bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Methylation-Based Interferon Scores Associate With Sub-Phenotypes in Primary Sjögren’s Syndrome
Authors: Imgenberg-Kreuz Juliana , Sandling Johanna K. , Norheim Katrine Brække , Johnsen Svein Joar Auglænd , Omdal Roald , Syvänen Ann-Christine , Svenungsson Elisabet , Rönnblom Lars , Eloranta Maija-Leena , Nordmark Gunnel
Published: July 2021

Primary Sjögren’s syndrome (pSS) is an autoimmune inflammatory disease with profound clinical heterogeneity, where excessive activation of the type I interferon (IFN) system is considered one of the key mechanisms in disease pathogenesis. Here we present a DNA methylation-based IFN system activation score (DNAm IFN score) and investigate its potential associations with sub-phenotypes of pSS. The study comprised 100 Swedish patients with pSS and 587 Swedish controls. For replication, 48 patients with pSS from Stavanger, Norway, were included. IFN scores were calculated from DNA methylation levels at the IFN-induced genes RSAD2, IFIT1 and IFI44L. A high DNAm IFN score, defined as > meancontrols +2SDcontrols (IFN score >4.4), was observed in 59% of pSS patients and in 4% of controls (p=1.3x10-35). Patients with a high DNAm IFN score were on average seven years younger at symptom onset (p=0.017) and at diagnosis (p=3x10-3). The DNAm IFN score levels were significantly higher in pSS positive for both SSA and SSB antibodies compared to SSA/SSB negative patients (pdiscovery=1.9x10-8, preplication=7.8x10-4). In patients positive for both SSA subtypes Ro52 and Ro60, an increased score was identified compared to single positive patients (p=0.022). Analyzing the discovery and replication cohorts together, elevated DNAm IFN scores were observed in pSS with hypergammaglobulinemia (p=2x10-8) and low C4 (p=1.5x10-3) compared to patients without these manifestations. Patients < 70 years with ongoing lymphoma at DNA sampling or lymphoma at follow-up (n=7), presented an increased DNAm IFN score compared to pSS without lymphoma (p=0.025). In conclusion, the DNAm-based IFN score is a promising alternative to mRNA-based scores for identification of patients with activation of the IFN system and may be applied for patient stratification guiding treatment decisions, monitoring and inclusion in clinical trials.
Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca
Authors: de Paiva Cintia S. , Trujillo-Vargas Claudia M. , Schaefer Laura , Yu Zhiyuan , Britton Robert A. , Pflugfelder Stephen C.
Published: July 2021

Sjögren syndrome (SS) is an autoimmune condition that targets the salivary and lacrimal glands, with cardinal clinical signs of dry eye (keratoconjunctivitis sicca, KCS) and dry mouth. The conjunctiva of SS patients is often infiltrated by immune cells that participate in the induction and maintenance of local inflammation. The purpose of this study was to investigate immune-related molecular pathways activated in the conjunctiva of SS patients. Female SS patients (n=7) and controls (n=19) completed a series of oral, ocular surface exams. Symptom severity scores were evaluated using validated questionnaires (OSDI and SANDE). All patients fulfilled the ACR/EULAR criteria for SS and the criteria for KCS. Fluorescein and lissamine green dye staining evaluated tear-break-up time (TBUT), corneal and conjunctival disease, respectively. Impression cytology of the temporal bulbar conjunctiva was performed to collect cells lysed and subjected to gene expression analysis using the NanoString Immunology Panel. 53/594 differentially expressed genes (DEGs) were observed between SS and healthy controls; 49 DEGs were upregulated, and 4 were downregulated (TRAF5, TGFBI, KLRAP1, and CMKLRI). The top 10 DEGs in descending order were BST2, IFITM1, LAMP3, CXCL1, IL19, CFB, LY96, MX1, IL4R, CDKN1A. Twenty pathways had a global significance score greater or equal to 2. Spearman correlations showed that 29/49 upregulated DEGs correlated with either TBUT (inverse) or OSDI or conjunctival staining score (positive correlations). Venn diagrams identified that 26/29 DEGs correlated with TBUT, 5/26 DEGs correlated with OSDI, and 16/26 correlated with conjunctival staining scores. Five upregulated DEGs (CFB, CFI, IL1R1, IL2RG, IL4R) were uniquely negatively correlated with TBUT. These data indicate that the conjunctiva of SS patients exhibits a phenotype of immune activation, although some genes could be inhibitory. Some of the DEGs and pathways overlap with previous DEGs in salivary gland biopsies, but new DEGs were identified, and some of these correlated with symptoms and signs of dry eye. Our results indicate that gene analysis of conjunctiva imprints is a powerful tool to understand the pathogenesis of SS and develop new therapeutic targets.
Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α
Authors: Li Jiang , Kim Sang Yong , Lainez Nancy M. , Coss Djurdjica , Nair Meera G.
Published: July 2021

RELMα is a small, secreted protein expressed by type 2 cytokine-activated “M2” macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELMα is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMα TdTomato (Td) reporter/knockout (RαTd) mice and investigated RELMα function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMαTd/Td transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMα protein, while RELMα+/+ mice expressed RELMα and not Td. Functionally, RELMαTd/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα+/+ mice. Gene expression analysis indicated that RELMαTd/Td peritoneal macrophages were more proliferative and activated than RELMα+/+ macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that RαTd/Td macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4+ T cell effector responses when co-cultured with RELMα+/+ or RELMαTd/Td macrophages, however, RELMαTd/Td macrophages were impaired in their ability to sustain proliferation of FoxP3+ regulatory T cells (Treg). Supportive of the in vitro results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3+ cells in the RELMαTd/Td spleens compared to RELMα+/+ spleens. Taken together, these studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.
Saving the Last Unicorns: The Genetic Rescue of Florida’s Pillar Corals
Authors: Neely Karen L. , Lewis Cynthia L. , O’Neil Keri , Woodley Cheryl M. , Moore Jennifer , Ransom Zach , Moura Amelia , Nedimyer Ken , Vaughan David
Published: July 2021

As stony coral tissue loss disease (SCTLD) swept through the Florida Reef Tract, one of the most severely impacted species was the iconic pillar coral, Dendrogyra cylindrus. As the species’ population experienced a precipitous decline, a collaborative rescue project collected colony fragments for safekeeping at onshore and offshore nursery facilities. Between 2015 and 2019, a total of 574 fragments representing 128 genotypes were collected. These are currently dispersed among five facilities where they continue to provide opportunities to (1) refine best husbandry practices for D. cylindrus, (2) develop treatment options for SCTLD that have been adapted for use on other species, (3) maximize growth and fragmentation to provide the live tissue needed for eventual restoration, and (4) provide a source of parent colonies for assisted sexual reproduction and new genetic diversity. With the wild pillar coral population in Florida at the end of 2020 at less than 6% of its known 2014 population and continuing to decline, the rescued ex situ colonies represent the entirety of the restoration potential for this species in Florida.
COVID-19 Vaccination: Concerns About Its Accessibility, Affordability, and Acceptability
Authors: Ali Inayat , Ali Shahbaz , Iqbal Sehar
Published: July 2021

By the mid of June 2021, after an almost 1.5-year-long COVID-19 pandemic that has significantly affected the world in multiple ways, various vaccines against COVID-19 have arrived and started worldwide. Yet, economic, (geo)political, and socio-cultural factors may influence its uptake at individual and country levels. Several issues will (and already have been reported in media) revolve around this vaccination regarding its accessibility, affordability, and acceptability at an individual level and a country level. Given that in this commentary, we provoke a discussion: Who—a country as well as the individuals—would have access to it, and who would economically afford it, and who would accept it? Centering these intriguing questions, we revisit the body of literature that explicates vaccine hesitancy, refusal, and resistance, and we also draw on the current literature and media reports about vaccination against COVID-19. We suggest that these backdrops need essential attention so that everyone can afford, accept, and have access to it. Otherwise, the current risk in the face of a year-old pandemic will continue.
Prevalence and Incidence of Non-alcohol Fatty Liver Disease in Chronic Hepatitis B Population in Southeast China: A Community-Based Study
Authors: Zheng Yang , Xu Kaijin , Hu Haiyang , Draz Mohamed S. , Wu Wei , Li Lanjuan
Published: July 2021

Background: To investigate the prevalence and incidence of non-alcohol fatty liver disease (NAFLD) in a community-based chronic hepatitis B (CHB) population from Southeast China and evaluate the association between NAFLD and metabolic factors, viral factors, and underlying chronic diseases.

Methods: CHB patients were recruited in 2012 and followed up from 2017 to 2019 in Zhejiang, China. NAFLD prevalence of the last visit and NAFLD incidence were calculated. Potential risk factors, including metabolic and viral factors, were also evaluated using Logistic or Cox regression models.

Results: NAFLD prevalence of the last visit in 2019 was estimated at 26.76%. Waist circumference, body mass index (BMI), triglyceride (TG), low-density lipoprotein (LDL), and diabetes mellitus (DM) were found as associated factors. In subgroups analysis, HBV infection types were also identified as a risk factor in the non-diabetic population. HBeAg-negative hepatitis and immunotolerant had lower NAFLD prevalence than past CHB infection. NAFLD incidence was estimated at 22.63/1,000 person-years after 1,634.74 person-years of follow-up. Waist circumference, TG, LDL, and alkaline phosphatase (ALP) were identified as associated factors.

Conclusion: The NAFLD prevalence and incidence in our study were slightly lower than previous reports from East Asia. Health education and healthy living habits were extremely important in reducing the NAFLD burden. Metabolic factors, history of DM, and viral factors were associated with NAFLD in CHB patients.
An Immune Signature Robustly Predicts Clinical Deterioration for Hepatitis C Virus-Related Early-Stage Cirrhosis Patients
Authors: Guo Cheng , Dong Chenglai , Zhang Junjie , Wang Rui , Wang Zhe , Zhou Jie , Wang Wei , Ji Bing , Ma Boyu , Ge Yanli , Wang Zhirong
Published: July 2021

Hepatitis C virus (HCV)-related cirrhosis leads to a heavy global burden of disease. Clinical risk stratification in HCV-related compensated cirrhosis remains a major challenge. Here, we aim to develop a signature comprised of immune-related genes to identify patients at high risk of progression and systematically analyze immune infiltration in HCV-related early-stage cirrhosis patients. Bioinformatics analysis was applied to identify immune-related genes and construct a prognostic signature in microarray data set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were conducted with the “clusterProfiler” R package. Besides, the single sample gene set enrichment analysis (ssGSEA) was used to quantify immune-related risk term abundance. The nomogram and calibrate were set up via the integration of the risk score and clinicopathological characteristics to assess the effectiveness of the prognostic signature. Finally, three genes were identified and were adopted to build an immune-related prognostic signature for HCV-related cirrhosis patients. The signature was proved to be an independent risk element for HCV-related cirrhosis patients. In addition, according to the time-dependent receiver operating characteristic (ROC) curves, nomogram, and calibration plot, the prognostic model could precisely forecast the survival rate at the first, fifth, and tenth year. Notably, functional enrichment analyses indicated that cytokine activity, chemokine activity, leukocyte migration and chemotaxis, chemokine signaling pathway and viral protein interaction with cytokine and cytokine receptor were involved in HCV-related cirrhosis progression. Moreover, ssGSEA analyses revealed fierce immune-inflammatory response mechanisms in HCV progress. Generally, our work developed a robust prognostic signature that can accurately predict the overall survival, Child-Pugh class progression, hepatic decompensation, and hepatocellular carcinoma (HCC) for HCV-related early-stage cirrhosis patients. Functional enrichment and further immune infiltration analyses systematically elucidated potential immune response mechanisms.
Sulfamethoxazole-Altered Transcriptomein Green Alga Raphidocelis subcapitata Suggests Inhibition of Translation and DNA Damage Repair
Authors: Guo Jiahua , Zhang Yibo , Mo Jiezhang , Sun Haotian , Li Qi
Published: July 2021

Occurrence of sulfonamide antibiotics has been reported in surface waters with the exposures ranging from < 1 ng L–1 to approximately 11 μg L–1, which may exert adverse effects on non-target algal species, inhibiting algal growth and further hindering the delivery of several ecosystem services. Yet the molecular mechanisms of sulfonamide in algae remain undetermined. The aims of the present work are: (1) to test the hypothesis whether sulfamethoxazole (SMX) inhibits the folate biosynthesis in a model green alga Raphidocelis subcapitata; and (2) to explore the effects of SMX at an environmentally relevant concentration on algal health. Here, transcriptomic analysis was applied to investigate the changes at the molecular levels in R. subcapitata treated with SMX at the concentrations of 5 and 300 μg L–1. After 7-day exposure, the algal density in the 5 μg L–1 group was not different from that in the controls, whereas a marked reduction of 63% in the high SMX group was identified. Using the adj p < 0.05 and absolute log2 fold change > 1 as a cutoff, we identified 1 (0 up- and 1 downregulated) and 1,103 (696 up- and 407 downregulated) differentially expressed genes (DEGs) in the 5 and 300 μg L–1 treatment groups, respectively. This result suggested that SMX at an environmentally relevant exposure may not damage algal health. In the 300 μg L–1 group, DEGs were primarily enriched in the DNA replication and repair, photosynthesis, and translation pathways. Particularly, the downregulation of base and nucleotide excision repair pathways suggested that SMX may be genotoxic and cause DNA damage in alga. However, the folate biosynthesis pathway was not enriched, suggesting that SMX does not necessarily inhibit the algal growth via its mode of action in bacteria. Taken together, this study revealed the molecular mechanism of action of SMX in algal growth inhibition.
A Metagenome-Wide Association Study of the Gut Microbiome and Metabolic Syndrome
Authors: Qin Qian , Yan Su , Yang Yang , Chen Jingfeng , Li Tiantian , Gao Xinxin , Yan Hang , Wang Youxiang , Wang Jiao , Wang Shoujun , Ding Suying
Published: July 2021

Metabolic syndrome (MetS) is a wide-ranging disorder, which includes insulin resistance, altered glucose and lipid metabolism, and increased blood pressure and visceral obesity. MetS symptoms combine to result in a significant increase in cardiovascular risk. It is therefore critical to treat MetS in the early stages of the disorder. In this study, 123 MetS patients and 304 controls were recruited to determine whether the gut microbiome plays a role in MetS development and progression. By using whole-genome shotgun sequencing, we found that the gut microbiomes of MetS patients were different from those of controls, with MetS patients possessing significantly lower gut microbiome diversity. In addition, 28 bacterial species were negatively correlated with waist circumstance, with Alistipes onderdonkii showing the strongest correlation, followed by Bacteroides thetaiotaomicron, Clostridium asparagiforme, Clostridium citroniae, Clostridium scindens, and Roseburia intestinalis. These species were also enriched in controls relative to MetS patients. In addition, pathways involved in the biosynthesis of carbohydrates, fatty acids, and lipids were enriched in the MetS group, indicating that microbial functions related to fermentation may play a role in MetS. We also found that microbiome changes in MetS patients may aggravate inflammation and contribute to MetS diseases by inhibiting the production of short-chain fatty acids (SCFAs). Taken together, these results indicate the potential utility of beneficial gut microbiota as a potential therapeutic to alleviate MetS.
Synergistic Inactivation of Bacteria Using a Combination of Erythorbyl Laurate and UV Type-A Light Treatment
Authors: Chang Yoonjee , Bai Jaewoo , Yu Hyunjong , Chang Pahn-Shick , Nitin Nitin
Published: July 2021

This study evaluated the synergistic antimicrobial activity of erythorbyl laurate (EL) and UV type-A (UVA). To investigate the mode of synergism, changes in gene expression and bacterial inactivation activity were examined. Individual treatments with EL (10 mM) or UVA caused a 1.9- or 0.5-log CFU/ml reduction respectively, whereas EL/UVA co-treatment resulted in a 5.5-log CFU/ml reduction in Escherichia coli viable cell numbers. Similarly, treatment with either EL (2 mM) or UVA for 30 min resulted in a 2.8- or 0.1-log CFU/ml reduction in Listeria innocua, respectively, whereas combined treatment with both EL and UVA resulted in a 5.4-log CFU/ml reduction. Measurements of gene expression levels showed that EL and UVA treatment synergistically altered the gene expression of genes related to bacterial membrane synthesis/stress response. However, addition of 10–50-fold excess concentration of exogenous antioxidant compared to EL reduced the synergistic effect of EL and UVA by approximately 1 log. In summary, the results illustrate that synergistic combination of EL and UVA enhanced membrane damage independent of the oxidative stress damage induced by UVA and thus illustrate a novel photo-activated synergistic antimicrobial approach for the inactivation of both the Gram-positive and Gram-negative bacteria. Overall, this study illustrates mechanistic evaluation of a novel photochemical approach for food and environmental applications.
Escherichia coli O157:H7 in Retail Lettuce (Lactuca sativa) in Addis Ababa City: Magnitude of Contamination and Antimicrobial Susceptibility Pattern
Authors: Haile Aklilu Feleke , Alonso Silvia , Berhe Nega , Bekele Atoma Tizeta , Boyaka Prosper N. , Grace Delia
Published: July 2021

Escherichia coli O157:H7 is an important foodborne pathogen but largely under investigated in Africa. The objectives of this study were to estimate the prevalence and pattern of antimicrobial resistance of E. coli O157:H7 in lettuce in Addis Ababa, Ethiopia. A total of 390 retail lettuce samples were collected across the 10 subcities of Addis Ababa. E. coli O157:H7 was isolated and identified following ISO-16654:2001 standard. The isolates were further tested for antimicrobial susceptibility to 13 antimicrobials using the Kirby–Bauer disk diffusion method. Out of the 390 lettuce samples examined, two (0.51%) carried E. coli O157:H7. The antimicrobial susceptibility pattern of strains showed resistance to ampicillin (100%) and tetracycline (50.0%). One of the two isolates was multidrug resistant to two antimicrobials tested. The results of this study demonstrate the presence of drug-resistant E. coli O157:H7 in lettuce in markets in Addis Ababa. Despite the low prevalence, its presence in a product that is eaten raw highlights potential public health risk in the area associated with this pathogen.
Pathogen Challenge and Dietary Shift Alter Microbiota Composition and Activity in a Mucin-Associated in vitro Model of the Piglet Colon (MPigut-IVM) Simulating Weaning Transition
Authors: Gresse Raphaële , Chaucheyras-Durand Frédérique , Garrido Juan J. , Denis Sylvain , Jiménez-Marín Angeles , Beaumont Martin , Van de Wiele Tom , Forano Evelyne , Blanquet-Diot Stéphanie
Published: July 2021

Enterotoxigenic Escherichia coli (ETEC) is the principal pathogen responsible for post-weaning diarrhea in newly weaned piglets. Expansion of ETEC at weaning is thought to be the consequence of various stress factors such as transient anorexia, dietary change or increase in intestinal inflammation and permeability, but the exact mechanisms remain to be elucidated. As the use of animal experiments raise more and more ethical concerns, we used a recently developed in vitro model of piglet colonic microbiome and mucobiome, the MPigut-IVM, to evaluate the effects of a simulated weaning transition and pathogen challenge at weaning. Our data suggested that the tested factors impacted the composition and functionality of the MPigut-IVM microbiota. The simulation of weaning transition led to an increase in relative abundance of the Prevotellaceae family which was further promoted by the presence of the ETEC strain. In contrast, several beneficial families such as Bacteroidiaceae or Ruminococcaceae and gut health related short chain fatty acids like butyrate or acetate were reduced upon simulated weaning. Moreover, the incubation of MPigut-IVM filtrated effluents with porcine intestinal cell cultures showed that ETEC challenge in the in vitro model led to an increased expression of pro-inflammatory genes by the porcine cells. This study provides insights about the etiology of a dysbiotic microbiota in post-weaning piglets.
Chlamydia trachomatis Polymorphic Membrane Proteins (Pmps) Form Functional Homomeric and Heteromeric Oligomers
Authors: Favaroni Alison , Hegemann Johannes H.
Published: July 2021

Chlamydiae are Gram-negative, obligate intracellular bacteria, which infect animals and humans. Adhesion to host cells, the first step in the infection process, is mediated by polymorphic membrane proteins (Pmps). Pmps constitute the largest chlamydial protein family, with 9 members (subdivided into six subtypes) in C. trachomatis and 21 in C. pneumoniae, and are characterized by the presence of multiple copies of GGA(I,L,V) and FxxN motifs. Motif-rich fragments of all nine C. trachomatis Pmps act as adhesins and are essential for infection. As autotransporters, most Pmp proteins are secreted through their β-barrel domain and localize on the surface of the chlamydial cell, where most of them are proteolytically processed. Classical autotransporters are monomeric proteins, which can function as toxins, proteases, lipases and monoadhesive adhesins. Here we show that selected recombinant C. trachomatis Pmp fragments form functional adhesion-competent multimers. They assemble into homomeric and heteromeric filaments, as revealed by non-denaturing gel electrophoresis, size-exclusion chromatography and electron microscopy. Heteromeric filaments reach 2 μm in length, significantly longer than homomeric structures. Filament formation was independent of the number of motifs present in the fragment(s) concerned and their relative affinity for host cells. Our functional studies demonstrated that only adhesion-competent oligomers were able to block a subsequent infection. Pre-loading of infectious chlamydial cells with adhesion-competent Pmp oligomers maintained the subsequent infection, while adhesion-incompetent structures reduced infectivity, presumably by blocking the function of endogenous Pmps. The very large number of possible heteromeric and homomeric Pmp complexes represents a novel mechanism to ensure stable adhesion and possibly host cell immune escape.
Binding of Tetracyclines to Acinetobacter baumannii TetR Involves Two Arginines as Specificity Determinants
Authors: Sumyk Manuela , Himpich Stephanie , Foong Wuen Ee , Herrmann Andrea , Pos Klaas M. , Tam Heng-Keat
Published: July 2021

Acinetobacter baumannii is an important nosocomial pathogen that requires thoughtful consideration in the antibiotic prescription strategy due to its multidrug resistant phenotype. Tetracycline antibiotics have recently been re-administered as part of the combination antimicrobial regimens to treat infections caused by A. baumannii. We show that the TetA(G) efflux pump of A. baumannii AYE confers resistance to a variety of tetracyclines including the clinically important antibiotics doxycycline and minocycline, but not to tigecycline. Expression of tetA(G) gene is regulated by the TetR repressor of A. baumannii AYE (AbTetR). Thermal shift binding experiments revealed that AbTetR preferentially binds tetracyclines which carry a O-5H moiety in ring B, whereas tetracyclines with a 7-dimethylamino moiety in ring D are less well-recognized by AbTetR. Confoundingly, tigecycline binds to AbTetR even though it is not transported by TetA(G) efflux pump. Structural analysis of the minocycline-bound AbTetR-Gln116Ala variant suggested that the non-conserved Arg135 interacts with the ring D of minocycline by cation-π interaction, while the invariant Arg104 engages in H-bonding with the O-11H of minocycline. Interestingly, the Arg135Ala variant exhibited a binding preference for tetracyclines with an unmodified ring D. In contrast, the Arg104Ala variant preferred to bind tetracyclines which carry a O-6H moiety in ring C except for tigecycline. We propose that Arg104 and Arg135, which are embedded at the entrance of the AbTetR binding pocket, play important roles in the recognition of tetracyclines, and act as a barrier to prevent the release of tetracycline from its binding pocket upon AbTetR activation. The binding data and crystal structures obtained in this study might provide further insight for the development of new tetracycline antibiotics to evade the specific efflux resistance mechanism deployed by A. baumannii.
Riboregulation in the Major Gastric Pathogen Helicobacter pylori
Authors: Tejada-Arranz Alejandro , De Reuse Hilde
Published: July 2021

Helicobacter pyloriis a Gram-negative bacterial pathogen that colonizes the stomach of about half of the human population worldwide. Infection byH. pyloriis generally acquired during childhood and this bacterium rapidly establishes a persistent colonization.H. pyloricauses chronic gastritis that, in some cases, progresses into peptic ulcer disease or adenocarcinoma that is responsible for about 800,000 deaths in the world every year.H. pylorihas evolved efficient adaptive strategies to colonize the stomach, a particularly hostile acidic environment. Few transcriptional regulators are encoded by the smallH. pylorigenome and post-transcriptional regulation has been proposed as a major level of control of gene expression in this pathogen. The transcriptome and transcription start sites (TSSs) ofH. pyloristrain 26695 have been defined at the genome level. This revealed the existence of a total of 1,907 TSSs among which more than 900 TSSs for non-coding RNAs (ncRNAs) including 60 validated small RNAs (sRNAs) and abundant anti-sense RNAs, few of which have been experimentally validated. An RNA degradosome was shown to play a central role in the control of mRNA and antisense RNA decay inH. pylori. Riboregulation, genetic regulation by RNA, has also been revealed and depends both on antisense RNAs and small RNAs. Known examples will be presented in this review. Antisense RNA regulation was reported for some virulence factors and for several type I toxin antitoxin systems, one of which controls the morphological transition ofH. pylorispiral shape to round coccoids. Interestingly, the few documented cases of small RNA-based regulation suggest that their mechanisms do not follow the same rules that were well established in the model organismEscherichia coli. First, the genome ofH. pyloriencodes none of the two well-described RNA chaperones, Hfq and ProQ that are important for riboregulation in several organisms. Second, some of the reported small RNAs target, through “rheostat”-like mechanisms, repeat-rich stretches in the 5′-untranslated region of genes encoding important virulence factors. In conclusion, there are still many unanswered questions about the extent and underlying mechanisms of riboregulation inH. pyloribut recent publications highlighted original mechanisms making this important pathogen an interesting study model.
The Structural E/I Balance Constrains the Early Development of Cortical Network Activity
Authors: Xing Wenxi , de Lima Ana Dolabela , Voigt Thomas
Published: July 2021

Neocortical networks have a characteristic constant ratio in the number of glutamatergic projection neurons (PN) and GABAergic interneurons (IN), and deviations in this ratio are often associated with developmental neuropathologies. Cultured networks with defined cellular content allowed us to ask if initial PN/IN ratios change the developmental population dynamics, and how different ratios impact the physiological excitatory/inhibitory (E/I) balance and the network activity development. During the first week in vitro, the IN content modulated PN numbers, increasing their proliferation in networks with higher IN proportions. The proportion of INs in each network set remained similar to the initial plating ratio during the 4 weeks cultivation period. Results from additional networks generated with more diverse cellular composition, including early-born GABA neurons, suggest that a GABA-dependent mechanism may decrease the survival of additional INs. A large variation of the PN/IN ratio did not change the balance between isolated spontaneous glutamatergic and GABAergic postsynaptic currents charge transfer (E/I balance) measured in PNs or INs. In contrast, the E/I balance of multisynaptic bursts reflected differences in IN content. Additionally, the spontaneous activity recorded by calcium imaging showed that higher IN ratios were associated with increased frequency of network bursts combined with a decrease of participating neurons per event. In the 4th week in vitro, bursting activity was stereotypically synchronized in networks with very few INs but was more desynchronized in networks with higher IN proportions. These results suggest that the E/I balance of isolated postsynaptic currents in single cells may be regulated independently of PN/IN proportions, but the network bursts E/I balance and the maturation of spontaneous network activity critically depends upon the structural PN/IN ratio.
Treatment Results of Geotropic and Apogeotropic Horizontal Canal Benign Paroxysmal Positional Vertigo in a Tertiary Dizziness Clinic
Authors: Maas Britta D. P. J. , van Leeuwen Roeland B. , Masius-Olthof Sylvia , van Benthem Peter Paul G. , Bruintjes Tjasse D.
Published: July 2021

Purpose: To determine the effectiveness of our treatment protocol for geotropic and apogeotropic horizontal canal benign paroxysmal positional vertigo (h-BPPV).

Methods: We retrospectively evaluated patients with newly diagnosed geotropic and apogeotropic h-BPPV who visited our clinic between July 2017 and December 2019. Patients were treated according to our treatment protocol, which was implemented in 2017. Patients with geotropic h-BPPV were preferably treated with the Gufoni maneuver. In patients with apogeotropic h-BPPV we executed the modified Gufoni maneuver to achieve conversion to the geotropic type. We looked at the number of successful treatments and the number of recurrences within 1 year.

Results: We included 102 patients with h-BPPV, 62 (61%) of whom were treated for geotropic h-BPPV. The ratio of apogeotropic to geotropic h-BPPV was 0.65. After the first visit, we observed resolution of horizontal canal BPPV in 71 and 63% of the geotropic and the apogeotropic group, respectively. After the second visit, this percentage increased to 92% for geotropic h-BPPV and 78% for apogeotropic h-BPPV. After 1 year of follow-up we determined a recurrence rate of 32 and 24% for the geotropic and apogeotropic group, respectively.

Conclusion: With our treatment protocol we managed to achieve high rates of symptom resolution in the geotropic and apogeotropic type of h-BPPV with acceptable recurrence rates. We observed a relatively high ratio of apogeotropic h-BPPV to geotropic h-BPPV.
Super-Selective Reconstruction of Causal and Direct Connectivity With Application to in vitro iPSC Neuronal Networks
Authors: Puppo Francesca , Pré Deborah , Bang Anne G. , Silva Gabriel A.
Published: July 2021

Despite advancements in the development of cell-based in-vitro neuronal network models, the lack of appropriate computational tools limits their analyses. Methods aimed at deciphering the effective connections between neurons from extracellular spike recordings would increase utility of in vitro local neural circuits, especially for studies of human neural development and disease based on induced pluripotent stem cells (hiPSC). Current techniques allow statistical inference of functional couplings in the network but are fundamentally unable to correctly identify indirect and apparent connections between neurons, generating redundant maps with limited ability to model the causal dynamics of the network. In this paper, we describe a novel mathematically rigorous, model-free method to map effective—direct and causal—connectivity of neuronal networks from multi-electrode array data. The inference algorithm uses a combination of statistical and deterministic indicators which, first, enables identification of all existing functional links in the network and then reconstructs the directed and causal connection diagram via a super-selective rule enabling highly accurate classification of direct, indirect, and apparent links. Our method can be generally applied to the functional characterization of any in vitro neuronal networks. Here, we show that, given its accuracy, it can offer important insights into the functional development of in vitro hiPSC-derived neuronal cultures.
Loss of IL-34 Expression Indicates Poor Prognosis in Patients With Lung Adenocarcinoma
Authors: Wang Zhendong , Zhu Jun , Wang Tianyi , Zhou Hao , Wang Jinjie , Huang Zhanghao , Zhang Haijian , Shi Jiahai
Published: July 2021

Interleukin 34 (IL-34), an additional ligand of the colony-stimulating factor-1 receptor (CSF-1R), promotes the secretion of pro-inflammatory cytokines and stimulates NF-κB and JNK-related signaling pathways. However, the potential mechanism and prognostic value of IL-34 in lung adenocarcinoma (LUAD) remain obscure. In this study, IL-34 was found to be downregulated in LUAD tissues compared with para-carcinoma tissues, and loss of IL-34 expression was correlated with shorter overall survival (OS), which was validated by bioinformatics\ analysis in TCGA (The Cancer Genome Atlas) cohort and immunohistochemical analysis in the NTU (Nantong University) cohort, respectively. Subsequently, loss of IL-34 promotes negative regulation of the immune system and inhibits the infiltration of immune cells. Moreover, IL-34 deficiency was shown to be an independent adverse prognostic factor for patients with LUAD, and subgroup analysis indicated that IL-34 might contribute to the stratified management of patients with LUAD. IL-34-based nomogram model significantly improved the accuracy of prognostic predictions for OS of patients with LUAD, both in the TCGA cohort and the NTU cohort. Taken together, our data suggested that loss of IL-34 expression is associated with poor prognosis and negative regulation of the immune system of patients with LUAD, contributing to the stratified management of patients with LUAD.
The Role of Immunotherapy to Overcome Resistance in Viral-Associated Head and Neck Cancer
Authors: Pharaon Rebecca R. , Xing Yan , Agulnik Mark , Villaflor Victoria M.
Published: July 2021

A subset of head and neck cancers arising in the oropharynx and the nasopharynx are associated with human papillomavirus or Epstein–Barr virus. Unfortunately, limited treatment options exist once patients develop recurrent or metastatic disease in these cancers. Interest has risen in utilizing novel strategies including combination immune checkpoint inhibitors, vaccines, and adoptive cellular therapy, to improve treatment response and outcomes. Several ongoing studies are investigating the potential to overcome resistance to standard of care chemoradiation therapy with monotherapy or combination immunotherapy strategies in these viral-associated head and neck cancers.
Decreased Survival of Invasive Ductal Breast Cancer Patients With Two Macrometastatic Lymph Nodes Among Few Resected Ones: Should Current Sentinel-Lymph-Node Guidelines Be Revised?
Authors: Luz Felipe A. C. , Araújo Rogério A. , Silva Marcelo J. B.
Published: July 2021

Purpose

Sentinel-lymph-node (SLN) biopsy (SLB) is an efficient and safe axillary surgical approach with decreased morbidity than total axillary lymph node dissection (ALND) in initial patients (T1–T2). Current guidelines strongly suggest avoiding completion of ALND in patients with one or two positive SLNs that will be submitted to whole-breast radiation therapy, but must be done when three SLNs are affected.

Methods

We performed a SEER-based study with breast invasive ductal carcinoma patients treated between 2010 and 2015. Optimal cutoffs of positive LNs predictive of survival were obtained with ROC curves and survival as a continuous variable. Bias was reduced through propensity score matching. Cox regression was employed to estimate prognosis. Nomograms were constructed to analyze the predictive value of clinicopathological factors for axillary burden.

Results

Of 43,239 initial patients that had one to three analyzed LNs, only 425 had two positive LNs and matched analysis demonstrated no survival difference versus pN2 patients [HR: 0.960 (0.635–1.452), p = 0.846]. The positive-to-analyzed LN proportion demonstrated a strong prognostic factor for a low rate (1 positive to ≤1.5 analyzed) [HR = 1.567 (1.156–2.126), p = 0.004], and analysis derived from the results demonstrated that a “negative LN margin” improves survival. Nomograms shows that tumor size is the main factor of axillary burden.

Conclusion

Macrometastasis of two LNs is a poor prognostic factor, similar to pN2, in SLNB (-like) patients; more extensive studies including preconized therapies must be done in order to corroborate or refute the resistance of this prognostic difference in patients with two macrometastatic lymph nodes within few resected.
Development and Validation of a Nomogram and a Comprehensive Prognostic Analysis of an LncRNA-Associated Competitive Endogenous RNA Network Based on Immune-Related Genes for Locally Advanced Rectal Cancer With Neoadjuvant Therapy
Authors: Wei Fang-Ze , Mei Shi-Wen , Wang Zhi-Jie , Chen Jia-Nan , Shen Hai-Yu , Zhao Fu-Qiang , Li Juan- , Xiao Ti-Xian , Liu Qian
Published: July 2021

Colorectal cancer (CRC) is a common digestive tract tumor worldwide. In recent years, neoadjuvant chemoradiotherapy (CRT) has been the most comprehensive treatment for locally advanced rectal cancer (LARC). In this study, we explored immune infiltration in rectal cancer (RC) and identified immune-related differentially expressed genes (IRDEGs). Then, we identified response markers in datasets in GEO databases by principal component analysis (PCA). We also utilized three GEO datasets to identify the up- and downregulated response-related genes simultaneously and then identified genes shared between the PCA markers and three GEO datasets. Based on the hub IRDEGs, we identified target mRNAs and constructed a ceRNA network. Based on the ceRNA network, we explored prognostic biomarkers to develop a prognostic model for RC through Cox regression. We utilized the specimen to validate the expression of the two biomarkers. We also utilized LASSO regression to screen hub IRDEGs and built a nomogram to predict the response of LARC patients to CRT. All of the results show that the nomogram and prognostic model offer good prognostic value and that the ceRNA network can effectively highlight the regulatory relationship. hsa-mir-107 and WDFY3-AS2 may be prognostic biomarkers for RC.
The Exercise Oncology Knowledge Mobilization Initiative: An International Modified Delphi Study
Authors: Adams Scott C. , Smith-Turchyn Jenna , Santa Mina Daniel , Neil-Sztramko Sarah , Cormie Prue , Culos-Reed S. Nicole , Campbell Kristin L. , Pugh Gemma , Langelier David , Schmitz Kathryn H. , Phipps David J. , Nadler Michelle , Sabiston Catherine M.
Published: July 2021

Introduction

Exercise is vital to health and well-being after a cancer diagnosis yet is poorly integrated in cancer care. Knowledge mobilization (KM) is essential to enhance exercise opportunities. We aimed to (1) develop and refine a list of highly important exercise oncology research and KM themes and (2) establish the relative importance of the themes for supporting the implementation of exercise as a standard of care for people living with and beyond cancer.

Methods

Informed by the Co-Produced Pathway to Impact KM framework, a modified Delphi study approach was used to develop, rate, and rank exercise oncology research and KM themes through an international stakeholder workshop and a three-round iterative online survey. Open-ended stakeholder feedback from cancer survivors, healthcare practitioners (HCPs), qualified exercise professionals (QEPs), policy makers, and researchers was used to update themes between survey rounds. Themes were ranked from highest to lowest importance and agreement was examined across all stakeholders and within stakeholder groups.

Results

A total of 269 exercise oncology stakeholders from 13 countries participated in the study. Twelve final exercise oncology research and KM themes were produced. The final top ranked research themes were related to: (1) QEP integration into primary cancer care teams, (2) Exercise oncology education for HCPs, and (3) Accessibility of cancer exercise programs & support services. There was statistically significant agreement between stakeholders (p<0.001) and within stakeholder groups (p’s≤0.02) on the general rankings of themes (i.e., some themes generally ranked higher and lower compared to others). Low Kendall’s W statistics indicated variability related to the specific ranked order of the themes between stakeholders and within stakeholder groups. Moreover, there were key differences in the rankings for specific themes between policy makers and other stakeholder groups that highlight potentially important discordance in the research and KM priorities for policy makers that warrants further study.

Conclusion

These findings can be used to guide initiatives and align stakeholders on priorities to support exercise implementation as a standard of cancer care. Additional research is needed to better understand the differences in the proposed research and KM priorities across stakeholders.
A Guidance for Concomitant Drug Reconciliation Prior to Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults
Authors: Apsel Winger Beth , Long Susie E. , Brooks Jordan , Gupta Ashish O. , Dvorak Christopher C. , Long-Boyle Janel Renee
Published: July 2021

Pediatric diseases treated by allogeneic hematopoietic stem cell transplantation (alloHCT) are complex and associated with significant comorbidities and medication requirements that can complicate the transplant process. It is critical to reconcile pre-transplant concomitant medications (pcon-meds) in the weeks prior to alloHCT and to consider the potential for pcon-meds to cause harmful drug-drug interactions (DDIs) or overlapping toxicities with conditioning agents. In this perspective, we describe a systematic process to review pcon-meds and determine the drug modifications needed to avoid DDIs with conditioning regimens. We provide an extensive appendix with timelines for discontinuation or modification of common pcon-meds that patients are taking when presenting to the HCT medical team. The timelines are based on the pharmacokinetic (PK) properties of both the pcon-meds and the planned conditioning medications, as well as anticipated DDIs. They also account for the ages seen at pediatric transplant centers (0–30 years old). Common scenarios, such as when pcon-med discontinuation is not an option, are discussed. Since alloHCT patients are often dependent upon psychiatric medications with problematic DDIs, a table of alternative, non-interacting psychiatric medications is also presented. The appendix provides details regarding how to adjust pcon-meds prior to the start of chemotherapy for children and young adults undergoing alloHCT, however patient-specific circumstances always need to be taken into account. Careful attentiveness to pcon-meds at the time the decision is made to pursue transplant will result in more consistent HCT outcomes, with lower toxicity and increased efficacy of conditioning agents.
P-Rex1 Cooperates With TGFβR2 to Drive Lung Fibroblast Migration in Pulmonary Fibrosis
Authors: Liang Qing , Chang Yanhua , Liu Jing , Yu Yan , Qiu Wancheng , Li Jiajia , Yang Xu , Sun Guangchun
Published: July 2021

Pulmonary fibrosis is a kind of interstitial lung disease with progressive pulmonary scar formation, leading to irreversible loss of lung functions. The TGF-β1/Smad signaling pathway plays a key role in fibrogenic processes. It is associated with the increased synthesis of extracellular matrix, enhanced proliferation of fibroblasts, and transformation of alveolar epithelial cells into interstitial cells. We investigated P-Rex1, a PIP3-Gβγ–dependent guanine nucleotide exchange factor (GEF) for Rac, for its potential role in TGF-β1–induced pulmonary fibrosis. A high expression level of P-Rex1 was identified in the lung tissue of patients with pulmonary fibrosis than that from healthy donors. Using the P-Rex1 knockdown and overexpression system, we established a novel player of P-Rex1 in mouse lung fibroblast migration. P-Rex1 contributed to fibrogenic processes in lung fibroblasts by targeting the TGF-β type Ⅱ receptor (TGFβR2). The RNA-seq analysis for expression profiling confirmed the modulation of P-Rex1 in cell migration and the involvement of P-Rex1 in TGF-β1 signaling. These results identified P-Rex1 as a signaling molecule involved in TGF-β1–induced pulmonary fibrosis, suggesting that P-Rex1 may be a potential target for pulmonary fibrosis treatment.