bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunopotentiation by Lymph-Node Targeting of a Malaria Transmission-Blocking Nanovaccine
Authors: Howard Gregory P. , Bender Nicole G. , Khare Prachi , López-Gutiérrez Borja , Nyasembe Vincent , Weiss William J. , Simecka Jerry W. , Hamerly Timothy , Mao Hai-Quan , Dinglasan Rhoel R.
Published: September 2021

A successful malaria transmission blocking vaccine (TBV) requires the induction of a high antibody titer that leads to abrogation of parasite traversal of the mosquito midgut following ingestion of an infectious bloodmeal, thereby blocking the cascade of secondary human infections. Previously, we developed an optimized construct UF6b that elicits an antigen-specific antibody response to a neutralizing epitope of Anopheline alanyl aminopeptidase N (AnAPN1), an evolutionarily conserved pan-malaria mosquito midgut-based TBV target, as well as established a size-controlled lymph node targeting biodegradable nanoparticle delivery system that leads to efficient and durable antigen-specific antibody responses using the model antigen ovalbumin. Herein, we demonstrate that co-delivery of UF6b with the adjuvant CpG oligodeoxynucleotide immunostimulatory sequence (ODN ISS) 1018 using this biodegradable nanoparticle vaccine delivery system generates an AnAPN1-specific immune response that blocks parasite transmission in a standard membrane feeding assay. Importantly, this platform allows for antigen dose-sparing, wherein lower antigen payloads elicit higher-quality antibodies, therefore less antigen-specific IgG is needed for potent transmission-reducing activity. By targeting lymph nodes directly, the resulting immunopotentiation of AnAPN1 suggests that the de facto assumption that high antibody titers are needed for a TBV to be successful needs to be re-examined. This nanovaccine formulation is stable at -20°C storage for at least 3 months, an important consideration for vaccine transport and distribution in regions with poor healthcare infrastructure. Together, these data support further development of this nanovaccine platform for malaria TBVs.
Transcriptome Analysis of Immune Receptor Activation and Energy Metabolism Reduction as the Underlying Mechanisms in Interleukin-6-Induced Skeletal Muscle Atrophy
Authors: Sun Hualin , Sun Junjie , Li Ming , Qian Lei , Zhang Lilei , Huang Ziwei , Shen Yuntian , Law Betty Yuen-Kwan , Liu Liang , Gu Xiaosong
Published: September 2021

Background

Inflammation may trigger skeletal muscle atrophy induced by cancer cachexia. As a pro-inflammatory factor, interleukin-6 may cause skeletal muscle atrophy, but the underlying molecular mechanisms have not been explored.

Methods

In this experimental study, we used adult male ICR mice, weighing 25 ± 2 g, and the continuous infusion of interleukin-6 into the tibialis anterior muscle to construct a skeletal muscle atrophy model (experimental group). A control group received a saline infusion. RNA-sequencing was used to analyze the differentially expressed genes in tissue samples after one and three days. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analysis were applied to define the function of these genes, and protein-protein interaction analysis was performed to identify potential transcription factors. Fluorescence microscopy was used to determine the muscle fiber cross-sectional area after 14 days.

Results

Continuous infusion of interleukin-6 for 14 days caused significant muscle atrophy. RNA-sequencing found 359 differentially expressed genes in the 1- and 3-day tissue samples and 1748 differentially expressed genes only in the 3-day samples. Functional analysis showed that the differentially expressed genes found in both the 1- and 3-day samples were associated with immune receptor activation, whereas the differentially expressed genes found only in the 3-day sample were associated with reduced energy metabolism. The expression of multiple genes in the oxidative phosphorylation and tricarboxylic acid cycle pathways was down-regulated. Furthermore, differentially expressed transcription factors were identified, and their interaction with interleukin-6 and the differentially expressed genes was predicted, which indicated that STAT3, NF-κB, TP53 and MyoG may play an important role in the process of interleukin-6-induced muscle atrophy.

Conclusions

This study found that interleukin-6 caused skeletal muscle atrophy through immune receptor activation and a reduction of the energy metabolism. Several transcription factors downstream of IL-6 have the potential to become new regulators of skeletal muscle atrophy. This study not only enriches the molecular regulation mechanism of muscle atrophy, but also provides a potential target for targeted therapy of muscle atrophy.
Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes
Authors: Peng Tao , Phasouk Khamsone , Sodroski Catherine N. , Sun Sijie , Hwangbo Yon , Layton Erik D. , Jin Lei , Klock Alexis , Diem Kurt , Magaret Amalia S. , Jing Lichen , Laing Kerry , Li Alvason , Huang Meei-Li , Mertens Max , Johnston Christine , Jerome Keith R. , Koelle David M. , Wald Anna , Knipe David M. , Corey Lawrence , Zhu Jia
Published: September 2021

Tissue-resident-memory T cells (TRM) populate the body’s barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.
Cerebral-Cardiac Syndrome and Diabetes: Cardiac Damage After Ischemic Stroke in Diabetic State
Authors: Lin Hong-Bin , Li Feng-Xian , Zhang Jin-Yu , You Zhi-Jian , Xu Shi-Yuan , Liang Wen-Bin , Zhang Hong-Fei
Published: September 2021

Cerebral-cardiac syndrome (CCS) refers to cardiac dysfunction following varying brain injuries. Ischemic stroke is strongly evidenced to induce CCS characterizing as arrhythmia, myocardial damage, and heart failure. CCS is attributed to be the second leading cause of death in the post-stroke stage; however, the responsible mechanisms are obscure. Studies indicated the possible mechanisms including insular cortex injury, autonomic imbalance, catecholamine surge, immune response, and systemic inflammation. Of note, the characteristics of the stroke population reveal a common comorbidity with diabetes. The close and causative correlation of diabetes and stroke directs the involvement of diabetes in CCS. Nevertheless, the role of diabetes and its corresponding molecular mechanisms in CCS have not been clarified. Here we conclude the features of CCS and the potential role of diabetes in CCS. Diabetes drives establish a “primed” inflammatory microenvironment and further induces severe systemic inflammation after stroke. The boosted inflammation is suspected to provoke cardiac pathological changes and hence exacerbate CCS. Importantly, as the key element of inflammation, NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is indicated to play an important role in diabetes, stroke, and the sequential CCS. Overall, we characterize the corresponding role of diabetes in CCS and speculate a link of NLRP3 inflammasome between them.
Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate Improves Host Control of Salmonella enterica Serovar Typhimurium Infection in Human Macrophages
Authors: van Doorn Cassandra L. R. , Schouten Gina K. , van Veen Suzanne , Walburg Kimberley V. , Esselink Jeroen J. , Heemskerk Matthias T. , Vrieling Frank , Ottenhoff Tom H. M.
Published: September 2021

Global increases in the prevalence of antimicrobial resistance highlight the urgent need for novel strategies to combat infectious diseases. Recent studies suggest that host metabolic pathways play a key role in host control of intracellular bacterial pathogens. In this study we explored the potential of targeting host metabolic pathways for innovative host-directed therapy (HDT) against intracellular bacterial infections. Through gene expression profiling in human macrophages, pyruvate metabolism was identified as potential key pathway involved in Salmonella enterica serovar Typhimurium (Stm) infections. Next, the effect of targeting pyruvate dehydrogenase kinases (PDKs) – which are regulators of the metabolic checkpoint pyruvate dehydrogenase complex (PDC) – on macrophage function and bacterial control was studied. Chemical inhibition of PDKs by dichloroacetate (DCA) induced PDC activation and was accompanied with metabolic rewiring in classically activated macrophages (M1) but not in alternatively activated macrophages (M2), suggesting cell-type specific effects of dichloroacetate on host metabolism. Furthermore, DCA treatment had minor impact on cytokine and chemokine secretion on top of infection, but induced significant ROS production by M1 and M2. DCA markedly and rapidly reduced intracellular survival of Stm, but interestingly not Mycobacterium tuberculosis, in human macrophages in a host-directed manner. In conclusion, DCA represents a promising novel HDT compound targeting pyruvate metabolism for the treatment of Stm infections.
Driving CARs to BARs: The Winding Road to Specific Regulatory T Cells for Tolerance
Authors: Scott David W.
Published: September 2021

Chimeric antigen receptor (CAR) transduced T cells have significantly improved cancer immunotherapy. Similarly, engineering regulatory T cells (Treg) with specific receptors to endow specificity and increase efficacy of Tregs holds great promise for therapy of a variety of adverse immune responses. In this review, we focus on our approaches using retroviral transduction of specific T-cell receptors, single chain variable fragments (scFv) or antigen in models of monogenic diseases, autoimmunity and allergy. The advantages of each of these for different targets diseases are discussed as well as their potential for clinical translation.
An Economic Perspective on Policies to Save the Vaquita: Conservation Actions, Wildlife Trafficking, and the Structure of Incentives
Authors: Sanjurjo-Rivera Enrique , Mesnick Sarah L. , Ávila-Forcada Sara , Poindexter Oriana , Lent Rebecca , Felbab-Brown Vanda , Cisneros-Montemayor Andrés M. , Squires Dale , Sumaila U. Rashid , Munro Gordon , Ortiz-Rodriguez Rafael , Rodriguez Ramses , Sainz Jade F.
Published: September 2021

The Upper Gulf of California is a diverse and highly productive ecosystem supporting some of the most important fisheries in Mexico, yet a history of weak fisheries management and illegal fishing threaten the area’s biodiversity and undermine human well-being in the communities along its shores. The vaquita (Phocoena sinus)is endemic to these waters and is on the brink of extinction due to incidental entanglement in gillnets used by small-scale fishers. The resurgence of an illegal gillnet fishery for totoaba (Totoaba macdonaldi), whose swim bladders are highly prized in Hong Kong and continental China, has accelerated the steep decline of the vaquita population. Vaquita is one of a growing number of cases linking illegal wildlife trade, organized crime, and biodiversity decline. This paper provides a summary of key reflections of a panel of fisheries economists gathered at the ninth forum of the North American Association of Fisheries Economists (NAAFE) to evaluate the policies implemented in the Upper Gulf through an economic lens and updated to reflect more recent developments. The panel recognized that poor fisheries management, lack of effective enforcement, distant demand for an illegal product, corruption, and few viable economic alternatives confound efforts to address vaquita bycatch. The complexity of these problems requires a holistic, multidisciplinary approach, combining top-down, direct regulation and bottom-up, participatory and incentive-based instruments. Addressing chronic deficiencies in enforcement, particularly in the very small area where the remaining vaquitas are found, is crucial to prevent imminent extinction. Equally crucial are sustained actions to support legal fishers able to make a good living – with a direct stake in healthy marine ecosystems – as key components of policies to address bycatch and reduce wildlife trafficking. The situation in the Upper Gulf of California is dire, yet similar threats to other marine mammals and wildlife trafficked species may benefit from the experience of the vaquita.
Mixing and Phytoplankton Growth in an Upwelling System
Authors: Comesaña Antonio , Fernández-Castro Bieito , Chouciño Paloma , Fernández Emilio , Fuentes-Lema Antonio , Gilcoto Miguel , Pérez-Lorenzo María , Mouriño-Carballido Beatriz
Published: September 2021

Previous studies focused on understanding the role of physical drivers on phytoplankton bloom formation mainly used indirect estimates of turbulent mixing. Here we use weekly observations of microstructure turbulence, dissolved inorganic nutrients, chlorophyll a concentration and primary production carried out in the Ría de Vigo (NW Iberian upwelling system) between March 2017 and May 2018 to investigate the relationship between turbulent mixing and phytoplankton growth at different temporal scales. In order to interpret our results, we used the theoretical framework described by the Critical Turbulent Hypothesis (CTH). According to this conceptual model if turbulence is low enough, the depth of the layer where mixing is active can be shallower than the mixed-layer depth, and phytoplankton may receive enough light to bloom. Our results showed that the coupling between turbulent mixing and phytoplankton growth in this system occurs at seasonal, but also at shorter time scales. In agreement with the CTH, higher phytoplankton growth rates were observed when mixing was low during spring-summer transitional and upwelling periods, whereas low values were described during periods of high mixing (fall-winter transitional and downwelling). However, low mixing conditions were not enough to ensure phytoplankton growth, as low phytoplankton growth was also found under these circumstances. Wavelet spectral analysis revealed that turbulent mixing and phytoplankton growth were also related at shorter time scales. The higher coherence between both variables was found in spring-summer at the ~16–30 d period and in fall-winter at the ~16–90 d period. These results suggest that mixing could act as a control factor on phytoplankton growth over the seasonal cycle, and could be also involved in the formation of occasional short-lived phytoplankton blooms.
Light Induced Changes in Pigment and Lipid Profiles of Bryopsidales Algae
Authors: Giossi Chiara E. , Cruz Sónia , Rey Felisa , Marques Rúben , Melo Tânia , Domingues Maria do Rosário , Cartaxana Paulo
Published: September 2021

Bryopsidales (Chlorophyta) are cultured and consumed in several regions of the planet and are known for their high nutritional value and bioprospection potential, due to a high content of relevant polar lipids and polysaccharides. Among other characteristic features, these marine algae are known for possessing unique photosynthetic pigment-protein complexes and for the absence (in nearly all species investigated) of a functional xanthophyll cycle, a ubiquitous photoprotection mechanism present in most algae and plants. With the aim of characterizing the photophysiology of this atypical group of algae, we investigated the changes in pigment content and polar lipidome of two Bryopsidales species (Codium tomentosumandBryopsis plumosa) exposed for 7 days to low or high irradiance (20 vs. 1,000 μmol photons m–2s–1). Our results show that high light has a strong effect on the pigment composition, triggering the time-dependent accumulation of all-trans-neoxanthin (t-Neo) and violaxanthin (Viola). High light-acclimated macroalgae also displayed a shift in the characteristic polar lipidome, including a trend of accumulation of lyso-glycolipids, and highly unsaturated phospholipids and betaine lipids. We hypothesize that the observed shifts on the lipid composition could promote the interaction betweent-Neo and Viola with the siphonaxanthin–chlorophyll–protein complexes (SCP) of photosystem II (PSII) within the thylakoid membranes of the chloroplasts. Light induced changes in pigment and lipid composition could contribute to the fitness of Bryopsidales algae by reducing damages to the photosynthetic apparatus under increased irradiance.
An Efficient Approach to Describe the Fiber Effect on Mechanical Performance of Pultruded GFRP Profiles
Authors: Gribniak Viktor , Rimkus Arvydas , Plioplys Linas , Misiūnaitė Ieva , Garnevičius Mantas , Boris Renata , Šapalas Antanas
Published: September 2021

This study focuses on the flexural behavior of pultruded glass fiber-reinforced polymer (GFRP) profiles developed for structural applications. Fiber content is a commonly accepted measure for estimating the resistance of such components, and technical datasheets describe this essential parameter. However, its direct implementation to the numerical simulations can face substantial problems because of the limitations of standard test protocols. Furthermore, the fiber mass percentage understandable for producers is unsuitable for typical software considered the volumetric reinforcement content. This manuscript exemplifies the above situation both experimentally and analytically, investigating two GFRP square hollow section (SHS) profiles available at the market. A three-point bending test determines the mechanical performance of the profiles in this experimental program; a digital image correlation system captures deformations and failure mechanisms of the SHS specimens; a standard tensile test defines the material properties. A simplified finite element (FE) model is developed based on the smeared reinforcement concept to predict the stiffness and load-bearing capacity of the profiles. An efficient balance between the prediction accuracy and computation time characterizes the developed FE approach that does not require specific descriptions of reinforcement geometry and refined meshes necessary for modeling the discrete fibers. The proposed FE approach is also used to analyze the fiber efficiency in reinforcing the polymer matrix. The efficiency is understood as the model’s ability to resist mechanical load proportional to the dry filaments’ content and experimental elastic modulus value. Scanning electron microscopy relates the composite microstructure and the mechanical performance of the selected profiles in this study.
Numerical Investigation on the Effect of the Oxymethylene Ether-3 (OME3) Blending Ratio in Premixed Sooting Ethylene Flames
Authors: Schmitz Robert , Sirignano Mariano , Hasse Christian , Ferraro Federica
Published: September 2021

Synthetic fuels, especially oxygenated fuels, which can be used as blending components, make it possible to modify the emission properties of conventional fossil fuels. Among oxygenated fuels, one promising candidate is oxymethylene ether-3 (OME3). In this work, the sooting propensity of ethylene (C2H4) blended with OME3 is numerically investigated on a series of laminar burner-stabilized premixed flames with increasing amounts of OME3, from pure ethylene to pure OME3. The numerical analysis is performed using the Conditional Quadrature Method of Moments combined with a detailed physico-chemical soot model. Two different equivalence ratios corresponding to a lightly and a highly sooting flame condition have been investigated. The study examines how different blending ratios of the two fuels affect soot particle formation and a correlation between OME3 blending ratio and corresponding soot reduction is established. The soot precursor species in the gas-phase are analyzed along with the soot volume fraction of small nanoparticles and large aggregates. Furthermore, the influence of the OME3 blending on the particle size distribution is studied applying the entropy maximization concept. The effect of increasing amounts of OME3 is found to be different for soot nanoparticles and larger aggregates. While OME3 blending significantly reduces the amount of larger aggregates, only large amounts of OME3, close to pure OME3, lead to a considerable suppression of nanoparticles formed throughout the flame. A linear correlation is identified between the OME3 content in the fuel and the reduction in the soot volume fraction of larger aggregates, while smaller blending ratios may lead to an increased number of nanoparticles for some positions in the flame for the richer flame condition.
Ayurvedic vs. Conventional Nutritional Therapy Including Low-FODMAP Diet for Patients With Irritable Bowel Syndrome—A Randomized Controlled Trial
Authors: Jeitler Michael , Wottke Till , Schumann Dania , Puerto Valencia Laura M. , Michalsen Andreas , Steckhan Nico , Mittwede Martin , Stapelfeldt Elmar , Koppold-Liebscher Daniela , Cramer Holger , Wischnewsky Manfred , Murthy Vijayendra , Kessler Christian S.
Published: September 2021

Aims: To compare the effects of Ayurvedic and conventional nutritional therapy in patients with irritable bowel syndrome (IBS).

Methods: Sixty-nine patients with IBS were randomized to Ayurvedic (n = 35) or conventional nutritional therapy according to the recommendations of the German Nutrition Society including the low-FODMAP diet (n = 34). Study visits took place at baseline and after 1, 3, and 6 months. The primary outcome was IBS symptom severity (IBS-SSS) after 3 months; secondary outcomes included stress (CPSS), anxiety and depression (HADS), well-being (WHO-5) and IBS-specific quality of life (IBS-QOL). A repeated measures general linear model (GLM) for intent-to-treat-analyses was applied in this explorative study.

Results: After 3 months, estimated marginal means for IBS-SSS reductions were 123.8 [95% confidence interval (95% CI) = 92.8–154.9; p < 0.001] in the Ayurvedic and 72.7 (95% CI = 38.8–106.7; p < 0.001) in the conventional group. The IBS-SSS reduction was significantly higher in the Ayurveda group compared to the conventional therapy group (estimated marginal mean = 51.1; 95% CI = 3.8–98.5; p = 0.035) and clinically meaningful. Sixty-eight percentage of the variance in IBS-SSS reduction after 3 months can be explained by treatment, 6.5% by patients' expectations for their therapies and 23.4% by IBS-SSS at pre-intervention. Both therapies are equivalent in their contribution to the outcome variance. The higher the IBS-SSS score at pre-intervention and the larger the patients' expectations, the greater the IBS-SSS reduction. There were no significant group differences in any secondary outcome measures. No serious adverse events occurred in either group.

Conclusion: Patients with IBS seem to benefit significantly from Ayurvedic or conventional nutritional therapy. The results warrant further studies with longer-term follow-ups and larger sample sizes.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03019861, identifier: NCT03019861.
Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19?
Authors: Devaux Christian A. , Melenotte Cléa , Piercecchi-Marti Marie-Dominique , Delteil Clémence , Raoult Didier
Published: September 2021

Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.
Characteristics and Associated Factors of Flat Irregular Pigment Epithelial Detachment With Choroidal Neovascularization in Chronic Central Serous Chorioretinopathy
Authors: Su Yongyue , Zhang Xiongze , Gan Yuhong , Ji Yuying , Wen Feng
Published: September 2021

Purpose: Flat irregular pigment epithelial detachment (FIPED) in chronic central serous chorioretinopathy (CSC) is strongly associated with type 1 choroidal neovascularization (CNV). The present study aimed to describe the multimodal imaging characteristics of FIPED in patients with chronic CSC and investigate the factors associated with vascularized FIPED.

Methods: We included 55 chronic CSC eyes with vascularized FIPED (47 patients) and 55 chronic CSC eyes with avascular FIPED from age-matched patients (47 patients). None of the included eyes had a history of previous treatment with anti-vascular endothelial growth factor, photodynamic therapy, focal laser, or vitrectomy. The demographic and multimodal imaging data were reviewed. The location, angiography features, height and width, presence of retinal pigment epithelium (RPE) aggregations, RPE thickness, and choroid status of the FIPED area were compared between the groups.

Results: The mean age of the included chronic CSC patients was 54.3 ± 7.8 years (range: 33–72 years), and 85.1% were male. Vascularized FIPED eyes had a larger width (1,556.4 ± 731.6 vs. 931.1 ± 486.2 μm, p < 0.001), larger subfoveal RPE thickness (33.4 ± 15.3 vs. 26.3 ± 6.6 μm, p = 0.004), larger maximum RPE thickness of the FIPED area (46.3 ± 20.5 vs. 31.5 ± 8.3 μm, p < 0.001), and more RPE aggregations in the FIPED area (94.5 vs. 54.5%, p < 0.001) than avascular FIPED eyes. RPE aggregations in the FIPED area were an independent factor strongly associated with vascularized FIPED (OR = 7.922, 95% CI = 1.346–46.623, p = 0.022).

Conclusion: FIPED with a larger width and RPE thickening may suggest the presence of an underlying type 1 CNV. FIPED with RPE aggregations had an increased occurrence of neovascularization in chronic CSC.
Allogeneic Cultivated Limbal Epithelial Sheet Transplantation in Reconstruction of Conjunctival Sac After Chemical and Thermal Burns
Authors: Wang Ting , Shan Fengmei , Zhou Qingjun , Shi Weiyun , Xie Lixin
Published: September 2021

The study aims to evaluate the effect of allogeneic cultivated limbal epithelial cell sheet transplantation (CLET) in reconstructing conjunctival sac for severe symblepharon after chemical and thermal burns. A retrospective, non-comparative case series. Thirty-six eyes (36 patients) underwent CLET for severe symblepharon and conjunctival sac stenosis or atresia. Symblepharon was separated, and pseudopterygium was preserved to replace the palpebral conjunctiva. Allogeneic cultivated limbal epithelial cell sheet using human amniotic membrane as a carrier was transplanted into the recipient's eye to reconstruct the conjunctival sac. The effect of conjunctival sac reconstruction, eye and eyelid movement, ocular surface restitution, and symblepharon recurrence were analyzed after surgery. Symblepharon was completely relieved in 30 of the 36 eyes (83.3%) by a single surgical procedure, with fornix reconstruction, as well as free movement of eye globe and eyelids. Strip-like symblepharon remained in 6 eyes (16.7%) and was completely relieved after the second CLET. Twenty patients without visual function received prostheses 3 months after surgery and the other sixteen patients underwent different corneal transplantation for visual acuity improvement. During the follow-up period, no one had symblepharon recurrence. The transplantation of cultivated allogeneic limbal epithelial sheets offers an effective and safe alternative in the treatment of symblepharon and reconstruction of conjunctival sac in eyes with severe ocular burns, which lays the foundation for subsequent treatments.
A Protocol for the Use of Case Reports/Studies and Case Series in Systematic Reviews for Clinical Toxicology
Authors: Nambiema Aboubakari , Sembajwe Grace , Lam Juleen , Woodruff Tracey , Mandrioli Daniele , Chartres Nicholas , Fadel Marc , Le Guillou Adrien , Valter Remi , Deguigne Marie , Legeay Marion , Bruneau Chloe , Le Roux Gaël , Descatha Alexis
Published: September 2021

Introduction: Systematic reviews are routinely used to synthesize current science and evaluate the evidential strength and quality of resulting recommendations. For specific events, such as rare acute poisonings or preliminary reports of new drugs, we posit that case reports/studies and case series (human subjects research with no control group) may provide important evidence for systematic reviews. Our aim, therefore, is to present a protocol that uses rigorous selection criteria, to distinguish high quality case reports/studies and case series for inclusion in systematic reviews.

Methods: This protocol will adapt the existing Navigation Guide methodology for specific inclusion of case studies. The usual procedure for systematic reviews will be followed. Case reports/studies and case series will be specified in the search strategy and included in separate sections. Data from these sources will be extracted and where possible, quantitatively synthesized. Criteria for integrating cases reports/studies and case series into the overall body of evidence are that these studies will need to be well-documented, scientifically rigorous, and follow ethical practices. The instructions and standards for evaluating risk of bias will be based on the Navigation Guide. The risk of bias, quality of evidence and the strength of recommendations will be assessed by two independent review teams that are blinded to each other.

Conclusion: This is a protocol specified for systematic reviews that use case reports/studies and case series to evaluate the quality of evidence and strength of recommendations in disciplines like clinical toxicology, where case reports/studies are the norm.
Effect of Oral Sodium Bicarbonate Treatment on 24-Hour Ambulatory Blood Pressure Measurements in Patients With Chronic Kidney Disease and Metabolic Acidosis
Authors: Gaggl Martina , Repitz Alexandra , Riesenhuber Sonja , Aigner Christof , Sliber Christopher , Fraunschiel Melanie , Cejka Daniel , Sunder-Plassmann Gere
Published: September 2021

Background: Sodium bicarbonate supplementation is a mainstay in the treatment of metabolic acidosis in patients with chronic kidney disease (CKD). Recent studies showed reduction of progression of CKD and reduced all-cause mortality. However, additional sodium loading could worsen arterial hypertension, a well-known contributor to progression of CKD. This patient-relevant and economically negative side effect is under-studied in prospective studies up until now.

Objective: The aim of this study was to analyze the effect of sodium bicarbonate treatment on arterial blood pressure at baseline and after 8 weeks.

Methods: The SoBic study is an ongoing randomized controlled trial, in which patients with CKD receive either a high dose of oral sodium bicarbonate or a rescue treatment, if necessary. We used standardized office blood pressure and 24-hour ambulatory blood pressure monitoring (24h-ABPM). Regression models were adjusted for estimated glomerular filtration rate and change of antihypertensives.

Results: 47 subjects were enrolled and the mean age was 57 (±14.6) years and 18 (38%) were female. In 43 randomized subjects with sufficiently performed 24h-ABPM neither systolic 24h-ABPM (2.522; 95%CI: −2.364, 7.408; mmHg) nor diastolic 24h-ABPM (0.868; 95%CI: −2.411, 4.147; mmHg) was affected by study group allocation. When looking at the effect of individual sodium bicarbonate dose on 24h-ABPM, the fully adjusted model suggested an increase of 0.047 (95%CI: −0.026, 0.119) mmHg by each mg/kg per day increase of sodium bicarbonate dose.

Conclusion: Sodium bicarbonate supplementation over 8 weeks did not significantly increase blood pressure measured by 24h-ABPM in CKD patients.

Trial Registration: EUDRACT Number: 2012-001824-36; 12/07/2012 (https://www.clinicaltrialsregister.eu).
Hyponatremia Intervention Trial (HIT): Study Protocol of a Randomized, Controlled, Parallel-Group Trial With Blinded Outcome Assessment
Authors: Refardt Julie , Pelouto Anissa , Potasso Laura , Hoorn Ewout J. , Christ-Crain Mirjam
Published: September 2021

Background: Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. In contrast to acute hyponatremia where the need for immediate treatment is well-recognized, chronic hyponatremia is often considered not clinically relevant. This is illustrated by reports showing that appropriate laboratory tests are ordered in <50% of patients and that up to 75% are still hyponatremic at discharge. At the same time, emerging evidence suggests an association between hyponatremia and adverse events including increased risk of mortality and rehospitalization.

Methods: This is a randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center trial with blinded outcome assessment. In total 2,278 participants will be enrolled. Participants will be randomly assigned to undergo either targeted correction of plasma sodium levels or standard of care during hospitalization. The primary outcome is the combined risk of death or re-hospitalization within 30 days.

Discussion: All data on hyponatremia and mortality are derived from observational studies and often lack methodologic robustness. Consequently, the direct impact of hyponatremia on mortality and rehospitalization risk is still debated, resulting in a clinical equipoise whether in-hospital chronic hyponatremia should be treated or not. Therefore, a randomized controlled trial is required to study whether targeted plasma sodium correction reduces the risk of mortality and rehospitalization associated with hyponatremia.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03557957.
High Efficacy of Therapeutic Equine Hyperimmune Antibodies Against SARS-CoV-2 Variants of Concern
Authors: Moreira-Soto Andres , Arguedas Mauricio , Brenes Hebleen , Buján Willem , Corrales-Aguilar Eugenia , Díaz Cecilia , Echeverri Ann , Flores-Díaz Marietta , Gómez Aarón , Hernández Andrés , Herrera María , León Guillermo , Macaya Román , Kühne Arne , Molina-Mora José Arturo , Mora Javier , Sanabria Alfredo , Sánchez Andrés , Sánchez Laura , Segura Álvaro , Segura Eduardo , Solano Daniela , Soto Claudio , Stynoski Jennifer L. , Vargas Mariángela , Villalta Mauren , Reusken Chantal B. E. M. , Drosten Christian , Gutiérrez José María , Alape-Girón Alberto , Drexler Jan Felix
Published: September 2021

SARS-CoV-2 variants of concern show reduced neutralization by vaccine-induced and therapeutic monoclonal antibodies; therefore, treatment alternatives are needed. We tested therapeutic equine polyclonal antibodies (pAbs) that are being assessed in clinical trials in Costa Rica against five globally circulating variants of concern: alpha, beta, epsilon, gamma and delta, using plaque reduction neutralization assays. We show that equine pAbs efficiently neutralize the variants of concern, with inhibitory concentrations in the range of 0.146–1.078 μg/mL, which correspond to extremely low concentrations when compared to pAbs doses used in clinical trials. Equine pAbs are an effective, broad coverage, low-cost and a scalable COVID-19 treatment.
The Transcriptional Response of Soil Bacteria to Long-Term Warming and Short-Term Seasonal Fluctuations in a Terrestrial Forest
Authors: Roy Chowdhury Priyanka , Golas Stefan M. , Alteio Lauren V. , Stevens Joshua T. E. , Billings Andrew F. , Blanchard Jeffrey L. , Melillo Jerry M. , DeAngelis Kristen M.
Published: September 2021

Terrestrial ecosystems are an important carbon store, and this carbon is vulnerable to microbial degradation with climate warming. After 30 years of experimental warming, carbon stocks in a temperate mixed deciduous forest were observed to be reduced by 30% in the heated plots relative to the controls. In addition, soil respiration was seasonal, as was the warming treatment effect. We therefore hypothesized that long-term warming will have higher expressions of genes related to carbohydrate and lipid metabolism due to increased utilization of recalcitrant carbon pools compared to controls. Because of the seasonal effect of soil respiration and the warming treatment, we further hypothesized that these patterns will be seasonal. We used RNA sequencing to show how the microbial community responds to long-term warming (~30 years) in Harvard Forest, MA. Total RNA was extracted from mineral and organic soil types from two treatment plots (+5°C heated and ambient control), at two time points (June and October) and sequenced using Illumina NextSeq technology. Treatment had a larger effect size on KEGG annotated transcripts than on CAZymes, while soil types more strongly affected CAZymes than KEGG annotated transcripts, though effect sizes overall were small. Although, warming showed a small effect on overall CAZymes expression, several carbohydrate-associated enzymes showed increased expression in heated soils (~68% of all differentially expressed transcripts). Further, exploratory analysis using an unconstrained method showed increased abundances of enzymes related to polysaccharide and lipid metabolism and decomposition in heated soils. Compared to long-term warming, we detected a relatively small effect of seasonal variation on community gene expression. Together, these results indicate that the higher carbohydrate degrading potential of bacteria in heated plots can possibly accelerate a self-reinforcing carbon cycle-temperature feedback in a warming climate.
Microbial Composition and Co-occurrence Patterns in the Gut Microbial Community of Normal and Obese Mice in Response to Astaxanthin
Authors: Gao Yuan , Liu Fang , Li Robert W. , Li Chunjun , Xue Changhu , Tang Qingjuan
Published: September 2021

The changes and interaction of gut microbiota, which respond to dietary supplements, play critical roles on improving human health. The modulating effect of astaxanthin on gut microbiota has been reported. However, little is known about the co-occurrence patterns among microbial taxa in response to astaxanthin. In this study, the gut microbial composition, co-occurrence patterns, and microbial correlations with physiological parameters in astaxanthin-fed normal and obese mice were studied. Astaxanthin altered the microbial composition and co-occurrence patterns in normal and obese mice. Furthermore, astaxanthin gave more profound impacts on microbiota in obesity when compared with normal mice. In group A (normal or obese mice supplemented with astaxanthin), the abundance of Acinetobacter was decreased, and Alistipes was increased by astaxanthin, which also occurred in the MA group (obese mice supplemented with astaxanthin). An operational taxonomic unit (OTU) (GreenGeneID# 4029632) assigned to the genus Bacteroides acted as a connector in the global network of A and MA groups. It may play critical roles in bridging intimate interactions between the host and other bacteria intervened by astaxanthin. Several modules correlated with physiological parameters were detected. For example, modules A12 and MA10 were significantly and negatively correlated with lipopolysaccharide (LPS) and fasting blood glucose (FBG) levels, respectively. A positive correlation was found between the node connectivity of the OTUs belonging to Clostridiaceae with LPS in obese mice, which indicated the role of Clostridiales as a potential pathological marker. Our findings provided a new interpretation of the role of astaxanthin in health and may contribute to further research on microbial community engineering.
Novel Insights Into Cellular Changes in HPV8-E7 Positive Keratinocytes: A Transcriptomic and Proteomic Analysis
Authors: Kirschberg Matthias , Syed Adnan Shahzad , Dönmez Hanife Güler , Heuser Sandra , Wilbrand-Hennes Astrid , Alonso Angel , Hufbauer Martin , Akgül Baki
Published: September 2021

Human papillomavirus type 8 (HPV8) is associated with the development of non-melanoma skin cancer. In the past we already delved into the mechanisms involved in keratinocyte invasion, showing that the viral E7 oncoprotein is a key player that drives invasion of basal keratinocytes controlled by the extracellular protein fibronectin. To unravel further downstream effects in E7 expressing keratinocytes we now aimed at characterizing gene and protein/phosphoprotein alterations to narrow down on key cellular targets of HPV8-E7. We now show that gene expression of GADD34 and GDF15 are strongly activated in the presence of E7 in primary human keratinocytes. Further analyses of fibronectin-associated factors led to the identification of the Src kinase family members Fyn and Lyn being aberrantly activated in the presence of HPV8-E7. Phospho-proteomics further revealed that E7 not only targets cell polarity and cytoskeletal organization, but also deregulates the phosphorylation status of nuclear proteins involved in DNA damage repair and replication. Many of these differentially phosphorylated proteins turned out to be targets of Fyn and Lyn. Taken together, by using unbiased experimental approaches we have now arrived at a deeper understanding on how fibronectin may affect the signaling cascades in HPV8 positive keratinocytes, which may be key for skin tumorigenesis and that may also aid in the development of novel therapeutic approaches for betaHPV-mediated cancers.
Prospects for the Mechanism of Spiroplasma Swimming
Authors: Sasajima Yuya , Miyata Makoto
Published: September 2021

Spiroplasma are helical bacteria that lack a peptidoglycan layer. They are widespread globally as parasites of arthropods and plants. Their infectious processes and survival are most likely supported by their unique swimming system, which is unrelated to well-known bacterial motility systems such as flagella and pili. Spiroplasma swims by switching the left- and right-handed helical cell body alternately from the cell front. The kinks generated by the helicity shift travel down along the cell axis and rotate the cell body posterior to the kink position like a screw, pushing the water backward and propelling the cell body forward. An internal structure called the “ribbon” has been focused to elucidate the mechanisms for the cell helicity formation and swimming. The ribbon is composed of Spiroplasma-specific fibril protein and a bacterial actin, MreB. Here, we propose a model for helicity-switching swimming focusing on the ribbon, in which MreBs generate a force like a bimetallic strip based on ATP energy and switch the handedness of helical fibril filaments. Cooperative changes of these filaments cause helicity to shift down the cell axis. Interestingly, unlike other motility systems, the fibril protein and Spiroplasma MreBs can be traced back to their ancestors. The fibril protein has evolved from methylthioadenosine/S-adenosylhomocysteine (MTA/SAH) nucleosidase, which is essential for growth, and MreBs, which function as a scaffold for peptidoglycan synthesis in walled bacteria.
Single-Strand Conformation Polymorphism Fingerprint Method for Dictyostelids
Authors: Pasookhush Phongthana , Usmani Asmatullah , Suwannahong Kowit , Palittapongarnpim Prasit , Rukseree Kamolchanok , Ariyachaokun Kanchiyaphat , Buates Sureemas , Siripattanapipong Suradej , Ajawatanawong Pravech
Published: September 2021

Dictyostelid social amoebae are a highly diverse group of eukaryotic soil microbes that are valuable resources for biological research. Genetic diversity study of these organisms solely relies on molecular phylogenetics of the SSU rDNA gene, which is not ideal for large-scale genetic diversity study. Here, we designed a set of PCR–single-strand conformation polymorphism (SSCP) primers and optimized the SSCP fingerprint method for the screening of dictyostelids. The optimized SSCP condition required gel purification of the SSCP amplicons followed by electrophoresis using a 9% polyacrylamide gel under 4°C. We also tested the optimized SSCP procedure with 73 Thai isolates of dictyostelid that had the SSU rDNA gene sequences published. The SSCP fingerprint patterns were related to the genus-level taxonomy of dictyostelids, but the fingerprint dendrogram did not reflect the deep phylogeny. This method is rapid, cost-effective, and suitable for large-scale sample screening as compared with the phylogenetic analysis of the SSU rDNA gene sequences.