bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Two Structurally Related Human Milk Oligosaccharide Conjugates in a Model of Diet-Induced Obesity
Authors: Ramadhin Jessica , Silva-Moraes Vanessa , Nagy Tamas , Norberg Thomas , Harn Donald
Published: May 2021

Obesity is the largest risk factor for the development of chronic diseases in industrialized countries. Excessive fat accumulation triggers a state of chronic low-grade inflammation to the detriment of numerous organs. To address this problem, our lab has been examining the anti-inflammatory mechanisms of two human milk oligosaccharides (HMOs), lacto-N-fucopentaose III (LNFPIII) and lacto-N-neotetraose (LNnT). LNFPIII and LNnT are HMOs that differ in structureviapresence/absence of an α1,3-linked fucose. We utilize LNFPIII and LNnT in conjugate form, where 10-12 molecules of LNFPIII or LNnT are conjugated to a 40 kDa dextran carrier (P3DEX/NTDEX). Previous studies from our lab have shown that LNFPIII conjugates are anti-inflammatory, act on multiple cell types, and are therapeutic in a wide range of murine inflammatory disease models. The α1,3-linked fucose residue on LNFPIII makes it difficult and more expensive to synthesize. Therefore, we asked if LNnT conjugates induced similar therapeutic effects to LNFPIII. Herein, we compare the therapeutic effects of P3DEX and NTDEX in a model of diet-induced obesity (DIO). MaleC57BL/6mice were placed on a high-fat diet for six weeks and then injected twice per week for eight weeks with 25µg of 40 kDa dextran (DEX; vehicle control), P3DEX, or NTDEX. We found that treatment with P3DEX, but not NTDEX, led to reductions in body weight, adipose tissue (AT) weights, and fasting blood glucose levels. Mice treated with P3DEX also demonstrated improvements in glucose homeostasis and insulin tolerance. Treatment with P3DEX or NTDEX also induced different profiles of serum chemokines, cytokines, adipokines, and incretin hormones, with P3DEX notably reducing circulating levels of leptin and resistin. P3DEX also reduced WAT inflammation and hepatic lipid accumulation, whereas NTDEX seemed to worsen these parameters. These results suggest that the small structural difference between P3DEX and NTDEX has significant effects on the conjugates’ therapeutic abilities. Future work will focus on identifying the receptors for these conjugates and delineating the mechanisms by which P3DEX and NTDEX exert their effects.
An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment
Authors: Abou Khouzam Raefa , Rao Shyama Prasad , Venkatesh Goutham Hassan , Zeinelabdin Nagwa Ahmed , Buart Stephanie , Meylan Maxime , Nimmakayalu Manjunath , Terry Stéphane , Chouaib Salem
Published: May 2021

Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature’s ability to discern an immune “cold”, hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.
Lactoferrin Retargets Human Adenoviruses to TLR4 to Induce an Abortive NLRP3-Associated Pyroptotic Response in Human Phagocytes
Authors: Chéneau Coraline , Eichholz Karsten , Tran Tuan Hiep , Tran Thi Thu Phuong , Paris Océane , Henriquet Corinne , Bajramovic Jeffrey J. , Pugniere Martine , Kremer Eric J.
Published: May 2021

Despite decades of clinical and preclinical investigations, we still poorly grasp our innate immune response to human adenoviruses (HAdVs) and their vectors. In this study, we explored the impact of lactoferrin on three HAdV types that are being used as vectors for vaccines. Lactoferrin is a secreted globular glycoprotein that influences direct and indirect innate immune response against a range of pathogens following a breach in tissue homeostasis. The mechanism by which lactoferrin complexes increases HAdV uptake and induce maturation of human phagocytes is unknown. We show that lactoferrin redirects HAdV types from species B, C, and D to Toll-like receptor 4 (TLR4) cell surface complexes. TLR4-mediated internalization of the HAdV-lactoferrin complex induced an NLRP3-associated response that consisted of cytokine release and transient disruption of plasma membrane integrity, without causing cell death. These data impact our understanding of HAdV immunogenicity and may provide ways to increase the efficacy of HAdV-based vectors/vaccines.
Food Web Trophic Structure at Marine Ranch Sites off the East Coast of Korea
Authors: Kang Hee Yoon , Lee Young-Jae , Kim Changseong , Kim Dongyoung , Kim Doo-Ho , Kim Jun-Ho , Choi Dong-Lim , Kang Chang-Keun
Published: May 2021

Understanding the trophic ecology of the giant Pacific octopusEnteroctopus dofleiniis challenging in developing marine ranches and in reestablishing its regional stocks against the severe stress of fishing. We adopted carbon and nitrogen stable isotope techniques (termed δ13C and δ15N, respectively) to identify the trophic niche (i.e., pathways and positions) of this species systematically in the entire food webs of two marine ranches off the east coast of the Korean peninsula. While a slight spatial shift in the isotopic nestedness of faunal communities was observed, the δ13C and δ15N values of consumers were distinct and separate among functional groups at both ranches. The consumer δ13C values spanned a broad range between pelagic and benthic sources of organic matter, and their δ15N values recorded a stepwise trophic-level enrichment, indicating that suspension feeders and herbivore-deposit feeders served as baselines of pelagic- and benthic-based trophic pathways, respectively. The δ13C values of predators, includingE. dofleini, were arrayed between the two primary consumer groups. Neither δ13C nor δ15N values showed any remarkable variations with increasing octopus weight. Dietary mixing-model calculations indicated thatE. dofleiniis a generalist predator relying on both benthic- and pelagic-affinity prey, similar to some teleost species that consume a diverse spectrum of prey. In contrast, other teleost groups showed prevalent trophic links with either pelagic- or benthic-based pathways. The trophic-level estimations revealed thatE. dofleinioccupies an intermediate position slightly below the teleosts. A lack of discrete trophic positions betweenE.dofleiniand teleosts seemed to be indicative of the released teleost predation but instead reflects the imposed food competition. Overall, the results demonstrated that despite compositional changes in the taxa constituting individual trophic groups,E.dofleinioccupied a very similar trophic niche in both ranching systems. Finally, as extracted from information based on octopus marine ranches launched on natural rocky bottoms, our isotopic evidence provides a greater understanding of the trophic ecology of this octopus species in nearshore natural habitats along the southwestern margin of its distribution range.
Dietary Lipid Effects on Gut Microbiota of First Feeding Atlantic Salmon (Salmo salar L.)
Authors: Nikouli Eleni , Kormas Konstantinos Ar. , Jin Yang , Olsen Yngvar , Bakke Ingrid , Vadstein Olav
Published: May 2021

Decline in fish oil and fish meal availability has forced the aquaculture sector to investigate alternative and sustainable aquafeed ingredients. Despite that several studies have evaluated the effect of fish oil replacement in aquaculture fish species, there is a knowledge gap on the effects of alternative dietary lipid sources on the gut microbiota in early life stages of Salmo salar. The present study evaluated the influence of dietary administration of two different lipid sources (fish oil and vegetable oil) on the intestinal microbiota of first feeding Atlantic salmon (S. salar) up to 93 days post first feeding (dpff). The two diets used in this study, FD (fish oil diet) and VD (blend of rapeseed, linseed and palm oils diet), were formulated to cover the fish nutritional requirements. Apart from the lipid source, the rest of the feed components were identical in the two diets. Hindgut samples were collected at 0, 35, 65, and 93 dpff. Moreover, fertilized eggs, yolk sac larvae, rearing water and feed were also collected in order to assess a possible contribution of their microbiota to the colonization and bacterial succession of the fish intestines. To analyze the bacterial communities, amplicon sequencing was used targeting the V3–V4 region of the 16S rRNA gene. The findings indicate that feeding on either fish oil or vegetable oil-based diet, fish growth variables (mean wet weight and total length) did not differ significantly during the experiment (p > 0.05). No significant differences were also found between the two dietary groups, regarding their gut bacteria composition, after the analysis of the 16S rRNA sequencing data. Instead, gut microbiota changed with age, and each stage was characterized by different dominant bacteria. These operational taxonomic units (OTUs) were related to species that provide different functions and have been isolated from a variety of environments. The results also show little OTUs overlap between the host and rearing environment microbiota. Overall, this study revealed the occurrence of a core microbiota in early life of Atlantic salmon independent of the feed-contained oil origin.
Intersecting Social Science and Conservation
Authors: Sanborn Thomas , Jung Julia
Published: May 2021

There is a growing consensus that current conservation strategies are unable to cope with the acceleration of human-caused environmental degradation. The philosophies that underpin and shape traditional conservation initiatives have begun to shift toward a “people and nature” approach, based on a new and deeper understanding of relational values. With this shift, there is increasing concern about the social impacts of conservation and a need to consider not only the environmental aspects of conservation, but also issues of equity and social justice. This is especially important for marine conservation to avoid repeating the exclusionary and unjust protective measures sometimes seen in traditional terrestrial conservation. Additionally, lack of compliance with management schemes, and failure to consider the social dimensions and realities of local communities have hindered the success of conservation initiatives. Therefore, increasing engagement with social science and a better understanding of human-wildlife and human-nature connections are necessary. Community-based conservation approaches and payment for ecosystem service schemes can provide important insights and lessons for such improved participatory management. Furthermore, the use of social science offers a range of methods and approaches that can be used to improve the consideration of those social dimensions. These include different theoretical frameworks for understanding the relationships between people, society, and nature, innovative participatory methods and more flexible, adaptive systems-based approaches for understanding complex socio-ecological systems. Increasing and mainstreaming the inclusion of the social dimensions of conservation will also depend on overcoming current institutional barriers such as lack of capacity, time, and funding opportunities especially in the context of marine social science.
Clinical Profile, Prognostic Factors, and Outcome Prediction in Hospitalized Patients With Bloodstream Infection: Results From a 10-Year Prospective Multicenter Study
Authors: Jin Longyang , Zhao Chunjiang , Li Henan , Wang Ruobing , Wang Qi , Wang Hui
Published: May 2021

Background: Bloodstream infection (BSI) is one of the most common serious bacterial infections worldwide and also a major contributor to in-hospital mortality. Determining the predictors of mortality is crucial for prevention and improving clinical prognosis in patients with nosocomial BSI.

Methods: A nationwide prospective cohort study was conducted from 2007 until 2016 in 16 teaching hospitals across China. Microbiological results, clinical information, and patient outcomes were collected to investigate the pathogenic spectrum and mortality rate in patients with BSI and identify outcome predictors using multivariate regression, prediction model, and Kaplan–Meier analysis.

Results: No significant change was observed in the causative pathogen distribution during the 10-year period and the overall in-hospital mortality was 12.83% (480/3,741). An increased trend was found in the mortality of patients infected with Pseudomonas aeruginosa or Acinetobacter baumannii, while a decreased mortality rate was noted in Staphylococcus aureus-related BSI. In multivariable-adjusted models, higher mortality rate was significantly associated with older age, cancer, sepsis diagnosis, ICU admission, and prolonged hospital stay prior to BSI onset, which were also determined using machine learning-based predictive model achieved by random forest algorithm with a satisfactory performance in outcome prediction.

Conclusions: Our study described the clinical and microbiological characteristics and mortality predictive factors in patients with BSI. These informative predictors would inform clinical practice to adopt effective therapeutic strategies to improve patient outcomes.
Genomic Epidemiology of SARS-CoV-2 From Mainland China With Newly Obtained Genomes From Henan Province
Authors: Song Ning , Cui Guang-Lin , Zeng Qing-Lei
Published: May 2021

Even though the COVID-19 epidemic in China has been successfully put under control within a few months, it is still very important to infer the origin time and genetic diversity from the perspective of the whole genome sequence of its agent, SARS-CoV-2. Yet, the sequence of the entire virus genome from China in the current public database is very unevenly distributed with reference to time and place of collection. In particular, only one sequence was obtained in Henan province, adjacent to China's worst-case province, Hubei Province. Herein, we used high-throughput sequencing techniques to get 19 whole-genome sequences of SARS-CoV-2 from 18 severe patients admitted to the First Affiliated Hospital of Zhengzhou University, a provincial designated hospital for the treatment of severe COVID-19 cases in Henan province. The demographic, baseline, and clinical characteristics of these patients were described. To investigate the molecular epidemiology of SARS-CoV-2 of the current COVID-19 outbreak in China, 729 genome sequences (including 19 sequences from this study) sampled from Mainland China were analyzed with state-of-the-art comprehensive methods, including likelihood-mapping, split network, ML phylogenetic, and Bayesian time-scaled phylogenetic analyses. We estimated that the evolutionary rate and the time to the most recent common ancestor (TMRCA) of SARS-CoV-2 from Mainland China were 9.25 × 10−4 substitutions per site per year (95% BCI: 6.75 × 10−4 to 1.28 × 10−3) and October 1, 2019 (95% BCI: August 22, 2019 to November 6, 2019), respectively. Our results contribute to studying the molecular epidemiology and genetic diversity of SARS-CoV-2 over time in Mainland China.
Effect of Different Nuclear Localization Signals on the Subcellular Localization and Anti-HIV-1 Function of the MxB Protein
Authors: Chai Keli , Wang Zhen , Pan Qinghua , Tan Juan , Qiao Wentao , Liang Chen
Published: May 2021

Interferon exerts its antiviral activity by stimulating the expression of antiviral proteins. These interferon stimulate genes (ISGs) often target a group of viruses with unique molecular mechanisms. One such ISG is myxovirus resistance B (MxB) that has been reported to inhibit human immunodeficiency virus type 1 (HIV-1) by targeting viral capsid and impairing nuclear import of viral DNA. The antiviral specificity of MxB is determined by its N-terminal 25 amino acids sequence which has the nuclear localization activity, therefore functions as a nuclear localization signal (NLS). In this study, we report that the bipartite NLS, but not the classic NLS, the PY-NLS, nor the arginine-rich NLS, when used to replace the N-terminal sequence of MxB, drastically suppress HIV-1 gene expression and virus production, thus creates a new anti-HIV-1 mechanism. MxB preserves its anti-HIV-1 activity when its N-terminal sequence is replaced by the arginine-rich NLS. Interestingly, the arginine-rich NLS allows MxB to inhibit HIV-1 CA mutants that are otherwise resistant to wild type MxB, which suggests sequence specific targeting of viral capsid. Together, these data implicate that it is not the nuclear import function itself, but rather the sequence and the mechanism of action of the NLS which define the antiviral property of MxB.
Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide
Authors: Nangraj Asma Sindhoo , Khan Abbas , Umbreen Shaheena , Sahar Sana , Arshad Maryam , Younas Saba , Ahmad Sajjad , Ali Shahid , Ali Syed Shujait , Ali Liaqat , Wei Dong-Qing
Published: May 2021

Pyrazinamide (PZA) is the first-line drug commonly used in treating Mycobacterium tuberculosis (Mtb) infections and reduces treatment time by 33%. This prodrug is activated and converted to an active form, Pyrazinoic acid (POA), by Pyrazinamidase (PZase) enzyme. Mtb resistance to PZA is the outcome of mutations frequently reported in pncA, rpsA, and panD genes. Among the mentioned genes, pncA mutations contribute to 72–99% of the total resistance to PZA. Thus, considering the vital importance of this gene in PZA resistance, its frequent mutations (D49N, Y64S, W68G, and F94A) were investigated through in-depth computational techniques to put conclusions that might be useful for new scaffolds design or structure optimization to improve the efficacy of the available drugs. Mutants and wild type PZase were used in extensive and long-run molecular dynamics simulations in triplicate to disclose the resistance mechanism induced by the above-mentioned point mutations. Our analysis suggests that these mutations alter the internal dynamics of PZase and hinder the correct orientation of PZA to the enzyme. Consequently, the PZA has a low binding energy score with the mutants compared with the wild type PZase. These mutations were also reported to affect the binding of Fe2+ ion and its coordinated residues. Conformational dynamics also revealed that β-strand two is flipped, which is significant in Fe2+ binding. MM-GBSA analysis confirmed that these mutations significantly decreased the binding of PZA. In conclusion, these mutations cause conformation alterations and deformities that lead to PZA resistance.
Localizing Clinical Patterns of Blast Traumatic Brain Injury Through Computational Modeling and Simulation
Authors: Miller Scott T. , Cooper Candice F. , Elsbernd Paul , Kerwin Joseph , Mejia-Alvarez Ricardo , Willis Adam M.
Published: May 2021

Blast traumatic brain injury is ubiquitous in modern military conflict with significant morbidity and mortality. Yet the mechanism by which blast overpressure waves cause specific intracranial injury in humans remains unclear. Reviewing of both the clinical experience of neurointensivists and neurosurgeons who treated service members exposed to blast have revealed a pattern of injury to cerebral blood vessels, manifested as subarachnoid hemorrhage, pseudoaneurysm, and early diffuse cerebral edema. Additionally, a seminal neuropathologic case series of victims of blast traumatic brain injury (TBI) showed unique astroglial scarring patterns at the following tissue interfaces: subpial glial plate, perivascular, periventricular, and cerebral gray-white interface. The uniting feature of both the clinical and neuropathologic findings in blast TBI is the co-location of injury to material interfaces, be it solid-fluid or solid-solid interface. This motivates the hypothesis that blast TBI is an injury at the intracranial mechanical interfaces. In order to investigate the intracranial interface dynamics, we performed a novel set of computational simulations using a model human head simplified but containing models of gyri, sulci, cerebrospinal fluid (CSF), ventricles, and vasculature with high spatial resolution of the mechanical interfaces. Simulations were performed within a hybrid Eulerian—Lagrangian simulation suite (CTH coupledviaZapotec to Sierra Mechanics). Because of the large computational meshes, simulations required high performance computing resources. Twenty simulations were performed across multiple exposure scenarios—overpressures of 150, 250, and 500 kPa with 1 ms overpressure durations—for multiple blast exposures (front blast, side blast, and wall blast) across large variations in material model parameters (brain shear properties, skull elastic moduli). All simulations predict fluid cavitation within CSF (where intracerebral vasculature reside) with cavitation occurring deep and diffusely into cerebral sulci. These cavitation events are adjacent to high interface strain rates at the subpial glial plate. Larger overpressure simulations (250 and 500kPa) demonstrated intraventricular cavitation—also associated with adjacent high periventricular strain rates. Additionally, models of embedded intraparenchymal vascular structures—with diameters as small as 0.6 mm—predicted intravascular cavitation with adjacent high perivascular strain rates. The co-location of local maxima of strain rates near several of the regions that appear to be preferentially damaged in blast TBI (vascular structures, subpial glial plate, perivascular regions, and periventricular regions) suggest that intracranial interface dynamics may be important in understanding how blast overpressures leads to intracranial injury.
Cerebral Hemodynamic Evaluation of Main Cerebral Vessels in Epileptic Patients Based on Transcranial Doppler
Authors: Meng Jihong , Li Chun , Ma Weining
Published: May 2021

Objective: To study whether there is a difference in peak and mean blood flow velocity between the left and right major cerebral vessels in patients with epilepsy.

Methods: Sixteen patients with epilepsy underwent FDG18-PET-CT (PET) scan and electroencephalogram (EEG) examinations. Transcranial Doppler (TCD) was used to detect the peak flow velocity (PFV), mean flow velocity (MFV), and other hemodynamic indicators of bilateral anterior, middle, and posterior cerebral arteries in each patient. According to different patterns of the PET or interictal EEG, the differences in PFV, and MFV of corresponding vessels on both sides under different patterns were compared.

Results: According to the PET of the low-metabolism region corresponding to the supplying artery, the PFV and MFV of the supplying artery in the low-metabolism region were lower than the value of the corresponding contralateral vessel. The PFV and MFV on the low metabolic side of PET were lower than that of the corresponding vessels on the opposite side. The PFV and MFV on the discharge side of interictal EEG were also lower than the PFV and MFV of the corresponding vessels on the opposite side. The MFV of posterior cerebral artery on the low metabolic side of PET or the interictal discharge side was significantly different from that of the contralateral vessels (P < 0.05). However, the other aforementioned differences in PFV and MFV did not achieve statistical significance.

Conclusion: In epileptic patients, the PFV and MFV of main cerebral vessels on the PET hypometabolized side or the interictal discharge side was lower than that of corresponding vessels on the contralateral side. To some extent, the difference in the MFV of PCA between the bilateral sides can facilitate the lateral diagnosis of the epileptogenic zone.
Neuroimaging in the Understanding of Acupuncture Analgesia: A Review of Acupuncture Neuroimaging Study Based on Experimental Pain Models
Authors: Peihong Ma , Yuzhu Qu , Tao Yin , Zhaoxuan He , Shirui Cheng , Yuke Teng , Kunnan Xie , Shenghong Li , Ruirui Sun , Fang Zeng
Published: May 2021

With the development of real-time and visualized neuroimaging techniques, the studies on the central mechanism of acupuncture analgesia gain increasing attention. The experimental pain models have been widely used in acupuncture-analgesia neuroimaging studies with quantitative and controlled advantages. This review aimed to analyze the study design and main findings of acupuncture neuroimaging studies to provide reference for future study. The original studies were collected and screened in English databases (PubMed, EMBASE, and Cochrane Library) and Chinese databases (Chinese Nation Knowledge Infrastructure, Chinese Biomedical Literature Database, the Chongqing VIP Database, and Wanfang Database). As a result, a total of 27 articles were included. Heat stimulation and electroacupuncture were the mostly used pain modeling method and acupuncture modality, respectively. The neuroimaging scanning process can be divided into two models and five subtypes. The anterior cingulate cortex and insula were the most commonly reported brain regions involved in acupuncture analgesia with experimental pain models.
lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
Authors: Zhu Xuewei , Liu Li , Wang Yang , Cong Jianan , Lin Zhang , Wang Yongsen , Liu Qi , Wang Leiming , Yang Ben , Li Tao
Published: May 2021

Cisplatin-based chemotherapy and radiotherapy are the main first-line treatment strategies for nasopharyngeal carcinoma (NPC) patients. Unfortunately, resistance is a major obstacle in the clinical management of NPC patients. We prove that the expression level of high-mobility group box 1 (HMGB1) is dramatically increased in resistant NPC cells than that in sensitive cells. HMGB1 induces the expression and secretion of IL6, which leads to constitutive autocrine activation of the JAK2/STAT3 pathway and eventually contributes to chemoresistance in NPC cells. Long non-coding RNAs (lncRNAs) have been identified as key regulators involved in drug resistance. In this study, using GO analysis of the biological process and differential expression analysis, we find 12 significantly altered IncRNAs in NPC cell lines, which may be involved in regulating gene expression. Furthermore, we determine that elevated lncRNA MIAT level upregulates HMGB1 expression, contributing to cisplatin resistance in NPC cells. We find that the deficiency of the lncRNA MIAT/HMGB1 axis, inhibition of JAK2/STAT3, or neutralization of IL6 by antibodies significantly re-sensitizes resistant NPC cells to cisplatin in resistant NPC cells. Moreover, we provide the in vivo evidence that the deficiency of HMGB1 reduces cisplatin-resistant tumor growth. Most importantly, we provide clinical evidence showing that the expression level of the lncRNA MIAT/HMGB1/IL6 axis is elevated in resistant NPC tumors, which is highly correlated with poor clinical outcome. Our findings identify a novel chemoresistance mechanism regulated by the lncRNA MIAT/HMGB1/IL6 axis, which indicates the possibilities for lncRNA MIAT, HMGB1, and IL6 as biomarkers for chemoresistance and targets for developing novel strategies to overcome resistance in NPC patients.
Regulation of ERα Stability and Estrogen Signaling in Breast Cancer by HOIL-1
Authors: Ding Jianing , Kuang Peng
Published: May 2021

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy.
Exploiting Radiation Therapy to Restore Immune Reactivity of Glioblastoma
Authors: De Martino Mara , Padilla Oscar , Daviaud Camille , Wu Cheng-Chia , Gartrell Robyn D. , Vanpouille-Box Claire
Published: May 2021

Glioblastoma (GBM) is among the most aggressive of brain tumors and confers a dismal prognosis despite advances in surgical technique, radiation delivery methods, chemotherapy, and tumor-treating fields. While immunotherapy (IT) has improved the care of several adult cancers with previously dismal prognoses, monotherapy with IT in GBM has shown minimal response in first recurrence. Recent discoveries in lymphatics and evaluation of blood brain barrier offer insight to improve the use of ITs and determine the best combinations of therapies, including radiation. We highlight important features of the tumor immune microenvironment in GBM and potential for combining radiation and immunotherapy to improve prognosis in this devastating disease.
Prophylactic Erythropoietin for Neuroprotection in Very Preterm Infants: A Meta-Analysis Update
Authors: Fischer Hendrik S. , Reibel Nora J. , Bührer Christoph , Dame Christof
Published: May 2021

A meta-analysis update of randomized controlled trials investigating recombinant human erythropoietin suggests improved neurodevelopmental outcome in preterm infants. There was substantial heterogeneity, which could be ascribed to a single trial. Exclusion of this trial featuring a high risk of bias abolished heterogeneity and any effects of recombinant human erythropoietin treatment.
Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature
Authors: Contreras Josefina Longeri , Ladino Mabel A. , Aránguiz Katherine , Mendez Gonzalo P. , Coban-Akdemir Zeynep , Yuan Bo , Gibbs Richard A. , Burrage Lindsay C. , Lupski James R. , Chinn Ivan K. , Vogel Tiphanie P. , Orange Jordan S. , Poli M. Cecilia
Published: May 2021

Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in SLC7A7. The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.
Dynamics of Nanoparticle Self-Assembly by Liquid Crystal Sorting in Two Dimensions
Authors: Segura-Fernández F. Gael , Serrato-García Erick F. , Flores-Calderón J. Emmanuel , Guzmán Orlando
Published: May 2021

We study nonlinear dynamical equations for coupled conserved and non-conserved fields describing nanoparticle concentration and liquid crystal order parameter, respectively, and solve them numerically over bidimensional domains. These equations model the rapid segregation of nanoparticles away from nematic domains, which has been observed experimentally in a suspension of gold nanoparticles in 5CB below the isotropic-nematic transition temperature. We contrast the different behaviors obtained when the LC order parameter is treated as a scalar or a tensor, as well as the different rates of evolution observed with each of these. We find, after an instantaneous quench lowering the temperature below the transition one, an initial linear regime where the ordering of the nematic phase proceeds exponentially with time. Only after a lag period the nanoparticle material couples effectively to the LC order parameter and segregates to regions that are less orientationally ordered (extended domain walls for a scalar order parameter, but point disclinations for a tensor one). The lag period is followed by the onset of nonlinear dynamics and saturation of the order parameter. The choice of a scalar or tensor LC order parameter does not change this sequence but results in a clear overshooting of the nonlinear saturation level for the tensor order parameter case. These results are found to be insensitive to weak anchoring due to coupling of gradients of the conserved and non-conserved variables, for the nanoparticle concentrations and anchoring parameters studied. Our modeling approach can be extended in a straightforward manner to cases where the cooling rate is finite and to other systems where a locally conserved concentration is coupled to a orientation field, such as active Langmuir monolayers, and possibly to other examples of nonlinear dynamics in ecological or excitable media problems.
Photo-Induced Coupled Nuclear and Electron Dynamics in the Nucleobase Uracil
Authors: Bäuml Lena , Schnappinger Thomas , Kling Matthias F. , de Vivie-Riedle Regina
Published: May 2021

Photo-initiated processes in molecules often involve complex situations where the induced dynamics is characterized by the interplay of nuclear and electronic degrees of freedom. The interaction of the molecule with an ultrashort laser pulse or the coupling at a conical intersection (CoIn) induces coherent electron dynamics which is subsequently modified by the nuclear motion. The nuclear dynamics typically leads to a fast electronic decoherence but also, depending on the system, enables the reappearance of the coherent electron dynamics. We study this situation for the photo-induced nuclear and electron dynamics in the nucleobase uracil. The simulations are performed with our ansatz for the coupled description of the nuclear and electron dynamics in molecular systems (NEMol). After photo-excitation uracil exhibits an ultrafast relaxation mechanism mediated by CoIn's. Both processes, the excitation by a laser pulse and the non-adiabatic relaxation, are explicitly simulated and the coherent electron dynamics is monitored using our quantum mechanical NEMol approach. The electronic coherence induced by the CoIn is observable for a long time scale due to the delocalized nature of the nuclear wavepacket.
β-Lactoglobulin and Glycodelin: Two Sides of the Same Coin?
Authors: Sawyer Lindsay
Published: May 2021

The two lipocalins, β-lactoglobulin (βLg) and glycodelin (Gd), are possibly the most closely related members of the large and widely distributed lipocalin family, yet their functions appear to be substantially different. Indeed, the function of β-lactoglobulin, a major component of ruminant milk, is still unclear although neonatal nutrition is clearly important. On the other hand, glycodelin has several specific functions in reproduction conferred through distinct, tissue specific glycosylation of the polypeptide backbone. It is also associated with some cancer outcomes. The glycodelin gene,PAEP, reflecting one of its names, progestagen-associated endometrial protein, is expressed in many though not all primates, but the name has now also been adopted for the β-lactoglobulin gene (HGNC,www.genenames.org). After a general overview of the two proteins in the context of the lipocalin family, this review considers the properties of each in the light of their physiological functional significance, supplementing earlier reviews to include studies from the past decade. While the biological function of glycodelin is reasonably well defined, that of β-lactoglobulin remains elusive.
Nobiletin Alleviates Non-alcoholic Steatohepatitis in MCD-Induced Mice by Regulating Macrophage Polarization
Authors: Wang Si-wei , Lan Tian , Sheng Hao , Zheng Fang , Lei Mei-kang , Wang Li-xia , Chen Hang-fei , Xu Chun-yi , Zhang Feng
Published: May 2021

Non-alcoholic steatohepatitis (NASH) is an inflammatory disorder that is characterized by chronic activation of the hepatic inflammatory response and subsequent liver damage. The regulation of macrophage polarization in liver is closely related to the progression of NASH. The orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) and Krüppel-like factor 4 (KLF4) are key regulators which promote hepatic macrophages toward M2 phenotype and protect against NASH in mice. Nobiletin (NOB), a natural polymethoxylated flavone, is previously reported as a RORα regulator in diet-induced obese mice. However, it is still unclear whether NOB has the protective effect on NASH. In this study, we investigated the role of NOB in NASH using a methionine and choline deficient (MCD)-induced NASH mouse model. Our results showed that NOB ameliorated hepatic damage and fibrosis in MCD fed mice. NOB treatment reduced the infiltration of macrophages and neutrophils in the liver in MCD-fed mice. Of importance, NOB significantly increased the proportion of M2 macrophages and the expression of anti-inflammatory factors in vivo and in vitro. Meanwhile, NOB also decreased the population of M1 macrophages and the expression of proinflammatory cytokines. Mechanistically, NOB elevated KLF4 expression in macrophages. Inhibition of KLF4 abolished NOB regulated macrophage polarization. Furthermore, the regulation of NOB in KLF4 expression was dependent on RORα.
Opening the Treasure Chest: The Current Status of Research on Brassica oleracea and B. rapa Vegetables From ex situ Germplasm Collections
Authors: Witzel Katja , Kurina Anastasia B. , Artemyeva Anna M.
Published: May 2021

Germplasm collections reflect the genetic variability in crops and their wild relatives. Hence, those genetic resources are tremendously valuable for breeders and researchers, especially in light of climatic change and stagnant crop production rates. In order to achieve improvements in crop production and end-use quality, favorable traits and donor alleles present in germplasm collections need to be identified and utilized. This review covers recent reports on the utilization of germplasm material to isolate genotypes of Brassica oleracea and B. rapa vegetables, focusing on high nutrient use efficiency, accumulation of biologically active metabolites, pest resistance, and favorable phenotypic appearance. We discuss the current state of Brassica vegetable collections in genebanks and summarize studies directed to the molecular characterization of those collections.
Home Confinement in Previously Active Older Adults: A Cross-Sectional Analysis of Physical Fitness and Physical Activity Behavior and Their Relationship With Depressive Symptoms
Authors: Carvalho Joana , Borges-Machado Flávia , Pizarro Andreia N. , Bohn Lucimere , Barros Duarte
Published: May 2021

Aim

The aim of our study was to analyze physical activity levels, sitting time, physical fitness, and their relationship with depressive symptoms after home confinement in previously active older adults.

Methods

This cross-sectional study sample comprised 68 older adults (74.24 ± 5.67 years) from a community-based exercise program conducted in Porto, Portugal. After home confinement, participants were assessed in person for lower-body strength (30-s chair stand test), cardiorespiratory fitness (6-min walking test), agility/dynamic balance (8-ft up-and-go test), handgrip strength, and anthropometry. Telephone interviews were performed to evaluate depressive symptoms with the Geriatric Depression Scale – 15 items (GDS-15) and physical activity levels through the International Physical Activity Questionnaire (IPAQ-SV). Individuals were also asked to self-report changes in their physical activity levels and time spent sitting.

Results

Ninety percent of older adults self-reported a decrease in overall physical activity levels, and nearly 65% increased daily sitting time during the home confinement. However, previously active older adults still presented high levels of physical fitness (scores above 50th compared with Portuguese normative values) after 11 weeks of home confinement. Overall, 52.9% of participants scored 5 or more points on GDS-15, which is suggestive of depression. Higher levels of moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness were found in the non-depressed group compared with the depressed group. Finally, results from multiple regression analysis revealed that MVPA was negatively associated with depression. This model explained 16.4% of the variability seen in depression score, controlled for age, gender, and education.

Conclusion

Even reporting a decline in physical activity, older adults who previously participated in a formal exercise program, still presented high levels of physical fitness after 11 weeks of home confinement. However, MVPA, but not physical fitness, seems to be an associated depression score in previously active older adults. These results reinforce the importance of older adults to remain physically active, since higher levels of MVPA may have a protective effect on depressive symptoms and, therefore, mitigate the negative impact of home confinement on mental health. Future longitudinal research studies are needed to ascertain these results.
Perception of Nigerian Dùndún Talking Drum Performances as Speech-Like vs. Music-Like: The Role of Familiarity and Acoustic Cues
Authors: Durojaye Cecilia , Fink Lauren , Roeske Tina , Wald-Fuhrmann Melanie , Larrouy-Maestri Pauline
Published: May 2021

It seems trivial to identify sound sequences as music or speech, particularly when the sequences come from different sound sources, such as an orchestra and a human voice. Can we also easily distinguish these categories when the sequence comes from the same sound source? On the basis of which acoustic features? We investigated these questions by examining listeners’ classification of sound sequences performed by an instrument intertwining both speech and music: the dùndún talking drum. The dùndún is commonly used in south-west Nigeria as a musical instrument but is also perfectly fit for linguistic usage in what has been described as speech surrogates in Africa. One hundred seven participants from diverse geographical locations (15 different mother tongues represented) took part in an online experiment. Fifty-one participants reported being familiar with the dùndún talking drum, 55% of those being speakers of Yorùbá. During the experiment, participants listened to 30 dùndún samples of about 7s long, performed either as music or Yorùbá speech surrogate (n= 15 each) by a professional musician, and were asked to classify each sample as music or speech-like. The classification task revealed the ability of the listeners to identify the samples as intended by the performer, particularly when they were familiar with the dùndún, though even unfamiliar participants performed above chance. A logistic regression predicting participants’ classification of the samples from several acoustic features confirmed the perceptual relevance of intensity, pitch, timbre, and timing measures and their interaction with listener familiarity. In all, this study provides empirical evidence supporting the discriminating role of acoustic features and the modulatory role of familiarity in teasing apart speech and music.
Inspired and Effective: The Role of the Ideal Self in Employee Engagement, Well-Being, and Positive Organizational Behaviors
Authors: Martinez Hector A. , Rochford Kylie , Boyatzis Richard E. , Rodriguez-Chaves Sofia
Published: May 2021

This study explores the efficacy of a specific tool – the articulation of the ideal self – in job engagement, psychological well-being, and organizational citizenship behavior. We hypothesized that employees who can visualize their jobs as part of their ideal self – in particular how it helps in its development and realization – would feel higher levels of engagement and fulfillment in their lives, as well as engage in greater amounts of helping and voice OCB. A total of 239 full time employees from five companies in Costa Rica filled out the ideal self questionnaire, the job engagement, and psychological well-being surveys, and were evaluated by their peers on task behavior and helping and voice OCB. Results of the SEM model showed that the ideal self was positively related to job engagement, psychological well-being and helping and voice. These findings contribute to the research on the impact and importance for organizations to help employees find meaningfulness in their work.