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•Severe COVID19 patients display a dysregulation in host inflammatory responses characterized by low IFN and high proinflammatory cytokine expression.•Comprehensive studies have ...identified viral antagonists of PAMP recognition, IFN induction, and IFN receptor signaling.•SARS-CoV-2 proteins indirectly inhibit host immune responses by disrupting nuclear trafficking, RNA maturation, mRNA translation, and protein trafficking.•The development of replication competent viruses and the implementation of varied cell and animal models will continue to shape our understanding of host-pathogen interaction that shape SARS-CoV-2 disease outcomes.
Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by a delayed interferon (IFN) response and high levels of proinflammatory cytokine expression. Type I and III IFNs serve as a first line of defense during acute viral infections and are readily antagonized by viruses to establish productive infection. A rapidly growing body of work has interrogated the mechanisms by which SARS-CoV-2 antagonizes both IFN induction and IFN signaling to establish productive infection. Here, we summarize these findings and discuss the molecular interactions that prevent viral RNA recognition, inhibit the induction of IFN gene expression, and block the response to IFN treatment. We also describe the mechanisms by which SARS-CoV-2 viral proteins promote host shutoff. A detailed understanding of the host-pathogen interactions that unbalance the IFN response is critical for the design and deployment of host-targeted therapeutics to manage COVID-19.
Introduction
Growing evidence shows a causal role of high-risk humane papillomavirus (HPV) infections in the development of head and neck cancer. A recent case report shows two patients suffering ...from tonsillar cancer without any risk factors apart from their work as gynecologists doing laser ablations and loop electrosurgical excision procedures (LEEP). The aim of the present investigation is to evaluate whether surgical plume resulting from routine LEEPs of HSIL of the cervix uteri might be contaminated with the DNA of high-risk HPV.
Materials and methods
The prospective pilot study is done at the Department of Gynecology and Obstetrics of the University of Lübeck, Germany. The primary outcome was defined as HPV subtype in resected cone and in surgical plume resulting from LEEPs of HSIL of the cervix uteri. Plume resulting from LEEPs was analyzed using a Whatman FTA Elute Indicating Card which was placed in the tube of an exhaust suction device used to remove the resulting aerosols. For detection of HPV and analysis of its subtype, the novel EUROArray HPV test was performed. Resected cones of LEEPs were evaluated separately for HPV subtypes.
Results
Four samples of surgical plume resulting from routine LEEPs indicated contamination with high-risk HPV and showed the same HPV subtype as identified in the resected cones.
Conclusion
Surgical plume resulting from routine LEEPs for HSIL of the cervix uteri has the risk of contamination with high-risk HPV. Further investigations of infectiousness of surgical plume are necessary for evaluation of potential hazards to involved healthcare professionals.
We studied the Pb, Sr, and U isotopic composition and the concentration of toxic metal elements in sediment core samples collected in Lake Balaton at a sediment trap that was deep dredged in 1979, to ...analyze their changes in the last 40 years. Pb isotopic composition profiles of cores taken from the sediment trap showed different
206
Pb/
207
Pb ratios ranging from 1.206 ± 0.002 at the bottom of the core (phase 1) compared to 1.185 ± 0.002 at the top of the core (phase 2). Phase 2 is the fraction reflecting isotopic signatures of the latest 40 years. At 80–100-cm depth, a transition zone was observed. Pb concentration together with Zn, Sb, Cu, Cd, and Fe showed elevated, 2–4 times higher values in the top phase of the sediment. The calculated Pb isotopic composition of pollutant Pb fraction was 1.177 ± 0.005 in the case of the
206
Pb/
207
Pb and 2.456 ± 0.004 for
208
Pb/
207
Pb, which shows good agreement with literature data for lead ores in Poland and Germany, but it is distinct from literature data for leaded fuel concerning Middle and Eastern Europe. The marked difference in the Pb signatures of phases enabled the construction of a sediment deposition rate map. U and Mo showed a characteristic concentration peak positioned exactly at the depth of the Pb signature transition. The isotopic signature of U based on
234
U and
235
U also showed a similar pattern. We suggest that the deposition of U and Mo can be related to cyanobacterial blooms in Lake Balaton in the late 1970s and early1980s.
Cylindrospermopsin (CYN) is a tricyclic guanidino alkaloid toxin produced by several cyanobacterial genera. It alters cellular functioning in eukaryotes, including animal and plant organisms. Over ...the past decades, more and more evidence shows its potential hazardous effects on animal and human health. In this review, we give a critical survey and interpretation of data currently available on its biochemical and consequently, cellular effects. CYN is considered to be a cytotoxin. Several reports suggest that it is a potent inhibitor of eukaryotic protein synthesis, though the exact mechanisms are not completely understood. Here we show that the biochemical changes induced by CYN are complex, possibly involving multiple modes of action. Glutathione metabolism and pyrimidine nucleotide synthesis is affected besides the proposed protein synthesis inhibition. Biochemical alterations lead to the following cellular/subcellular alterations both in animals and plants: (i) changes in cell division rates due to perturbations in chromatin and cytoskeleton; (ii) perturbations of structure and functioning of endomembranes including endoplasmic reticulum; (iii) general metabolic alterations leading to genotoxicity and programmed cell death/apoptosis. The underlying mechanisms and possible health consequences are discussed.
Abstract
Introduction
Data from the World Health Organization (WHO) demonstrates an increasing prevalence of obesity in Western countries. This study investigates the influence of obesity on the mode ...of delivery and the occurrence of hypoglycemia in newborns.
Materials and Methods
A retrospective analysis of all deliveries at the Department of Gynecology and Obstetrics of the University of Lübeck, Germany was conducted over a period of eleven years with the primary outcome as non-elective C-sections and hypoglycemia of newborns from obese mothers. Patients were divided into six subgroups according to WHO weight classifications as follows: control group body mass index (BMI) 18.5 – 24.9 kg/m
2
, n = 7712; general obesity BMI ≥ 25 kg/m
2
, n = 4227; overweight BMI 25 – 29.9 kg/m
2
, n = 2628; obesity I° BMI 30 – 34.9 kg/m
2
, n = 1017; obesity II° BMI 35 – 39.9 kg/m
2
, n = 370; obesity III° BMI ≥ 40 kg/m
2
, n = 212.
Results
Analysis of the primary outcome shows an increased incidence of non-elective C-sections with an elevated BMI (general obesity vs. control group: 20.5 vs. 15.9%, p < 0.001; OR 1.3; 95% CI 1.2 – 1.4) and elevated rates of neonatal hypoglycemia in newborns of obese mothers (general obesity vs. control group: 0.6 vs. 0.3%, p < 0.05; OR 1.8; 95% CI 1.0 – 3.0).
Conclusions
Obesity is an essential obstetric risk factor. Obese women face an increased risk of non-elective C-sections, and newborns of obese mothers suffer from elevated rates of hypoglycemia.
Fibroblast growth factor 2 (FGF2) exits cells by direct translocation across the plasma membrane, a type I pathway of unconventional protein secretion. This process is initiated by ...phosphatidylinositol-4,5-bisphosphate (PI(4,5)P
)-dependent formation of highly dynamic FGF2 oligomers at the inner plasma membrane leaflet, inducing the formation of lipidic membrane pores. Cell surface heparan sulfate chains linked to glypican-1 (GPC1) capture FGF2 at the outer plasma membrane leaflet, completing FGF2 membrane translocation into the extracellular space. While the basic steps of this pathway are well understood, the molecular mechanism by which FGF2 oligomerizes on membrane surfaces remains unclear. In the current study, we demonstrate the initial step of this process to depend on C95-C95 disulfide-bridge-mediated FGF2 dimerization on membrane surfaces, producing the building blocks for higher FGF2 oligomers that drive the formation of membrane pores. We find FGF2 with a C95A substitution to be defective in oligomerization, pore formation, and membrane translocation. Consistently, we demonstrate a C95A variant of FGF2 to be characterized by a severe secretion phenotype. By contrast, while also important for efficient FGF2 secretion from cells, a second cysteine residue on the molecular surface of FGF2 (C77) is not involved in FGF2 oligomerization. Rather, we find C77 to be part of the interaction interface through which FGF2 binds to the α1 subunit of the Na,K-ATPase, the landing platform for FGF2 at the inner plasma membrane leaflet. Using cross-linking mass spectrometry, atomistic molecular dynamics simulations combined with a machine learning analysis and cryo-electron tomography, we propose a mechanism by which disulfide-bridged FGF2 dimers bind with high avidity to PI(4,5)P
on membrane surfaces. We further propose a tight coupling between FGF2 secretion and the formation of ternary signaling complexes on cell surfaces, hypothesizing that C95-C95-bridged FGF2 dimers are functioning as the molecular units triggering autocrine and paracrine FGF2 signaling.
Purpose
The mode of delivery depends on multiple parameters. After assisted reproductive technology (ART), previous studies have shown elevated C-section rates but few studies differentiated between ...elective and emergency operations and different protocols of cryopreservation. Because these studies did not use multiparity as exclusion criteria which reduces confounding with previous pregnancies, aim of this study is to compare mode of delivery of different techniques of ART using data of primiparae only
1
,
2
.
Methods
Retrospective analysis of patient data treated at the university hospital of Luebeck in a period of 12 years. Patients were divided in different groups according to their way of conception: spontaneous conception and conception after ART. The group of ART was further divided into: (a) a group of fresh transferred embryos (IVF/ICSI), (b) vitrification and (c) slow freezing. Exclusion criteria were defined as: multiparity, delivery <24. + 0 p.m., incomplete data and treatment outside university of Luebeck. Main parameter of this study was mode of delivery which was divided into spontaneous delivery or C-section. C-sections were further differentiated into elective or emergency C-sections.
Results
The group of fresh transferred embryos and slow freezing showed higher risks for elective and emergency C-sections (elective C-sections odds ratio 2.0, CI 95% 1.6–2.6, emergency C-sections odds ratio 1.4, CI 95% 1.1–1.9). Moreover, all groups of ART show enhanced risk of significant perinatal bleeding.
Conclusion
Patients after ART treatment suffer from higher C-section rates during their stage of delivery.
There is increasing evidence for the induction of programmed cell death (PCD) in vascular plants by the cyanobacterial toxin microcystin-LR (MC-LR). Our aim was to detect the occurrence of ...PCD-related DNA strand breaks and their possible connections to specific nuclease and protease activities. DNA breaks were studied by the deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method in the photoperiodically grown dicot model of white mustard (Sinapis alba). In-gel nuclease and protease activity assays showed changes in the activities of specific isoenzymes during treatments with MC-LR. Strand breaks occurred both in the developing root epidermis and cortex. Several isoenzyme activities were related to these breaks, for example: an increase in the activity of neutral 80–75 kDa, acidic high MW (100–120 kDa) and, most importantly, an increase in the activity of neutral 26–20 kDa nucleases, all of them having single-stranded DNA cleaving (SSP nuclease) activities. Increases in the activities of alkaline proteases in the 61–41 kDa range were also detected and proved to be in relation with MC-LR-induced PCD. This is one of the first pieces of evidence on the correlation of PCD-related DNA strand breaks with specific hydrolase activities in a model dicot treated with a cyanobacterial toxin known to have environmental importance.
In the present study we provide cytological and biochemical evidence that the cyanotoxin cylindrospermopsin (CYN) induces programmed cell death (PCD) symptoms in two model vascular plants: the dicot ...white mustard (
Sinapis alba
) and the monocot common reed (
Phragmites australis
). Cytological data include chromatin fragmentation and the increase of the ratio of TUNEL-positive cells in roots, the latter being detected in both model systems studied. The strongest biochemical evidence is the elevation of the activity of several single-stranded DNA preferring nucleases-among them enzymes active at both acidic and alkaline conditions and are probably directly related to DNA breaks occurring at the initial stages of plant PCD: 80 kDa nucleases and a 26 kDa nuclease, both having dual (single- and double-stranded nucleic acid) specificity. Moreover, the total protease activity and in particular, a 53–56 kDa alkaline protease activity increases. This protease could be inhibited by PMSF, thus regarded as serine protease. Serine proteases are detected in all organs of
Brassicacea
e (Arabidopsis) having importance in differentiation of specialized plant tissue through PCD, in protein degradation/processing during early germination and defense mechanisms induced by a variety of biotic and abiotic stresses. However, knowledge of the physiological roles of these proteases and nucleases in PCD still needs further research. It is concluded that CYN treatment induces chromatin fragmentation and PCD in plant cells by activating specific nucleases and proteases. CYN is proposed to be a suitable molecule to study the mechanism of plant apoptosis.
Purpose
To construct a scoring system for pap smears to objectify cytological appraisal and to enhance the accuracy and comparability of pap smear interpretation in pregnancy.
Materials and methods
...For development of a scoring system for cell appraisal of pap smears the style of the Modified Masood’s Scoring Index for appraisal of cells from fine needle aspirations of breast lesions was used. Cohort analysis of
n
= 54 dysplastic pap smears for polymorphology of cells, anisonucleosis, structure of the nucleus, signs of tissue destruction, nucleus/plasma relation and signs of tumordiathesis. Each criteria was classified into three stages: The first with little evidence for dysplasia (one point), second stage with sporadic evidence (two points) or third stage with frequent evidence (three points). To further evaluate if pregnancy associated cells changes interfere with this scoring system we compared the results of pregnant and non-pregnant women. Histological result was used as an indicator of correctness of the score.
Results
Statistical analysis showed a good correlation of the scoring system with histological results. Especially in pregnancy statistical analysis shows promising results (sensitivity 86.67 %, Specificity 100 %, receiver operating characteristic analysis
p
≤ 0.05).
Conclusion
The Luebeck Score seems to be a useful approach for appraisal of pap smears in pregnancy. Further studies containing high numbers of cases are needed for further evaluation of potential benefits of the scoring system compared to conventional evaluation of pap smears.
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