bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Analyses of Sperm DNA Methylomes Among Three Commercial Pig Breeds Reveal Vital Hypomethylated Regions Associated With Spermatogenesis and Embryonic Development
Authors: Chen Siqian , Liu Shuli , Mi Siyuan , Li Wenlong , Zhang Shengli , Ding Xiangdong , Yu Ying
Published: October 2021

Identifying epigenetic changes is essential for an in-depth understanding of phenotypic diversity and pigs as the human medical model for anatomizing complex diseases. Abnormal sperm DNA methylation can lead to male infertility, fetal development failure, and affect the phenotypic traits of offspring. However, the whole genome epigenome map in pig sperm is lacking to date. In this study, we profiled methylation levels of cytosine in three commercial pig breeds, Landrace, Duroc, and Large White using whole-genome bisulfite sequencing (WGBS). The results showed that the correlation of methylation levels between Landrace and Large White pigs was higher. We found that 1,040–1,666 breed-specific hypomethylated regions (HMRs) were associated with embryonic developmental and economically complex traits for each breed. By integrating reduced representation bisulfite sequencing (RRBS) public data of pig testis, 1743 conservated HMRs between sperm and testis were defined, which may play a role in spermatogenesis. In addition, we found that the DNA methylation patterns of human and pig sperm showed high similarity by integrating public data from WGBS and chromatin immunoprecipitation sequencing (ChIP-seq) in other mammals, such as human and mouse. We identified 2,733 conserved HMRs between human and pig involved in organ development and brain-related traits, such as NLGN1 (neuroligin 1) containing a conserved-HMR between human and pig. Our results revealed the similarities and diversity of sperm methylation patterns among three commercial pig breeds and between human and pig. These findings are beneficial for elucidating the mechanism of male fertility, and the changes in commercial traits that undergo strong selection.
Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis
Authors: Ó Maoldomhnaigh Cilian , Cox Donal J. , Phelan James J. , Mitermite Morgane , Murphy Dearbhla M. , Leisching Gina , Thong Lorraine , O’Leary Seónadh M. , Gogan Karl M. , McQuaid Kate , Coleman Amy M. , Gordon Stephen V. , Basdeo Sharee A. , Keane Joseph
Published: October 2021

In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb.
Blockade of TLR2 and TLR4 Attenuates Inflammatory Response and Parasite Load in Cutaneous Leishmaniasis
Authors: Carneiro Pedro Paulo , Dórea Andreza S. , Oliveira Walker N. , Guimarães Luiz Henrique , Brodskyn Claúdia , Carvalho Edgar M. , Bacellar Olívia
Published: October 2021

Human cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a pronounced inflammatory response associated with ulcer development. Monocytes/macrophages, the main cells harboring parasites, are largely responsible for parasite control. Toll-like receptor (TLR) signaling leads to the transcription of inflammatory mediators, such as IL-1β and TNF during innate immune response. TLR antagonists have been used in the treatment of inflammatory disease. The neutralization of these receptors may attenuate an exacerbated inflammatory response. We evaluated the ability of TLR2 and TLR4 antagonists to modulate host immune response in L. braziliensis-infected monocytes and cells from CL patient skin lesions. Following TLR2 and TLR4 neutralization, decreased numbers of infected cells and internalized parasites were detected in CL patient monocytes. In addition, reductions in oxidative burst, IL-1β, TNF and CXCL9 production were observed. TNF production by cells from CL lesions also decreased after TLR2 and TLR4 neutralization. The attenuation of host inflammatory response after neutralizing these receptors suggests the potential of TLR antagonists as immunomodulators in association with antimonial therapy in human cutaneous leishmaniasis.
The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer
Authors: Subtil Beatriz , Cambi Alessandra , Tauriello Daniele V. F. , de Vries I. Jolanda M.
Published: October 2021

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
Development and Verification of the Hypoxia- and Immune-Associated Prognostic Signature for Pancreatic Ductal Adenocarcinoma
Authors: Chen Dongjie , Huang Hui , Zang Longjun , Gao Wenzhe , Zhu Hongwei , Yu Xiao
Published: October 2021

We aim to construct a hypoxia- and immune-associated risk score model to predict the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). By unsupervised consensus clustering algorithms, we generate two different hypoxia clusters. Then, we screened out 682 hypoxia-associated and 528 immune-associated PDAC differentially expressed genes (DEGs) of PDAC using Pearson correlation analysis based on the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression project (GTEx) dataset. Seven hypoxia and immune-associated signature genes (S100A16, PPP3CA, SEMA3C, PLAU, IL18, GDF11, and NR0B1) were identified to construct a risk score model using the Univariate Cox regression and the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, which stratified patients into high- and low-risk groups and were further validated in the GEO and ICGC cohort. Patients in the low-risk group showed superior overall survival (OS) to their high-risk counterparts (p < 0.05). Moreover, it was suggested by multivariate Cox regression that our constructed hypoxia-associated and immune-associated prognosis signature might be used as the independent factor for prognosis prediction (p < 0.001). By CIBERSORT and ESTIMATE algorithms, we discovered that patients in high-risk groups had lower immune score, stromal score, and immune checkpoint expression such as PD-L1, and different immunocyte infiltration states compared with those low-risk patients. The mutation spectrum also differs between high- and low-risk groups. To sum up, our hypoxia- and immune-associated prognostic signature can be used as an approach to stratify the risk of PDAC.
Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence
Authors: Le Phuong T. , Ha Ngoc , Tran Ngan K. , Newman Andrew G. , Esselen Katharine M. , Dalrymple John L. , Schmelz Eva M. , Bhandoola Avinash , Xue Hai-Hui , Singh Prim B. , Thai To-Ha
Published: October 2021

Immune checkpoint blockade (ICB) relieves CD8+T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targetingCbx3/HP1γ in CD8+T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity atLef1andIl21r. LEF-1 and IL-21R are necessary forCbx3/HP1γ-deficient CD8+effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence ofCbx3/HP1γ-deficient CD8+T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4+Tregs. Thus, CD8+T cells heightened effector function consequent toCbx3/HP1γ deficiency may be distinct from functional reactivation by ICB, implicatingCbx3/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.
Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis
Authors: Wen Shuting , He Long , Zhong Zhuotai , Zhao Runyuan , Weng Senhui , Mi Hong , Liu Fengbin
Published: October 2021

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.
A Systematic Review and Meta-Analysis of Inpatient Mortality Associated With Nosocomial and Community COVID-19 Exposes the Vulnerability of Immunosuppressed Adults
Authors: Ponsford Mark J. , Ward Tom J. C. , Stoneham Simon M. , Dallimore Clare M. , Sham Davina , Osman Khalid , Barry Simon M. , Jolles Stephen , Humphreys Ian R. , Farewell Daniel
Published: October 2021

Background

Little is known about the mortality of hospital-acquired (nosocomial) COVID-19 infection globally. We investigated the risk of mortality and critical care admission in hospitalised adults with nosocomial COVID-19, relative to adults requiring hospitalisation due to community-acquired infection.

Methods

We systematically reviewed the peer-reviewed and pre-print literature from 1/1/2020 to 9/2/2021 without language restriction for studies reporting outcomes of nosocomial and community-acquired COVID-19. We performed a random effects meta-analysis (MA) to estimate the 1) relative risk of death and 2) critical care admission, stratifying studies by patient cohort characteristics and nosocomial case definition.

Results

21 studies were included in the primary MA, describing 8,251 admissions across 8 countries during the first wave, comprising 1513 probable or definite nosocomial COVID-19, and 6738 community-acquired cases. Across all studies, the risk of mortality was 1.3 times greater in patients with nosocomial infection, compared to community-acquired (95% CI: 1.005 to 1.683). Rates of critical care admission were similar between groups (Relative Risk, RR=0.74, 95% CI: 0.50 to 1.08). Immunosuppressed patients diagnosed with nosocomial COVID-19 were twice as likely to die in hospital as those admitted with community-acquired infection (RR=2.14, 95% CI: 1.76 to 2.61).

Conclusions

Adults who acquire SARS-CoV-2 whilst already hospitalised are at greater risk of mortality compared to patients admitted following community-acquired infection; this finding is largely driven by a substantially increased risk of death in individuals with malignancy or who had undergone transplantation. These findings inform public health and infection control policy and argue for individualised clinical interventions to combat the threat of nosocomial COVID-19, particularly for immunosuppressed groups.

Systematic Review Registration

PROSPERO CRD42021249023
Safety, Immunogenicity, Efficacy and Effectiveness of Inactivated Influenza Vaccines in Healthy Pregnant Women and Children Under 5 Years: An Evidence-Based Clinical Review
Authors: Bansal Amit , Trieu Mai-Chi , Mohn Kristin G. I. , Cox Rebecca Jane
Published: October 2021

Annual influenza vaccination is often recommended for pregnant women and young children to reduce the risk of severe influenza. However, most studies investigating the safety, immunogenicity, and efficacy or effectiveness of influenza vaccines are conducted in healthy adults. In this evidence-based clinical review, we provide an update on the safety profile, immunogenicity, and efficacy/effectiveness of inactivated influenza vaccines (IIVs) in healthy pregnant women and children <5 years old. Six electronic databases were searched until May 27, 2021. We identified 3,731 articles, of which 93 met the eligibility criteria and were included. The IIVs were generally well tolerated in pregnant women and young children, with low frequencies of adverse events following IIV administration; however, continuous vaccine safety monitoring systems are necessary to detect rare adverse events. IIVs generated good antibody responses, and the seroprotection rates after IIVs were moderate to high in pregnant women (range = 65%–96%) and young children (range = 50%–100%), varying between the different influenza types/subtypes and seasons. Studies show vaccine efficacy/effectiveness values of 50%–70% in pregnant women and 20%–90% in young children against lab-confirmed influenza, although the efficacy/effectiveness depended on the study design, host factors, vaccine type, manufacturing practices, and the antigenic match/mismatch between the influenza vaccine strains and the circulating strains. Current evidence suggests that the benefits of IIVs far outweigh the potential risks and that IIVs should be recommended for pregnant women and young children.
Advances in Universal CAR-T Cell Therapy
Authors: Lin Haolong , Cheng Jiali , Mu Wei , Zhou Jianfeng , Zhu Li
Published: October 2021

Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.
Acute Graft-Versus-Host Disease, Infections, Vascular Events and Drug Toxicities Affecting the Central Nervous System
Authors: Vinnakota Janaki Manoja , Zeiser Robert
Published: October 2021

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for patients with hematological malignancies. Acute Graftversushost diseases (GVHD) is a major immune mediated side effect of allo-HCT that can affect the central nervous system (CNS) in addition to post-allo-HCT vascular events, drug toxicity or infections. Here we summarize and discuss recent preclinical data on the CNS as a target of acute GVHD and the known mechanisms contributing to neurotoxicity with a focus on microglia and T cells. We also discuss open questions in the field and place the findings made in mouse models in a clinical context. While in mice the neurological deficits can be assessed in a controlled fashion, in patients the etiology of the CNS damage is difficult to attribute to acute GVHDversusinfections, vascular events, and drug-induced toxicity. Ultimately, we discuss novel therapies for GVHD of the CNS. Our understanding of the biological mechanisms that lead to neurotoxicity after allo-HCT increased over the last decade. This review provides insights into CNS manifestations of GVHDversusother etiologies of CNS damage in mice and patients.
Words to Matter: De novo Architected Materials Design Using Transformer Neural Networks
Authors: Yang Zhenze , Buehler Markus J.
Published: October 2021

Transformer neural networks have become widely used in a variety of AI applications, enabling significant advances in Natural Language Processing (NLP) and computer vision. Here we demonstrate the use of transformer neural networks in the de novo design of architected materials using a unique approach based on text input that enables the design to be directed by descriptive text, such as “a regular lattice of steel”. Since transformer neural nets enable the conversion of data from distinct forms into one another, including text into images, such methods have the potential to be used as a natural-language-driven tool to develop complex materials designs. In this study we use the Contrastive Language-Image Pre-Training (CLIP) and VQGAN neural networks in an iterative process to generate images that reflect text prompt driven materials designs. We then use the resulting images to generate three-dimensional models that can be realized using additive manufacturing, resulting in physical samples of these text-based materials. We present several such word-to-matter examples, and analyze 3D printed material specimen through associated additional finite element analysis, especially focused on mechanical properties including mechanism design. As an emerging new field, such language-based design approaches can have profound impact, including the use of transformer neural nets to generate machine code for 3D printing, optimization of processing conditions, and other end-to-end design environments that intersect directly with human language.
Inter-Kingdom Signaling of Stress Hormones: Sensing, Transport and Modulation of Bacterial Physiology
Authors: Boukerb Amine Mohamed , Cambronel Melyssa , Rodrigues Sophie , Mesguida Ouiza , Knowlton Rikki , Feuilloley Marc G. J. , Zommiti Mohamed , Connil Nathalie
Published: October 2021

Prokaryotes and eukaryotes have coexisted for millions of years. The hormonal communication between microorganisms and their hosts, dubbed inter-kingdom signaling, is a recent field of research. Eukaryotic signals such as hormones, neurotransmitters or immune system molecules have been shown to modulate bacterial physiology. Among them, catecholamines hormones epinephrine/norepinephrine, released during stress and physical effort, or used therapeutically as inotropes have been described to affect bacterial behaviors (i.e., motility, biofilm formation, virulence) of various Gram-negative bacteria (e.g., Escherichia coli, Salmonella enterica serovar Typhimurium, Pseudomonas aeruginosa, Vibrio sp.). More recently, these molecules were also shown to influence the physiology of some Gram-positive bacteria like Enterococcus faecalis. In E. coli and S. enterica, the stress-associated mammalian hormones epinephrine and norepinephrine trigger a signaling cascade by interacting with the QseC histidine sensor kinase protein. No catecholamine sensors have been well described yet in other bacteria. This review aims to provide an up to date report on catecholamine sensors in eukaryotes and prokaryotes, their transport, and known effects on bacteria.
Response of Sugarcane Rhizosphere Bacterial Community to Drought Stress
Authors: Liu Qi , Zhao Xiaowen , Liu Yue , Xie Sasa , Xing Yuanjun , Dao Jicao , Wei Beilei , Peng Yunchang , Duan Weixing , Wang Ziting
Published: October 2021

Sugarcane is an important sugar and energy crop, and its yield is greatly affected by drought. Although a large number of studies have shown that rhizosphere microorganisms can help improve the adaptability of plants to biotic or abiotic stresses, there is a lack of studies on the adaptability of sugarcane rhizosphere microbial communities to host plants. Therefore, we conducted drought stress treatment and normal irrigation treatment on three sugarcane varieties GT21, GT31, and GT42 widely cultivated in Guangxi. Using 16S rDNA sequencing technology to analyze the changes in abundance of the sugarcane rhizosphere bacterial community under different treatments, combined with the determination of soil enzyme activity, soil nutrient content, and sugarcane physiological characteristics, we explored the sugarcane rhizosphere bacterial community response to drought stress. In addition, we used the structural equation model to verify the response path of sugarcane rhizosphere bacteria. The results show that the bacterial community structure in the rhizosphere of sugarcane is stable under normal water conditions. The change in the bacterial community structure under drought stress has a 25.2% correlation with the drought adaptability of sugarcane, but the correlation with drought stress is as high as 42.17%. The changes in abundance of rhizosphere bacteria under drought stress are mainly concentrated in the phylum Rhizobiales and Streptomycetales. This change is directly related to the physiological state of the host plant under drought stress, soil available phosphorus, soil urease and soil acid protease. We investigated the response species of rhizosphere microorganisms and their response pathways under drought stress, providing a scientific basis for rhizosphere microorganisms to assist host plants to improve drought adaptability.
Opening the Gap: Rare Lichens With Rare Cyanobionts – Unexpected Cyanobiont Diversity in Cyanobacterial Lichens of the Order Lichinales
Authors: Jung Patrick , Brust Katharina , Schultz Matthias , Büdel Burkhard , Donner Antje , Lakatos Michael
Published: October 2021

The last decades of research led to a change in understanding of lichens that are now seen as self-sustaining micro-ecosystems, harboring diverse microbial organisms in tight but yet not fully understood relationships. Among the diverse interdependencies, the relationship between the myco- and photobiont is the most crucial, determining the shape, and ecophysiological properties of the symbiotic consortium. Roughly 10% of lichens associate with cyanobacteria as their primary photobiont, termed cyanolichens. Up to now, the diversity of cyanobionts of bipartite lichens resolved by modern phylogenetic approaches is restricted to the filamentous and heterocytous genera of the order Nostocales. Unicellular photobionts were placed in the orders Chroococcales, Pleurocapsales, and Chroococcidiopsidales. However, especially the phylogeny and taxonomy of the Chroococcidiopsidales genera remained rather unclear. Here we present new data on the identity and phylogeny of photobionts from cyanolichens of the genera Gonohymenia, Lichinella, Peccania, and Peltula from a broad geographical range. A polyphasic approach was used, combining morphological and cultivation-depending characteristics (microscopy, staining techniques, life cycle observation, baeocyte motility, and nitrogen fixation test) with phylogenetic analyses of the 16S rRNA and 16S–23S ITS gene region. We found an unexpectedly high cyanobiont diversity in the cyanobacterial lichens of the order Lichinales, including two new genera and seven new species, all of which were not previously perceived as lichen symbionts. As a result, we describe the novel unicellular Chroococcidiopsidales genera Pseudocyanosarcina gen. nov. with the species Pseudocyanosarcina phycocyania sp. nov. (from Peltula clavata, Australia) and Compactococcus gen. nov. with the species Compactococcus sarcinoides sp. nov. (from Gonohymenia sp., Australia) and the new Chroococcidiopsidales species Aliterella compacta sp. nov. (from Peltula clavata, Australia), Aliterella gigantea sp. nov. (from Peltula capensis; South Africa), Sinocapsa ellipsoidea sp. nov. (from Peccania cerebriformis, Austria), as well as the two new Nostocales species Komarekiella gloeocapsoidea sp. nov. (from Gonohymenia sp., Czechia) and Komarekiella globosa sp. nov. (from Lichinella cribellifera, Canary Islands, Spain). Our study highlights the role of cyanolichens acting as a key in untangling cyanobacterial taxonomy and diversity. With this study, we hope to stimulate further research on photobionts, especially of rare cyanolichens.
Phage Selective Pressure Reduces Virulence of Hypervirulent Klebsiella pneumoniae Through Mutation of the wzc Gene
Authors: Song Lingjie , Yang Xianggui , Huang Jinwei , Zhu Xiaokui , Han Guohui , Wan Yan , Xu Ying , Luan Guangxin , Jia Xu
Published: October 2021

Hypervirulent Klebsiella pneumoniae (hvKp), one of the major community-acquired pathogens, can cause invasive infections such as liver abscess. In recent years, bacteriophages have been used in the treatment of K. pneumoniae, but the characteristics of the phage-resistant bacteria produced in the process of phage therapy need to be evaluated. In this study, two Podoviridae phages, hvKpP1 and hvKpP2, were isolated and characterized. In vitro and in vivo experiments demonstrated that the virulence of the resistant bacteria was significantly reduced compared with that of the wild type. Comparative genomic analysis of monoclonal sequencing showed that nucleotide deletion mutations of wzc and wcaJ genes led to phage resistance, and the electron microscopy and mucoviscosity results showed that mutations led to the loss of the capsule. Meanwhile, animal assay indicated that loss of capsule reduced the virulence of hvKp. These findings contribute to a better understanding of bacteriophage therapy, which not only can kill bacteria directly but also can reduce the virulence of bacteria by phage screening.
Comprehensive Comparative Genomics and Phenotyping of Methylobacterium Species
Authors: Alessa Ola , Ogura Yoshitoshi , Fujitani Yoshiko , Takami Hideto , Hayashi Tetsuya , Sahin Nurettin , Tani Akio
Published: October 2021

The pink-pigmented facultative methylotrophs (PPFMs), a major bacterial group found in the plant phyllosphere, comprise two genera:MethylobacteriumandMethylorubrum.They have been separated into three major clades: A, B (Methylorubrum), and C. Within these genera, however, some species lack either pigmentation or methylotrophy, which raises the question of what actually defines the PPFMs. The present study employed a comprehensive comparative genomics approach to reveal the phylogenetic relationship among the PPFMs and to explain the genotypic differences that confer their different phenotypes. We newly sequenced the genomes of 29 relevant-type strains to complete a dataset for almost all validly published species in the genera. Through comparative analysis, we revealed that methylotrophy, nitrate utilization, and anoxygenic photosynthesis are hallmarks differentiating the PPFMs from the otherMethylobacteriaceae. TheMethylobacteriumspecies in clade A, including the type speciesMethylobacterium organophilum, were phylogenetically classified into six subclades, each possessing relatively high genomic homology and shared phenotypic characteristics. One of these subclades is phylogenetically close toMethylorubrumspecies; this finding led us to reunite the two genera into a single genusMethylobacterium. Clade C, meanwhile, is composed of phylogenetically distinct species that share relatively higher percent G+C content and larger genome sizes, including larger numbers of secondary metabolite clusters. Most species of clade C and some of clade A have the glutathione-dependent pathway for formaldehyde oxidation in addition to the H4MPT pathway. Some species cannot utilize methanol due to their lack of MxaF-type methanol dehydrogenase (MDH), but most harbor an XoxF-type MDH that enables growth on methanol in the presence of lanthanum. The genomes of PPFMs encode between two and seven (average 3.7) genes for pyrroloquinoline quinone-dependent alcohol dehydrogenases, and their phylogeny is distinctly correlated with their genomic phylogeny. All PPFMs were capable of synthesizing auxin and did not induce any immune response in rice cells. Other phenotypes including sugar utilization, antibiotic resistance, and antifungal activity correlated with their phylogenetic relationship. This study provides the first inclusive genotypic insight into the phylogeny and phenotypes of PPFMs.
Maternal Choline Supplementation as a Potential Therapy for Down Syndrome: Assessment of Effects Throughout the Lifespan
Authors: Powers Brian E. , Velazquez Ramon , Strawderman Myla S. , Ginsberg Stephen D. , Mufson Elliott J. , Strupp Barbara J.
Published: October 2021

Maternal choline supplementation (MCS) has emerged as a promising therapy to lessen the cognitive and affective dysfunction associated with Down syndrome (DS). Choline is an essential nutrient, especially important during pregnancy due to its wide-ranging ontogenetic roles. Using the Ts65Dn mouse model of DS, our group has demonstrated that supplementing the maternal diet with additional choline (4-5 × standard levels) during pregnancy and lactation improves spatial cognition, attention, and emotion regulation in the adult offspring. The behavioral benefits were associated with a rescue of septohippocampal circuit atrophy. These results have been replicated across a series of independent studies, although the magnitude of the cognitive benefit has varied. We hypothesized that this was due, at least in part, to differences in the age of the subjects at the time of testing. Here, we present new data that compares the effects of MCS on the attentional function of adult Ts65Dn offspring, which began testing at two different ages (6 vs. 12 months of age). These data replicate and extend the results of our previous reports, showing a clear pattern indicating that MCS has beneficial effects in Ts65Dn offspring throughout life, but that the magnitude of the benefit (relative to non-supplemented offspring) diminishes with aging, possibly because of the onset of Alzheimer's disease-like neuropathology. In light of growing evidence that increased maternal choline intake during pregnancy is beneficial to the cognitive and affective functioning of all offspring (e.g., neurotypical and DS), the addition of this nutrient to a prenatal vitamin regimen would be predicted to have population-wide benefits and provide early intervention for fetuses with DS, notably including babies born to mothers unaware that they are carrying a fetus with DS.
Which Comes First in Sports Vision Training: The Software or the Hardware Update? Utility of Electrophysiological Measures in Monitoring Specialized Visual Training in Youth Athletes
Authors: Poltavski Dmitri , Biberdorf David , Praus Poltavski Carolina
Published: October 2021

In the present study we combined popular methods of sports vision training (SVT) with traditional oculomotor protocols of Optometric Vision Therapy (OVT) and electrophysiological indexes of EEG and VEP activity to monitor training progress and changes in performance of youth ice hockey players without the history of concussion. We hypothesized that administration of OVT protocols before SVT training may result in larger performance improvements compared to the reverse order due to the initial strengthening of visual hardware capable of handling greater demands during training of visuomotor integration and information processing skills (visual software). In a cross-over design 53 youth ice hockey players (ages 13–18) were randomly assigned to one of the two training groups. Group one (hardware-software group) completed 5 weeks of oculomotor training first followed by 5 weeks of software training. For group 2 (software-hardware) the order of procedures were reversed. After 10 weeks of training both groups significantly improved their performance on all but one measure of the Nike/Senaptec Sensory station measures. Additionally, the software-hardware training order resulted in significantly lower frontal theta-to-gamma amplitude ratios on the Nike/Senaptec test of Near-Far Quickness as well as in faster P100 latencies. Both training orders also resulted in significant decreases in post-treatment P100 amplitude to transient VEP stimuli as well as decreased theta-gamma ratios for perception span, Go/No-Go and Hand Reaction time. The observed changes in the electrophysiological indexes in the present study are thought to reflect greater efficiency in visual information processing and cognitive resource allocation following 10 weeks of visual training. There is also some evidence of the greater effectiveness of the software-hardware training order possibly due to the improved preparedness of the oculomotor system in the youth athletes for administration of targeted protocols of the Optometric Vision Therapy.
Neuroplasticity and Motor Rehabilitation in Multiple Sclerosis: A Systematic Review on MRI Markers of Functional and Structural Changes
Authors: Tavazzi Eleonora , Cazzoli Marta , Pirastru Alice , Blasi Valeria , Rovaris Marco , Bergsland Niels , Baglio Francesca
Published: October 2021

Background: Motor rehabilitation is routinely used in clinical practice as an effective method to reduce progressive disability gain in multiple sclerosis (MS), but rehabilitation approaches are typically unstandardized, and only few studies have investigated the impact of rehabilitation on brain neuroplasticity.

Objective: To summarize and critically analyze studies applying MRI markers of functional connectivity and structural changes to assess the effect of motor rehabilitation on brain neuroplasticity in MS.

Methods: Literature search was performed using PubMed and EMBASE, selecting studies having as a subject motor rehabilitation and advanced MRI techniques investigating neuroplasticity in adult patients affected by MS.

Results: Seventeen out of 798 papers were selected, of which 5 applied structural MRI (4 diffusion tensor imaging, 1 volumetric measurements), 7 applied functional fMRI (5 task-related fMRI, 2 resting-state fMRI) whereas the remaining 5 applied both structural and functional imaging.

Discussion: The considerable data heterogeneity and the small sample sizes characterizing the studies limit interpretation and generalization of the results. Overall, motor rehabilitation promotes clinical improvement, paralleled by positive adaptive brain changes, whose features and extent depend upon different variables, including the type of rehabilitation approach. MRI markers of functional and structural connectivity should be implemented in studies testing the efficacy of motor rehabilitation. They allow for a better understanding of neuroplastic mechanisms underlying rehabilitation-mediated clinical achievements, facilitating the identification of rehabilitation strategies tailored to patients' needs and abilities.
Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord
Authors: Jensen Thomas Leth , Gøtzsche Casper René , Woldbye David P. D.
Published: October 2021

In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.
Improving Healthy Food Choices in Low-Income Settings in the United States Using Behavioral Economic-Based Adaptations to Choice Architecture
Authors: Anderson Emma , Wei Ruobin , Liu Binkai , Plummer Rachel , Kelahan Heather , Tamez Martha , Marrero Abrania , Bhupathiraju Shilpa , Mattei Josiemer
Published: October 2021

Low diet quality is a significant public health problem in the United States, especially among low-income populations. The food environment influences dietary choices. When applied to eating behavior, behavioral economics (BE) recognizes that decision biases instigated by a food environment saturated with unhealthy foods may lead people to purchase such foods, even when they possess the necessary information and skills to make healthy dietary choices. Choice architecture, a BE concept that involves modifying the appeal or availability of choices to “nudge” people toward a certain choice, retains freedom of choice but makes unhealthy options less convenient or visible. Choice architecture has been demonstrated to influence food choices in various settings, including supermarkets, convenience stores, and food pantries. These modifications are low-cost and feasible to implement, making them a viable strategy to help “nudge” patrons toward healthier choices in food establishments serving low-income populations, including food pantries and retailers accepting the Supplemental Nutrition Assistance Program. This narrative review searched, appraised, and underscored the strengths and limitations of extant research studies that used choice architecture adaptations to influence food choices among low-income populations in the United States. Findings from studies in food pantry settings suggest the potential of BE strategies to improve the healthfulness of food choices and dietary intake in low-income populations. In food retail settings, research suggests that BE strategies increase sales of healthy foods, like fruits and vegetables. We identify new areas of research needed to determine if BE-based modifications in low-income settings have sustained impacts on diet quality.
Surgical Outcomes After Neoadjuvant Chemoimmunotherapy for Resectable Non-Small Cell Lung Cancer
Authors: Hu Yan , Ren Si-Ying , Wang Ruo-Yao , Zeng Chao , Li Ji-Na , Xiao Peng , Wu Fang , Yu Feng-Lei , Liu Wen-Liang
Published: October 2021

Background

Neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer (NSCLC) represents an important research topic. Despite the potential benefits of this approach, the inflammatory responses and adverse events associated with neoadjuvant chemoimmunotherapy can present technical challenges and compromise a planned resection. This study assessed the safety and feasibility of neoadjuvant chemoimmunotherapy followed by surgery for resectable NSCLC.

Methods

The study was conducted from May 2019 to March 2021. Patients who were age 18 years or older, were diagnosed with stage Ib–IIIb NSCLC, and received neoadjuvant chemoimmunotherapy followed by surgery were included. Demographic information, clinical and pathologic characteristics, data about neoadjuvant therapy, and surgical details were collected by retrospective chart review. Toxicity profiles were collected retrospectively or by telephone follow-up.

Results

Twenty patients were included in this study. The median age was 56 years (range, 48–72 years), and 18 patients (90%) were men. Squamous carcinoma (14/20, 70%) was the most common cancer type, followed by adenocarcinoma (4/20, 20%), adenosquamous carcinoma (1/20, 5%), and large cell neuroendocrine carcinoma (1/20, 5%). All patients received two to four cycles of neoadjuvant therapy, and the median interval between final therapy and surgery was 49 days (range, 23–133 days). Computed tomography evaluation after neoadjuvant therapy showed partial response in 15 patients (75%) and stable disease in 5 (25%). Final pathologic examinations showed major pathologic response in eight patients, including pathologic complete response in five (25%). Most patients (18/20, 90%) had reduced pathologic staging. Twelve patients (60%) underwent open thoracotomy; the other eight patients underwent minimally invasive surgery, which was uneventful and without intraoperative conversion to open thoracotomy. No perioperative deaths occurred, and only seven patients (35%) developed postoperative complications. Most patients experienced only grade 1–2 adverse effects and laboratory abnormalities during neoadjuvant therapy, and no grade 3 or worse adverse effects or laboratory abnormalities occurred. No patients experienced surgical delays as a result of immune-related adverse events.

Conclusions

Preoperative administration of chemoimmunotherapy for patients with resectable NSCLC was safe and feasible.
Tumor-Educated Platelet miR-18a-3p as a Novel Liquid-Biopsy Biomarker for Early Diagnosis and Chemotherapy Efficacy Monitoring in Nasopharyngeal Carcinoma
Authors: Sun Kaiyu , Wang Hui , Xu Xianqun , Wei Xiuqi , Su Jingyu , Zhu Kaidong , Fan Junli
Published: October 2021

Aims

To evaluate the value of tumor-educated platelet (TEP) miR-18a-3p in the early diagnosis and chemotherapy efficacy monitoring of nasopharyngeal carcinoma (NPC).

Methods

Expression levels of miR-18a-3p in platelets and plasma were detected by relative quantitative real-time PCR in NPC patients (n=54) and normal subjects (n=36). Diagnostic values of TEP miR-18a-3p for NPC was assessed by receiver operating characteristic (ROC) curve analysis. Follow up study was carried out to observe the dynamic changes of TEP miR-18a-3p with chemotherapy on 3 NPC patients.

Results

The expression levels of TEP miR-18a-3p in NPC patients were significantly higher than that in healthy controls (p < 0.0001). ROC curve analysis showed that the area under the curve (AUC) value was 0.841, the sensitivity and specificity for the diagnosis of NPC were 87% and 72.7%. No correlation was found between expression levels of TEP miR-18a-3p and patients’ clinical parameters and their NPC tumor-node-metastasis (TNM) stage. The positive rate of TEP miR-18a-3p and EBV DNA for NPC diagnosis were 85.4% and 66.7%. TEP miR-18a-3p expression were down-regulated after 77.8% (7 of 9) of chemotherapy, and in 66.7% (2 of 3) patients, TEP miR-18a-3p levels decreased after 3 cycles of chemotherapy.

Conclusion

The expression levels of TEP miR-18a-3p are upregulated in NPC and have a high probability to downregulated after chemotherapy, indicating a significant clinical value. TEP miR-18a-3p might serve as a novel type of liquid-biopsy biomarker for early diagnosis and chemotherapy efficacy monitoring in NPC.
Efficacy and Response Biomarkers of Apatinib in the Treatment of Malignancies in China: A Review
Authors: Tian Zhichao , Niu Xiaohui , Yao Weitao
Published: October 2021

Apatinib is a multitarget tyrosine kinase inhibitor marketed in China for the treatment of advanced gastric cancer (GC) and hepatocellular carcinoma (HCC). It has also been used off-label for the treatment of many other malignancies. To comprehensively evaluate the efficacy of apatinib as a targeted therapy in the treatment of malignancies, we conducted systematic online and manual searches of the literature on apatinib in the treatment of malignancies. In this review, we first summarized the efficacy of apatinib against various malignancies based on clinical trials where results have been reported. In prospectively registered trials, apatinib has been proven to be effective against GC, HCC, lung cancer, breast cancer, sarcoma, esophageal cancer, colorectal cancer, ovarian cancer, cervical cancer, cholangiocarcinoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, and differentiated thyroid cancer. The response biomarkers for apatinib were also reviewed. This review will serve as a good reference for the application of apatinib in clinical studies and the design of clinical trials.