled compounds showed that glycolysis and the TCA cycle were uncoupled. Thus, despite the high abundance of Thermoflexus in sediments of some geothermal systems, they appear to be highly focused on chemoorganotrophy, particularly protein degradation, and may interact extensively with other microorganisms in situ.
A Three-Gene Peripheral Blood Potential Diagnosis Signature for Acute Rejection in Renal Transplantation
Authors: Wang Yicun , Zhang Di , Hu Xiaopeng
Published: May 2021

Background: Acute rejection (AR) remains a major issue that negatively impacts long-term allograft survival in renal transplantation. The current study aims to apply machine learning methods to develop a non-invasive diagnostic test for AR based on gene signature in peripheral blood.

Methods: We collected blood gene expression profiles of 251 renal transplant patients with biopsy-proven renal status from three independent cohorts in the Gene Expression Omnibus database. After differential expression analysis and machine learning algorithms, selected biomarkers were applied to the least absolute shrinkage and selection operator (LASSO) logistic regression to construct a diagnostic model in the training cohort. The diagnostic ability of the model was further tested in validation cohorts. Gene set enrichment analysis and immune cell assessment were also conducted for further investigation.

Results: A novel diagnostic model based on three genes (TSEN15, CAPRIN1 and PRR34-AS1) was constructed in the training cohort (AUC = 0.968) and successfully verified in the validation cohort (AUC = 0.925) with high accuracy. Moreover, the diagnostic model also showed a promising value in discriminating T cell-mediated rejection (TCMR) (AUC = 0.786). Functional enrichment analysis and immune cell evaluation demonstrated that the AR model was significantly correlated with adaptive immunity, especially T cell subsets and dendritic cells.

Conclusion: We identified and validated a novel three-gene diagnostic model with high accuracy for AR in renal transplant patients, and the model also performed well in distinguishing TCMR. The current study provided a promising tool to be used as a precise and cost-effective non-invasive test in clinical practice.
Integrating Cycled Enzymatic DNA Amplification and Surface-Enhanced Raman Scattering for Sensitive Detection of Circulating Tumor DNA
Authors: Miao Xinxing , Fang Qianqian , Xiao Xiang , Liu Sidi , Wu Renfei , Yan Jun , Nie Baoqing , Liu Jian
Published: May 2021

Circulating tumor DNA (ctDNA) represents an emerging biomarker of liquid biopsies for the development of precision cancer diagnostics and therapeutics. However, sensitive detection of ctDNA remains challenging, due to their short half-life and low concentrations in blood samples. In this study, we report a new method to address this challenge by integrating cycled enzymatic DNA amplification technique and Au nanoparticle@silicon-assisted surface-enhanced Raman scattering (SERS) technique. We have demonstrated a reproducible identification of a single-base-mutated ctDNA sequence of diffuse intrinsic pontine gliomas (DIPGs), with the limit of detection (LOD) as low as 9.1 fM in the spiked blood samples. This approach can be used to analyze trace amounts of ctDNA in translational medicine for early diagnosis, therapeutic effect monitoring, and prognosis of patients with cancer.
Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling
Authors: Baranowski Bradley J. , Hayward Grant C. , Marko Daniel M. , MacPherson Rebecca E. K.
Published: May 2021

Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer’s disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p < 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p < 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.
The Time Burden of Specialty Clinic Visits in Persons With Neurologic Disease: A Case for Universal Telemedicine Coverage
Authors: Solomon Daniel L. , Dirlikov Benjamin , Shem Kazuko L. , Elliott Christopher S.
Published: May 2021

Objective: Those with chronic neurologic disorders are often burdened not only by the condition itself but also an increased need for subspecialty medical care. This may require long distance travel, while even small distances can be a hardship secondary to impaired mobility and transportation. We sought to examine the burden of time associated with clinical visits for those with chronic neurologic disorders and their family/caregivers. These topics are discussed as an argument to support universal coverage for telemedicine in this population.

Design: Cohort Study.

Setting: Specialty clinic at community hospital.

Participants: 208 unique patients with chronic neurologic disability at physical medicine and rehabilitation or neurourology clinic over a 3-month period.

Main Outcome Measures: Patient survey on commute distance, time, difficulties, and need for caregiver assistance to attend visits.

Results: Approximately 40% of patients were covered by Medicare. Many patients (42%) perceived it difficult to attend their clinic visit with transportation difficulties, commute time, and changes to their daily schedule being the most commonly cited reasons. Most patients (75%) lived within 25 miles of our clinics and experienced an average commute time of 79.4 min, though 10% required 3 h or more. Additional family/caregiver assistance was required for 76% of patients, which resulted in an inclusive average commute time of 138.2 min per patient.

Conclusion: Chronically neurologically-disabled patients and their caregivers may be burdened by the commute to outpatient appointments. To minimize this burden, increased emphasis on telemedicine coverage for those with chronic neurologic disability should be considered by all payors.
Magnetic Suppression of Perceptual Accuracy Is Not Reduced in Visual Snow Syndrome
Authors: Eren Ozan E. , Ruscheweyh Ruth , Rauschel Veronika , Eggert Thomas , Schankin Christoph J. , Straube Andreas
Published: May 2021

Objective: Patients with visual snow syndrome (VSS) suffer from continuous (“TV snow-like”) visual disturbance of unknown pathoetiology. In VSS, changes in cortical excitability in the primary visual cortex and the visual association cortex are discussed, with recent imaging studies tending to point to higher-order visual areas. Migraine, especially migraine with aura, is a common comorbidity. In chronic migraine and episodic migraine with aura but not in episodic migraine without aura, a reduced magnetic suppression of perceptual accuracy (MSPA) reflects a probably reduced inhibition of the primary visual cortex. Here we investigated the inhibition of the primary visual cortex using MSPA in patients with VSS, comparing that with MSPA in controls matched for episodic migraine.

Methods: Seventeen patients with VSS were compared to 17 age- and migraine-matched controls. Visual accuracy was assessed by letter recognition and modulated by transcranial magnetic stimulation delivered to the occipital cortex at different intervals with respect to the letter presentation (40, 100, and 190 ms).

Results: Suppression of visual accuracy at the 100-ms interval was present without significant differences between VSS patients and age- and migraine-matched controls (percentage of correctly recognized trigrams, control: 46.4 ± 34.3; VSS: 52.5 ± 25.4, p = 0.56).

Conclusions: In contrast to migraine with aura, occipital cortex inhibition, as assessed with MSPA, may not be affected in VSS.
Association of Plasma Glucose to Potassium Ratio and Mortality After Aneurysmal Subarachnoid Hemorrhage
Authors: Jung Hyun Min , Paik Jin Hui , Kim Sin Young , Hong Dae Young
Published: May 2021

Objectives: Hyperglycemia and hypokalemia are common problems in patients with aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to determine whether the plasma glucose to potassium ratio (GPR) predicts mortality due to aSAH.

Methods: We prospectively recruited aSAH patients and healthy controls between March 2007 and May 2017. Clinical outcomes included mortality and poor outcome (modified Rankin scale score of 3-6) after 3 months. Multivariable analysis was used to determine the association between plasma GPR and 3-month mortality in aSAH patients.

Results: A total of 553 patients were recruited, and the mortality rate was 11%. The GPR was significantly elevated in aSAH patients compared with controls, in patients with a poor outcome than with a good outcome and in non-survivals than in survivals. Multivariable analysis showed that the plasma GPR was an independent factor associated with 3-month mortality. The area under the curve of the GPR was 0.747 in predicting 3-month mortality.

Conclusion: The plasma GPR on admission has potential as a predictor of 3-month mortality in patients with aSAH.
Conflict Test Battery for Studying the Act of Facing Threats in Pursuit of Rewards
Authors: Illescas-Huerta Elizabeth , Ramirez-Lugo Leticia , Sierra Rodrigo O. , Quillfeldt Jorge A. , Sotres-Bayon Francisco
Published: May 2021

Survival depends on the ability of animals to avoid threats and approach rewards. Traditionally, these two opposing motivational systems have been studied separately. In nature, however, they regularly compete for the control of behavior. When threat- and reward-eliciting stimuli (learned or unlearned) occur simultaneously, a motivational conflict emerges that challenges individuals to weigh available options and execute a single behavioral response (avoid or approach). Most previous animal models using approach/avoidance conflicts have often focused on the ability to avoid threats by forgoing or delaying the opportunity to obtain rewards. In contrast, behavioral tasks designed to capitalize on the ability to actively choose to execute approach behaviors despite threats are scarce. Thus, we developed a behavioral test battery composed of three conflict tasks to directly study rats confronting threats to obtain rewards guided by innate and conditioned cues. One conflict task involves crossing a potentially electrified grid to obtain food on the opposite end of a straight alley, the second task is based on the step-down threat avoidance paradigm, and the third one is a modified version of the open field test. We used diazepam to pharmacologically validate conflict behaviors in our tasks. We found that, regardless of whether competing stimuli were conditioned or innate, a low diazepam dose decreased risk assessment and facilitated taking action to obtain rewards in the face of threats during conflict, without affecting choice behavior when there was no conflict involved. Using this pharmacologically validated test battery of ethologically designed innate/learned conflict tasks could help understand the fundamental brain mechanisms underlying the ability to confront threats to achieve goals.
QPLOT Neurons—Converging on a Thermoregulatory Preoptic Neuronal Population
Authors: Upton Brian A. , D’Souza Shane P. , Lang Richard A.
Published: May 2021

The preoptic area of the hypothalamus is a homeostatic control center. The heterogeneous neurons in this nucleus function to regulate the sleep/wake cycle, reproduction, thirst and hydration, as well as thermogenesis and other metabolic responses. Several recent studies have analyzed preoptic neuronal populations and demonstrated neuronal subtype-specific roles in suppression of thermogenesis. These studies showed similar thermogenesis responses to chemogenetic modulation, and similar synaptic tracing patterns for neurons that were responsive to cold, to inflammatory stimuli, and to violet light. A reanalysis of single-cell/nucleus RNA-sequencing datasets of the preoptic nucleus indicate that these studies have converged on a common neuronal population that when activated, are sufficient to suppress thermogenesis. Expanding on a previous name for these neurons (Q neurons, which reflect their ability to promote quiescence and expression of Qrfp), we propose a new name: QPLOT neurons, to reflect numerous molecular markers of this population and to capture its broader roles in metabolic regulation. Here, we summarize previous findings on this population and present a unified description of QPLOT neurons, the excitatory preoptic neuronal population that integrate a variety of thermal, metabolic, hormonal and environmental stimuli in order to regulate metabolism and thermogenesis.
Whole-Body MRI vs. PET/CT for the Detection of Bone Metastases in Patients With Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Zhan Yuefu , Zhang Guangming , Li Mingliang , Zhou Xiaobo
Published: May 2021

Purpose: A recent meta-analysis in patients with non-small cell lung cancer showed no difference between whole-body magnetic resonance imaging (WBMRI) and positron emission tomography/computed tomography (PET/CT), but no such study is available for prostate cancer (PCa). This study aimed to compare WBMRI and PET/CT for bone metastasis detection in patients with PCa.

Materials and Methods: PubMed, Embase, and the Cochrane library were searched for papers published up to April 2020. The population was the patients with untreated prostate cancer diagnosed by WBMRI or PET/CT. The outcomes were the true positive and negative and false positive and negative rates for WBMRI and PET/CT. The summarized sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic odds ratios (DOR) were calculated with their 95% confidence intervals (CIs).

Results: Four prospective and one retrospective study are included (657 patients). Significant differences are observed between WBMRI and PET/CT for sensitivity (WBMRI/PET/CT: 0.896; 95% CI: 0.813–0.987; P = 0.025) and NLR (WBMRI/PET/CT: 2.38; 95% CI: 1.13–5.01; P = 0.023), but not for specificity (WBMRI/PET/CT: 0.939; 95% CI: 0.855–1.031; P = 0.184) and PLR (WBMRI/PET/CT: 0.42; 95% CI: 0.08–2.22; P = 0.305). WBMRI has a similar a DOR compared with PET/CT (WBMRI/PET/CT: 0.13; 95% CI: 0.02–1.11; P = 0.062). The summary area under the receiver operating characteristic curves for WBMRI is 0.88 (standard error: 0.032) and 0.98 (standard error: 0.013) for PET/CT for diagnosing bone metastases in PCa.

Conclusion: PET/CT presents a higher sensitivity and NLR for the bone metastasis detection from PCa, whereas no differences are found for specificity and PLR, compared with WBMRI.
SNHG9, a Papillary Thyroid Cancer Cell Exosome-Enriched lncRNA, Inhibits Cell Autophagy and Promotes Cell Apoptosis of Normal Thyroid Epithelial Cell Nthy-ori-3 Through YBOX3/P21 Pathway
Authors: Wen Duo , Liu Wan-lin , Lu Zhong-wu , Cao Yi-ming , Ji Qing-hai , Wei Wen-jun
Published: May 2021

Thyroid cancer is the most common type of endocrine malignancy. Although the general prognosis is good, the treatment of advanced disease is still challenging. Exosomes are vesicle units containing specific components that transmit information between cells. In order to explore its role in papillary thyroid cancer (PTC), our study screened exosome enriched lncRNA SNHG9 by lncRNA chip and explored its biological function. We used lncRNA chips combined with bioinformatics analysis to screen lncRNA SNHG9 enriched in exosomes. GO analysis suggested its relationship with autophagy and apoptosis. Quantitative PCR showed SNHG9 was highly expressed in PTC cells and exosomes and its correlation with PTC tumor size was analyzed by clinical characteristics. SNHG9 could inhibit the protective cell autophagy induced by starvation of human normal thyroid epithelial cell line Nthy-ori-3 and promote its apoptosis through PTC cell exosomes. RNA-pull down combined with protein spectrum showed that SNHG9 could interact with YBOX3. Western blot and RNA immunoprecipitation further confirmed their interaction. Western blot showed that SNHG9 could induce degradation of YBOX3, thus interfering with the stability of P21 mRNA and inducing cell apoptosis. In conclusion, our study identified SNHG9 as a PTC cell exosome-enriched lncRNA. SNHG9 could inhibit cell autophagy and promote apoptosis of Nthy-ori-3 cell through YBOX3/P21 pathway.
Preoperative Staging in Breast Cancer: Intraindividual Comparison of Unenhanced MRI Combined With Digital Breast Tomosynthesis and Dynamic Contrast Enhanced-MRI
Authors: Rizzo Veronica , Moffa Giuliana , Kripa Endi , Caramanico Claudia , Pediconi Federica , Galati Francesca
Published: May 2021

Objectives

To evaluate the accuracy in lesion detection and size assessment of Unenhanced Magnetic Resonance Imaging combined with Digital Breast Tomosynthesis (UE-MRI+DBT) and Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), in women with known breast cancer.

Methods

A retrospective analysis was performed on 84 patients with histological diagnosis of breast cancer, who underwent MRI on a 3T scanner and DBT over 2018-2019, in our Institution. Two radiologists, with 15 and 7 years of experience in breast imaging respectively, reviewed DCE-MRI and UE-MRI (including DWI and T2-w) + DBT images in separate reading sections, unaware of the final histological examination. DCE-MRI and UE-MRI+DBT sensitivity, positive predictive value (PPV) and accuracy were calculated, using histology as the gold standard. Spearman correlation and regression analyses were performed to evaluate lesion size agreement between DCE-MRI vs Histology, UE-MRI+DBT vs Histology, and DCE-MRI vs UE-MRI+DBT. Inter-reader agreement was evaluated using Cohen’s κ coefficient. McNemar test was used to identify differences in terms of detection rate between the two methodological approaches. Spearman’s correlation analysis was also performed to evaluate the correlation between ADC values and histological features.

Results

109 lesions were confirmed on histological examination. DCE-MRI showed high sensitivity (100% Reader 1, 98% Reader 2), good PPV (89% Reader 1, 90% Reader 2) and accuracy (90% for both readers). UE-MRI+DBT showed 97% sensitivity, 91% PPV and 92% accuracy, for both readers. Lesion size Spearman coefficient were 0.94 (Reader 1) and 0.91 (Reader 2) for DCE-MRI vs Histology; 0.91 (Reader 1) and 0.90 (Reader 2) for UE-MRI+DBT vs Histology (p-value <0.001). DCE-MRI vs UE-MRI+DBT regression coefficient was 0.96 for Reader 1 and 0.94 for Reader 2. Inter-reader agreement was 0.79 for DCE-MRI and 0.94 for UE-MRI+DBT. McNemar test did not show a statistically significant difference between DCE-MRI and UE-MRI+DBT (McNemar test p-value >0.05). Spearman analyses showed an inverse correlation between ADC values and histological grade (p-value <0.001).

Conclusions

DCE-MRI was the most sensitive imaging technique in breast cancer preoperative staging. However, UE-MRI+DBT demonstrated good sensitivity and accuracy in lesion detection and tumor size assessment. Thus, UE-MRI could be a valid alternative when patients have already performed DBT.
Case Report: Various Abnormalities in Lipid and Glucose Metabolism Induced by Capecitabine
Authors: Anno Takatoshi , Yamatsuji Tomoki , Tomoda Koichi , Nakanishi Shuhei , Kaneto Hideaki
Published: May 2021

Capecitabine has been used for the treatment of various types of tumors. The rare side effects induced by capecitabine have been reported as hypertriglyceridemia, acute pancreatitis associated with hypertriglyceridemia and hypertriglyceridemia complicated with hyperglycemia. The mechanisms of capecitabine-induced hypertriglyceridemia are unclear. In this report, we present a subject with sigmoid colon cancer and capecitabine-induced dyslipidemia. LDL-cholesterol level was markedly elevated throughout the long period of treatment with capecitabine. In addition, triglyceride level was high and not stable during the treatment period. Her dyslipidemia was ameliorated by the treatment with 5 mg of rosuvastatin, which is one of the HMG-CoA reductase inhibitors.
Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer
Authors: Fang Likui , Zhao Wuchen , Ye Bo , Chen Da
Published: May 2021

Brain metastases remain a critical issue in the management of non-small cell lung cancer (NSCLC) because of the high frequency and poor prognosis, with survival rates often measured in just months. The local treatment approach remains the current standard of care, but management of multiple asymptomatic brain metastases always involves systemic therapy. Given that anti-angiogenic agents and immune checkpoint inhibitors (ICIs) both target the tumor microenvironment (TME), this combination therapy has become a promising strategy in clinical practice. Increasing number of preclinical and clinical studies have shown remarkable anti-tumor activity of the combination therapy, but the efficacy in brain metastases is unclear due to the strict selection criteria adopted in most clinical trials. This review briefly summarizes the potential synergistic anti-tumor effect and clinical development of the combination of anti-angiogenic agents and ICIs in NSCLC brain metastases, and discusses the existing challenges and problems.
Rapid BMI Increases and Persistent Obesity in Small-for-Gestational-Age Infants
Authors: Wu Dan , Zhu Jianzheng , Wang Xiulian , Shi Huiqing , Huo Yanyan , Liu Meiyan , Sun Fanfan , Lan Hongyan , Guo Chong , Liu Honghua , Li Tingting , Jiang Lian , Hu Xiangying , Li Tianshu , Xu Jing , Yao Guoying , Zhu Guowei , Yu Guangjun , Chen Jinjin
Published: May 2021

Purpose: In order to compensate for the early intrauterine growth restriction, small-for-gestational age (SGA) infants have “catch-up growth” after birth. Increased caloric intake has been suggested for SGA infants conventionally. It is important to determine if the early growth rate of body mass index (BMI) is associated with risk of persistent obesity later in life. In this longitudinal cohort study, we assessed the BMI of a large cohort of children who were SGA at birth to determine their risk of persistent obesity at school age (6–7 years) due to excessive weight gain in the first 3 years of life.

Methods: We collected the height and weight data of 23,871 SGA babies. A polynomial function was used to fit the BMI-for-age z-score (BAZ) values of 0–6 years old SGA children and interpolate their growth trajectory. In addition, we screened out 6,959 children from 23,871 children to further evaluate the dynamic changes of early childhood BMI. We divided the school-age children into groups as non-obese (BAZ < 2) and obese (BAZ > 2), and determined the association between changes in BMI and school-age obesity.

Results: From the perspective of BMI distribution, the interpolated growth trajectory indicated that SGA children reaching overweight status or developing obesity by 3 years of age, continued to have obesity until school age (R2, 0.65; R2, 0.21). The retrospective analysis showed that children who were overweight and had obesity during school age had a high BMI from early age. By analyzing the changes in early BMI, we found that the fastest growth of SGA children occurred in the early infancy before 6 months and they continued to grow rapidly for a period of time. Interestingly, former SGA children who maintained a near overweight (1 < BAZ < 2) status before the age of 2 maintained an appropriate growth rate and usually did not develop obesity.

Conclusions: A rapid increase in BMI during early infancy in former SGA newborns leads to a persistent risk of obesity. The energy intake of SGA infants should appropriately meet the infants' growth needs and early BMI changes should be closely monitored for an optimal integrated management.
Surgery in Neonatal and Pediatric ECMO Patients Other Than Congenital Diaphragmatic Hernia Repair: A 10-Year Experience
Authors: Kersten Casper M. , Hermelijn Sergei M. , Wijnen René M. H. , Tibboel Dick , Houmes Robert J. M. , Schnater J. Marco
Published: May 2021

Aim of Study: The use of extracorporeal membrane oxygenation (ECMO) has increased as a result of technological developments and the expansion of indications. Relatedly, the number of patients undergoing surgery during ECMO is also rising, at least in the adult population. Little is known on surgery in children during ECMO-therapy. We therefore aimed to assess the frequencies and types of surgical interventions in neonatal and pediatric patients on ECMO and to analyze surgery-related morbidity and mortality.

Methods: We retrospectively collected information of all patients on ECMO over a 10-year period in a single tertiary and designated ECMO-center, excluding patients undergoing cardiac surgery, and correction of congenital diaphragmatic hernia. Chi-squared test and Mann-Whitney U test were used to analyze data.

Main Results: Thirty-two of 221 patients (14%) required surgery when on ECMO. Common interventions were thoracotomy (32%), laparotomy (23%), fasciotomy (17%), and surgical revision of ECMO (15%). Complications occurred in 28 cases (88%), resulting in a 50% in-hospital mortality rate. Surgical patients had a longer ICU stay and longer total hospital stay compared to those not receiving surgery during ECMO. No significant difference in mortality was found when comparing surgical to non-surgical patients (50 vs. 41%).

Conclusions: Approximately one in seven neonatal or pediatric patients required surgical intervention during ECMO, of whom almost 90% developed a complication, resulting in a 50% mortality rate. These results should be taken into account in counseling.
The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
Authors: Bricher Choque Pamela Nithzi , Vieira Rodolfo P. , Ulloa Luis , Grabulosa Caren , Irigoyen Maria Claudia , De Angelis Katia , Ligeiro De Oliveira Ana Paula , Tracey Kevin J. , Pavlov Valentin A. , Consolim-Colombo Fernanda Marciano
Published: May 2021

Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1β, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS.
Set and Setting in the Santo Daime
Authors: Hartogsohn Ido
Published: May 2021

Set and setting is a fundamental concept in the field of psychedelic drug research, which points to the profound dependence of psychedelic effects on psychological, social, and cultural factors. Santo Daime is a Brazilian religion that makes elaborate use of ordering principles, techniques, and symbology to shape and direct the effects of the hallucinogenic brew ayahuasca. This paper systematically explores the tapestry of, inter alia, symbolic, social, cultural, psychological, aesthetic and musical elements that participate in the shaping of the psychedelic experience in the context of the Santo Daime ayahuasca religion. The methodically rich under the hood description of the mechanics of entheogenic initiation within the Santo Daime tradition provides a template for future studies of the role of context in psychedelic experimentation.
Geniposide and Chlorogenic Acid Combination Improves Non-Alcoholic Fatty Liver Disease Involving the Potent Suppression of Elevated Hepatic SCD-1
Authors: Chen Cheng , Xin Xin , Liu Qian , Tian Hua-Jie , Peng Jing-Hua , Zhao Yu , Hu Yi-Yang , Feng Qin
Published: May 2021

Background: Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of hepatic triglycerides (TGs), has become a worldwide chronic liver disease. But efficient therapy keeps unsettled. Our previous works show that geniposide and chlorogenic acid combination (namely the GC combination), two active chemical components combined with a unique ratio (67.16:1), presents beneficial effects on high-fat diet-induced NAFLD rodent models. Notably, microarray highlighted the more than 5-fold down-regulated SCD-1 gene in the GC combination group. SCD-1 is an essential lipogenic protein for monounsaturated fatty acids’ biosynthesis and serves as a key regulatory enzyme in the last stage of hepatic de novo lipogenesis (DNL).

Methods: NAFLD mice model was fed with 16 weeks high-fat diet (HFD). The pharmacological effects, primarily on hepatic TG, TC, FFA, and liver enzymes, et al. of the GC combination and two individual components were evaluated. Furthermore, hepatic SCD-1 expression was quantified with qRT-PCR, immunoblotting, and immunohistochemistry. Finally, the lentivirus-mediated over-expressed cell was carried out to confirm the GC combination’s influence on SCD-1.

Results: The GC combination could significantly reduce hepatic TG, TC, and FFA in NAFLD rodents. Notably, the GC combination presented synergetic therapeutic effects, compared with two components, on normalizing murine hepatic lipid deposition and disordered liver enzymes (ALT and AST). Meanwhile, the robust SCD-1 induction induced by HFD and FFA in rodents and ALM-12 cells was profoundly blunted, and this potent suppression was recapitulated in lentivirus-mediated SCD-1 over-expressed cells.

Conclusion: Taken together, our data prove that the GC combination shows a substantial and synergetic anti-lipogenesis effect in treating NAFLD, and these amelioration effects are highly associated with the potent suppressed hepatic SCD-1 and a blunted DNL process.