bluuebunny/crossref_metadata_2025 huggingface dataset:
CyTOF-Enabled Analysis Identifies Class-Switched B Cells as the Main Lymphocyte Subset Associated With Disease Relapse in Children With Idiopathic Nephrotic Syndrome
Authors: Fribourg Miguel , Cioni Michela , Ghiggeri GianMarco , Cantarelli Chiara , Leventhal Jeremy S. , Budge Kelly , Bin Sofia , Riella Leonardo V. , Colucci Manuela , Vivarelli Marina , Angeletti Andrea , Perin Laura , Cravedi Paolo
Published: September 2021

B cell depleting therapies permit immunosuppressive drug withdrawal and maintain remission in patients with frequently relapsing nephrotic syndrome (FRNS) or steroid–dependent nephrotic syndrome (SDNS), but lack of biomarkers for treatment failure. Post-depletion immune cell reconstitution may identify relapsing patients, but previous characterizations suffered from methodological limitations of flow cytometry. Time-of-flight mass cytometry (CyTOF) is a comprehensive analytic modality that simultaneously quantifies over 40 cellular markers. Herein, we report CyTOF-enabled immune cell comparisons over a 12-month period from 30 children with SDNS receiving B cell depleting therapy who either relapsed (n = 17) or remained stable (n = 13). Anti-CD20 treatment depleted all B cells subsets and CD20 depleting agent choice (rituximabvsofatumumab) did not affect B cell subset recovery. Despite equal total numbers of B cells, 5 subsets of B cells were significantly higher in relapsing individuals; all identified subsets of B cells were class-switched. T cell subsets (including T follicular helper cells and regulatory T cells) and other major immune compartments were largely unaffected by B cell depletion, and similar between relapsing and stable children. In conclusion, CyTOF analysis of immune cells from anti-CD20 antibody treated patients identifies class-switched B cells as the main subset whose expansion associates with disease relapse. Our findings set the basis for future studies exploring how identified subsets can be used to monitor treatment response and improve our understanding of the pathogenesis of the disease.
Endogenous Interleukin-33 Acts as an Alarmin in Liver Ischemia-Reperfusion and Is Associated With Injury After Human Liver Transplantation
Authors: Barbier Louise , Robin Aurélie , Sindayigaya Rémy , Ducousso Héloïse , Dujardin Fanny , Thierry Antoine , Hauet Thierry , Girard Jean-Philippe , Pellerin Luc , Gombert Jean-Marc , Herbelin André , Salamé Ephrem
Published: September 2021

Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33–deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.
Granulocytic Myeloid-Derived Suppressor Cells in Cystic Fibrosis
Authors: Tucker Samantha L. , Sarr Demba , Rada Balázs
Published: September 2021

Cystic Fibrosis (CF) is a genetic disease that causes chronic and severe lung inflammation and infection associated with high rates of mortality. In CF, disrupted ion exchange in the epithelium results in excessive mucus production and reduced mucociliary clearance, leading to immune system exacerbation and chronic infections with pathogens such as P. aeruginosa and S. aureus. Constant immune stimulation leads to altered immune responses including T cell impairment and neutrophil dysfunction. Specifically, CF is considered a Th17-mediated disease, and it has been proposed that both P. aeruginosa and a subset of neutrophils known as granulocytic myeloid suppressor cells (gMDSCs) play a role in T cell suppression. The exact mechanisms behind these interactions are yet to be determined, but recent works demonstrate a role for arginase-1. It is also believed that P. aeruginosa drives gMDSC function as a means of immune evasion, leading to chronic infection. Herein, we review the current literature regarding immune suppression in CF by gMDSCs with an emphasis on T cell impairment and the role of P. aeruginosa in this dynamic interaction.
Relationships Between Northern Hemisphere Teleconnection Patterns and Phytoplankton Productivity in the Neva Estuary (Northeastern Baltic Sea)
Authors: Golubkov Mikhail , Golubkov Sergey
Published: September 2021

Teleconnection patterns can be an important tool for investigating the impact of climate change on biological communities. The aim of the study was, using 2003–2020 data on chlorophyll a concentrations (CHL) and plankton primary production (PP) in midsummer, to determine which of the teleconnection patterns have most pronounced effects on phytoplankton productivity in the estuary located on the border between western and eastern Europe. CHL correlated significantly with the winter values of the North Atlantic Oscillation (NAOw) and Scandinavia (SCANDw) indices, as well as with the values of the annual Polar/Eurasian (POLy) and annual Arctic Oscillation (AOy) indices. PP was significantly correlated with the values of POLy. East Atlantic/Western Russia pattern showed no significant correlation with both phytoplankton indicators. Stepwise multiple linear regressions were performed to determine the most influential indices affecting CHL and PP in the Neva Estuary. POLy, SCANDw, and NAOw appeared to be the main predictors in CHL multiple regression model, while the values of POLy and the July NAO and SCAND values were the main predictors in the PP model. According to our research, the productivity of phytoplankton in the Neva Estuary, located in the most northeastern part of the Baltic Sea, showed a significant relationship with the POL, which determines weather conditions in the northeastern regions of Eurasia. Possible mechanisms of the influence of these teleconnection patterns on phytoplankton productivity are discussed. Using the obtained multi-regression equations and the values of climatic indices, we calculated the values of CHL and PP for 1951–2002 and compared them with the results of field observations. The calculated and measured values of CHL and PP showed a significant increase in phytoplankton productivity in the Neva Estuary in the second half of the 2010s compared to earlier periods. In some years of the 1950s, 1980s, and late 1990s, CHL could also be above average and the low phytoplankton productivity should have been observed in the 1960s–1970s. This indicates a significant contribution of current climate change to fluctuation in phytoplankton productivity observed in recent decades, which should be taken into account when developing measures to protect aquatic ecosystems from eutrophication.
Research of the Potential Vaginal Microbiome Biomarkers for High-Grade Squamous Intraepithelial Lesion
Authors: Chao Xiaopei , Wang Lan , Wang Shu , Lang Jinghe , Tan Xianjie , Fan Qingbo , Shi Honghui
Published: September 2021

Vaginal microbiome may have a role in HPV infection and cervical neoplasm. To explore potential vaginal microbiome biomarkers for high-grade squamous intraepithelial lesion (HSIL), and to find the best scheme to facilitate the current cervical cancer screening strategy. This study enrolled 272 women, including 83 confirmed with HSIL, 86 with HPV infection but without cervical neoplasm, and 103 without HPV infection as controls. Vaginal microbiome composition was determined by sequencing of barcoded 16S rDNA gene fragments (V4) on Illumina HiSeq2500. The relative increasing abundance of Stenotrophomonas, Streptococcus, and Pseudomonas, and a concomitant paucity of Dialister, unidentified Prevotellaceae, Faecalibacterium, Bifidobacterium, and Bacteroides, were related with HSIL, which can be used to predict the development of HISL in high-risk HPV infected patients. The relative abundance of Stenotrophomonas being over 0.0090387%, or Faecalibacterium being under 0.01420015%, or Bifidobacterium being under 0.0116183% maybe a good predictor for HSIL for those infected with HPV 16 and/or 18. The relative abundance of Stenotrophomonas being over 0.01549105%, or Streptococcus being over 0.48409585%, or Bacteroides being under 0.0296912% maybe a good predictor for HSIL for those infected with the 12 other high-risk types of HPV with concurrent abnormal TCT results. This study revealed that potential vaginal microbiome biomarkers may relate to HSIL, and can facilitate the cervical cancer screening.
The Circadian Syndrome Predicts Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia Better Than Metabolic Syndrome in Aging Males: A 4-Year Follow-Up Study
Authors: Xiong Yang , Zhang Fuxun , Wu Changjing , Zhang Yangchang , Huang Xiaoyingzi , Qin Feng , Yuan Jiuhong
Published: September 2021

Background: The prevalence of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (BPH) increases in men. Although several risk factors, including metabolic syndrome (MetS) and depression, were identified, the underlying etiological factor remains unclear. Recently, circadian syndrome (CircS) was proposed as a novel risk cluster based on MetS. To compare the predictive power of the CircS and MetS for LUTS/BPH, this study was performed.

Materials and Methods: In the baseline survey, 4,390 men older than 40 years from the China Health and Retirement Longitudinal Study were enrolled. Of them, 3,658 men were followed in the 2015 survey. Logistic regression was adopted to examine the relationships between CircS, MetS, and LUTS/BPH. To further verify the association, propensity score matching was used for sensitivity analyses. Moreover, the participants who had LUTS/BPH at the baseline were excluded to test the longitudinal relationships between CircS, MetS, and LUTS/BPH. In addition, we employed the receiver operating characteristic (ROC) curve analysis to compare the predictive power using the number of components of CircS and MetS. The DeLong test was used to test the disparities of area under the curves (AUCs).

Results: The prevalence of CircS and MetS in aging men was 30.23 and 38.36%, respectively. The odds ratios for prevalent LUTS/BPH were 1.61 (95% CI = 1.29–2.00, P < 0.001) and 1.34 (95% CI = 1.08–1.66, P < 0.01), respectively, in aging men. This increased risk was also observed in incident LUTS/BPH. The prevalence of LUTS/BPH in normal, CircS alone, MetS alone, and both CircS and MetS groups was 6.96, 8.77, 7.83, and 10.77%, respectively. The AUCs for CircS predicting prevalent and incident LUTS/BPH were higher than those for MetS (0.582 vs. 0.556 for incident LUTS/BPH, P < 0.001; 0.574 vs. 0.561 for prevalent LUTS/BPH, P < 0.05).

Conclusions: The CircS predicts both incident and prevalent LUTS/BPH better than MetS.
TRPC5 Channel Inhibition Protects Podocytes in Puromycin-Aminonucleoside Induced Nephrosis Models
Authors: Zhou Yiming , Kim Choah , Pablo Juan Lorenzo B. , Zhang Fan , Jung Ji Yong , Xiao Li , Bazua-Valenti Silvana , Emani Maheswarareddy , Hopkins Corey R. , Weins Astrid , Greka Anna
Published: September 2021

Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of kidney disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated rats, human iPSC-derived podocytes, and kidney organoids. We first established that systemic administration of the TRPC5 inhibitor AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis rats, an established model of podocyte injury. TRPC5 current was recorded in the human iPSC-derived podocytes and was blocked by AC1903. PAN treatment caused podocyte injury in human iPSC-derived podocytes and kidney organoids. Inhibition of TRPC5 channels reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of TRPC5 channel inhibition in puromycin-aminonucleoside induced nephrosis models, highlighting the potential of this therapeutic strategy for patients.
Reliability of the Multiplex CytoBead CeliAK Immunoassay to Assess Anti-tTG IgA for Celiac Disease Screening
Authors: Abdukhakimova Diyora , Dossybayeva Kuanysh , Grechka Anna , Almukhamedova Zhaina , Boltanova Alyona , Kozina Larissa , Nurgaliyeva Kadisha , Hasanova Liliya , Tanko Matthew N. , Poddighe Dimitri
Published: September 2021

Background and Objective: The diagnosis of Celiac Disease (CD) is first based on the positivity for specific serological markers. The CytoBead CeliAK immunoassay simultaneously measures antibodies (IgA) directed to tissue transglutaminase (tTG), endomysium (EMA), and deamidated gliadin (DG), in addition to providing a control for total IgA levels. The aim of this study is to assess the reliability of this multiplex assay to detect anti-tTG IgA positive patients, compared with a conventional single-parameter enzyme-linked immunosorbent assay (ELISA).

Methods: Serum samples from 149 pediatric patients were assessed by both CytoBead CeliAK immunoassay and ELISA, in order to evaluate their concordance for the measurement of anti-tTG IgA.

Results: The measurement of anti-tTG IgA by CytoBead CeliAK immunoassay basically showed a complete concordance rate with the conventional and single-parameter ELISA, according to the respective cutoff values (3 U/ml and 10 U/ml).

Conclusions: Our comparative analysis demonstrates a substantial equivalency between multiplex CytoBead CeliAK assay and the single-parameter conventional ELISA to assess anti-tTG IgA antibody in the context of the screening for CD in children. Importantly, CytoBead CeliAK assay could present some preanalytic, analytic, and economic advantages.
Taxonomy and Phylogeny of the Dileptid Ciliate Genus Paradileptus (Protista: Ciliophora), With a Brief Review and Redescriptions of Two Species Isolated From a Wetland in Northern China
Authors: Chi Yong , Wang Zhe , Lu Borong , Ma Honggang , Mu Changjun , Warren Alan , Zhao Yan
Published: September 2021

Members of the genus Paradileptus are apex predators in microbial food webs. They are often encountered in freshwater biotopes and have been used in research on water quality monitoring and ecology. Nevertheless, our understanding of the biodiversity of Paradileptus, especially its ecological and genetic diversities, is very poor which hinders our ability to understand the ecosystem services it provides. The present study gives a detailed account of two Chinese populations of Paradileptus elephantinus and P. conicus including their living morphology, infraciliature, and molecular phylogenies based on 18S, 5.8S, and ITS ribosomal DNA sequences. The phylogenetic relationships between these two species and other rhynchostomatians are investigated. We also explore the potential contribution of differentiation of the proboscis (e.g., extrusomes, dorsal brush, and differentiated kineties) to niche partitioning and speciation in Paradileptus. The global distribution of Paradileptus is summarized based on published data. Finally, a key to the identification of the valid species of Paradileptus is provided.
Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments
Authors: Martini Caroline Lopes , Coronado Amada Zambrana , Melo Maria Celeste Nunes , Gobbi Clarice Neffa , Lopez Úrsula Santos , de Mattos Marcos Correa , Amorim Thais Tavares , Botelho Ana Maria Nunes , Vasconcelos Ana Tereza Ribeiro , Almeida Luiz Gonzaga Paula , Planet Paul J. , Zingali Russolina Benedeta , Figueiredo Agnes Marie Sá , Ferreira-Carvalho Bernadete Teixeira
Published: September 2021

Streptococcus pyogenes (group A Streptococcus-GAS) is an important pathogen for humans. GAS has been associated with severe and invasive diseases. Despite the fact that these bacteria remain universally susceptible to penicillin, therapeutic failures have been reported in some GAS infections. Many hypotheses have been proposed to explain these antibiotic-unresponsive infections; however, none of them have fully elucidated this phenomenon. In this study, we show that GAS strains have the ability to form antimicrobial persisters when inoculated on abiotic surfaces to form a film of bacterial agglomerates (biofilm-like environment). Our data suggest that efflux pumps were possibly involved in this phenomenon. In fact, gene expression assays by real-time qRT-PCR showed upregulation of some genes associated with efflux pumps in persisters arising in the presence of penicillin. Phenotypic reversion assay and whole-genome sequencing indicated that this event was due to non-inherited resistance mechanisms. The persister cells showed downregulation of genes associated with protein biosynthesis and cell growth, as demonstrated by gene expression assays. Moreover, the proteomic analysis revealed that susceptible cells express higher levels of ribosome proteins. It is remarkable that previous studies have reported the recovery of S. pyogenes viable cells from tissue biopsies of patients presented with GAS invasive infections and submitted to therapy with antibiotics. The persistence phenomenon described herein brings new insights into the origin of therapeutic failures in S. pyogenes infections. Multifactorial mechanisms involving protein synthesis inhibition, cell growth impairment and efflux pumps seem to play roles in the formation of antimicrobial persisters in S. pyogenes.
Morphological and Genomic Features of the New Klosneuvirinae Isolate Fadolivirus IHUMI-VV54
Authors: Andreani Julien , Schulz Frederik , Di Pinto Fabrizio , Levasseur Anthony , Woyke Tanja , La Scola Bernard
Published: September 2021

Since the discovery of Mimivirus, viruses with large genomes encoding components of the translation machinery and other cellular processes have been described as belonging to the nucleocytoplasmic large DNA viruses. Recently, genome-resolved metagenomics led to the discovery of more than 40 viruses that have been grouped together in a proposed viral subfamily named Klosneuvirinae. Members of this group had genomes of up to 2.4Mb in size and featured an expanded array of translation system genes. Yet, despite the large diversity of the Klosneuvirinae in metagenomic data, there are currently only two isolates available. Here, we report the isolation of a novel giant virus known as Fadolivirus from an Algerian sewage site and provide morphological data throughout its replication cycle in amoeba and a detailed genomic characterization. The Fadolivirus genome, which is more than 1.5Mb in size, encodes 1,452 predicted proteins and phylogenetic analyses place this viral isolate as a near relative of the metagenome assembled Klosneuvirus and Indivirus. The genome encodes for 66 tRNAs, 23 aminoacyl-tRNA synthetases and a wide range of transcription factors, surpassing Klosneuvirus and other giant viruses. The Fadolivirus genome also encodes putative vacuolar-type proton pumps with the domains D and A, potentially constituting a virus-derived system for energy generation. The successful isolation of Fadolivirus will enable future hypothesis-driven experimental studies providing deeper insights into the biology of the Klosneuvirinae.
The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases
Authors: Olehnovics Edgar , Yin Junqi , Pérez Adrià , De Fabritiis Gianni , Bonomo Robert A. , Bhowmik Debsindhu , Haider Shozeb
Published: September 2021

Class A β-lactamases are known for being able to rapidly gain broad spectrum catalytic efficiency against most β-lactamase inhibitor combinations as a result of elusively minor point mutations. The evolution in class A β-lactamases occurs through optimisation of their dynamic phenotypes at different timescales. At long-timescales, certain conformations are more catalytically permissive than others while at the short timescales, fine-grained optimisation of free energy barriers can improve efficiency in ligand processing by the active site. Free energy barriers, which define all coordinated movements, depend on the flexibility of the secondary structural elements. The most highly conserved residues in class A β-lactamases are hydrophobic nodes that stabilize the core. To assess how the stable hydrophobic core is linked to the structural dynamics of the active site, we carried out adaptively sampled molecular dynamics (MD) simulations in four representative class A β-lactamases (KPC-2, SME-1, TEM-1, and SHV-1). Using Markov State Models (MSM) and unsupervised deep learning, we show that the dynamics of the hydrophobic nodes is used as a metastable relay of kinetic information within the core and is coupled with the catalytically permissive conformation of the active site environment. Our results collectively demonstrate that the class A enzymes described here, share several important dynamic similarities and the hydrophobic nodes comprise of an informative set of dynamic variables in representative class A β-lactamases.
Rhizosphere-Associated Microbiomes of Rice (Oryza sativa L.) Under the Effect of Increased Nitrogen Fertilization
Authors: Dong Hangyu , Fan Shuxiu , Sun Haoyuan , Chen Conglin , Wang Aixin , Jiang Linlin , Ma Dianrong
Published: September 2021

Crops assemble and rely on rhizosphere-associated microbiomes for plant nutrition, which is crucial to their productivity. Historically, excessive nitrogen fertilization did not result in continuously increasing yields but rather caused environmental issues. A comprehensive understanding should be developed regarding the ways in which crops shape rhizosphere-associated microbiomes under conditions of increased nitrogen fertilization. In this study, we applied 16S and 18S ribosomal RNA gene profiling to characterize bacterial and fungal communities in bulk and rhizosphere soil of rice subjected to three levels of nitrogen fertilization for 5 years. Soil biochemical properties were characterized, and carbon-, nitrogen-, and phosphorus-related soil enzyme activities were investigated, by assays. Increasing nitrogen fertilization led to a decreasing trend in the variation of microbial community structures and demonstrated a more definite influence on fungal rather than bacterial community compositions and functions. Changes in the level of nitrogen fertilization significantly affected chemical properties such as soil pH, nutrient content, and microbial biomass levels in both rhizosphere and bulk soil. Soil enzyme activity levels varied substantially across nitrogen fertilization intensities and correlated more with the fungal than with the bacterial community. Our results indicated that increased nitrogen input drives alterations in the structures and functions of microbial communities, properties of soil carbon, nitrogen, and phosphorus, as well as enzyme activities. These results provide novel insights into the associations among increased nitrogen input, changes in biochemical properties, and shifts in microbial communities in the rhizosphere of agriculturally intensive ecosystems.
Decoding Partner Specificity of Opioid Receptor Family
Authors: Barreto Carlos A. V. , Baptista Salete J. , Preto António J. , Silvério Daniel , Melo Rita , Moreira Irina S.
Published: September 2021

This paper describes an exciting big data analysis compiled in a freely available database, which can be applied to characterize the coupling of different G-Protein coupled receptors (GPCRs) families with their intracellular partners. Opioid receptor (OR) family was used as case study in order to gain further insights into the physiological properties of these important drug targets, known to be associated with the opioid crisis, a huge socio-economic issue directly related to drug abuse. An extensive characterization of all members of the ORs family (μ (MOR), δ (DOR), κ (KOR), nociceptin (NOP)) and their corresponding binding partners (ARRs: Arr2, Arr3; G-protein: Gi1, Gi2, Gi3, Go, Gob, Gz, Gq, G11, G14, G15, G12, Gssh, Gslo) was carried out. A multi-step approach including models’ construction (multiple sequence alignment, homology modeling), complex assembling (protein complex refinement with HADDOCK and complex equilibration), and protein-protein interface characterization (including both structural and dynamics analysis) were performed. Our database can be easily applied to several GPCR sub-families, to determine the key structural and dynamical determinants involved in GPCR coupling selectivity.
Family and Community Support, Brain-Derived Neurotrophic Factor, and Cognitive Performance in Older Adults: Findings From the Health, Wellbeing and Aging Study Population-Based Cohort
Authors: Souza-Talarico Juliana Nery , Bromberg Elke , Santos Jair Licio Ferreira , Freitas Betania Souza , Silva Diego Ferreira , Duarte Yeda Aparecida Oliveira
Published: September 2021

Background: Social networks can modulate physiological responses, protects against the detrimental consequences of prolonged stress, and enhance health outcomes. Family ties represent an essential source of social networks among older adults. However, the impact of family support on cognitive performance and the biological factors influencing that relationship is still unclear. We aimed to determine the relationship between family support, cognitive performance and BDNF levels.

Methods: Cross-sectional data from three-hundred, eight-six individuals aged on average 60 years enrolled in the Health, Wellbeing and Aging Study (SABE), a population-cohort study, were assessed for family support, community support and cognitive performance. Structural and functional family support was evaluated based on family size and interactions allied to scores in the Family APGAR questionnaire. Community assistance (received or provided) assessed the community support. Cognitive performance was determined using the Mini-Mental State Examination (MMSE), verbal fluency (animals per minute) and backward digital span. Blood samples were obtained to determine BDNF levels.

Results: Multivariate analysis showed that functional family support, but not structural, was associated with higher MMSE, verbal fluency and digit span scores, even controlling for potential cofounders (p < 0.001). Providing support to the community, rather than receiving support from others, was associated with better cognitive performance (p < 0.001). BDNF concentration was not associated with community support, family function, or cognitive performance.

Conclusion: These findings suggest that emotional components of functional family and community support (e.g., loving and empathic relationship) may be more significant to cognitive health than size and frequency of social interactions.
Surgical Clipping of Previously Coiled Recurrent Intracranial Aneurysms: A Single-Center Experience
Authors: Zheng Yongtao , Zheng Lili , Sun Yuhao , Lin Dong , Wang Baofeng , Sun Qingfang , Bian Liuguan
Published: September 2021

Objective: This study reviews our experiences in surgical clipping of previously coiled aneurysms, emphasizing on recurrence mechanism of intracranial aneurysms (IAs) and surgical techniques for different types of recurrent IAs.

Method: We performed a retrospective study on 12 patients who underwent surgical clipping of aneurysms following endovascular treatment between January 2010 and October 2020. The indications for surgery, surgical techniques, and clinical outcomes were analyzed.

Result: Twelve patients with previously coiled IAs were treated with clipping in this study, including nine females and three males. The reasons for the patients having clipping were as follows: early surgery (treatment failure in two patients, postoperative early rebleeding in one patient, and intraprocedural aneurysm rupture during embolization in one patient) and late surgery (aneurysm recurrence in five patients, SAH in one, mass effect in one, and aneurysm regrowth in one). All aneurysms were clipped directly, and coil removal was performed in four patients. One patient died (surgical mortality, 8.3%), 1 patient (8.3%) experienced permanent neurological morbidity, and the remaining 10 patients (83.4%) had good outcomes. Based on our clinical data and previous studies, we classified the recurrence mechanism of IAs into coil compaction, regrowth, coil migration, and coil loosening. Then, we elaborated the specific surgical planning and timing of surgery depending on the recurrence type of IAs.

Conclusion: Surgical clipping can be a safe and effective treatment strategy for the management of recurrent coiled IAs, with acceptable morbidity and mortality in properly selected cases. Our classification of recurrent coiled aneurysms into four types helps to assess the optimal surgical approach and the associated risks in managing them.
Mapping Epileptic Networks Using Simultaneous Intracranial EEG-fMRI
Authors: Chaudhary Umair J. , Centeno Maria , Carmichael David W. , Diehl Beate , Walker Matthew C. , Duncan John S. , Lemieux Louis
Published: September 2021

Background:Potentially curative epilepsy surgery can be offered if a single, discrete epileptogenic zone (EZ) can be identified. For individuals in whom there is no clear concordance between clinical localization, scalp EEG, and imaging data, intracranial EEG (icEEG) may be needed to confirm a predefined hypothesis regarding irritative zone (IZ), seizure onset zone (SOZ), and EZ prior to surgery. However, icEEG has limited spatial sampling and may fail to reveal the full extent of epileptogenic network if predefined hypothesis is not correct. Simultaneous icEEG-fMRI has been safely acquired in humans and allows exploration of neuronal activity at the whole-brain level related to interictal epileptiform discharges (IED) captured intracranially.

Methods:We report icEEG-fMRI in eight patients with refractory focal epilepsy who had resective surgery and good postsurgical outcome. Surgical resection volume in seizure-free patients post-surgically reflects confirmed identification of the EZ. IEDs on icEEG were classified according to their topographic distribution and localization (Focal, Regional, Widespread, and Non-contiguous). We also divided IEDs by their location within the surgical resection volume [primary IZ (IZ1) IED] or outside [secondary IZ (IZ2) IED]. The distribution of fMRI blood oxygen level-dependent (BOLD) changes associated with individual IED classes were assessed over the whole brain using a general linear model. The concordance of resulting BOLD map was evaluated by comparing localization of BOLD clusters with surgical resection volume. Additionally, we compared the concordance of BOLD maps and presence of BOLD clusters in remote brain areas: precuneus, cuneus, cingulate, medial frontal, and thalamus for different IED classes.

Results:A total of 38 different topographic IED classes were identified across the 8 patients: Focal (22) and non-focal (16, Regional = 9, Widespread = 2, Non-contiguous = 5). Twenty-nine IEDs originated from IZ1 and 9 from IZ2. All IED classes were associated with BOLD changes. BOLD maps were concordant with the surgical resection volume for 27/38 (71%) IED classes, showing statistical global maximum BOLD cluster or another cluster in the surgical resection volume. The concordance of BOLD maps with surgical resection volume was greater (p< 0.05) for non-focal (87.5%, 14/16) as compared to Focal (59%, 13/22) IED classes. Additionally, BOLD clusters in remote cortical and deep brain areas were present in 84% (32/38) of BOLD maps, more commonly (15/16; 93%) for non-focal IED-related BOLD maps.

Conclusions:Simultaneous icEEG-fMRI can reveal BOLD changes at the whole-brain level for a wide range of IEDs on icEEG. BOLD clusters within surgical resection volume and remote brain areas were more commonly seen for non-focal IED classes, suggesting that a wider hemodynamic network is at play.
AMPA Receptors: A Key Piece in the Puzzle of Memory Retrieval
Authors: Pereyra Magdalena , Medina Jorge H.
Published: September 2021

Retrieval constitutes a highly regulated and dynamic phase in memory processing. Its rapid temporal scales require a coordinated molecular chain of events at the synaptic level that support transient memory trace reactivation. AMPA receptors (AMPAR) drive the majority of excitatory transmission in the brain and its dynamic features match the singular fast timescales of memory retrieval. Here we provide a review on AMPAR contribution to memory retrieval regarding its dynamic movements along the synaptic compartments, its changes in receptor number and subunit composition that take place in activity dependent processes associated with retrieval. We highlight on the differential regulations exerted by AMPAR subunits in plasticity processes and its impact on memory recall.
The Role of Reproductive Hormones in Sex Differences in Sleep Homeostasis and Arousal Response in Mice
Authors: Choi Jinhwan , Kim Staci J. , Fujiyama Tomoyuki , Miyoshi Chika , Park Minjeong , Suzuki-Abe Haruka , Yanagisawa Masashi , Funato Hiromasa
Published: September 2021

There are various sex differences in sleep/wake behaviors in mice. However, it is unclear whether there are sex differences in sleep homeostasis and arousal responses and whether gonadal hormones are involved in these sex differences. Here, we examined sleep/wake behaviors under baseline condition, after sleep deprivation by gentle handling, and arousal responses to repeated cage changes in male and female C57BL/6 mice that are hormonally intact, gonadectomized, or gonadectomized with hormone supplementation. Compared to males, females had longer wake time, shorter non-rapid eye movement sleep (NREMS) time, and longer rapid eye movement sleep (REMS) episodes. After sleep deprivation, males showed an increase in NREMS delta power, NREMS time, and REMS time, but females showed a smaller increase. Females and males showed similar arousal responses. Gonadectomy had only a modest effect on homeostatic sleep regulation in males but enhanced it in females. Gonadectomy weakened arousal response in males and females. With hormone replacement, baseline sleep in gonadectomized females was similar to that of intact females, and baseline sleep in gonadectomized males was close to that of intact males. Gonadal hormone supplementation restored arousal response in males but not in females. These results indicate that male and female mice differ in their baseline sleep–wake behavior, homeostatic sleep regulation, and arousal responses to external stimuli, which are differentially affected by reproductive hormones.
Sex Differences in the Nicotinic Acetylcholine Receptor System of Rodents: Impacts on Nicotine and Alcohol Reward Behaviors
Authors: Moen Janna K. , Lee Anna M.
Published: September 2021

Alcohol and nicotine are the two most widely used and misused drugs around the world, and co-consumption of both substances is highly prevalent. Multiple lines of evidence show a profound effect of sex in many aspects of alcohol and nicotine reward, with women having more difficulty quitting smoking and showing a faster progression toward developing alcohol use disorder compared with men. Both alcohol and nicotine require neuronal nicotinic acetylcholine receptors (nAChRs) to elicit rewarding effects within the mesolimbic system, representing a shared molecular pathway that likely contributes to the frequent comorbidity of alcohol and nicotine dependence. However, the majority of preclinical studies on the mechanisms of alcohol and nicotine reward behaviors utilize only male rodents, and thus our understanding of alcohol and nicotine neuropharmacology relies heavily on male data. As preclinical research informs the development and refinement of therapies to help patients reduce drug consumption, it is critical to understand the way biological sex and sex hormones influence the rewarding properties of alcohol and nicotine. In this review, we summarize what is known about sex differences in rodent models of alcohol and nicotine reward behaviors with a focus on neuronal nAChRs, highlighting exciting areas for future research. Additionally, we discuss the way circulating sex hormones may interact with neuronal nAChRs to influence reward-related behavior.
Individualized Target Fortification of Breast Milk: Optimizing Macronutrient Content Using Different Fortifiers and Approaches
Authors: Fusch Stephanie , Fusch Gerhard , Yousuf Efrah I. , Rochow Markus , So Hon Yiu , Fusch Christoph , Rochow Niels
Published: September 2021

Background: Native breast milk composition displays significant inter- and intra-individual variation which persists after standard fortification with fixed doses and challenges target fortification. This study aims to analyze the macronutrient composition of different commercially available fortifiers and the effect of different fortification strategies on nutritional intake of preterm infants.

Methods: In 103 preterm infants, native breast milk samples were collected from 24-h feeding batches (n = 3,338) and fat, protein and carbohydrate contents were analyzed. Nutrient content was compared for breast milk that had undergone either (i) standard fortification, (ii) targeted fortification, (iii) selective batching according to breast milk composition, or (iv) partial lyophilization. For (i) eight commercially available standard fortifiers were tested. Targeted fortification (ii) involved the addition of single component modulars of either protein, fat or carbohydrates to standard fortified breast milk. Using a mathematical growth model, the combined effect of protein, fat and carbohydrate intake on growth was assessed. The best composition of standard fortifiers as the initial step for target fortification was explored assuming three clinical scenarios for milk analysis.

Results: Macronutrient content was highly variable between native breast milk samples, and this variation was still present after standard fortification, however at elevated macronutrient levels. Standard fortification, breast milk batching, as well as partial lyophilization of human milk resulted in deficient and imbalanced enteral intakes in a significant proportion of infants. Target fortification reduced this variation in a, respectively, higher percentage of samples. The effect size was dependent on the number of measurements per week. The optimum composition of standard fortifiers was dependent on the clinical scenario (measurement frequency) for target fortification.

Conclusions: To provide precise and accurate intakes of macronutrients, breast milk should be target fortified. Standard fortified breast milk can result in excess above recommended intakes of some macronutrients which limits the efficiency of target fortification. Standard fortifiers with improved composition are needed for target fortification.
Fungal Contamination and Aflatoxin B1 Detected in Hay for Dairy Cows in South Italy
Authors: Ceniti Carlotta , Costanzo Nicola , Spina Anna Antonella , Rodolfi Marinella , Tilocca Bruno , Piras Cristian , Britti Domenico , Morittu Valeria Maria
Published: September 2021

The growth of filamentous fungi on fodder is recognized as responsible for fungal deterioration and mycotoxin contamination of the plant mass leads to economic losses in the dairy cow production system. Mycotoxin contamination has significant implications for human and animal health and is one of the major concerns in the food and feed chain. This research provides an insight into the variety of viable molds (i.e., filamentous microfungi) that can be isolated from hay produced in South Italy and destined to dairy cows. On different lots of hay (n= 55) collected from 20 dairy farms, a total of 33 different fungal species were identified. The most representative wasCladosporium cladosporioides(n= 46, 84%) followed byAlternaria alternata(n= 25, 45%), andRhizopus stolonifer(n= 24, 44%). The species most closely related to aflatoxin (AF) contamination,Aspergillus flavus, was often isolated (n= 11, 20%). Regarding AF detection, all the hay samples were found to be scarcely contaminated by AFB1 and showed values from 0.0020 to 0.0077 mg/kg, below the limits established by European Union (EU legislation) (0.02 mg/kg). None of the samples were positive forAspergilliaand tested for AFB1 showed results exceeding established limits. Additionally, hay with moisture between 15.0 and 19.2% or crude ash on dry matter content ranging from 14.0 to 15.5% reported an increased presence of AFB1 (p< 0.05) compared to the other samples. All the analyzed hay samples, besides the presence of molds, can be considered safe for the presence of AFB1. Prevention of mold spoilage is mandatory to reduce the exposure of humans and animals to mycotoxins.
Comparison of PD-1 Inhibitors in Patients With Advanced Esophageal Squamous Cell Carcinoma in the Second-Line Setting
Authors: Zhou Yi-Xin , Chen Ping , Sun Yu-Ting , Zhang Bei , Qiu Miao-Zhen
Published: September 2021

Background

KEYNOTE-181, ATTRACTION-3, and ESCORT trials have opened the era of programmed death 1 (PD-1) inhibitors in the second-line therapy for esophageal squamous cell carcinoma (ESCC). There is no head-to-head comparison of pembrolizumab vs. nivolumab vs. camrelizumab in the second-line setting for ESCC. We performed an indirect comparison to explore the optimal choice of immune checkpoint inhibitor (ICI) for advanced ESCC.

Methods

Patients in ATTRACTION-3 and ESCORT were all squamous carcinoma, while KEYNOTE-181 enrolled both adenocarcinoma and squamous carcinoma patients. We only extract information of patients with squamous carcinoma from KEYNOTE 181 study and all the patients from ATTRACTION-3 and ESCORT. The main clinical outcomes for this study were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs).

Results

Indirect analysis showed similar survival benefit among three PD-1 inhibitors. Nivolumab was comparable with pembrolizumab in most subgroups except that nivolumab was slightly better for patients with performance status (PS) score of 1 [HRnivo/pembro: 0.68 (95% confidence interval (CI): 0.45–1.02], p = 0.07). Compared with nivolumab indirectly, pembrolizumab and camrelizumab had better PFS [HRpembro/nivo: 0.85 (95% CI: 0.63–1.14), p = 0.29; HRcam/nivo: 0.64 (95% CI: 0.47–0.87), p = 0.004] and significantly higher ORR [RRpembro/nivo: 2.51 (95% CI: 1.22–5.15), p = 0.01; RRcam/nivo: 3.52 (95% CI: 1.73–7.18), p = 0.001]. Compared with camrelizumab indirectly, pembrolizumab had slightly worse PFS [HRpembro/cam: 1.33 (95% CI: 0.99–1.79), p = 0.057] and comparable ORR [RRpembro/cam: 0.71 (95% CI: 0.32–1.60; p = 0.41)]. Camrelizumab had a significantly higher rate of all grade TRAEs than both pembrolizumab and nivolumab.

Conclusions

Combining the safety and potential survival benefit, we recommend nivolumab for ESCC patients with PS score of 1 and pembrolizumab or camrelizumab for patients with better PS and seeking for higher efficacy or longer PFS.
Identification of Gender-Specific Molecular Differences in Glioblastoma (GBM) and Low-Grade Glioma (LGG) by the Analysis of Large Transcriptomic and Epigenomic Datasets
Authors: Khan Md Tipu , Prajapati Bharat , Lakhina Simran , Sharma Mridula , Prajapati Sachin , Chosdol Kunzang , Sinha Subrata
Published: September 2021

Differences in the incidence and outcome of glioma between males and females are well known, being more striking for glioblastoma (GB) than low-grade glioma (LGG). The extensive and well-annotated data in publicly available databases enable us to analyze the molecular basis of these differences at a global level. Here, we have analyzed The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases to identify molecular indicators for these gender-based differences by different methods. Based on the nature of data available/accessible, the transcriptomic profile was studied in TCGA by using DeSeq2 and in CGGA by T-test, after correction based. Only IDH1 wild-type tumors were studied in CGGA. Using weighted gene co-expression network analysis (WGCNA), network analysis was done, followed by the assessment of modular differential connectivity. Differentially affected signaling pathways were identified. The gender-based effects of differentially expressed genes on survival were determined. DNA methylation was studied as an indicator of gender-based epigenetic differences. The results clearly showed gender-based differences in both GB and LGG, whatever method or database was used. While there were differences in the results obtained between databases and methods used, some major signaling pathways such as Wnt signaling and pathways involved in immune processes and the adaptive immune response were common to different assessments. There was also a differential gender-based influence of several genes on survival. Also, the autosomal genes NOX, FRG1BP, and AL354714.2 and X-linked genes such as PUDP, KDM6A, DDX3X, and SYAP1 had differential DNA methylation and expression profile in male and female GB, while for LGG, these included autosomal genes such as CNIH3 and ANKRD11 and X-linked genes such as KDM6A, MAOB, and EIF2S3. Some, such as FGF13 and DDX3X, have earlier been shown to have a role in tumor behavior, though their dimorphic effects in males and females have not been identified. Our study thus identifies several crucial differences between male and female glioma, which could be validated further. It also highlights that molecular studies without consideration of gender can obscure critical elements of biology and emphasizes the importance of parallel but separate analyses of male and female glioma.