bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice
Authors: Tarrés-Freixas Ferran , Trinité Benjamin , Pons-Grífols Anna , Romero-Durana Miguel , Riveira-Muñoz Eva , Ávila-Nieto Carlos , Pérez Mónica , Garcia-Vidal Edurne , Perez-Zsolt Daniel , Muñoz-Basagoiti Jordana , Raïch-Regué Dàlia , Izquierdo-Useros Nuria , Andrés Cristina , Antón Andrés , Pumarola Tomàs , Blanco Ignacio , Noguera-Julián Marc , Guallar Victor , Lepore Rosalba , Valencia Alfonso , Urrea Victor , Vergara-Alert Júlia , Clotet Bonaventura , Ballana Ester , Carrillo Jorge , Segalés Joaquim , Blanco Julià
Published: May 2022

The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection. In silico modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2.
T-G-A Deficiency Pattern in Protein-Coding Genes and Its Potential Reason
Authors: Jin Yan-Ting , Pu Dong-Kai , Guo Hai-Xia , Deng Zixin , Chen Ling-Ling , Guo Feng-Biao
Published: May 2022

If a stop codon appears within one gene, then its translation will be terminated earlier than expected. False folding of premature protein will be adverse to the host; hence, all functional genes would tend to avoid the intragenic stop codons. Therefore, we hypothesize that there will be less frequency of nucleotides corresponding to stop codons at each codon position of genes. Here, we validate this inference by investigating the nucleotide frequency at a large scale and results from 19,911 prokaryote genomes revealed that nucleotides coinciding with stop codons indeed have the lowest frequency in most genomes. Interestingly, genes with three types of stop codons all tend to follow a T-G-A deficiency pattern, suggesting that the property of avoiding intragenic termination pressure is the same and the major stop codon TGA plays a dominant role in this effect. Finally, a positive correlation between the TGA deficiency extent and the base length was observed in start-experimentally verified genes of Escherichia coli (E. coli). This strengthens the proof of our hypothesis. The T-G-A deficiency pattern observed would help to understand the evolution of codon usage tactics in extant organisms.
Epidemiology, Environmental Risks, Virulence, and Resistance Determinants of Klebsiella pneumoniae From Dairy Cows in Hubei, China
Authors: Wu Xiangyun , Liu Jiayi , Feng Jiawei , Shabbir Muhammad Abu Bakr , Feng Yali , Guo Rui , Zhou Meifang , Hou Sulin , Wang Guiqiang , Hao Haihong , Cheng Guyue , Wang Yulian
Published: May 2022

Klebsiella pneumoniae (K. pneumoniae) is an opportunistic pathogen, which causes serious infections in humans and animals. To investigate the antimicrobial resistance pattern and virulence profile of K. pneumoniae, a total of 887 samples were collected from both the healthy and mastitis cows and the bedding, feed, feces, air, drinking water, spraying water, washing water, and milk cup swabs from five dairy farms in Hubei, China, during 2019 and 2020. K. pneumoniae was isolated and identified using PCR of the khe and 16S rDNA sequencing. A genotypic characterization was performed for K. pneumoniae isolates using wzi typing and multilocus sequence typing (MLST). Antimicrobial resistances were confirmed using broth microdilution against 17 antimicrobial agents and resistance and virulence genes were determined by PCR. The prevalence of K. pneumoniae was 26.94% (239/887) distributed in 101 wzi allele types (199/239, 83.26%) and 100 sequence types (STs) (209/239, 87.45%), including 5 new wzi allele type and 25 new STs. Phylogenetic analysis showed that K. pneumoniae isolated from milk, nipple swab, feed, and feces is classified in the same clone complex. By comparing with the PubMLST database, at least 67 STs have the risk of spreading in different species and regions. Interestingly, 60 STs have been isolated from humans. The isolates were highly sensitive to meropenem and colistin, but resistant to ampicillin (100%), sulfisoxazole (94.56%), cephalothin (47.28%), streptomycin (30.13%), and so on. Noteworthy, multidrug-resistant (MDR) rate was found to be 43.93% in this study. By PCR, 30 of 68 antimicrobial resistance (AMR) genes were identified; the prevalence rate of blaTEM, blaSHV, strA, strB, aadA1, and aac(6′)-Ib-cr was more than 50%. Eleven CTX-M-producing K. pneumoniae were found. The detection rate of fimH, mrkD, uge, wabG, entB, iutA, iroN, and ureA was over 85%. This study reinforces the epidemiological importance of K. pneumoniae in food-producing animals in Hubei. The emergence and spread of environmental MDR K. pneumoniae may pose a potential threat to food safety and public health.
Characterizing Natural Organic Matter Transformations by Microbial Communities in Terrestrial Subsurface Ecosystems: A Critical Review of Analytical Techniques and Challenges
Authors: Cabugao Kristine Grace M. , Gushgari-Doyle Sara , Chacon Stephany S. , Wu Xiaoqin , Bhattacharyya Amrita , Bouskill Nicholas , Chakraborty Romy
Published: May 2022

Determining the mechanisms, traits, and pathways that regulate microbial transformation of natural organic matter (NOM) is critical to informing our understanding of the microbial impacts on the global carbon cycle. The capillary fringe of subsurface soils is a highly dynamic environment that remains poorly understood. Characterization of organo-mineral chemistry combined with a nuanced understanding of microbial community composition and function is necessary to understand microbial impacts on NOM speciation in the capillary fringe. We present a critical review of the popular analytical and omics techniques used for characterizing complex carbon transformation by microbial communities and focus on how complementary information obtained from the different techniques enable us to connect chemical signatures with microbial genes and pathways. This holistic approach offers a way forward for the comprehensive characterization of the formation, transformation, and mineralization of terrestrial NOM as influenced by microbial communities.
Assessment on the Fermentation Quality and Bacterial Community of Mixed Silage of Faba Bean With Forage Wheat or Oat
Authors: Li Hongliang , Zeng Tairu , Du Zhaochang , Dong Xintan , Xin Yafen , Wu Yushan , Huang Linkai , Liu Lin , Kang Bo , Jiang Dongmei , Wu Bihua , Yang Wenyu , Yan Yanhong
Published: May 2022

Faba bean (Vicia faba L.), although a kind of high-quality and high-yield forage, could hardly achieve a great quality of silage because of its high buffering capacity. Mixed silage of faba bean with forage wheat (Triticum aestivum L.) or oat (Avena sativa L.) at different ratios could improve the fermentation quality and bacterial community. Compared with 100% faba bean silage (BS), mixed silage improved the fermentation quality, not only increased lactic acid production and reduced pH, but reduced the production of propionic acid and ammonia nitrogen. The chemical compositions of faba bean with forage wheat (BT) mixed silage were better than that of faba bean with oat (BO) mixed silage, and that of 3:7, 5:5 (fresh matter basis) mixing ratios were better than 1:9. However, the fermentation quality of BO mixed silage was better than that of BT, and that of 3:7 mixed silage (BO30) was the best overall. Analysis of the bacterial community showed that mixed silage increased the relative abundance of lactic acid bacteria after ensiling, and the relatively higher abundance of Lactobacillus showed the inhibitory effects on the proliferation of Serratia and Hafnia_Obesumbacterium, so that it alleviated their negative effects on silage and stabilized the fermentation quality. This present study exhibited that mixed silage of faba bean with forage wheat or oat not only had significant effects on chemical compositions and fermentation quality of materials but modified bacterial community so that improved the fermentation quality effectively. The mixed silage of 30% faba bean with 70% oat (BO30) is recommended in the faba bean mixed silage.
Two New Sulfate-Modified Dibenzopyrones With Anti-foodborne Bacteria Activity From Sponge-Derived Fungus Alternaria sp. SCSIOS02F49
Authors: Chen Yaping , Liu Chuanna , Kumaravel Kaliaperumal , Nan Lihong , Tian Yongqi
Published: May 2022

At present, foodborne diseases (FBDs) caused by bacteria are gradually increasing every year, and the development of new antibiotics is an urgent necessity for human beings. To find novel antibacterial compounds, three sponge-derived fungal strains (SCSIOS02F40, F46, and F49) were investigated. As a result, Alternaria sp. SCSIOS02F49 was selected for investigation on its secondary metabolites because its ethyl acetate (EtOAc) extract of potato dextrose broth (PDB) culture showed rich metabolites and strong antibacterial activity. Two new dibenzopyrones with rare sulfate group (1–2), together with 10 known compounds (3–12), were isolated from the Alternaria sp. SCSIOS02F49. Their structures were confirmed by nuclear magnetic resonance (NMR), mass spectrometry (MS) data, and comparison with data from the relevant literature. Almost all compounds showed moderate inhibitory activity against eight foodborne bacteria (FBB) with minimum inhibitory concentration (MIC) values in the range of 15.6–250 μg/ml, and minimum bactericidal concentration (MBC) values in the range of 31.3–250 μg/ml. The antibacterial mechanism of compound 1 was preliminarily investigated using growth curves, scanning electron microscopy (SEM), and flow cytometry (FCM), which revealed that compound 1 altered the external structure of Staphylococcus aureus and caused the rupture or deformation of the cell membranes. This research provides lead compounds for the development of new antibiotics or microbial preservatives.
Linking Microbial Community Succession With Substance Transformation in a Thermophilic Ectopic Fermentation System
Authors: Wen Ping , Wang Yueqiang , Huang Wenfeng , Wang Weiwu , Chen Tao , Yu Zhen
Published: May 2022

Ectopic fermentation system (EFS) is an effective technology for treating mass livestock manure. However, the associations between microbial communities and substance transformation remain controversial. This study aimed to investigate chicken manure EFS lasting 170 days using 16S rRNA sequencing and electrochemical, spectroscopic, and chromatographic analyses. The results showed a noticeable transformation of protein-like substances into humus-like substances. Meanwhile, the electron–accepting capacity increased persistently, effectively reflecting the humification of organic substances. The contents of phenols that promoted electron transfer continued to increase from 2.80 to 6.00%, which could be used as a maturity indicator for EFS. During the heating period, the dominant microbial communities were Chloroflexi and Proteobacteria, whereas thermotolerant bacteria Cyanobacteria and Planctomycetes were significantly enriched from 1.64 to 50.15% during the continuous thermophilic period of EFS. The correlation analysis manifested that these thermotolerant bacteria were the major functional bacteria for the formation of phenols and the key to driving the humification of organic substances. This study provides insights into understanding the humification mechanisms and implementing regulatory strategies in EFS.
Combined Phenanthrene and Copper Pollution Imposed a Selective Pressure on the Rice Root-Associated Microbiome
Authors: Li Mingyue , Xu Minmin , Su Aoxue , Zhang Ying , Niu Lili , Xu Yan
Published: May 2022

Combined organic and inorganic pollutants can greatly impact crops and microbes, but the interaction between coexisted pollutants and their effects on root-associated microbes under flooding conditions remains poorly understood. In this study, greenhouse experiments were conducted to investigate the individual and combined effects of phenanthrene (PHE) and copper (Cu) on rice uptake and root-associated microbial coping strategies. The results showed that more than 90% of phenanthrene was degraded, while the existence of Cu significantly reduced the dissipation of PHE in the rhizosphere, and the coexistence of phenanthrene and copper promoted their respective accumulation in plant roots. Copper played a dominant role in the interaction between these two chemicals. Microbes that can tolerate heavy metals and degrade PAHs, e.g., Herbaspirillum, Sphingobacteriales, and Saccharimonadales, were enriched in the contaminated soils. Additionally, microbes associated with redox processes reacted differently under polluted treatments. Fe reducers increased in Cu-treated soils, while sulfate reducers and methanogens were considerably inhibited under polluted treatments. In total, our results uncover the combined effect of heavy metals and polycyclic aromatic hydrocarbons on the assemblage of root-associated microbial communities in anaerobic environments and provide useful information for the selection of effective root-associated microbiomes to improve the resistance of common crops in contaminated sites.
The Past, Present, and Future of a Human T-Cell Leukemia Virus Type 1 Vaccine
Authors: Tu Joshua J. , Maksimova Victoria , Ratner Lee , Panfil Amanda R.
Published: May 2022

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus which causes a lifelong infection. An estimated 5–10 million persons are infected with HTLV-1 worldwide – a number which is likely higher due to lack of reliable epidemiological data. Most infected individuals remain asymptomatic; however, a portion of HTLV-1-positive individuals will develop an aggressive CD4+ T-cell malignancy called adult T-cell leukemia/lymphoma (ATL), or a progressive neurodegenerative disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Few treatment options exist for HAM/TSP outside of palliative care and ATL carries an especially poor prognosis given the heterogeneity of the disease and lack of effective long-term treatments. In addition, the risk of HTLV-1 disease development increases substantially if the virus is acquired early in life. Currently, there is no realistic cure for HTLV-1 infection nor any reliable measure to prevent HTLV-1-mediated disease development. The severity of HTLV-1-associated diseases (ATL, HAM/TSP) and limited treatment options highlights the need for development of a preventative vaccine or new therapeutic interventions. This review will highlight past HTLV-1 vaccine development efforts, the current molecular tools and animal models which might be useful in vaccine development, and the future possibilities of an effective HTLV-1 vaccine.
Discrete Biochemical Systems Theory
Authors: Voit Eberhard O. , Olivença Daniel V.
Published: May 2022

Almost every biomedical systems analysis requires early decisions regarding the choice of the most suitable representations to be used. De facto the most prevalent choice is a system of ordinary differential equations (ODEs). This framework is very popular because it is flexible and fairly easy to use. It is also supported by an enormous array of stand-alone programs for analysis, including many distinct numerical solvers that are implemented in the main programming languages. Having selected ODEs, the modeler must then choose a mathematical format for the equations. This selection is not trivial as nearly unlimited options exist and there is seldom objective guidance. The typical choices include ad hoc representations, default models like mass-action or Lotka-Volterra equations, and generic approximations. Within the realm of approximations, linear models are typically successful for analyses of engineered systems, but they are not as appropriate for biomedical phenomena, which often display nonlinear features such as saturation, threshold effects or limit cycle oscillations, and possibly even chaos. Power-law approximations are simple but overcome these limitations. They are the key ingredient of Biochemical Systems Theory (BST), which uses ODEs exclusively containing power-law representations for all processes within a model. BST models cover a vast repertoire of nonlinear responses and, at the same time, have structural properties that are advantageous for a wide range of analyses. Nonetheless, as all ODE models, the BST approach has limitations. In particular, it is not always straightforward to account for genuine discreteness, time delays, and stochastic processes. As a new option, we therefore propose here an alternative to BST in the form of discrete Biochemical Systems Theory (dBST). dBST models have the same generality and practicality as their BST-ODE counterparts, but they are readily implemented even in situations where ODEs struggle. As a case study, we illustrate dBST applied to the dynamics of the aryl hydrocarbon receptor (AhR), a signal transduction system that simultaneously involves time delays and stochasticity.
The Relationship Between Adverse Childhood Experiences and Alzheimer's Disease: A Systematic Review
Authors: Corney Kayla B. , West Emma C. , Quirk Shae E. , Pasco Julie A. , Stuart Amanda L. , Manavi Behnaz Azimi , Kavanagh Bianca E. , Williams Lana J.
Published: May 2022

Background

Alzheimer's disease is a global health concern, and with no present cure, prevention is critical. Exposure to adverse childhood experiences may increase the risk of developing Alzheimer's disease. This systematic review was conducted to synthesize the evidence on the associations between adverse childhood experiences (<18 years) and the risk of Alzheimer's disease in adulthood.

Methods

A search strategy was developed and conducted to identify articles investigating the associations between exposure to adverse childhood experiences and the onset of Alzheimer's disease by searching key databases (CINAHL, MEDLINE and PsycInfo). Two reviewers independently determined the eligibility of studies according to pre-determined criteria, and assessed the methodological quality using the US National Heart, Lung and Blood Institute 14-item checklist for observational cohort and cross-sectional studies, respectively. Due to limited studies, a descriptive synthesis was performed. The protocol for this review is published in BMJ Open and registered with PROSPERO (CRD42020191439).

Results

Our search yielded 781 articles, of which three (two separate analyses from the same cohort study and one cross-sectional study) met the predetermined eligibility criteria. The methodological quality assessment yielded an overall mean score of 78.9% (range 66.6 – 84.6%). All studies found adverse childhood experiences were associated with an increased risk of Alzheimer's disease. However, there was a limited number of available studies to inform the synthesis.

Conclusions

Adverse childhood experiences appear to be associated with an increased risk of Alzheimer's disease, although, further research is needed.

Registration and Protocol

The protocol for this review is registered with PROSPERO (CRD42020191439) and published with BMJ Open (Corney et al., 2021).
Abnormal Visual Evoked Responses to Emotional Cues Correspond to Diagnosis and Disease Severity in Fibromyalgia
Authors: Goldway Noam , Petro Nathan M. , Ablin Jacob , Keil Andreas , Ben Simon Eti , Zamir Yoav , Weizman Libat , Greental Ayam , Hendler Talma , Sharon Haggai
Published: May 2022

Background

Chronic pain disorders are often associated with cognitive-emotional dysregulation. However, the relations between such dysregulation, underlying brain processes, and clinical symptom constellations, remain unclear. Here, we aimed to characterize the abnormalities in cognitive-emotional processing involved in fibromyalgia syndrome (FMS) and their relation to disease severity.

Methods

Fifty-eight participants, 39 FMS patients (35F), and 19 healthy control subjects (16F) performed an EEG-based paradigm assessing attention allocation by extracting steady-state visually evoked potentials (ssVEP) in response to affective distractors presented during a cognitive task. Patients were also evaluated for pain severity, sleep quality, depression, and anxiety.

Results

EEG ssVEP measurement indicated that, compared to healthy controls, FMS patients displayed impaired affective discrimination, and sustained attention to negative distractors. Moreover, patients displayed decreased task-related fronto-occipital EEG connectivity. Lack of adaptive attentional discrimination, measured via EEG, was predictive of pain severity, while impairments in fronto-occipital connectivity were predictive of impaired sleep.

Conclusions

FMS patients display maladaptive affective attention modulation, which predicts disease symptoms. These findings support the centrality of cognitive-emotional dysregulation in the pathophysiology of chronic pain.
A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress
Authors: Csabai Dávid , Sebők-Tornai Abigél , Wiborg Ove , Czéh Boldizsár
Published: May 2022

Exposure to severe, uncontrollable and long-lasting stress is a strong risk factor for the development of numerous mental and somatic disorders. Animal studies document that chronic stress can alter neuronal morphology and functioning in limbic brain structures such as the prefrontal cortex. Mitochondria are intracellular powerhouses generating chemical energy for biochemical reactions of the cell. Recent findings document that chronic stress can lead to changes in mitochondrial function and metabolism. Here, we studied putative mitochondrial damage in response to chronic stress in neurons of the medial prefrontal cortex. We performed a systematic quantitative ultrastructural analysis to examine the consequences of 9-weeks of chronic mild stress on mitochondria number and morphology in the infralimbic cortex of adult male rats. In this preliminary study, we analyzed 4,250 electron microscopic images and 67000 mitochondria were counted and examined in the brains of 4 control and 4 stressed rats. We found significantly reduced number of mitochondria in the infralimbic cortex of the stressed animals, but we could not detect any significant alteration in mitochondrial morphology. These data support the concept that prolonged stress can lead to mitochondrial loss. This in turn may result in impaired energy production. Reduced cellular energy may sensitize the neurons to additional injuries and may eventually trigger the development of psychopathologies.
Correlated Activity in the Degenerate Retina Inhibits Focal Response to Electrical Stimulation
Authors: Ahn Jungryul , Cha Seongkwang , Choi Kwang-Eon , Kim Seong-Woo , Yoo Yongseok , Goo Yong Sook
Published: May 2022

Retinal prostheses have shown some clinical success in patients with retinitis pigmentosa and age-related macular degeneration. However, even after the implantation of a retinal prosthesis, the patient’s visual acuity is at best less than 20/420. Reduced visual acuity may be explained by a decrease in the signal-to-noise ratio due to the spontaneous hyperactivity of retinal ganglion cells (RGCs) found in degenerate retinas. Unfortunately, abnormal retinal rewiring, commonly observed in degenerate retinas, has rarely been considered for the development of retinal prostheses. The purpose of this study was to investigate the aberrant retinal network response to electrical stimulation in terms of the spatial distribution of the electrically evoked RGC population. An 8 × 8 multielectrode array was used to measure the spiking activity of the RGC population. RGC spikes were recorded in wild-type [C57BL/6J; P56 (postnatal day 56)], rd1 (P56), rd10 (P14 and P56) mice, and macaque [wild-type and drug-induced retinal degeneration (RD) model] retinas. First, we performed a spike correlation analysis between RGCs to determine RGC connectivity. No correlation was observed between RGCs in the control group, including wild-type mice, rd10 P14 mice, and wild-type macaque retinas. In contrast, for the RD group, including rd1, rd10 P56, and RD macaque retinas, RGCs, up to approximately 400–600 μm apart, were significantly correlated. Moreover, to investigate the RGC population response to electrical stimulation, the number of electrically evoked RGC spikes was measured as a function of the distance between the stimulation and recording electrodes. With an increase in the interelectrode distance, the number of electrically evoked RGC spikes decreased exponentially in the control group. In contrast, electrically evoked RGC spikes were observed throughout the retina in the RD group, regardless of the inter-electrode distance. Taken together, in the degenerate retina, a more strongly coupled retinal network resulted in the widespread distribution of electrically evoked RGC spikes. This finding could explain the low-resolution vision in prosthesis-implanted patients.
Random Practice Enhances Retention and Spatial Transfer in Force Field Adaptation
Authors: Herzog Michael , Focke Anne , Maurus Philipp , Thürer Benjamin , Stein Thorsten
Published: May 2022

The contextual-interference effect is a frequently examined phenomenon in motor skill learning but has not been extensively investigated in motor adaptation. Here, we first tested experimentally if the contextual-interference effect is detectable in force field adaptation regarding retention and spatial transfer, and then fitted state-space models to the data to relate the findings to the “forgetting-and-reconstruction hypothesis”. Thirty-two participants were divided into two groups with either a random or a blocked practice schedule. They practiced reaching to four targets and were tested 10 min and 24 h afterward for motor retention and spatial transfer on an interpolation and an extrapolation target, and on targets which were shifted 10 cm away. The adaptation progress was participant-specifically fitted with 4-slow-1-fast state-space models accounting for generalization and set breaks. The blocked group adapted faster (p = 0.007) but did not reach a better adaptation at practice end. We found better retention (10 min), interpolation transfer (10 min), and transfer to shifted targets (10 min and 24 h) for the random group (each p < 0.05). However, no differences were found for retention or for the interpolation target after 24 h. Neither group showed transfer to the extrapolation target. The extended state-space model could replicate the behavioral results with some exceptions. The study shows that the contextual-interference effect is partially detectable in practice, short-term retention, and spatial transfer in force field adaptation; and that state-space models provide explanatory descriptions for the contextual-interference effect in force field adaptation.
Effect of the Menstrual Cycle on Electroencephalogram Alpha and Beta Bands During Motor Imagery and Action Observation
Authors: Souza Rafaela Faustino Lacerda de , Mendes Thatiane Maria Almeida Silveira , Lima Luana Adalice Borges de Araujo , Brandão Daniel Soares , Laplagne Diego Andrés , Sousa Maria Bernardete Cordeiro de
Published: May 2022

Female sex steroids (FSS) can affect the motor system, modulating motor cortex excitability as well as performance in dexterity and coordination tasks. However, it has not yet been explored whether FSS affects the cognitive components of motor behavior. Mu is a sensorimotor rhythm observed by electroencephalography (EEG) in alpha (8–12 Hz) and beta (15–30 Hz) frequency bands in practices such as motor imagery (MI) and action observation (AO). This rhythm represents a window for studying the activity of neural circuits involved in motor cognition. Herein we investigated whether the alpha-mu and beta-mu power in the sensorimotor region (C3 and C4, hypothesis-driven approach) and the alpha and beta power over frontal, parietal, and occipital regions (data-driven approach) are modulated differently in the menstrual, follicular, and luteal phases of menstrual cycles in right-handed dominant women. To do so, these women underwent MI and AO in the three menstrual cycle phases. The spectral activity of the cortical regions for the alpha and beta bands were compared between phases of the menstrual cycle and a correlation analysis was also performed in relation to estrogen and progesterone levels. For the hypothesis-based approach, beta-mu event-related desynchronization (ERD) was significantly stronger in the C3 channel in the follicular phase than in the menstrual and luteal phases. For the data-driven approach, beta ERD during MI was higher in the follicular phase than in the menstrual and luteal phases in the frontal region. These findings suggest the effect of FSS on executive movement control. No effect of menstrual cycle phases was observed in cortical areas investigated during OA, but alpha and beta bands correlated positively with the follicular phase plasma estradiol level. Thus, the attenuation of alpha and beta bands referring to mirror neuron activities appears to be associated with inhibition of cortical activity when estradiol levels are lower, improving cognitive processing of motor action.
Buprenorphine Exposure Alters the Development and Migration of Interneurons in the Cortex
Authors: Nieto-Estévez Vanesa , Donegan Jennifer J. , McMahon Courtney L. , Elam Hannah B. , Chavera Teresa A. , Varma Parul , Berg Kelly A. , Lodge Daniel J. , Hsieh Jenny
Published: May 2022

The misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the United States suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy. Opioid use during pregnancy has been associated with increased risk of obstetric complications and adverse neonatal outcomes, including neonatal abstinence syndrome. Currently, opioid use disorder in pregnant women is treated with long-acting opioid agonists, including buprenorphine. Although buprenorphine reduces illicit opioid use during pregnancy and improves infant outcomes at birth, few long-term studies of the neurodevelopmental consequences have been conducted. The goal of the current experiments was to examine the effects of buprenorphine on the development of the cortex using fetal brain tissue, 3D brain cultures, and rodent models. First, we demonstrated that we can grow cortical and subpallial spheroids, which model the cellular diversity, connectivity, and activity of the developing human brain. Next, we show that cells in the developing human cortex express the nociceptin opioid (NOP) receptor and that buprenorphine can signal through this receptor in cortical spheroids. Using subpallial spheroids to grow inhibitory interneurons, we show that buprenorphine can alter interneuron development and migration into the cortex. Finally, using a rodent model of prenatal buprenorphine exposure, we demonstrate that alterations in interneuron distribution can persist into adulthood. Together, these results suggest that more research is needed into the long-lasting consequences of buprenorphine exposure on the developing human brain.
Structural, Physicochemical, and Functional Properties of Wheat Bran Insoluble Dietary Fiber Modified With Probiotic Fermentation
Authors: Liao Ai-Mei , Zhang Jie , Yang Zhen-Lin , Huang Ji-Hong , Pan Long , Hou Yin-Chen , Li Xiao-Xiao , Zhao Peng-Hui , Dong Yu-Qi , Hu Zhe-Yuan , Hui Ming
Published: May 2022

Insoluble dietary fiber (IDF) were isolated from wheat bran (WB) after microbial fermentation with single or mixed strain [Lactobacillus plantarum, Lactobacillus acidophilus, Bacillus subtilis or mixed lactic acid bacteria (L. plantarum and L. acidophilus with ration of 1:1)]. Structure, physicochemical, functional properties, and antioxidant activity of the wheat bran insoluble dietary fiber (W-IDF) modified by fermentation were studied. Fourier transformed infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM) analysis suggested the successful modification of W-IDF. After fermentation with L. plantarum and mixed lactic acid bacteria, the water retention capacity (WRC), oil retention capacity (ORC), and water swelling capacity (WSC) of W-IDF were improved. The sodium cholate adsorption capacity (SCAC), and cation exchange capacity (CEC) of W-IDF modified with L. acidophilus fermentation were significantly increased. Although the cholesterol adsorption capacity (CAC) of W-IDF decreased after modification with probiotic fermentation, nitrite ion adsorption capacity (NIAC), and total phenolic content (TPC) were enhanced. Additionally, W-IDF modified by fermentation with B. subtilis or mixed lactic acid bacteria exhibited superior antioxidant capacity verified by DPPH, ABTS and total reducing power assays. Results manifested that microbial fermentation is a promising methods to modify the W-IDF to provide high-quality functional IDF for food processing and human health management.
Focal Adhesion-Related Signatures Predict the Treatment Efficacy of Chemotherapy and Prognosis in Patients with Gastric Cancer
Authors: Tang Xiaohuan , Wu Xiaolong , Guo Ting , Jia Fangzhou , Hu Ying , Xing Xiaofang , Gao Xiangyu , Li Ziyu
Published: May 2022

Background

The current tumor-node-metastasis (TNM) staging system is insufficient for predicting the efficacy of chemotherapy in patients with gastric cancer (GC). This study aimed to analyze the association between the focal adhesion pathway and therapeutic efficacy of chemotherapy in patients with GC.

Methods

RNA sequencing was performed on 33 clinical samples from patients who responded or did not respond to treatment prior to neoadjuvant chemotherapy. The validation sets containing 696 GC patients with RNA data from three cohorts (PKUCH, TCGA, and GSE14210) were analyzed. A series of machine learning and bioinformatics approaches was combined to build a focal adhesion-related signature model to predict the treatment efficacy and prognosis of patients with GC.

Results

Among the various signaling pathways associated with cancer, focal adhesion was identified as a risk factor related to the treatment efficacy of chemotherapy and prognosis in patients with GC. The focal adhesion-related gene model (FAscore) discriminated patients with a high FAscore who are insensitive to neoadjuvant chemotherapy in our training cohort, and the predicted value was further verified in the GSE14210 cohort. Survival analysis also demonstrated that patients with high FAscores had a relatively shorter survival compared to those with low FAscores. In addition, we found that the levels of tumor mutation burden (TMB) and microsatellite instability (MSI) increased with an increase in FAscore, and the tumor microenvironment (TME) also shifted to a pro-tumor immune microenvironment.

Conclusion

The FAscore model can be used to predict the treatment efficacy of chemotherapy and select appropriate treatment strategies for patients with GC.
Combination Therapy With Lenvatinib and Radiofrequency Ablation for Patients With Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child–Pugh Class A Liver function: A Pilot Study
Authors: Wang Feiqian , Numata Kazushi , Komiyama Satoshi , Miwa Haruo , Sugimori Kazuya , Ogushi Katsuaki , Moriya Satoshi , Nozaki Akito , Chuma Makoto , Ruan Litao , Maeda Shin
Published: May 2022

Background

The present study aimed to evaluate the efficacy and safety of combined lenvatinib (first-line systemic therapy) and radiofrequency ablation (RFA) therapy in patients with intermediate-stage hepatocellular carcinoma with beyond up-to-seven criteria and Child–Pugh Class A liver function (CP A B2-HCC).

Methods

Twenty-two patients with CP A B2-HCC were enrolled in the study. The patients had no history of systemic treatment. For the initial lenvatinib administration in this study, all of the patients had an adequate course of treatment (no less than two weeks) and were administered the recommended dose. Of them, 13 were treated by means of lenvatinib monotherapy (monotherapy group), while the 9 patients with no contraindication to RFA operation and who had consented to RFA received initial lenvatinib plus subsequent RFA (combination group). The clinical outcomes that were considered to evaluate the treatments included tumor response, prognosis (recurrence and survivals), and possible adverse events (serum liver enzymes and clinically visible complications).

Results

The combination group exhibited a higher object response rate (9/9, 100%) as best tumor response than the monotherapy group (10/13, 76.9%). Longer progression-free survival (PFS) (12.5 months) and overall survival (OS) (21.3) were demonstrated in the combination group than in the monotherapy group (PFS: 5.5 months; OS:17.1 months). The combination group achieved a higher PFS rate (1-year: 74.1%) and OS rate (2-year: 80%) than the monotherapy group (1-year PFS rate: 0%; 2-year OS rate: 25.6%; for PFS, p<0.001; for OS, p=0.022). The treatment strategy was the independent factor for PFS (HR: 18.215 for monotherapy, p =0.010), which was determined by Cox regression analysis, suggesting that a combination strategy may reduce tumor progression when compared to the use of lenvatinib alone. There were no statistically significant intergroup differences that were observed in terms of adverse events, with the exception of ALT elevation (p=0.007) in the combination group.

Conclusion

Our newly proposed combination therapy may potentially be effective and safe for CP A B2-HCC beyond up-to-seven criteria. A larger scale, multicenter, prospective study is warranted to confirm our findings.
Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models
Authors: Canals Hernaez Diana , Hughes Michael R. , Li Yicong , Mainero Rocca Ilaria , Dean Pamela , Brassard Julyanne , Bell Erin M. , Samudio Ismael , Mes-Masson Anne-Marie , Narimatsu Yoshiki , Clausen Henrik , Blixt Ola , Roskelley Calvin D. , McNagny Kelly M.
Published: May 2022

Podocalyxin (Podxl) is a CD34-related cell surface sialomucin that is normally highly expressed by adult vascular endothelia and kidney podocytes where it plays a key role in blocking adhesion. Importantly, it is also frequently upregulated on a wide array of human tumors and its expression often correlates with poor prognosis. We previously showed that, in xenograft studies, Podxl plays a key role in metastatic disease by making tumor initiating cells more mobile and invasive. Recently, we developed a novel antibody, PODO447, which shows exquisite specificity for a tumor-restricted glycoform of Podxl but does not react with Podxl expressed by normal adult tissue. Here we utilized an array of glycosylation defective cell lines to further define the PODO447 reactive epitope and reveal it as an O-linked core 1 glycan presented in the context of the Podxl peptide backbone. Further, we show that when coupled to monomethyl auristatin E (MMAE) toxic payload, PODO447 functions as a highly specific and effective antibody drug conjugate (ADC) in killing ovarian, pancreatic, glioblastoma and leukemia cell lines in vitro. Finally, we demonstrate PODO447-ADCs are highly effective in targeting human pancreatic and ovarian tumors in xenografted NSG and Nude mouse models. These data reveal PODO447-ADCs as exquisitely tumor-specific and highly efficacious immunotherapeutic reagents for the targeting of human tumors. Thus, PODO447 exhibits the appropriate characteristics for further development as a targeted clinical immunotherapy.
Recent Advances of Autophagy in Non-Small Cell Lung Cancer: From Basic Mechanisms to Clinical Application
Authors: Guo Weina , Du Keye , Luo Shanshan , Hu Desheng
Published: May 2022

Lung cancer is characterized by the most common oncological disease and leading cause of cancer death worldwide, of which a group of subtypes known as non-small cell lung cancer (NSCLC) accounts for approximately 85%. In the past few decades, important progression in the therapies of NSCLC has enhanced our understanding of the biology and progression mechanisms of tumor. The application of immunotherapy and small molecule tyrosine kinase inhibitors has brought significant clinical benefits in certain patients. However, early metastasis and the emergence of resistance to antitumor therapy have resulted in the relatively low overall cure and survival rates for NSCLC. Autophagy is a conserved process that allows cells to recycle unused or damaged organelles and cellular components. It has been reported to be related to the progression of NSCLC and resistance to targeted therapy and cytotoxic chemotherapy. Therefore, autophagy is considered as a potential therapeutic target for NSCLC. Mounting results have been reported about the combination of tyrosine kinase inhibitors and inhibitors of autophagy in models of NSCLC. This review aims to provide a comprehensive review on the roles of autophagy in NSCLC, focusing on related clinical data of agents that regulate autophagy in NSCLC. Furthermore, this study will provide a theoretical basis for further improvement of autophagy-based cancer therapy.
The Impact of Postoperative Tumor Burden on Patients With Brain Metastases
Authors: Aftahy Amir Kaywan , Barz Melanie , Lange Nicole , Baumgart Lea , Thunstedt Cem , Eller Mario Antonio , Wiestler Benedikt , Bernhardt Denise , Combs Stephanie E. , Jost Philipp J. , Delbridge Claire , Liesche-Starnecker Friederike , Meyer Bernhard , Gempt Jens
Published: May 2022

Background

Brain metastases were considered to be well-defined lesions, but recent research points to infiltrating behavior. Impact of postoperative residual tumor burden (RTB) and extent of resection are still not defined enough.

Patients and Methods

Adult patients with surgery of brain metastases between April 2007 and January 2020 were analyzed. Early postoperative MRI (<72 h) was used to segment RTB. Survival analysis was performed and cutoff values for RTB were revealed. Separate (subgroup) analyses regarding postoperative radiotherapy, age, and histopathological entities were performed.

Results

A total of 704 patients were included. Complete cytoreduction was achieved in 487/704 (69.2%) patients, median preoperative tumor burden was 12.4 cm3 (IQR 5.2–25.8 cm3), median RTB was 0.14 cm3 (IQR 0.0–2.05 cm3), and median postoperative tumor volume of the targeted BM was 0.0 cm3 (IQR 0.0–0.1 cm3). Median overall survival was 6 months (IQR 2–18). In multivariate analysis, preoperative KPSS (HR 0.981982, 95% CI, 0.9761–0.9873, p < 0.001), age (HR 1.012363; 95% CI, 1.0043–1.0205, p = 0.0026), and preoperative (HR 1.004906; 95% CI, 1.0003–1.0095, p = 0.00362) and postoperative tumor burden (HR 1.017983; 95% CI; 1.0058–1.0303, p = 0.0036) were significant. Maximally selected log rank statistics showed a significant cutoff for RTB of 1.78 cm3 (p = 0.0022) for all and 0.28 cm3 (p = 0.0047) for targeted metastasis and cutoff for the age of 67 years (p < 0.001). (Stereotactic) Radiotherapy had a significant impact on survival (p < 0.001).

Conclusions

RTB is a strong predictor for survival. Maximal cytoreduction, as confirmed by postoperative MRI, should be achieved whenever possible, regardless of type of postoperative radiotherapy.
Radiomics for Predicting Response of Neoadjuvant Chemotherapy in Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis
Authors: Yang Chao , Jiang Zekun , Cheng Tingting , Zhou Rongrong , Wang Guangcan , Jing Di , Bo Linlin , Huang Pu , Wang Jianbo , Zhang Daizhou , Jiang Jianwei , Wang Xing , Lu Hua , Zhang Zijian , Li Dengwang
Published: May 2022

Purpose

This study examined the methodological quality of radiomics to predict the effectiveness of neoadjuvant chemotherapy in nasopharyngeal carcinoma (NPC). We performed a meta-analysis of radiomics studies evaluating the bias risk and treatment response estimation.

Methods

Our study was conducted through a literature review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included radiomics-related papers, published prior to January 31, 2022, in our analysis to examine the effectiveness of neoadjuvant chemotherapy in NPC. The methodological quality was assessed using the radiomics quality score. The intra-class correlation coefficient (ICC) was employed to evaluate inter-reader reproducibility. The pooled area under the curve (AUC), pooled sensitivity, and pooled specificity were used to assess the ability of radiomics to predict response to neoadjuvant chemotherapy in NPC. Lastly, the Quality Assessment of Diagnostic Accuracy Studies technique was used to analyze the bias risk.

Results

A total of 12 studies were eligible for our systematic review, and 6 papers were included in our meta-analysis. The radiomics quality score was set from 7 to 21 (maximum score: 36). There was satisfactory ICC (ICC = 0.987, 95% CI: 0.957–0.996). The pooled sensitivity and specificity were 0.88 (95% CI: 0.71–0.95) and 0.82 (95% CI: 0.68–0.91), respectively. The overall AUC was 0.91 (95% CI: 0.88–0.93).

Conclusion

Prediction response of neoadjuvant chemotherapy in NPC using machine learning and radiomics is beneficial in improving standardization and methodological quality before applying it to clinical practice.
Exosomes Derived From Dendritic Cells Infected With Toxoplasma gondii Show Antitumoral Activity in a Mouse Model of Colorectal Cancer
Authors: Lu Jinmiao , Wei Nana , Zhu Shilan , Chen Xiaoyu , Gong Haiyan , Mi Rongsheng , Huang Yan , Chen Zhaoguo , Li Guoqing
Published: May 2022

Pathogen-based cancer therapies have been widely studied. Parasites, such as Toxoplasma gondii have elicited great interest in cancer therapy. Considering safety in clinical applications, we tried to develop an exosome-based immunomodulator instead of a live parasite for tumor treatment. The exosomes, called DC-Me49-exo were isolated from culture supernatants of dendritic cells (DCs) infected with the Me49 strain of T. gondii and identified. We assessed the antitumoral effect of these exosomes in a mouse model of colorectal cancer (CRC). Results showed that the tumor growth was significantly inhibited after treatment with DC-Me49-exo. Proportion of polymorphonuclear granulocytic bone marrow-derived suppressor cells (G-MDSCs, CD11b+Ly6G+) and monocytic myeloid-derived suppressor cells (M-MDSCs, CD11b+Ly6C+) were decreased in the DC-Me49-exo group compared with the control groups in vitro and in vivo. The proportion of DCs (CD45+CD11c+) increased significantly in the DC-Me49-exo group. Levels of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly decreased after treatment with DC-Me49-exo. Furthermore, we found that DC-Me49-exo regulated the lever of MDSC mainly by inhibiting the signal transducer and activator of transcription (STAT3) signaling pathway. These results indicated that exosomes derived from DCs infected with T. gondii could be used as part of a novel cancer therapeutic strategy by reducing the proportion of MDSCs.