bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Cardiac Dysfunction Based on Killip Classification on Gastrointestinal Bleeding in Acute Myocardial Infarction
Authors: Liu Yu , Feng De-Jing , Wang Le-Feng , Liu Li-Hong , Ren Zheng-Hong , Hao Jian-Yu , Li Kui-Bao , Chen Mu-Lei
Published: June 2022

Background

Owing to limited data, the effect of cardiac dysfunction categorized according to the Killip classification on gastrointestinal bleeding (GIB) in patients with acute myocardial infarction (AMI) is unclear. The present study aimed to investigate the impact of cardiac dysfunction on GIB in patients with AMI and to determine if patients in the higher Killip classes are more prone to it.

Methods

This retrospective study was comprised of patients with AMI who were admitted to the cardiac intensive care unit in the Heart Center of the Beijing Chaoyang Hospital between December 2010 and June 2019. The in-hospital clinical data of the patients were collected. Both GIB and cardiac function, according to the Killip classification system, were confirmed using the discharge diagnosis of the International Classification of Diseases, Tenth Revision coding system. Univariate and multivariate conditional logistic regression models were constructed to test the association between GIB and the four Killip cardiac function classes.

Results

In total, 6,458 patients with AMI were analyzed, and GIB was diagnosed in 131 patients (2.03%). The multivariate logistic regression analysis showed that the risk of GIB was significantly correlated with the cardiac dysfunction [compared with the Killip class 1, Killip class 2’s odds ratio (OR) = 1.15, 95% confidence interval (CI): 0.73–1.08; Killip class 3’s OR = 2.63, 95% CI: 1.44–4.81; and Killip class 4’s OR = 4.33, 95% CI: 2.34–8.06].

Conclusion

This study demonstrates that the degree of cardiac dysfunction in patients with acute myocardial infarction is closely linked with GIB. The higher Killip classes are associated with an increased risk of developing GIB.
Genomic Insights of Enterococcus faecium UC7251, a Multi-Drug Resistant Strain From Ready-to-Eat Food, Highlight the Risk of Antimicrobial Resistance in the Food Chain
Authors: Belloso Daza Mireya Viviana , Milani Giovanni , Cortimiglia Claudia , Pietta Ester , Bassi Daniela , Cocconcelli Pier Sandro
Published: June 2022

The presence of multi-drug resistant (MDR) bacteria in ready-to-eat foods comprises a threat for public health due to their ability to acquire and transfer antibiotic-resistant determinants that could settle in the microbiome of the human digestive tract. In this study, Enterococcus faecium UC7251 isolated from a fermented dry sausage was characterized phenotypically and genotypically to hold resistance to multiple antibiotics including aminoglycosides, macrolides, β-lactams, and tetracyclines. We further investigated this strain following a hybrid sequencing and assembly approach (short and long reads) and determined the presence of various mobile genetic elements (MGEs) responsible of horizontal gene transfer (HGT). On the chromosome of UC7251, we found one integrative and conjugative element (ICE) and a conjugative transposon Tn916-carrying tetracycline resistance. UC7251 carries two plasmids: one small plasmid harboring a rolling circle replication and one MDR megaplasmid. The latter was identified as mobilizable and containing a putative integrative and conjugative element-like region, prophage sequences, insertion sequences, heavy-metal resistance genes, and several antimicrobial resistance (AMR) genes, confirming the phenotypic resistance characteristics. The transmissibility potential of AMR markers was observed through mating experiments, where Tn916-carried tetracycline resistance was transferred at intra- and inter-species levels. This work highlights the significance of constant monitoring of products of animal origin, especially RTE foodstuffs, to stimulate the development of novel strategies in the race for constraining the spread of antibiotic resistance.
The Effect of the Ratio of Gamma Aminobutyric Acid-Producing Saccharomyces cerevisiae DL6–20 and Kluyveromyces marxianus B13–5 Addition on Cheese Quality
Authors: Li Shan , Zhang Yan , Li Xu , Yin Pingping , Wang Tengbin , Li Yandie , Zhang Kaili , Sheng Huayang , Lu Shiling , Ji Hua , Fan Zhexin , Li Baokun
Published: June 2022

Kazakh cheese is a traditional dairy product in Xinjiang, China. The function and potential probiotic characteristics of Saccharomyces cerevisiae DL6–20 and Kluyveromyces marxianus B13–5 in Kazakh cheese and its contribution to cheese fermentation was studied. In this study, the effect of the addition ratio of gamma aminobutyric acid (GABA)-producing S. cerevisiae DL6–20 and K. marxianus B13–5 on cheese quality was investigated. Cheeses were prepared by fermentations with a total of six treatments: comercial culture alone as control (CS), a combination with one yeast, either; K. marxianus B13–5 (CSM); S. cerevisiae DL6–20 (CSS); and three different proportions of this two yeasts (CSM:CSS 1:1, 1:2, 2:1). We measured the GABA content of cheese, as well as basic physical and chemical indicators, microbial content, free amino acid (FAA) content, texture, and flavor compound content. The total FAA content of mixed bacteria fermentation was higher than that of the single bacteria alone. The GABA content CSM:CSS 1:2 GABA content was 0.114 g/100 g, CSM:CSS 2:1 GABA content was 0.12 g/100 g, CSM:CSS1:1 content of GABA produced in the late ripening period of cheese was the highest, reaching 0.189 g/100 g and the number of LAB and yeasts in CSM:CSS 1:1 was higher than that of other cheeses. The mixed-strain fermentation generally produced cheeses with a higher protein content than that of the single-strain fermentation in the late stage of the maturation process, especially the protein content of CSM:CSS 1:1 during the ripening period, when the protein content was highest at day 50. CSM:CSS 1:1 had a low moisture content, making it easy to store. With the exception of water and protein content, there is no significant difference in other physical and chemical indicators. CSM:CSS 1:1 contributed to the formation of cheese texture. In addition, multivariate statistical analysis indicated that mixed-strain fermentation was beneficial to the production of cheese aroma, with the aroma production performance of CSM:CSS 1:2 and CSM:CSS 2:1 found to be better than that of CSM: CSS 1:1.
Integrated Metabolomic, Molecular Networking, and Genome Mining Analyses Uncover Novel Angucyclines From Streptomyces sp. RO-S4 Strain Isolated From Bejaia Bay, Algeria
Authors: Ouchene Rima , Stien Didier , Segret Juliette , Kecha Mouloud , Rodrigues Alice M. S. , Veckerlé Carole , Suzuki Marcelino T.
Published: June 2022

Multi-omic approaches have recently made big strides toward the effective exploration of microorganisms, accelerating the discovery of new bioactive compounds. We combined metabolomic, molecular networking, and genomic-based approaches to investigate the metabolic potential of theStreptomycessp. RO-S4 strain isolated from the polluted waters of Bejaia Bay in Algeria. Antagonistic assays againstmethicillin-resistant Staphylococcus aureuswith RO-S4 organic extracts showed an inhibition zone of 20 mm by using the agar diffusion method, and its minimum inhibitory concentration was 16 μg/ml. A molecular network was created using GNPS and annotated through the comparison of MS/MS spectra against several databases. The predominant compounds in the RO-S4 extract belonged to the angucycline family. Three compounds were annotated as known metabolites, while all the others were putatively new to Science. Notably, all compounds had fridamycin-like aglycones, and several of them had a lactonized D ring analogous to that of urdamycin L. The whole genome ofStreptomycesRO-S4 was sequenced to identify the biosynthetic gene cluster (BGC) linked to these angucyclines, which yielded a draft genome of 7,497,846 bp with 72.4% G+C content. Subsequently, a genome mining analysis revealed 19 putative biosynthetic gene clusters, including a grincamycin-like BGC with high similarity to that ofStreptomycessp. CZN-748, that was previously reported to also produce mostly open fridamycin-like aglycones. As the ring-opening process leading to these compounds is still not defined, we performed a comparative analysis with other angucycline BGCs and advanced some hypotheses to explain the ring-opening and lactonization, possibly linked to the uncoupling between the activity ofGcnEandGcnMhomologs in the RO-S4 strain. The combination of metabolomic and genomic approaches greatly improved the interpretation of the metabolic potential of the RO-S4 strain.
NLR, A Convenient Early-Warning Biomarker of Fatal Outcome in Patients With Severe Fever With Thrombocytopenia Syndrome
Authors: Wei Yuanyuan , Wang Zilong , Kang Luyang , He Lingling , Sheng Nan , Qin Jiangfeng , Ma Shuangshuang , Xu Honghai , Hu Lifen , Zou Guizhou , Gao Yufeng , Li Jiabin
Published: June 2022

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that greatly threatens public health. This study aimed to examine a convenient early-warning biomarker of fatal outcomes in patients with SFTS to reduce mortality.

Methods

A retrospective cohort study was performed, and patients with confirmed SFTS were enrolled in the top two hospitals in Anhui Province, China from 1 May 2016 to 31 October 2019. The clinical symptoms, laboratory indicators, and treatment data of patients with SFTS were evaluated. All patients with SFTS were followed up till 28 days from the start of admission. The laboratory indicators that could be used to predict the fatal outcome were identified.

Results

A total of 228 patients with SFTS were enrolled, 177 patients were enrolled in the survival group, and 51 patients in the death group. The median age of all 228 patients with SFTS was 63 years. Five laboratory indicators (SFTSV viral load, neutrophil to lymphocyte ratio (NLR), aspartate transaminase (AST)/alanine aminotransferase (ALT), ALT, and blood urea nitrogen (BUN)) were identified as the predicting factors of the fatal outcome of patients with SFTS. The area under the receiver operating characteristic (ROC) curve (AUC) of SFTSV viral load was the highest (0.919), then NLR (0.849), followed by AST/ALT (0.758), AST (0.738), and BUN (0.709). The efficacy of SFTVS viral load and NLR in predicting fatal outcomes was significantly higher than AST/ALT, AST, and BUN. The Kaplan–Meier survival curves show that the case fatality rate was significantly increased in patients whose SFTSV viral load was higher than 500,000 or NLR higher than 2.0. Gamma-globulin treatment showed a significant difference between the survival group and the death group, and the duration of gamma-globulin that had been proposed should not be <3 days.

Conclusion

The SFTSV viral load and NLR showed great efficacy in predicting the fatal outcome of patients with SFTS, and NLR is a convenient and efficient early-warning biomarker that helps healthcare workers focus on patients with high risks of fatal outcomes. The efficacy of gamma-globulin provided a new idea for the treatment of SFTS, which needs further analysis in future studies.
Exosomes as Theranostic Targets: Implications for the Clinical Prognosis of Aggressive Cancers
Authors: Gulati Richa , Nandi Dhruva , Sarkar Koustav , Venkataraman P. , Ramkumar K. M. , Ranjan Priya , Janardhanan Rajiv
Published: June 2022

Exosomes are extracellular vesicles produced by various cell types and extensively distributed in physiological fluids. Because of their significant role in cancer progression, they have been a focal point for the novel cancer therapy approach. Exosomes are highly efficient at transporting proteins, RNAs, and small drugs into cancer cells for therapeutic purposes. In addition to their prominent role as potential biomarkers for transporting targeted information from their progenitor cells, exosomes have also emerged as a new avenue for developing more effective clinical diagnostics and therapeutic techniques, also known as exosome theranostics. Lipids, proteins, and nucleic acids transported by exosomes were investigated as potential biomarkers for cancer diagnosis, prognosis, and future cancer treatment targets. The unique mechanism of exosomes and their therapeutic as well as diagnostic uses, also known as theranostic applications of exosomes in malignancies, are discussed in this review.
Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulated in Exercise in a Mouse Model of Parkinson’s Disease
Authors: Tong Weifang , Zhang Kunshan , Yao Hongkai , Li Lixi , Hu Yong , Zhang Jingxing , Song Yunping , Guan Qiang , Li Siguang , Sun Yi E. , Jin Lingjing
Published: June 2022

Background

Exercise plays an essential role in improving motor symptoms in Parkinson’s disease (PD), but the underlying mechanism in the central nervous system remains unclear.

Methods

Motor ability was observed after 12-week treadmill exercise on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. RNA-sequencing on four brain regions (cerebellum, cortex, substantia nigra (SN), and striatum) from control animals, MPTP-induced PD, and MPTP-induced PD model treated with exercise for 12 weeks were performed. Transcriptional networks on the four regions were further identified by an integrative network biology approach.

Results

The 12-week treadmill exercise significantly improved the motor ability of an MPTP-induced mouse model of PD. RNA-seq analysis showed SN and striatum were remarkably different among individual region’s response to exercise in the PD model. Especially, synaptic regulation pathways about axon guidance, synapse assembly, neurogenesis, synaptogenesis, transmitter transport-related pathway, and synaptic regulation genes, including Neurod2, Rtn4rl2, and Cd5, were upregulated in SN and striatum. Lastly, immunofluorescence staining revealed that exercise rescued the loss of TH+ synapses in the striatal region in PD mice, which validates the key role of synaptic regulation pathways in exercise-induced protective effects in vivo.

Conclusion

SN and striatum are important brain regions in which critical transcriptional changes, such as in synaptic regulation pathways, occur after the exercise intervention on the PD model.
Topologically Organized Networks in the Claustrum Reflect Functional Modularization
Authors: Ham Gao Xiang , Augustine George J.
Published: June 2022

Using genetic strategies and viral-based directional tracers, we investigated the topological location and output networks of claustrum (CLA) neuron populations projecting to either the retrosplenial cortex, primary motor cortex, or basolateral amygdala. We found that all three CLA neuron populations clearly reside in distinct topological locations within the CLA complex and project broadly to multiple downstream targets. Each neuron population projects to different targets, suggesting that each CLA subzone coordinates a unique set of brain-wide functions. Our findings establish that the claustrum complex encompasses at least three minimally overlapping networks that are compartmentalized into different topological subzones. Such modularity is likely to be important for CLA function.
Organizational Effects of Estrogens and Androgens on Estrogen and Androgen Receptor Expression in Pituitary and Adrenal Glands in Adult Male and Female Rats
Authors: Lagunas Natalia , Fernández-García José Manuel , Blanco Noemí , Ballesta Antonio , Carrillo Beatriz , Arevalo Maria-Angeles , Collado Paloma , Pinos Helena , Grassi Daniela
Published: June 2022

Sex steroid hormones, such as androgens and estrogens, are known to exert organizational action at perinatal periods and activational effects during adulthood on the brain and peripheral tissues. These organizational effects are essential for the establishment of biological axes responsible for regulating behaviors, such as reproduction, stress, and emotional responses. Estradiol (E2), testosterone, and their metabolites exert their biological action through genomic and non-genomic mechanisms, bounding to canonical receptors, such as estrogen receptor (ER)α, ERβ, and androgen receptor (AR) or membrane receptors, such as the G protein-coupled estrogen receptor (GPER), respectively. Expression of ERs and AR was found to be different between males and females both in the brain and peripheral tissues, suggesting a sex-dependent regulation of their expression and function. Therefore, studying the ERs and AR distribution and expression levels is key to understand the central and peripheral role of sex steroids in the establishment of sex-specific behaviors in males and females. We investigated the organizational effects of estrogens and androgens in the pituitary and adrenal glands of adult male and female rats. For this, selective blockade of AR with flutamide or 5α-reductase with finasteride or aromatase with letrozole during the first 5 days of life has been performed in male and female pups and then quantification of ERs and AR expression in both glands has been carried out in adulthood. Data show that inhibition of dihydrotestosterone (DHT) and E2 production during the first five postnatal days mainly decreases the ER expression in male to female values and AR expression in female to male levels in the pituitary gland and increases AR expression in female to male levels in the adrenal gland. In contrast, blocking the action of androgens differentially modulates the ERs in males and females and decreases AR in both males and females in both glands. Altogether, the results suggest that neonatal modifications of the androgen and estrogen pathways can potentially lead to permanent modifications of the neuroendocrine functions of the pituitary and adrenal glands in the adulthood of both sexes.
The Protective Effects of Zeaxanthin on Amyloid-β Peptide 1–42-Induced Impairment of Learning and Memory Ability in Rats
Authors: Li Xiaoying , Zhang Ping , Li Hongrui , Yu Huiyan , Xi Yuandi
Published: June 2022

Background and Objectives

Zeaxanthin (ZEA) as one of the biologically active phytochemicals presents a neuroprotective effect. Since ZEA may play its anti-oxidative role in neurodegenerative diseases including Alzheimer’s disease (AD), we hypothesized cognitive defects could be prevented or deferred by ZEA pre-treatment.

Methods and Study Design

All the rats were randomly divided into four groups (control, Aβ1–42, ZEA, and ZEA + Aβ groups). Learning and memory ability of rats, cerebrovascular ultrastructure changes, the redox state, endothelin-1 (ET-1) level, and amyloid-β peptide (Aβ) level in plasma and the Aβ transport receptors which are advanced glycation end products (RAGEs) and LDL receptor-related protein-1 (LRP-1) and interleukin-1β (IL-1β) expressions in the cerebrovascular tissue were measured in the present study.

Results

The escape latency and frequency of spanning the position of platform showed significant differences between the Aβ group and ZEA treatment groups. ZEA could prevent the ultrastructure changes of cerebrovascular tissue. In addition, ZEA also showed the protective effects on regulating redox state, restraining ET-1 levels, and maintaining Aβ homeostasis in plasma and cerebrovascular. Moreover, the disordered expressions of RAGE and LRP-1 and IL-1β induced by Aβ1–42 could be prevented by the pre-treatment of ZEA.

Conclusion

ZEA pre-treatment could prevent learning and memory impairment of rats induced by Aβ1–42. This neuroprotective effect might be attributable to the anti-oxidative and anti-inflammatory effects of ZEA on maintaining the redox state and reducing the Aβ level through regulating the Aβ transport receptors and inflammatory cytokine of the cerebrovascular tissue.
Phonological Working Memory Representations in the Left Inferior Parietal Lobe in the Face of Distraction and Neural Stimulation
Authors: Yue Qiuhai , Martin Randi C.
Published: June 2022

The neural basis of phonological working memory (WM) was investigated through an examination of the effects of irrelevant speech distractors and disruptive neural stimulation from transcranial magnetic stimulation (TMS). Embedded processes models argue that the same regions involved in speech perception are used to support phonological WM whereas buffer models assume that a region separate from speech perception regions is used to support WM. Thus, according to the embedded processes approach but not the buffer approach, irrelevant speech and TMS to the speech perception region should disrupt the decoding of phonological WM representations. According to the buffer account, decoding of WM items should be possible in the buffer region despite distraction and should be disrupted with TMS to this region. Experiment 1 used fMRI and representational similarity analyses (RSA) with a delayed recognition memory paradigm using nonword stimuli. Results showed that decoding of memory items in the speech perception regions (superior temporal gyrus, STG) was possible in the absence of distractors. However, the decoding evidence in the left STG was susceptible to interference from distractors presented during the delay period whereas decoding in the proposed buffer region (supramarginal gyrus, SMG) persisted. Experiment 2 examined the causal roles of the speech processing region and the buffer region in phonological WM performance using TMS. TMS to the SMG during the early delay period caused a disruption in recognition performance for the memory nonwords, whereas stimulations at the STG and an occipital control region did not affect WM performance. Taken together, results from the two experiments are consistent with predictions of a buffer model of phonological WM, pointing to a critical role of the left SMG in maintaining phonological representations.
Improved Interpretability of Brain-Behavior CCA With Domain-Driven Dimension Reduction
Authors: Liu Zhangdaihong , Whitaker Kirstie J. , Smith Stephen M. , Nichols Thomas E.
Published: June 2022

Canonical Correlation Analysis (CCA) has been widely applied to study correlations between neuroimaging data and behavioral data. Practical use of CCA typically requires dimensionality reduction with, for example, Principal Components Analysis (PCA), however, this can result in CCA components that are difficult to interpret. In this paper, we introduce a Domain-driven Dimension Reduction (DDR) method, reducing the dimensionality of the original datasets and combining human knowledge of the structure of the variables studied. We apply the method to the Human Connectome Project S1200 release and compare standard PCA across all variables with DDR applied to individual classes of variables, finding that DDR-CCA results are more stable and interpretable, allowing the contribution of each class of variable to be better understood. By carefully designing the analysis pipeline and cross-validating the results, we offer more insights into the interpretation of CCA applied to brain-behavior data.
Cortico-Hippocampal Oscillations Are Associated With the Developmental Onset of Hippocampal-Dependent Memory
Authors: García-Pérez María A. , Irani Martin , Tiznado Vicente , Bustamante Tamara , Inostroza Marion , Maldonado Pedro E. , Valdés José L.
Published: June 2022

Hippocampal-dependent memories emerge late during postnatal development, aligning with hippocampal maturation. During sleep, the two-stage memory formation model states that through hippocampal-neocortical interactions, cortical slow-oscillations (SO), thalamocortical Spindles, and hippocampal sharp-wave ripples (SWR) are synchronized, allowing for the consolidation of hippocampal-dependent memories. However, evidence supporting this hypothesis during development is still lacking. Therefore, we performed successive object-in-place tests during a window of memory emergence and recorded in vivo the occurrence of SO, Spindles, and SWR during sleep, immediately after the memory encoding stage of the task. We found that hippocampal-dependent memory emerges at the end of the 4th postnatal week independently of task overtraining. Furthermore, we observed that those animals with better performance in the memory task had increased Spindle density and duration and lower density of SWR. Moreover, we observed changes in the SO-Spindle and Spindle-SWR temporal-coupling during this developmental period. Our results provide new evidence for the onset of hippocampal-dependent memory and its relationship to the oscillatory phenomenon occurring during sleep that helps us understand how memory consolidation models fit into the early stages of postnatal development.
Sleep Disturbance and Its Association With Sluggish Cognitive Tempo and Attention in Pediatric Brain Tumor Survivors
Authors: Olsthoorn Ineke M. , Holland Alice Ann , Hawkins Raymond C. , Cornelius Allen E. , Baig Muhammad Usman , Yang Grace , Holland Daniel C. , Zaky Wafik , Stavinoha Peter L.
Published: June 2022

Background

Pediatric brain tumor (PBT) survivors are at risk for developing sleep disturbances. While in other pediatric populations sleep disturbance has been associated with worse cognitive functioning, it is unclear to what extent this relationship generalizes to PBT survivors. The aim of the current study was to assess the relationship between sleep disturbance and aspects of cognition, including sluggish cognitive tempo (SCT) as well as attention and working memory.

Materials and Methods

Eighty-three PBT survivors 6–18 years of age who were at least 3 months post-treatment were included in the present cross-sectional study. Level of sleep disturbance was measured as a composite score reflecting various sleep problems as rated by caregivers. Cognitive measures included caregiver-ratings of sluggish cognitive tempo and attention problems, as well as performance-based cognitive measures assessing attention and executive functioning. Hierarchical regression analysis was used to assess associations between sleep and cognition.

Results

Of all caregivers, 32.5% reported one or more sleep disturbances as “very/often true” and over 68% of caregivers rated at least one sleep-related item as “somewhat true.” Of all cognitive variables, scores were most frequently impaired for SCT (30%). A higher level of sleep disturbance was associated with worse SCT and parent-rated attention problems. Associations between sleep and performance-based cognitive measures assessing attention and working memory were not statistically significant.

Conclusion

Findings of the current study highlight the importance of further investigation into the relationship between sleep and cognition in PBT survivors, which may assist efforts to maximize cognitive outcome and health-related quality of life in PBT survivors. The current study additionally suggests further investigation of SCT in this population is warranted, as it may be more sensitive to detecting possible associations with sleep disturbance relative to discrete measures that assess cognitive performance under ideal circumstances.
Advancements in Genomic and Behavioral Neuroscience Analysis for the Study of Normal and Pathological Brain Function
Authors: Baratta Annalisa M. , Brandner Adam J. , Plasil Sonja L. , Rice Rachel C. , Farris Sean P.
Published: June 2022

Psychiatric and neurological disorders are influenced by an undetermined number of genes and molecular pathways that may differ among afflicted individuals. Functionally testing and characterizing biological systems is essential to discovering the interrelationship among candidate genes and understanding the neurobiology of behavior. Recent advancements in genetic, genomic, and behavioral approaches are revolutionizing modern neuroscience. Although these tools are often used separately for independent experiments, combining these areas of research will provide a viable avenue for multidimensional studies on the brain. Herein we will briefly review some of the available tools that have been developed for characterizing novel cellular and animal models of human disease. A major challenge will be openly sharing resources and datasets to effectively integrate seemingly disparate types of information and how these systems impact human disorders. However, as these emerging technologies continue to be developed and adopted by the scientific community, they will bring about unprecedented opportunities in our understanding of molecular neuroscience and behavior.
Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22
Authors: Li Mengjie , Liu Fen , Hao Xiaoyan , Fan Yu , Li Jiadi , Hu Zhengwei , Shi Jingjing , Fan Liyuan , Zhang Shuo , Ma Dongrui , Guo Mengnan , Xu Yuming , Shi Changhe
Published: June 2022

Spinocerebellar ataxia 19/22 (SCA19/22) is a rare neurodegenerative disorder caused by mutations of theKCND3gene, which encodes the Kv4. 3 protein. Currently, only 22KCND3single-nucleotide mutation sites of SCA19/22 have been reported worldwide, and detailed pathogenesis remains unclear. In this study, Sanger sequencing was used to screen 115 probands of cerebellar ataxia families in 67 patients with sporadic cerebellar ataxia and 200 healthy people to identifyKCND3mutations. Mutant gene products showed pathogenicity damage, and the polarity was changed. Next, we established induced pluripotent stem cells (iPSCs) derived from SCA19/22 patients. Using a transcriptome sequencing technique, we found that protein processing in the endoplasmic reticulum was significantly enriched in SCA19/22-iPS-derived neurons and was closely related to endoplasmic reticulum stress (ERS) and apoptosis. In addition, Western blotting of the SCA19/22-iPS-derived neurons showed a reduction in Kv4.3; but, activation of transcription factor 4 (ATF4) and C/EBP homologous protein was increased. Therefore, the c.1130 C>T (p.T377M) mutation of theKCND3gene may mediate misfold and aggregation of Kv4.3, which activates the ERS and further induces neuron apoptosis involved in SCA19/22.
A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures
Authors: Williams Riley A. , Johnson Kenneth W. , Lee Francis S. , Hemmings Hugh C. , Platholi Jimcy
Published: June 2022

Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis by isoflurane was acutely irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met; rs6265) compared to neurons from wild-type mice. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism in persistent changes of synaptic function following isoflurane exposure. These short-term persistent alterations in excitatory synaptic transmission indicate a role for human genetic variation in anesthetic effects on synaptic plasticity and neurocognitive function.
Induction Chemotherapy and Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy for Inoperable Pancreas Cancer
Authors: Chuong Michael D. , Herrera Roberto , Kaiser Adeel , Rubens Muni , Romaguera Tino , Alvarez Diane , Kotecha Rupesh , Hall Matthew D. , McCulloch James , Ucar Antonio , DeZarraga Fernando , Aparo Santiago , Joseph Sarah , Asbun Horacio , Jimenez Ramon , Narayanan Govindarajan , Gutierrez Alonso N. , Mittauer Kathryn E.
Published: June 2022

Background

Radiation therapy (RT) dose for inoperable pancreatic ductal adenocarcinoma (PDAC) has historically been non-ablative to avoid injuring gastrointestinal (GI) organs at risk (OARs). Accruing data suggest that dose escalation, in select patients, may significantly improve clinical outcomes. Early results of ablative stereotactic magnetic resonance image-guided adaptive radiation therapy (A-SMART) have been encouraging, although long-term outcomes are not well understood.

Methods

A single institution retrospective analysis was performed of inoperable non-metastatic PDAC patients who received induction chemotherapy then 5-fraction A-SMART on a 0.35T-MR Linac from 2018-2021.

Results

Sixty-two patients were evaluated with a median age of 66 years (range 35-91) and nearly all achieved Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (96.8%). Locally advanced disease was common (72.6%), otherwise borderline resectable (22.6%), or medically inoperable (4.8%). All received induction chemotherapy for a median 4.2 months (range, 0.2-13.3) most commonly FOLFIRINOX (n=43; 69.4%). Median prescribed dose was 50 Gy (range 40-50); median biologically effective dose (BED10) was 100 Gy10. The median local control (LC), progression-free survival (PFS), and overall survival (OS) from diagnosis were not reached, 20 months, and 23 months, respectively. Also, 2-year LC, PFS, and OS were 68.8%, 40.0%, and 45.5%, respectively. Acute and late grade 3+ toxicity rates were 4.8% and 4.8%, respectively.

Conclusions

To our knowledge, this is the largest series of induction chemotherapy followed by ablative 5-fraction SMART delivered on an MR Linac for inoperable PDAC. The potential for this novel treatment strategy is to achieve long-term LC and OS, compared to chemotherapy alone, and warrants prospective evaluation.
Integrated Multi-Omics Data Analysis Reveals Associations Between Glycosylation and Stemness in Hepatocellular Carcinoma
Authors: Liu Peiyan , Zhou Qi , Li Jia
Published: June 2022

Background

Glycosylation plays an essential role in driving the progression and treatment resistance of hepatocellular carcinoma (HCC). However, its function in regulating the acquisition and maintenance of the cancer stemness-like phenotype in HCC remains largely unknown. There is also very little known about how CAD and other potential glycosylation regulators may influence stemness. This study explores the relationship between glycosylation and stemness in HCC.

Methods

Gene set variance analysis (GSVA) was used to assess the TCGA pan-cancer enrichment in glycosylation-related pathways. Univariate, LASSO, and multivariate COX regression were then used to identify prognostic genes in the TCGA-LIHC and construct a prognostic signature. HCC patients were classified into high- and low-risk subgroups based on the signature. The relationship between gene expression profiles and stemness was confirmed using bulk and single-cell RNA-sequencing data. The role of CAD and other genes in regulating the stemness of HCC was also validated by RT-qPCR, CCK-8, and colony formation assay. Copy number variation (CNV), immune infiltration, and clinical features were further analyzed in different subgroups and subsequent gene expression profiles. Sensitive drugs were also screened.

Results

In the pan-cancer analysis, HCC was shown to have specific glycosylation alterations. Five genes, CAD, SLC51B, LGALS3, B3GAT3, and MT3, identified from 572 glycosylation-related genes, were used to construct a gene signature and predict HCC patient survival in the TCGA cohort. The results demonstrated a significant positive correlation between patients in the high-risk group and both elevated gene expression and HCC dedifferentiation status. A significant reduction in the stemness-related markers, CD24, CD44, CD20, FOXM1, and EpCAM, was found after the knockdown of CAD and other genes in HepG2 and Huh7 cells. Frequent mutations increased CNVs, immune-suppressive responses, and poor prognosis were also associated with the high-risk profile. The ICGC-LIRI-JP cohort confirmed a similar relationship between glycosylation-related subtypes and stemness. Finally, 84 sensitive drugs were screened for abnormal glycosylation of HCC, and carfilzomib was most highly correlated with CAD.

Conclusions

Glycosylation-related molecular subtypes are associated with HCC stemness and disease prognosis. These results provide new directions for further research on the relationship between glycosylation and stemness phenotypes.
Development and Validation of Nomograms to Predict Cancer-Specific Survival and Overall Survival in Elderly Patients With Prostate Cancer: A Population-Based Study
Authors: Zhang Zhaoxia , Zhanghuang Chenghao , Wang Jinkui , Tian Xiaomao , Wu Xin , Li Maoxian , Mi Tao , Liu Jiayan , Jin Liming , Li Mujie , He Dawei
Published: June 2022

Objective

Prostate cancer (PC) is the most common non-cutaneous malignancy in men worldwide. Accurate predicting the survival of elderly PC patients can help reduce mortality in patients. We aimed to construct nomograms to predict cancer-specific survival (CSS) and overall survival (OS) in elderly PC patients.

Methods

Information on PC patients aged 65 years and older was downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression models were used to determine independent risk factors for PC patients. Nomograms were developed to predict the CSS and OS of elderly PC patients based on a multivariate Cox regression model. The accuracy and discrimination of the prediction model were tested by the consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve. Decision curve analysis (DCA) was used to test the clinical value of the nomograms compared with the TNM staging system and D’Amico risk stratification system.

Results

135183 elderly PC patients in 2010-2018 were included. All patients were randomly assigned to the training set (N=94764) and the validation set (N=40419). Univariate and multivariate Cox regression model analysis revealed that age, race, marriage, histological grade, TNM stage, surgery, chemotherapy, radiotherapy, biopsy Gleason score (GS), and prostate-specific antigen (PSA) were independent risk factors for predicting CSS and OS in elderly patients with PC. The C-index of the training set and the validation set for predicting CSS was 0.883(95%CI:0.877-0.889) and 0.887(95%CI:0.877-0.897), respectively. The C-index of the training set and the validation set for predicting OS was 0.77(95%CI:0.766-0.774)and 0.767(95%CI:0.759-0.775), respectively. It showed that the proposed model has excellent discriminative ability. The AUC and the calibration curves also showed good accuracy and discriminability. The DCA showed that the nomograms for CSS and OS have good clinical potential value.

Conclusions

We developed new nomograms to predict CSS and OS in elderly PC patients. The models have been internally validated with good accuracy and reliability and can help doctors and patients to make better clinical decisions.
The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia
Authors: Zhuang Xiaomei , Pei Han Zhong , Li Tianwen , Huang Junbin , Guo Yao , Zhao Yuming , Yang Ming , Zhang Dengyang , Chang Zhiguang , Zhang Qi , Yu Liuting , He Chunxiao , Zhang Liqing , Pan Yihang , Chen Chun , Chen Yun
Published: June 2022

Gain-of-function mutations of isocitrate dehydrogenases 1/2 (IDH1/2) play crucial roles in the development and progression of acute myeloid leukemia (AML), which provide promising therapeutic targets. Two small molecular inhibitors, ivosidenib and enasidenib have been approved for the treatment of IDH1- and IDH2-mutant AML, respectively. Although these inhibitors benefit patients with AML clinically, drug resistance still occurs and have become a major problem for targeted therapies of IDH-mutant AML. A number of up-to-date studies have demonstrated molecular mechanisms of resistance, providing rationales of novel therapeutic strategies targeting mutant IDH1/2. In this review, we discuss mechanisms of resistance to ivosidenib and enasidenib in patients with AML.
Xiaoyaosan Ameliorates Chronic Restraint Stress-Induced Depression-Like Phenotype by Suppressing A2AR Signaling in the Rat Striatum
Authors: Zhu Xiaoxu , Ma Qingyu , Yang Furong , Li Xiaojuan , Liu Yueyun , Chen Jianbei , Li Lan , Chen Man , Zou Xiaojuan , Yan Li , Chen Jiaxu
Published: June 2022

Depression is a common mental disorder characterized by pessimism and world-weariness. In our previous study, we found that Xiaoyaosan (XYS) could have antidepressive effects, however the underlying mechanisms remain unclear. Several studies have shown that adenosine A (2 A) receptor (A2AR) in the brain is a key point in the treatment of depression. Our present study aimed to investigate the effects of XYS on A2AR signaling in the striatum of rats exposed to chronic restraint stress (CRS). Ninety-six male Sprague–Dawley rats were randomly divided into 8 groups (control, model, negative control, XYS, A2AR antagonist, A2AR antagonist + XYS, A2AR agonist, A2AR agonist + XYS). The rats in the model group, XYS group, A2AR antagonist group and A2AR antagonist + XYS group were subjected to CRS for 3 h a day. The XYS decoction [2.224 g/(kg·d)] was intragastrical administered by oral gavage to the rats in the negative control group, XYS group, A2AR antagonist + XYS group, and A2AR agonist + XYS group. The rats in the A2AR antagonist group and A2AR antagonist + XYS group were treated with SCH 58261 [0.05 mg/(kg·d)], and the rats in the A2AR agonist and A2AR agonist + XYS group were treated with CGS 21680 [0.1 mg/(kg·d)]. These procedures were performed for 21 consecutive days. Behavioral studies including the open field test, elevated plus maze test, sucrose preference test and forced swimming test, were performed to examine depression-like phenotypes. Then, the effects of XYS on CRS- or A2AR agonist-induced striatal subcellular damage, microglial activation and A2AR signaling changes in the striatum were examined. Here, we report that XYS ameliorates depression-like phenotypes (such as body weight loss as well as depression- and anxiety-like behaviors) and improves synaptic survival and growth in the stratum of the CRS rats. Moreover, XYS reduces A2AR activity and suppresses hyper-activation of striatal microglia. The tissue and cellular effects of XYS were similar to those of the known A2AR antagonists. In conclusion, XYS alleviates depression in the CRS rats via inhibiting A2AR in the striatum.
CAR T-Cell Therapies in Italy: Patient Access Barriers and Recommendations for Health System Solutions
Authors: Jommi Claudio , Bramanti Stefania , Pani Marcello , Ghirardini Alessandro , Santoro Armando
Published: June 2022

CAR T-cell therapy has emerged as a potentially transformative immunotherapy for certain B-cell malignancies including relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Unhindered and appropriate access for eligible patients is essential to enable optimal outcomes and depends on effective interplay of stakeholders and processes along the patient’s therapeutic journey. In Italy, CAR T-cell therapies have been awarded innovation status by the Italian Medicines Agency (AIFA) and were integrated into routine patient care under specific criteria. However, our analysis indicates that fewer than one in five DLBCL patients eligible under the EMA authorization, or around one in three DLBCL patients eligible under the AIFA criteria, received treatment with a licensed CAR T-cell therapy product in 2020. This publication describes key patient access barriers to CAR T-cell therapies in Italy and provides recommendations on potential solutions at the health system level.
Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone
Authors: Bivona III Joseph J. , Mank Madeleine M. , Stapleton Renee D. , Files D. Clark , Toth Michael J. , Poynter Matthew E.
Published: June 2022

The abundance, anatomical distribution, and vascularity of skeletal muscle make it a potentially important contributor to local cytokine production and systemic cytokine abundance during inflammatory events. An orchestrated balance between the production of pro- and anti-inflammatory mediators is necessary for proper immune function, yet the contribution of the body’s largest organ system, comprised primarily of skeletal muscle myocytes that fuse to form myofibers, to this process is largely unknown. Endotoxin (lipopolysaccharide, LPS) stimulates toll-like receptor 4 (TLR4) to induce the production of several pro-inflammatory cytokines, including interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2), by a of myriad cell types. We sought to quantify the influence of myofibers on systemic cytokine concentrations following an acute endotoxemia challenge. To accomplish this, we generated muscle specific conditional knockouts for TLR4 (TLR4SMKO), IL-6 (IL6SMKO), and CCL2 (CCL2SMKO). We administered low concentrations of intravenous LPS (IV LPS) to these receptor and effector knockout mice and collected samples after 3 h. Using gene expression analysis of gastrocnemius muscle and serum cytokine measurements after IV LPS, we determined that deletion of myofiber IL-6 or CCL2 led to a 93% and 57% reduction of these specific cytokines in the systemic circulation, respectively. Myofiber specific TLR4 deletion decreased the expression of IL-6, CCL2, and C-X-C motif chemokine ligand 1 (CXCL1) in the gastrocnemius muscle. These data indicate the critical involvement and direct contribution of myofibers during the early systemic inflammatory cytokine response to endotoxin.
Results on Resistance Distance and Kirchhoff Index of Graphs With Generalized Pockets
Authors: Liu Qun , Li Jiaqi
Published: June 2022

F, Hv are considered simple connected graphs on n and m + 1 vertices, and v is a specified vertex of Hv and u1, u2, … uk ∈ F. The graph G = G[F, u1, … , uk, Hv] is called a graph with k pockets, obtained by taking one copy of F and k copies of Hv and then attaching the ith copy of Hv to the vertex ui, i = 1, … , k, at the vertex v of Hv. In this article, the closed-form formulas of the resistance distance and the Kirchhoff index of G = G[F, u1, … , uk, Hv] are obtained in terms of the resistance distance and Kirchhoff index F and Hv.
Racing and Pacing in the Reward System: A Multi-Clock Circadian Control Over Dopaminergic Signalling
Authors: Pradel Kamil , Drwięga Gniewosz , Chrobok Lukasz , Błasiak Tomasz
Published: June 2022

Level of motivation, responsiveness to rewards and punishment, invigoration of exploratory behaviours, and motor performance are subject to daily fluctuations that emerge from circadian rhythms in neuronal activity of the midbrain’s dopaminergic system. While endogenous circadian rhythms are weak in the ventral tegmental area and substantia nigra pars compacta, daily changes in expression of core clock genes, ion channels, neurotransmitter receptors, dopamine-synthesising enzymes, and dopamine transporters, accompanied by changes in electrical activity, are readily observed in these nuclei. These processes cause dopamine levels released in structures innervated by midbrain dopaminergic neurons (e.g., the striatum) to oscillate in a circadian fashion. Additionally, growing evidence show that the master circadian clock located in the suprachiasmatic nucleus of the hypothalamus (SCN) rhythmically influences the activity of the dopaminergic system through various intermediate targets. Thus, circadian changes in the activity of the dopaminergic system and concomitant dopamine release observed on a daily scale are likely to be generated both intrinsically and entrained by the master clock. Previous studies have shown that the information about the value and salience of stimuli perceived by the animal is encoded in the neuronal activity of brain structures innervating midbrain dopaminergic centres. Some of these structures themselves are relatively autonomous oscillators, while others exhibit a weak endogenous circadian rhythm synchronised by the SCN. Here, we place the dopaminergic system as a hub in the extensive network of extra-SCN circadian oscillators and discuss the possible consequences of its daily entrainment for animal physiology and behaviour.