bluuebunny/crossref_metadata_2025 huggingface dataset:
Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity
Authors: Goddi Anna , Carmona Alanis , Schroedl Liesl , White Jeremy M. , Piron Matthew J. , De Leon Avelino , Casimiro Isabel , Hoffman Alexandria , Gonzalez Porras Maria A. , Brey Eric M. , Brady Matthew J. , Cohen Ronald N.
Published: July 2021

Obesity affects nearly one billion globally and can lead to life-threatening sequelae. Consequently, there is an urgent need for novel therapeutics. We have previously shown that laminin, alpha 4 (Lama4) knockout in mice leads to resistance to adipose tissue accumulation; however, the relationship between LAMA4 and obesity in humans has not been established. In this study we measured laminin-α chain and collagen mRNA expression in the subcutaneous white adipose tissue (sWAT) of mice placed on chow (RCD) or 45% high fat diet (HFD) for 8 weeks, and also in HFD mice then placed on a “weight loss” regimen (8 weeks HFD followed by 6 weeks RCD). To assess extracellular matrix (ECM) components in humans with obesity, laminin subunit alpha mRNA and protein expression was measured in sWAT biopsies of female control subjects (BMI<30) or subjects with obesity undergoing bariatric surgery at the University of Chicago Medical Center (BMI>35) both before and three months after surgery. Lama4 was significantly higher in sWAT of HFD compared to RCD mice at both the RNA and protein level (p<0.001, p<0.05 respectively). sWAT from human subjects with obesity also showed significantly higher LAMA4 mRNA (p<0.01) and LAMA4 protein expression (p<0.05) than controls. Interestingly, even though LAMA4 expression was increased in both humans and murine models of obesity, no significant difference in Lama4 or LAMA4 expression was detected following short-term weight loss in either mouse or human samples, respectively. From these results we propose a significant association between obesity and elevated LAMA4 expression in humans, as well as in mouse models of obesity. Further studies should clarify the mechanisms underlying this association to target LAMA4 effectively as a potential therapy for obesity.
Feasibility and Safety of Outpatient Thyroidectomy: A Narrative Scoping Review
Authors: Philteos Justine , Baran Elif , Noel Christopher W. , Pasternak Jesse D. , Higgins Kevin M. , Freeman Jeremy L. , Chiodo Albino , Eskander Antoine
Published: July 2021

Background

Outpatient thyroid surgery is gaining popularity as it can reduce length of hospital stay, decrease costs of care, and increase patient satisfaction. There remains a significant variation in the use of this practice including a perceived knowledge gap with regards to the safety of outpatient thyroidectomies and how to go about implementing standardized institutional protocols to ensure safe same-day discharge. This review summarizes the information available on the subject based on existing published studies and guidelines.

Methods

This is a scoping review of the literature focused on the safety, efficacy and patient satisfaction associated with outpatient thyroidectomies. The review also summarizes and editorializes the most recent American Thyroid Association guidelines.

Results

In total, 11 studies were included in the analysis: 6 studies were retrospective analyses, 3 were retrospective reviews of prospective data, and 2 were prospective studies. The relative contraindications to outpatient thyroidectomy have been highlighted, including: complex medical conditions, anticipated difficult surgical dissection, patients on anticoagulation, lack of home support, and patient anxiety toward an outpatient procedure. Utilizing these identified features, an outpatient protocol has been proposed.

Conclusion

The salient features regarding patient safety and selection criteria and how to develop a protocol implementing ambulatory thyroidectomies have been identified and reviewed. In conclusion, outpatient thyroidectomy is safe, associated with high patient satisfaction and decreased health costs when rigorous institutional protocols are established and implemented. Successful outpatient thyroidectomies require standardized preoperative selection, clear discharge criteria and instructions, and interprofessional collaboration between the surgeon, anesthetist and same-day nursing staff.
Profiling of Insulin-Like Growth Factor Binding Proteins (IGFBPs) in Obesity and Their Association With Ox-LDL and Hs-CRP in Adolescents
Authors: Rahman Abdur , Hammad Maha M. , Al Khairi Irina , Cherian Preethi , Al-Sabah Reem , Al-Mulla Fahd , Abu-Farha Mohamed , Abubaker Jehad
Published: July 2021

Insulin-like growth factor binding proteins (IGFBPs) are critical modulators of metabolism. In adults, IGFBPs are associated with obesity and insulin resistance. However, the association of IGFBPs with metabolic homeostasis in children and adolescents is not yet fully characterized. In this study we investigated the association of plasma IGFBPs (IGFBP-1, 3 and 7) with weight, central adiposity and cardiovascular disease markers Hs-CRP and Ox-LDL. A total of 420 adolescents (age 11-14 years) were recruited from public middle schools in Kuwait. IGFBPs were measured using bead-based multiplexing while Hs-CRP and Ox-LDL were measured using ELISA. Results showed that levels of IGFBP-1 were significantly lower in obese and overweight children when compared to normal weight children. Correlation analysis showed negative association between the level of IGFBP-1 and waist circumference to height (WC/Ht) ratio. IGFBP-1 level was also negatively associated with Hs-CRP. It was also observed that the levels of IGFBP-3 and IGFBP-7 were negatively correlated with Ox-LDL. Our data demonstrate a strong negative association of IGFBP-1 with overweight/obesity, and the inflammatory marker Hs-CRP. This was not seen with the levels of IGFBP-3 and 7. The association of IGFBP-1 with central adiposity (WC/Ht ratio) was stronger than its association with BMI-for-age z-score. Therefore we suggest that IGFBP-1 could potentially be used as a sensitive biomarker for obesity and its subsequent effects in screening and monitoring of obesity-related metabolic complications in adolescents.
Marine Debris on New Zealand Beaches - Baseline Data to Evaluate Regional Variances
Authors: van Gool Ella , Campbell Marnie , Wallace Pip , Hewitt Chad L.
Published: July 2021

Terrestrial sources of marine debris on beaches are substantial, increasing, and are primarily a result of mismanaged waste on land. The scale, source, and composition of beached marine debris in New Zealand was determined by surveying 41 beaches, with triplicate belt transects, across the North and South Islands. Results demonstrated a significant spatial variance, with the South Island showing a significantly higher mean density than the more populated North Island by count as well as by weight. The majority of all anthropogenic marine debris detected was plastic and arrived through the water. Explanations for regional variances in debris presence are difficult to ascertain with certainty but could not be explained by population density and proximity. These findings contribute to the understudied field of marine debris research in New Zealand and the Southern Hemisphere and provide a starting point for evidence-based mitigation. Recommended changes to future monitoring programs are made. This first national baseline study of marine debris in New Zealand serves as a reference for follow-up studies, including research at other locations.
Reducing Anchorage in Ports: Changing Technologies, Opportunities and Challenges
Authors: Heaver Trevor D.
Published: July 2021

Developments in digitisation and the need to reduce carbon emissions have increased attention on port call optimisation. Just-in-time arrival for ships is recognised in the literature as being achieved more readily in container trades than in bulk trades. This paper examines the governance and trade logistics conditions in the bulk trades of Vancouver, Canada, as the increasing number of ships at anchor gives rise to the need to explore the absence of initiatives to limit anchorage and to identify what is done elsewhere to manage the incidence of anchorage. Newcastle, Australia, is used to identify critical governance and logistics factors that played a role in the development of innovative practices to reduce anchorage. The major obstacles to port call optimisation lie in the organisational and behavioural aspects of maritime logistics, not in the technology of digitisation.
Tandem Mass Spectrometry Screening for Inborn Errors of Metabolism in Newborns and High-Risk Infants in Southern China: Disease Spectrum and Genetic Characteristics in a Chinese Population
Authors: Tan Jianqiang , Chen Dayu , Chang Rongni , Pan Lizhen , Yang Jinling , Yuan Dejian , Huang Lihua , Yan Tizhen , Ning Haiping , Wei Jiangyan , Cai Ren
Published: July 2021

Inborn errors of metabolism (IEMs) often causing progressive and irreversible neurological damage, physical and intellectual development lag or even death, and serious harm to the family and society. The screening of neonatal IEMs by tandem mass spectrometry (MS/MS) is an effective method for early diagnosis and presymptomatic treatment to prevent severe permanent sequelae and death. A total of 111,986 healthy newborns and 7,461 hospitalized high-risk infants were screened for IEMs using MS/MS to understand the characteristics of IEMs and related gene mutations in newborns and high-risk infants in Liuzhou. Positive samples were analyzed by Sanger sequencing or next-generation sequencing. The results showed that the incidence of IEMs in newborns in the Liuzhou area was 1/3,733, and the incidence of IEMs in high-risk infants was 1/393. Primary carnitine deficiency (1/9,332), phenylketonuria (1/18,664), and isovaleric acidemia (1/37,329) ranked the highest in neonates, while citrullinemia type II ranked the highest in high-risk infants (1/1,865). Further, 56 mutations of 17 IEMs-related genes were found in 49 diagnosed children. Among these, HPD c.941T > C, CBS c.1465C > T, ACADS c.337G > A, c.1195C > T, ETFA c.737G > T, MMACHC 1076bp deletion, PCCB c.132-134delGACinsAT, IVD c.548C > T, c.757A > G, GCDH c.1060G > T, and HMGCL c.501C > G were all unreported variants. Some related hotspot mutations were found, including SLC22A5 c.51C > G, PAH c.1223G > A, IVD c.1208A > G, ACADS c.625G > A, and GCDH c.532G > A. These results show that the overall incidence of IEMs in the Liuzhou area is high. Hence, the scope of IEMs screening and publicity and education should be expanded for a clear diagnosis in the early stage of the disease.
Filtering of Data-Driven Gene Regulatory Networks Using Drosophila melanogaster as a Case Study
Authors: Cuesta-Astroz Yesid , Gischkow Rucatti Guilherme , Murgas Leandro , SanMartín Carol D. , Sanhueza Mario , Martin Alberto J. M.
Published: July 2021

Gene Regulatory Networks (GRNs) allow the study of regulation of gene expression of whole genomes. Among the most relevant advantages of using networks to depict this key process, there is the visual representation of large amounts of information and the application of graph theory to generate new knowledge. Nonetheless, despite the many uses of GRNs, it is still difficult and expensive to assign Transcription Factors (TFs) to the regulation of specific genes. ChIP-Seq allows the determination of TF Binding Sites (TFBSs) over whole genomes, but it is still an expensive technique that can only be applied one TF at a time and requires replicates to reduce its noise. Once TFBSs are determined, the assignment of each TF and its binding sites to the regulation of specific genes is not trivial, and it is often performed by carrying out site-specific experiments that are unfeasible to perform in all possible binding sites. Here, we addressed these relevant issues with a two-step methodology using Drosophila melanogaster as a case study. First, our protocol starts by gathering all transcription factor binding sites (TFBSs) determined with ChIP-Seq experiments available at ENCODE and FlyBase. Then each TFBS is used to assign TFs to the regulation of likely target genes based on the TFBS proximity to the transcription start site of all genes. In the final step, to try to select the most likely regulatory TF from those previously assigned to each gene, we employ GENIE3, a random forest-based method, and more than 9,000 RNA-seq experiments from D. melanogaster. Following, we employed known TF protein-protein interactions to estimate the feasibility of regulatory events in our filtered networks. Finally, we show how known interactions between co-regulatory TFs of each gene increase after the second step of our approach, and thus, the consistency of the TF-gene assignment. Also, we employed our methodology to create a network centered on the Drosophila melanogaster gene Hr96 to demonstrate the role of this transcription factor on mitochondrial gene regulation.
Discovery of miRNAs and Development of Heat-Responsive miRNA-SSR Markers for Characterization of Wheat Germplasm for Terminal Heat Tolerance Breeding
Authors: Sihag Pooja , Sagwal Vijeta , Kumar Anuj , Balyan Priyanka , Mir Reyazul Rouf , Dhankher Om Parkash , Kumar Upendra
Published: July 2021

A large proportion of the Asian population fulfills their energy requirements from wheat (Triticum aestivum L.). Wheat quality and yield are critically affected by the terminal heat stress across the globe. It affects approximately 40% of the wheat-cultivating regions of the world. Therefore, there is a critical need to develop improved terminal heat-tolerant wheat varieties. Marker-assisted breeding with genic simple sequence repeats (SSR) markers have been used for developing terminal heat-tolerant wheat varieties; however, only few studies involved the use of microRNA (miRNA)-based SSR markers (miRNA-SSRs) in wheat, which were found as key players in various abiotic stresses. In the present study, we identified 104 heat-stress-responsive miRNAs reported in various crops. Out of these, 70 miRNA-SSR markers have been validated on a set of 20 terminal heat-tolerant and heat-susceptible wheat genotypes. Among these, only 19 miRNA-SSR markers were found to be polymorphic, which were further used to study the genetic diversity and population structure. The polymorphic miRNA-SSRs amplified 61 SSR loci with an average of 2.9 alleles per locus. The polymorphic information content (PIC) value of polymorphic miRNA-SSRs ranged from 0.10 to 0.87 with a mean value of 0.48. The dendrogram constructed using unweighted neighbor-joining method and population structure analysis clustered these 20 wheat genotypes into 3 clusters. The target genes of these miRNAs are involved either directly or indirectly in providing tolerance to heat stress. Furthermore, two polymorphic markers miR159c and miR165b were declared as very promising diagnostic markers, since these markers showed specific alleles and discriminated terminal heat-tolerant genotypes from the susceptible genotypes. Thus, these identified miRNA-SSR markers will prove useful in the characterization of wheat germplasm through the study of genetic diversity and population structural analysis and in wheat molecular breeding programs aimed at terminal heat tolerance of wheat varieties.
Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases
Authors: Challa Anup P. , Zaleski Nicole M. , Jerome Rebecca N. , Lavieri Robert R. , Shirey-Rice Jana K. , Barnado April , Lindsell Christopher J. , Aronoff David M. , Crofford Leslie J. , Harris Raymond C. , Alp Ikizler T. , Mayer Ingrid A. , Holroyd Kenneth J. , Pulley Jill M.
Published: July 2021

Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study—a powerful regression method for generating hypotheses about new indications for an approved drug—with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, “go-no go” decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.
poreCov-An Easy to Use, Fast, and Robust Workflow for SARS-CoV-2 Genome Reconstruction via Nanopore Sequencing
Authors: Brandt Christian , Krautwurst Sebastian , Spott Riccardo , Lohde Mara , Jundzill Mateusz , Marquet Mike , Hölzer Martin
Published: July 2021

In response to the SARS-CoV-2 pandemic, a highly increased sequencing effort has been established worldwide to track and trace ongoing viral evolution. Technologies, such as nanopore sequencing via the ARTIC protocol are used to reliably generate genomes from raw sequencing data as a crucial base for molecular surveillance. However, for many labs that perform SARS-CoV-2 sequencing, bioinformatics is still a major bottleneck, especially if hundreds of samples need to be processed in a recurring fashion. Pipelines developed for short-read data cannot be applied to nanopore data. Therefore, specific long-read tools and parameter settings need to be orchestrated to enable accurate genotyping and robust reference-based genome reconstruction of SARS-CoV-2 genomes from nanopore data. Here we present poreCov, a highly parallel workflow written in Nextflow, using containers to wrap all the tools necessary for a routine SARS-CoV-2 sequencing lab into one program. The ease of installation, combined with concise summary reports that clearly highlight all relevant information, enables rapid and reliable analysis of hundreds of SARS-CoV-2 raw sequence data sets or genomes. poreCov is freely available on GitHub under the GNUv3 license: github.com/replikation/poreCov.
Enhancing Effects of Environmental Enrichment on the Functions of Natural Killer Cells in Mice
Authors: Xiao Run , Ali Seemaab , Caligiuri Michael A. , Cao Lei
Published: July 2021

The environment of an organism can convey a powerful influence over its biology. Environmental enrichment (EE), as a eustress model, has been used extensively in neuroscience to study neurogenesis and brain plasticity. EE has also been used as an intervention for the treatment and prevention of neurological and psychiatric disorders with limited clinical application. By contrast, the effects of EE on the immune system are relatively less investigated. Recently, accumulating evidence has demonstrated that EE can robustly impact immune function. In this review, we summarize the major components of EE, the impact of EE on natural killer (NK) cells, EE’s immunoprotective roles in cancer, and the underlying mechanisms of EE-induced NK cell regulation. Moreover, we discuss opportunities for translational application based on insights from animal research of EE-induced NK cell regulation.
Flood Control: How Milk-Derived Extracellular Vesicles Can Help to Improve the Intestinal Barrier Function and Break the Gut–Joint Axis in Rheumatoid Arthritis
Authors: Aarts Joyce , Boleij Annemarie , Pieters Bartijn C. H. , Feitsma Anouk L. , van Neerven R. J. Joost , ten Klooster Jean Paul , M’Rabet Laura , Arntz Onno J. , Koenders Marije I. , van de Loo Fons A. J.
Published: July 2021

Many studies provided compelling evidence that extracellular vesicles (EVs) are involved in the regulation of the immune response, acting as both enhancers and dampeners of the immune system, depending on the source and type of vesicle. Research, including ours, has shown anti-inflammatory effects of milk-derived EVs, using human breast milk as well as bovine colostrum and store-bought pasteurized cow milk, in in vitro systems as well as therapeutically in animal models. Although it is not completely elucidated which proteins and miRNAs within the milk-derived EVs contribute to these immunosuppressive capacities, one proposed mechanism of action of the EVs is via the modulation of the crosstalk between the (intestinal) microbiome and their host health. There is increasing awareness that the gut plays an important role in many inflammatory diseases. Enhanced intestinal leakiness, dysbiosis of the gut microbiome, and bowel inflammation are not only associated with intestinal diseases like colitis and Crohn’s disease, but also characteristic for systemic inflammatory diseases such as lupus, multiple sclerosis, and rheumatoid arthritis (RA). Strategies to target the gut, and especially its microbiome, are under investigation and hold a promise as a therapeutic intervention for these diseases. The use of milk-derived EVs, either as stand-alone drug or as a drug carrier, is often suggested in recent years. Several research groups have studied the tolerance and safety of using milk-derived EVs in animal models. Due to its composition, milk-derived EVs are highly biocompatible and have limited immunogenicity even cross species. Furthermore, it has been demonstrated that milk-derived EVs, when taken up in the gastro-intestinal tract, stay intact after absorption, indicating excellent stability. These characteristics make milk-derived EVs very suitable as drug carriers, but also by themselves, these EVs already have a substantial immunoregulatory function, and even without loading, these vesicles can act as therapeutics. In this review, we will address the immunomodulating capacity of milk-derived EVs and discuss their potential as therapy for RA patients.

Review criteria

The search terms “extracellular vesicles”, “exosomes”, “microvesicles”, “rheumatoid arthritis”, “gut-joint axis”, “milk”, and “experimental arthritis” were used. English-language full text papers (published between 1980 and 2021) were identified from PubMed and Google Scholar databases. The reference list for each paper was further searched to identify additional relevant articles.
Serum C-Reactive Protein and Periodontitis: A Systematic Review and Meta-Analysis
Authors: Machado Vanessa , Botelho João , Escalda Cláudia , Hussain Syed Basit , Luthra Shailly , Mascarenhas Paulo , Orlandi Marco , Mendes José João , D’Aiuto Francesco
Published: July 2021

Periodontitis has been associated with low-grade inflammation as assessed by C-reactive protein (CRP) levels and its treatment can decrease CRP serum levels. The aim of this systematic review was to critically appraise the evidence comparing CRP serum levels (standard and high-sensitivity [hs]) of otherwise healthy patients suffering from periodontitis when compared to controls. The impact of intensive and non-intensive nonsurgical periodontal treatment (NSPT) on hs-CRP was also investigated. Four electronic databases (Pubmed, The Cochrane Central Register of Controlled Trials [CENTRAL], EMBASE and Web of Science) were searched up to February 2021 and the review was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No. CRD42020167454). Observational and intervention studies that: 1) evaluated CRP and hs-CRP serum levels in patients with and without periodontitis, and; 2) hs- CRP levels after NSPT were included. Following risk of bias appraisal, both qualitative and quantitative analyses were performed. Pooled estimates were rendered through ratio of means (RoM) random-effects meta-analyses. After screening 485 studies, 77 case-control studies and 67 intervention trials were included. Chronic and aggressive periodontitis diagnoses were consistently associated with higher levels of CRP and hs-CRP (p<0.001). Patients with aggressive periodontitis exhibited on average more than 50% higher levels of CRP (RoM [95% confidence interval [CI]]: 1.56 [1.15; 2.12], p=0.0039) than patients with chronic periodontitis. Intensive NSPT induced an immediate increase of hs-CRP followed by a progressive decrease whilst non-intensive NSPT consistently decreased hs-CRP after treatment up to 180 days (p<0.001). These findings provide robust evidence that periodontitis is associated with systemic inflammation as measured by serum CRP levels. Periodontitis treatment induces a short-term acute inflammatory increase when performed in an intensive session, whilst a progressive reduction up to 6 months was demonstrated when performed in multiple visits.
Longitudinal Analysis of Dengue Virus–Specific Memory T Cell Responses and Their Association With Clinical Outcome in Subsequent DENV Infection
Authors: Sanchez-Vargas Luis Alberto , Anderson Kathryn B. , Srikiatkhachorn Anon , Currier Jeffrey R. , Friberg Heather , Endy Timothy P. , Fernandez Stefan , Mathew Anuja , Rothman Alan L.
Published: July 2021

Memory T cells resulting from primary dengue virus (DENV) infection are hypothesized to influence the clinical outcome of subsequent DENV infection. However, the few studies involving prospectively collected blood samples have found weak and inconsistent associations with outcome and variable temporal trends in DENV-specific memory T cell responses between subjects. This study used both ex-vivo and cultured ELISPOT assays to further evaluate the associations between DENV serotype-cross-reactive memory T cells and severity of secondary infection. Using ex-vivo ELISPOT assays, frequencies of memory T cells secreting IFN-γ in response to DENV structural and non-structural peptide pools were low in PBMC from multiple time points prior to symptomatic secondary DENV infection and showed a variable response to infection. There were no differences in responses between subjects who were not hospitalized (NH, n=6) and those who were hospitalized with dengue hemorrhagic fever (hDHF, n=4). In contrast, responses in cultured ELISPOT assays were more reliably detectable prior to secondary infection and showed more consistent increases after infection. Responses in cultured ELISPOT assays were higher in individuals with hDHF (n=8) compared to NH (n=9) individuals before the secondary infection, with no difference between these groups after infection. These data demonstrate an association of pre-existing DENV-specific memory responses with the severity of illness in subsequent DENV infection, and suggest that frequencies of DENV-reactive T cells measured after short-term culture may be of particular importance for assessing the risk for more severe dengue disease.
Gamma Delta TCR and the WC1 Co-Receptor Interactions in Response to Leptospira Using Imaging Flow Cytometry and STORM
Authors: Gillespie Alexandria , Gervasi Maria Gracia , Sathiyaseelan Thillainayagam , Connelley Timothy , Telfer Janice C. , Baldwin Cynthia L.
Published: July 2021

The WC1 cell surface family of molecules function as hybrid gamma delta (γδ) TCR co-receptors, augmenting cellular responses when cross-linked with the TCR, and as pattern recognition receptors, binding pathogens. It is known that following activation, key tyrosines are phosphorylated in the intracytoplasmic domains of WC1 molecules and that the cells fail to respond when WC1 is knocked down or, as shown here, when physically separated from the TCR. Based on these results we hypothesized that the colocalization of WC1 and TCR will occur following cellular activation thereby allowing signaling to ensue. We evaluated the spatio-temporal dynamics of their interaction using imaging flow cytometry and stochastic optical reconstruction microscopy. We found that in quiescent γδ T cells both WC1 and TCR existed in separate and spatially stable protein domains (protein islands) but after activation using Leptospira, our model system, that they concatenated. The association between WC1 and TCR was close enough for fluorescence resonance energy transfer. Prior to concatenating with the WC1 co-receptor, γδ T cells had clustering of TCR-CD3 complexes and exclusion of CD45. γδ T cells may individually express more than one variant of the WC1 family of molecules and we found that individual WC1 variants are clustered in separate protein islands in quiescent cells. However, the islands containing different variants merged following cell activation and before merging with the TCR islands. While WC1 was previously shown to bind Leptospira in solution, here we showed that Leptospira bound WC1 proteins on the surface of γδ T cells and that this could be blocked by anti-WC1 antibodies. In conclusion, γδ TCR, WC1 and Leptospira interact directly on the γδ T cell surface, further supporting the role of WC1 in γδ T cell pathogen recognition and cellular activation.
The Metabolic Landscape of Thymic T Cell Development In Vivo and In Vitro
Authors: Sun Victoria , Sharpley Mark , Kaczor-Urbanowicz Karolina E. , Chang Patrick , Montel-Hagen Amélie , Lopez Shawn , Zampieri Alexandre , Zhu Yuhua , de Barros Stéphanie C. , Parekh Chintan , Casero David , Banerjee Utpal , Crooks Gay M.
Published: July 2021

Although metabolic pathways have been shown to control differentiation and activation in peripheral T cells, metabolic studies on thymic T cell development are still lacking, especially in human tissue. In this study, we use transcriptomics and extracellular flux analyses to investigate the metabolic profiles of primary thymic and in vitro-derived mouse and human thymocytes. Core metabolic pathways, specifically glycolysis and oxidative phosphorylation, undergo dramatic changes between the double-negative (DN), double-positive (DP), and mature single-positive (SP) stages in murine and human thymus. Remarkably, despite the absence of the complex multicellular thymic microenvironment, in vitro murine and human T cell development recapitulated the coordinated decrease in glycolytic and oxidative phosphorylation activity between the DN and DP stages seen in primary thymus. Moreover, by inducing in vitro T cell differentiation from Rag1-/- mouse bone marrow, we show that reduced metabolic activity at the DP stage is independent of TCR rearrangement. Thus, our findings suggest that highly conserved metabolic transitions are critical for thymic T cell development.
Lineage Reprogramming of Effector Regulatory T Cells in Cancer
Authors: Dixon Michael L. , Leavenworth Jonathan D. , Leavenworth Jianmei W.
Published: July 2021

Regulatory T-cells (Tregs) are important for maintaining self-tolerance and tissue homeostasis. The functional plasticity of Tregs is a key feature of this lineage, as it allows them to adapt to different microenvironments, adopt transcriptional programs reflective of their environments and tailor their suppressive capacity in a context-dependent fashion. Tregs, particularly effector Tregs (eTregs), are abundant in many types of tumors. However, the functional and transcriptional plasticity of eTregs in tumors remain largely to be explored. Although depletion or inhibition of systemic Tregs can enhance anti-tumor responses, autoimmune sequelae have diminished the enthusiasm for such approaches. A more effective approach should specifically target intratumoral Tregs or subvert local Treg-mediated suppression. This mini-review will discuss the reported mechanisms by which the stability and suppressive function of tumoral Tregs are modulated, with the focus on eTregs and a subset of eTregs, follicular regulatory T (TFR) cells, and how to harness this knowledge for the future development of new effective cancer immunotherapies that selectively target the tumor local response while sparing the systemic side effects.
Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction
Authors: Piccinni Marie-Pierre , Raghupathy Raj , Saito Shigeru , Szekeres-Bartho Julia
Published: July 2021

Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly andviamediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine productionin vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and anti-trophoblast activities. These cytokine-modulating effects and the PIBF-inducing capabilities of dydrogesterone may contribute to the demonstrated beneficial effects of dydrogesterone in recurrent spontaneous miscarriage and threatened miscarriage. IL-17 and IL-22 produced by T helper cells are involved in allograft rejection, and therefore could account for the rejection of paternal HLA-C-expressing trophoblast. Th17 cells (producing IL-17 and IL-22) and Th22 cells (producing IL-22) exhibit plasticity and could produce IL-22 and IL-17 in association with Th2-type cytokines or with Th1-type cytokines. IL-17 and IL-22 producing Th cells are not harmful for the conceptus, if they also produce IL-4. Another important protective mechanism is connected with the expansion and action of regulatory T cells, which play a major role in the induction of tolerance both in pregnant women and in tumour-bearing patients. Clonally-expanded Treg cells increase at the feto-maternal interface and in tumour-infiltrating regions. While in cancer patients, clonally-expanded Treg cells are present in peripheral blood, they are scarce in pregnancy blood, suggesting that fetal antigen-specific tolerance is restricted to the foeto-maternal interface. The significance of Treg cells in maintaining a normal materno-foetal interaction is underlined by the fact that miscarriage is characterized by a decreased number of total effector Treg cells, and the number of clonally-expanded effector Treg cells is markedly reduced in preeclampsia. In this review we present an overview of the above mechanisms, attempt to show how they are connected, how they operate during normal gestation and how their failure might lead to pregnancy pathologies.
Hydrogel-Based Scaffolds in Oral Tissue Engineering
Authors: Ayala-Ham Alfredo , López-Gutierrez Jorge , Bermúdez Mercedes , Aguilar-Medina Maribel , Sarmiento-Sánchez Juan Ignacio , López-Camarillo César , Sanchez-Schmitz Guzman , Ramos-Payan Rosalio
Published: July 2021

Regenerative therapy in dentistry has gained interest given the complexity to restore dental and periodontal tissues with inert materials. The best approach for regeneration requires three elements for restoring functions of affected or diseased organ tissues: cells, bioactive molecules, and scaffolds. This triad is capable of modulating the processes to replace lost or damaged tissues and restore function, as it has an impact on diverse cellular processes, influencing cell behavior positively to induce the complete restoration of function and morphology of such complex tissues. Hydrogels (HG) have shown advantages as scaffolds as they are soft and elastic three-dimensional (3D) networks formed from hydrophilic homopolymers, copolymers, or macromers. Besides simple or hybrid, HG show chemical, mechanical and biological activities such as the incorporation of cells in their structures, the retention of high-water content which enhances the transportation of cell nutrients and waste, and elastic and flexible characteristics that emulate the native extracellular matrix (ECM). HG can induce changes in cellular processes such as chemotaxis, proliferation, angiogenesis, biomineralization, and expression of specific tissue biomarkers, enhancing the regeneration process. Besides some of them have anti-inflammatory and anti-bacterial effects. This review aims to show an extensive overview of the most used hydrogels in tissue engineering, emphasizing those that are studied for the regeneration of oral tissues, their biological effects, and their clinical implications. Even though most of the HG are still under investigation, some of them have been studied in vitro and in vivo with outstanding results that may lead to preclinical studies. Besides there are HG that have shown their efficacy in patients such as hyaluronan HG that enhances the healing of gingival tissue.
Remote Management of Prosthodontic Emergencies in the Geriatric Population During the Pandemic Outbreak of COVID-19
Authors: Aldhuwayhi Sami , Shaikh Saquib Ahmed , Thakare Amar Ashok , Mustafa Mohammed Ziauddeen , Mallineni Sreekanth Kumar
Published: July 2021

The global pandemic outbreak of coronavirus disease 2019 (COVID-19) has put the world in a panic situation. It has been evident that the geriatric population is more susceptible to acquire this infection. Thus, due to this ongoing crisis, geriatric individuals cannot visit a dental operatory, and there is the possibility of their dental needs and emergencies to remain unattended. Partial or complete edentulism is very prevalent among the geriatric population, and prosthodontic management of these patients is essential for their well-being. However, the prosthesis can lead to various emergencies of the oral and its supporting structures. There are currently no available recommendations to address these prosthodontic emergencies in geriatric individuals during this pandemic period. Hence, the aims of this minireview were to discuss the common prosthodontic emergencies in the geriatric population and provide recommendations to manage these issues during the COVID-19 pandemic outbreak.
Serum CXCL1 Is a Prognostic Factor for Patients With Hepatitis B Virus–Related Acute-On-Chronic Liver Failure
Authors: Xiao Lanlan , Tang Shima , Zhang Lingjian , Ma Shanshan , Zhao Yalei , Zhang Fen , Xie Zhongyang , Li Lanjuan
Published: July 2021

Purpose: Neutrophils and cytokines play a major role in the pathogenesis of acute-on-chronic liver failure (ACLF). We aimed to determine whether chemokine (CXC) ligand 1 (CXCL1), a key marker of neutrophil recruitment and activation, could predict the severity and prognosis of hepatitis B virus–related ACLF (HBV-ACLF).

Methods: Hospitalized patients with HBV-ACLF were enrolled in a prospective study and stratified as survivors (alive at 28 days) and nonsurvivors (deceased at 28 days). Serum CXCL1 levels were measured in healthy controls, patients with chronic HBV, patients with HBV-related compensated cirrhosis, and patients with HBV-ACLF. Univariate and multivariable logistic analyses, Pearson correlation analysis, area under the receiver operating characteristic curve (AUROC), and Z tests were used to evaluate the performance of CXCL1 as a marker in HBV-ACLF.

Results: Patients with HBV-ACLF had significantly higher serum levels of CXCL1 and neutrophil count than healthy controls and patients with chronic HBV or HBV-related compensated cirrhosis (P < 0.01, respectively). Among patients with HBV-ACLF, survivors had lower serum CXCL1 levels and neutrophil count than those of nonsurvivors (P < 0.001, P < 0.05, respectively). Serum CXCL1 level was positively correlated with neutrophil count (r = 0.256, P = 0.001), ACLF grade (r = 0.295, P < 0.001) and organ failure, including coagulation (r = 0.21, P = 0.005) and brain failure (r = 0.198, P = 0.008). Multivariable logistic analyses showed serum CXCL1 [OR (95% CI) = 1.017 (1.009–1.025), P < 0.001] was an independent risk factor for 28-day mortality in HBV-ACLF. Meanwhile, the AUROC analysis demonstrated that serum CXCL1 [0.741 (0.669–0.804)] might be a reliable prognostic biomarker for patients with HBV-ACLF.

Conclusions: Overall, serum CXCL1 can serve as a biomarker indicating the severity of disease and prognosis for patients with HBV-ACLF. CXCL1 might also be a therapeutic target in this disease.
Myofascial Release for Chronic Low Back Pain: A Systematic Review and Meta-Analysis
Authors: Wu Zugui , Wang Yi , Ye Xiangling , Chen Zehua , Zhou Rui , Ye Zixuan , Huang Jinyou , Zhu Yue , Chen Guocai , Xu Xuemeng
Published: July 2021

Background: Chronic low back pain (CLBP) is one of the most common musculoskeletal diseases in the elderly, which has a severe impact on the health of the elderly. However, CLBP treatment is very challenging, and more effective treatment methods are needed. Myofascial release may be an effective therapy for the management of chronic musculoskeletal pain. It is widely used clinically to treat CLBP, but its clinical efficacy is still controversial.

Objective: This study aims to systematically evaluate the effectiveness of myofascial release for patients with CLBP.

Methods: We selected PubMed, Cochrane Library, EMBASE database, and Web of Science database articles published until April 5, 2021. Randomized controlled trials (RCTs) of myofascial release for CLBP were included. Outcome measures included pain, physical function, quality of life, balance function, pain pressure-threshold, trunk mobility, and mental health. For each outcome, Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CIs) were calculated.

Results: Eight RCTs (n = 375) were included based on inclusion and exclusion criteria. The meta-analysis showed that the overall efficacy of myofascial release for CLBP was significant, including two aspects: pain [SMD = −0.37, 95% CI (−0.67, −0.08), I2 = 46%, P = 0.01] and physical function [SMD = −0.43, 95% CI (−0.75, −0.12), I2 = 44%, P = 0.007]. However, myofascial release did not significantly improve quality of life [SMD = 0.13, 95% CI (−0.38, 0.64), I2 = 53%, P = 0.62], balance function [SMD = 0.58, 95% CI (−0.49, 1.64), I2 = 82%, P = 0.29], pain pressure-threshold [SMD = 0.03,95% CI (−0.75, 0.69), I2 = 73%, P = 0.93], trunk mobility [SMD = 1.02, 95% CI (−0.09, 2.13), I2 = 92%, P = 0.07] and mental health [SMD = −0.06, 95% CI (−0.83, 0.71), I2 = 73%, P = 0.88].

Conclusions: In this study, we systematically reviewed and quantified the efficacy of myofascial release in treating CLBP. The meta-analysis results showed that myofascial release significantly improved pain and physical function in patients with CLBP but had no significant effects on balance function, pain pressure-threshold, trunk mobility, mental health, and quality of life. However, due to the low quality and a small number of included literature, more and more rigorously designed RCTs should be included in the future to verify these conclusions.
A Stochastic Characterization of Hydrogen Peroxide-Induced Regulated Cell Death in Microcystis aeruginosa
Authors: Giannuzzi Leda , Lombardo Tomás , Juárez Iván , Aguilera Anabella , Blanco Guillermo
Published: July 2021

Regulated cell death (RCD) encompasses the activation of cellular pathways that initiate and execute a self-dismissal process. RCD occur over a range of stressors doses that overcome pro-survival cellular pathways, while higher doses cause excessive damage leading to passive accidental cell death (ACD). Hydrogen peroxide (HP) has been proposed as a potential tool to control harmful cyanobacterial blooms, given its capacity to remove cyanobacterial cells and oxidize cyanotoxins. HP is a source of hydroxyl radicals and is expected to induce RCD only within a limited range of concentrations. This property makes this compound very useful to better understand stress-driven RCD. In this work, we analyzed cell death in microcystin-producing Microcystis aeruginosa by means of a stochastic dose response model using a wide range of HP concentrations (0, 0.29, 1.76, 3.67, 7.35, 14.70, and 29.5 mM). We used flow cytometry and unsupervised classification to study cell viability and characterize transitional cell death phenotypes after exposing cells to HP for 48 and 72 h. Non-linear regression was used to fit experimental data to a logistic cumulative distribution function (cdf) and calculate the half maximal effective concentration (EC50). The EC50 of M. aeruginosa exposed to HP were 3.77 ± 0.26 mM and 4.26 ± 0.22 mM at 48 and 72 h, respectively. The derivative of cdf (probability density function; pdf) provided theoretical and practical demonstration that EC50 is the minimal dose required to cause RCD in 50% of cells, therefore maximizing the probability of RCD occurrence. 1.76 mM HP lead to an antioxidant stress response characterized by increased reactive oxygen species (ROS) levels and HP decomposition activity. The exposure of 3.67 mM HP induced a dose-related transition in cell death phenotype, and produced several morphological changes (a less dense stroma, distortion of the cell membrane, partial disintegration of thylakoids, extensive cytoplasmic vacuolation and highly condensed chromatin). The EC50 and the stochastic cdf and pdf together with the multidimensional transitional phenotypic analysis of single cells contribute to further characterize cell death pathways in cyanobacteria.
MgrB Inactivation Confers Trimethoprim Resistance in Escherichia coli
Authors: Shi Hongmei , Li Ting , Xu Jintian , Yu Jifang , Yang Shanshan , Zhang Xian-En , Tao Shengce , Gu Jing , Deng Jiao-Yu
Published: July 2021

After several decades of use, trimethoprim (TMP) remains one of the key access antimicrobial drugs listed by the World Health Organization. To circumvent the problem of trimethoprim resistance worldwide, a better understanding of drug-resistance mechanisms is required. In this study, we screened the single-gene knockout library of Escherichia coli, and identified mgrB and other several genes involved in trimethoprim resistance. Subsequent comparative transcriptional analysis between ΔmgrB and the wild-type strain showed that expression levels of phoP, phoQ, and folA were significantly upregulated in ΔmgrB. Further deleting phoP or phoQ could partially restore trimethoprim sensitivity to ΔmgrB, and co-overexpression of phoP/Q caused TMP resistance, suggesting the involvement of PhoP/Q in trimethoprim resistance. Correspondingly, MgrB and PhoP were shown to be able to modulated folA expression in vivo. After that, efforts were made to test if PhoP could directly modulate the expression of folA. Though phosphorylated PhoP could bind to the promotor region of folA in vitro, the former only provided a weak protection on the latter as shown by the DNA footprinting assay. In addition, deleting the deduced PhoP box in ΔmgrB could only slightly reverse the TMP resistance phenotype, suggesting that it is less likely for PhoP to directly modulate the transcription of folA. Taken together, our data suggested that, in E. coli, MgrB affects susceptibility to trimethoprim by modulating the expression of folA with the involvement of PhoP/Q. This work broadens our understanding of the regulation of folate metabolism and the mechanisms of TMP resistance in bacteria.