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This paper examines anesthesiologist Henry K. Beecher’s funding relationship with pharmaceutical manufacturer Edward Mallinckrodt, Jr. Beecher is a familiar figure to both medical ethicists and historians of medicine for his role in the bioethics revolution of the 1960s and 1970s. In particular, his 1966 article “Ethics and Clinical Research” is widely considered a turning point in the post-World War II debate about informed consent. We argue that Beecher’s scientific interests should be understood in the context of his funding relationship with Mallinckrodt and that this relationship shaped the direction of his work in important ways. We also argue that Beecher’s views on research ethics reflected his assumption that collaboration with industry was a normal part of how academic science is conducted. In the conclusion of the paper we suggest that Beecher’s failure to consider his relationship with Mallinckrodt as worthy of ethical deliberation has important lessons for academic researchers who collaborate with industry today.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event ( Clinical Trial Registration: NCT01719055 ( ClinicalTrials.gov )

Funder: U.S. Military Academy, Funder: Centre for Misfolding Diseases, University of Cambridge, Funder: Gates Cambridge Trust, Funder: Army Research Laboratory, Funder: Defense Threat Reduction Agency, The molecular composition of the plasma membrane plays a key role in mediating the susceptibility of cells to perturbations induced by toxic molecules. The pharmacological regulation of the properties of the cell membrane has therefore the potential to enhance cellular resilience to a wide variety of chemical and biological compounds. In this study, we investigate the ability of claramine, a blood-brain barrier permeable small molecule in the aminosterol class, to neutralize the toxicity of acute biological threat agents, including melittin from honeybee venom and α-hemolysin from Staphylococcus aureus. Our results show that claramine neutralizes the toxicity of these pore-forming agents by preventing their interactions with cell membranes without perturbing their structures in a detectable manner. We thus demonstrate that the exogenous administration of an aminosterol can tune the properties of lipid membranes and protect cells from diverse biotoxins, including not just misfolded protein oligomers as previously shown but also biological protein-based toxins. Our results indicate that the investigation of regulators of the physicochemical properties of cell membranes offers novel opportunities to develop countermeasures against an extensive set of cytotoxic effects associated with cell membrane disruption.

Background: Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke. Methods: Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset. Results: Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001–12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006–45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237–0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity. Conclusions: The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.

Sarcomas comprise a vast and heterogenous group of rare tumors. Because of their diversity, it is challenging to study sarcomas as a whole with regard to their biological and molecular characteristics. This diverse set of tumors may also possess differences related to their tumor-associated vasculature, which in turn may impact the ability to deliver systemic therapies (e.g., chemotherapy, targeted therapies, and immunotherapy). Consequently, response to systemic treatment may also be variable as these depend on the ability of the therapy to reach the tumor target via the tumor-associated vasculature. There is a paucity of data regarding sarcoma-related tumor vessels, likely in part to the rarity and heterogeneity of this cancer as well as the previously limited ability to image tumor-associated vessels in real time. Our group has previously utilized confocal fluorescent imaging technology to observe and characterize tumor-associated vessels in real time during surgical resection of tumors, including cutaneous melanoma and carcinomatosis implants derived from gastrointestinal, gynecological, or primary peritoneal (e.g., mesothelioma) tumors. Our prior studies have demonstrated the feasibility of real-time, human intravital microscopy in the study of these tumor types, leading to early but important new data regarding tumor vessel characteristics and their potential implications on drug delivery and efficacy. In this brief report, we present our latest descriptive findings in a cohort of patients with sarcoma who underwent surgical resection and real-time, intravital microscopy of their tumors. Overall, intravital imaging was feasible during the surgical resection of large sarcomas.Clinical trial registrationsClinicalTrials.gov, identifier NCT03517852; ClinicalTrials.gov, identifier NCT03823144.

We present the first global analysis of generalized parton distributions (GPDs) combing lattice quantum chromodynamics (QCD) calculations and experiment measurements including global parton distribution functions (PDFs), form factors (FFs) and deeply virtual Compton scattering (DVCS) measurements. Following the previous work where we parameterize GPDs in terms of their moments, we extend the framework to allow for the global analysis at non-zero skewness. Together with the constraints at zero skewness, we fit GPDs to global DVCS measurements from both the recent JLab and the earlier Hadron-Electron Ring Accelerator (HERA) experiments with two active quark flavors and leading order QCD evolution. With certain choices of empirical constraints, both sea and valence quark distributions are extracted with the combined inputs, and we present the quark distributions in the proton correspondingly. We also discuss how to extend the framework to accommodate more off-forward constraints beyond the small $\xi$ expansion, especially the lattice calculated GPDs., Comment: 23 pages, 7 figures and 3 tables

We report on measurements of beam backgrounds during the first commissioning phase of the SuperKEKB collider in 2016, performed with the plastic scintillator and silicon photomultiplier-based CLAWS detector system. The sub-nanosecond time resolution and single particle detection capability of the sensors allow bunch-by-bunch measurements, enable CLAWS to perform a novel time resolved analysis of beam backgrounds, and make the system uniquely suited for the study of injection backgrounds. We present measurements of various aspects of regular beam background and injection backgrounds which include time structure and decay behavior of injection backgrounds, hit-energy spectra and overall background rates. These measurements show that the elevated background rates following an injection generally last for several milliseconds, with the majority of the background particles typically observed within the first 500 us. The injection backgrounds exhibit pronounced patterns in time, connected to betatron and synchrotron oscillations in the accelerator rings. The frequencies of these patterns are determined from detector data., 19 pages, 12 figures, published in EPJ C

BackgroundThe identification of the underlying mechanism in ischemic stroke has important implications for secondary prevention. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) has antithrombotic properties and was repeatedly implicated in the pathophysiology of stroke. In this study, we, therefore, aimed to investigate whether ADAMTS-13 is associated with stroke etiology and the burden of vascular risk factors.MethodsWe determined ADAMTS-13 activity in two prospectively recruited stroke cohorts in the long-term course after the event. Cohort 1 (n = 88) consisted of patients who suffered a stroke due to embolic stroke of undetermined source (ESUS), cardioembolic stroke due to atrial fibrillation (AF), large-artery atherosclerosis, or small vessel disease. In cohort 2, patients with cryptogenic stroke and patent foramen ovale (PFO) scheduled for PFO closure (n = 38) were enrolled. As measures of vascular risk factor burden, the CHA2DS2VASC score, the Essen Stroke Risk Score (ESRS), and the Risk of Paradoxical Embolism (RoPE) score were calculated, as appropriate.ResultsADAMTS-13 activity was lower in patients with AF-related stroke compared to patients with ESUS (p = 0.0227), which was, however, due to confounding by vascular risk factors. ADAMTS-13 activity inversely correlated with the ESRS (r = −0.452, p < 0.001) and CHA2DS2VASC (r = −0.375, p < 0.001) in cohort 1. In accordance with these findings, we found a positive correlation between ADAMTS-13 activity and the RoPE score in cohort 2 (r = 0.413, p = 0.010).ConclusionADAMTS-13 activity is inversely correlated with the number of vascular risk factors across different stroke etiologies. Further study is warranted to establish ADAMTS-13 as a mediator of cerebrovascular risk.

Background: A previous retrospective study documented restored patency to 48.2% of occluded enteral feeding tubes using alkalinized Creon pancreatic enzyme capsules. In light of the low efficacy rate, the institutional enteral feeding tube clearance protocol was subsequently revised to incorporate a newly marketed non–enteric-coated Viokace pancreatic enzyme tablet, despite the lack of published data for this indication. Objective: This study aims to evaluate the effectiveness of a Viokace-based alkalinized pancreatic enzyme protocol to clear occluded enteral feeding tubes in a university health system. Methods: This retrospective, cohort quality assurance study included adult and pediatric patients receiving a Viokace-based pancreatic enzyme protocol for enteral feeding tube occlusions in a university health system during a 12-month period. The primary outcome was effectiveness in enteral tube clearance as documented in the electronic medical record. Efficacy of the new protocol was also compared with a Creon-based alkalinized solution using historical data. Results: The Viokace protocol successfully cleared 176 of the 277 (63.5%) occluded enteral feeding tubes occurring in 205 patients included in the analysis. The revised protocol was significantly more effective at clearing occluded enteral feeding tubes ( P = 0.0056) than a protocol using Creon pancreatic enzyme capsules. Conclusion: According to this retrospective evaluation, an alkalinized Viokace pancreatic enzyme protocol was effective in clearing 63.5% of occluded enteral feeding tubes. This significantly higher success rate than previously documented with a Creon-based protocol supports the change in pancreatic enzyme formulations in the institutional protocol.

Background and Purpose Preexisting autoantibodies against N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB) in acute ischemic stroke patients with previously intact blood-brain-barrier were associated with smaller evolution of lesion size. Effects of chronic exposure to NMDAR1-AB long after stroke, however, have remained unclear. We investigated in a prospective follow-up study whether long-term neuropsychiatric outcome after stroke differs depending on NMDAR1-AB status. Methods Blood samples for NMDAR1-AB analysis were collected within 24 h after ischemic stroke from n = 114 patients. Outcome was assessed 1–3 years later using NIHSS, modified Rankin-scale, Barthel-Index, RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) subcategories (immediate/delayed memory, attention, visuoconstruction), anamnesis evaluating neuropsychiatric symptoms (e.g. hallucinations, psychomotor slowing, reduced alertness, depressiveness, fatigue) and questionnaires (Beck's Depression Inventory-BDI, Fatigue Impact Scale-FIS). Scores were generated to cover RBANS plus neuropsychiatric symptoms (Score A; n = 96) or only neuropsychiatric symptoms (Score B; n = 114, including patients unable to conduct RBANS). Depression/fatigue were measured in patients, capable to perform questionnaires (n = 86). Results NMDAR1-AB (IgM, IgA, IgG) were detected in n = 27 patients (23.7%). NMDAR1-AB seropositive patients showed inferior results in Score A (p = 0.006), Score B (p = 0.004), BDI (p = 0.013) and FIS (p = 0.018), compared to seronegative patients. Multiple regression analysis including covariates age, NIHSS at day 7 post-stroke, and days from stroke to follow-up, showed NMDAR1-AB seropositivity associated with worse outcome in Scores A (b: 1.517, 95%CI: 0.505–2.529, p = 0.004) and B (b: 0.803, 95%CI: 0.233–1.373; p = 0.006). Also FIS was unfavorably associated with NMDAR1-AB seropositivity (binary logistic regression: OR: 3.904, 95%CI: 1.200–12.695; p = 0.024). Conclusions Even though the numbers of included patients are low, our data apparently indicate that NMDAR1-AB seropositivity at the time point of acute ischemic stroke is associated with neuropsychiatric symptoms including cognitive dysfunction and fatigue years after stroke. Preclinical proof of a causal relation provided, targeted immunosuppression may be a future prophylactic option to be clinically evaluated.

Natural proteinaceous pore-forming agents can bind and permeabilize cell membranes, leading to ion dyshomeostasis and cell death. In the search for antidotes that can protect cells from peptide toxins, we discovered that the polyphenol epigallocatechin gallate (EGCG) interacts directly with melittin from honeybee venom, resulting in the elimination of its binding to the cell membrane and toxicity by markedly lowering the extent of its solvent-exposed hydrophobicity and promoting its oligomerization into larger species. These physicochemical parameters have also been shown to play a key role in the binding and associated cytotoxicity of misfolded protein oligomers associated with a host of neurodegenerative diseases to cells, where oligomer-membrane binding and associated toxicity have been shown to correlate negatively with oligomer size and positively with solvent-exposed hydrophobicity. For melittin, which is not an amyloid-forming protein and has a very distinct mechanism of toxicity compared to misfolded oligomers, we find that the size-hydrophobicity-toxicity relationship also rationalizes the pharmacological attenuation of melittin toxicity by EGCG. These results highlight the importance of the physicochemical properties of pore forming agents in mediating their interactions with cell membranes and suggest a possible therapeutic approach based on compounds with a similar mechanism of action as EGCG.

Mechanical thrombectomy (MT) is a highly efficient treatment in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, in a relevant proportion of LVO, no sufficient recanalization can be achieved. The composition of cerebral thrombi is highly heterogeneous and may constitute a relevant factor for insufficient reperfusion. We hypothesized that circulating cytokines and growth factors involved in thromboinflammation and platelet activation may be associated with reperfusion status and thrombus composition in patients undergoing MT. An according biomarker panel was measured in plasma specimens taken prior to MT and at a 7-day follow-up. The reperfusion status was categorized into sufficient or insufficient. The composition of retrieved thrombi was histologically analyzed. Differences of baseline biomarker concentrations between insufficient and sufficient reperfusions were highest for interferon (IFN)-γ, epidermal growth factor, platelet-derived growth factor (PDGF)-AB/BB, and IFN-γ-induced protein 10 (IP-10/CXCL10). After applying correction for multiple comparisons and logistic regression analysis adjusting for stroke etiology, intravenous thrombolysis, and vascular risk factors, PDGF-AB/BB was identified as an independent predictor of reperfusion status (odds ratio: 0.403; 95% confidence interval: 0.199–0.819). Histological analysis revealed that the majority of thrombi had a mixed composition. In conclusion, this study provides the first evidence that cytokines and growth factors are potential effectors in patients undergoing MT for the treatment of acute ischemic stroke.

Egyptis now developing and modernizing education via the administrations which cope with the age requirements. Those emphasize quality and competitive ability. Nevertheless, basic education in Egypt is confronted by various problems to reach assessment mechanics in addition to lack of formulating a paramount vision of syllabuses and school activities in order to reach common concepts which link workers, students and the local society. Besides, Students have no say about the syllabuses they study or the methods used to teach those syllabuses. Consequently, this weakens the application of quality pointers in schools. In addition, there are reasons related to the educational organizations themselves such as relying on traditional teaching methods, lack of professional development, the wide gap between the training programs and real needs of development, the weakness of school administrations to achieve reformation of quality and finally the lack of understanding and integration in internal functional roles. This research aims through seeking answers to the research questions concerning formulating assessment mechanics to the basic education total quality administration in the light of Egypt 2030 Strategy through: Assessing the basic stage effectiveness in general in the light of Egypt Strategy 2030. And Assessing the basic stage quality and accountability mechanics in the light of Egypt Strategy 2030. The importance of this research is that it is hoped to lend a helping hand to policy makers and decision takers in educational administrations to recognize the downsides of traditional school administrations, and how far workers are in need of such a kind of administration in order to be able to do their best. It is also hoped that the study presents a suggested concept of the mechanics to assess total quality. That concept is to cope with the world trends and the current efforts to reform education and which focus on achieving quality in educational organizations. Among the most important recommendations are the necessity of using modern teaching strategies which satisfy the students’ needs through training teachers to the recent strategies and providing the required technological methods to apply those strategies in order to better the internal competence through modifying the quality and quantity of inputs so that they can be used in the best means ever. he study was characterized by objective, human, place and time limitations. By objective limitations, the study was restricted to assessing effectiveness in general and assessing the mechanisms of quality and accountability needed to basic stages of education. Human limitations mean that the field study comprised a random sample of zone directors, heads of sectors, boards of trustee members in addition to school directors. Place limitations refer to some schools in Cairo, Behira, and The New Valley Governorates. Finally, time limitations signify that the field study was applied in the first semester of the school year 2019-2020

espanolEl objetivo de este trabajo fue evaluar el enraizamiento de estacas de Croton urucurana Baill., Tabernaemontana catharinensis A. DC. y Paullinia elegans Cambess conocidas en Argentina como “Sangre de drago” (SD), “Horquetero” (TC) y “Ojo de muneca” (PE), respectivamente. Se recolectaron 200 estacas lenosas por especie; una vez defoliadas se aplico acido naftalen acetico (ANA) en las siguientes dosis: 0, 1000, 2500 y 3500 mg.L-1 en SD y TC y 0, 500, 1000 y 2500 mg.L-1 en PE. Se evaluo la formacion y calidad de raices y el diametro de las estacas a la altura del cuello (DAC). En SD las dosis de ANA ≥1000 mg.L-1 aumentaron la probabilidad de enraizamiento de 0,36 a 0,71. En PE hubo baja probabilidad de enraizamiento (0,13) independientemente de la dosis de ANA, pero aumento en funcion del DAC. No se observo formacion de raices en TC. La calidad de enraizamiento no fue afectada por la diferentes dosis de ANA, pero si el DAC en SD. EnglishEffect of NAA concentrations on rooting of hardwood cuttings of Croton urucurana Baill., Tabernaemontana catharinensis A. DC. and Paullinia elegans Cambess. The objective of this work was to evaluate the rooting potential of “Sangre de Drago” (SD: Croton urucurana Baill.), “Horquetero” (TC: Tabernaemontana catharinensis A. DC.) and “Ojo de muneca” (PE: Paullinia elegans Cambess.) cuttings by immersion in 1-Naphthaleneacetic acid (NAA). Two hundred cuttings without leaves per species were collected and immersed in 0, 1000, 2500 and 3500 ppm of NAA (for SD and TC) and 0, 500, 1000 and 2500 ppm of NAA for PE. At the end of the rooting period the following variables were registered on each cutting; the presence of roots, diameter at the base of the cutting (DAC) and rooting quality. Rooting probability was highest (0.76) for NAA than control (0.36) on SD cuttings. The rooting probability was very low on PE regardless of the NAA dose (0.13) but was directly proportional to the DAC. Root formation was not observed on TC, regardless of the NAA dose nor DAC. Rooting quality was unaffected by NAA dose but highly related to DAC in SD.

Moisture transfer characteristics of dambu-nama (DN) as influenced by addition of citric acid, salt and sugar as hurdles were investigated. Four products comprising DN with 0.1% citric acid + 2% salt and 2% sugar (DNC0.1); DN+ 0.2% citric + 2% salt + 2% sugar (DNC0.2); DN + 0.3% citric acid +2% salt + 2% sugar (DNC0.3) and a control DN without citric acid , salt or sugar (DNC0) were produced and subjected to moisture sorption studies at different temperatures (30, 40, 50 and 60oC) and relative humidities of(10-96%). Incorporation of the hurdles into dambu-nama resulted in increase in monolayer moisture contents, surface areas, net isoteric heats and entropy of sorption. The isotherms obtained were best described by the Henderson model followed by the GAB and Oswin models. The hurdles also resulted to a J-shaped isotherm instead of the sigmoidal isotherm shape.

Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. The cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid overload and may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle.

We present the calculation of the leading contribution to the quark Sivers function at small-Bjorken x as in [1]. This calculation uses the high energy scattering approximation and operator formalism developed in [2,3] to obtain a dominant contribution to the quark Sivers function coming from the spin-dependent odderon, in agreement with the results of [4]. We then calculate this dominant contribution in the diquark model of the proton to obtain a small-x estimate for the Sivers function.

Study question Do Musashi proteins mechanistically contribute to the pathogenetic properties of endometriotic cells? Summary answer Silencing of Musashi-1 and Muashi-2 reduces the expression of stemness-related genes, inhibits spheroid growth and viability, and increases apoptosis in endometriotic cells. What is known already Putative stem cells expressing the RNA binding protein Musashi-1 are more frequent in endometriotic lesions compared to healthy secretory endoemtrium. Musashi-1 is a positive regulator of the stemness-associated notch signaling pathway. Loss of Musashi-1 and Musashi-2 function in breast and ovarian cancer cells is associated with increased apoptosis and reduced cell viability. Study design, size, duration In vitro laboratory study on an immortalized endometriotic cell line (12Z) and primary endometriotic stroma cells (N > 3 replicates). Gene expression analysis utilizing the Endomet Turku Endometriosis database (82 samples of healthy tissue and 576 samples of endometriotic tissue). Participants/materials, setting, methods Gene expression associated with notch signaling pathway and stem cell function was analysed in tissue samples of 82 healthy controls and 576 endometriosis patients from the Endomet Turku Endometriosis database. In vitro studies were performed using siRNA double-knockdown of Muashi-1 and Musashi-2 in the endometriotic cell line 12Z and primary endometriotic stroma cells derived from ectopic lesions of two patients.Cell viability, apoptosis, sphere formation and gene expression (qPCR/Flow cytometriy) were studied in vitro. Main results and the role of chance The expression of Musashi genes and Notch signaling are dysregulated in patients with endometriosis (p Limitations, reasons for caution Our gene expression study is based on a single patient collective and has not been confirmed in an independent cohort. The in vitro study is partially based on an immortalised cell line. siRNA transfection may have caused toxic side effects.Studies on endometriotic cells only do not address the lesion microenvironment, Wider implications of the findings The Musashi genes have an impact on Notch signaling and the pathogenesis of endometriosis through dthe reduction of proliferation and stemness characteristics and upregulation of apoptosis and necrosis. A targeting of the Muashi-Notch axis may be a therapeutic concept worth evaluating. Trial registration number not applicable

Epithelial, connective tissue and immune cells contribute in various ways to the pathophysiology of chronic rhinosinusitis (CRS). However, data of their distribution in upper airway mucosa are sparse. We aimed to provide quantitative, purely informative data on the distribution of these cell lineages and their coexpression patterns, which might help identifying, e.g., cells in the epithelium undergoing through epithelial–mesenchymal transition (EMT). For this purpose, we used immunofluorescence multichannel image cytometry (IMIC). We examined fixed paraffin-embedded tissue samples (FFPE) of six patients with chronic rhinosinusitis (CRS) and of three patients without CRS (controls). The direct-conjugated antibodies pancytokeratin, vimentin and CD45/CD18 were used for coexpression analysis in epithelial layer and lamina propria. Image acquisition and analysis were performed with TissueFAXS and StrataQuest, respectively. To distinguish positive from negative expression, a ratio between cell-specific immunostaining intensity and background was developed. Isotype controls were used as negative controls. Per patient, a 4.5-mm2 tissue area was scanned and a median of 14,875 cells was recognized. The most common cell types were cytokeratin-single-positive (26%), vimentin-single-positive (13%) and CD45/CD18-single-positive with CD45/CD18–vimentin-double-positive cells (29%). In the patients with CRS, CD45/CD18-single-positive cells were 3–6 times higher compared to the control patients. In the epithelial layer, cytokeratin–vimentin-double-positive EMT cells were observed 3–5 times higher in the patients with CRS than in the control patients. This study provided quantitative data for the distribution of crucial cell types in CRS. Future studies may focus on the distribution and coexpression patterns of different immune cells in CRS or even cancer tissue. Electronic supplementary material The online version of this article (10.1007/s00418-020-01945-y) contains supplementary material, which is available to authorized users.

Staghorn corals represent dominant reef-builders in lagoons and back reefs in Guam. These habitats experience peak seawater temperatures close to 36°C during the hottest months of the year which ca...

Mosquitoes act as vectors to induce various dreadful diseases which continue to cause fatal effect on human beings. Aedes aegypti (Ae. aegypti) is one among the vectors which causes yellow fever, dengue and chikungunya, and Culex quinquefasciatus (C. quinquefasciatus) is another which can cause lymphatic filariasis, a widely distributed tropical disease across the world. In line with the larvicidal activity of sea grasses against the disease vectors, the present contribution has been focused. Two seagrasses namely Enhalus acoroides (L.f) Royle (E. acoroides) and H. ovalis (R.Br) Hook.f. (H. ovalis) collected from the Mandapam Coast, Rameswaram, Tamil Nadu located in South India were washed, shade dried, blended and made in to a fine powder. Sea grass extracts of different concentrations from 62.5 ppm to 500 ppm were prepared in the ratio 1:3 (w/v) using hexane, dichloromethane and ethanol as solvents. The results showed that the hexane extract (500 ppm) of E. acoroides exhibited the larvicidal activity of 62% against the Ae. aegypti after 24 h whereas its ethanol extracts (500 ppm) showed 50% of larvicial activity against C. quinquefasciatus. It could be inferred that the H. ovalis displayed a lesser larvicidal potentiality against Ae. aegypti than that of E. acoroides. The FT Infra-Red characterization of E. acoroides was carried out for the identification of various functional groups. The presence of about 11 organic compounds in E. acoroides was analysed using GC – MS. The significant role of solvents’ polarity in enabling the bioactive compounds to combat against two different mosquito vectors has been discussed. Statistical data such as LC50 (concentration of compound that kills 50% of larva), LC90 (concentration of compound that kills 90% of larva), correlation coefficient (r), χ2 and p values are calculated and discussed.

An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.

This paper describes one possible origin point for fraudulent behavior within the American pharmaceutical industry. We argue that during the late nineteenth century therapeutic reformers sought to promote both laboratory science and increasingly systematized forms of clinical experiment as a new basis for therapeutic knowledge. This process was intertwined with a transformation in the ethical framework in which medical science took place, one in which monopoly status was replaced by clinical utility as the primary arbiter of pharmaceutical legitimacy. This new framework fundamentally altered the set of epistemic virtues—a phrase we draw from the philosophical field of virtue epistemology—considered necessary to conduct reliable scientific inquiry regarding drugs. In doing so, it also made possible new forms of fraud in which newly emergent epistemic virtues were violated. To make this argument, we focus on the efforts of Francis E. Stewart and George S. Davis of Parke, Davis & Company. Therapeutic reformers within the pharmaceutical industry, such as Stewart and Davis, were an important part of the broader normative and epistemic transformation we describe in that they sought to promote laboratory science and systematized clinical trials toward the twin goals of improving pharmaceutical science and promoting their own commercial interests. Yet, as we suggest, Parke, Davis & Company also serves as an example of a company that violated the very norms that Stewart and Davis helped introduce. We thus seek to describe one possible origin point for the widespread fraudulent practices that now characterize the pharmaceutical industry. We also seek to describe an origin point for why we conceptualize such practices as fraudulent in the first place.

Struthiopteris (Blechnaceae) has recently been classified on the basis of molecular and morphological evidence, and some of its species are now included in the sister genus Spicantopsis. However, the lack of studies on several important morphological features impedes a sound assessment of their congruence with this new systematic arrangement, as well as of their range of variation and taxonomic value in this group of ferns. Here we present a study on the spores and sporangia using both light and scanning electron microscopy in Struthiopteris and Spicantopsis, using samples of all their species, and almost all their varieties. We provide full morphological descriptions of the spores and sporangia of all these taxa. We point out that the perispore structure and ornamentation and the number and the thickness of stomium cells in the sporangium clearly distinguish both genera.

Several firefly luciferases eliciting light emission in the yellow-green range of the spectrum and with distinct kinetic properties have been already cloned, sequenced, and characterized. Some of them are currently being applied as analytical reagents and reporter genes for bioimaging and biosensors, and more recently as potential color tuning indicators of intracellular pH and toxic metals. They were cloned from the subfamilies Lampyrinae (Photinini: Photinus pyralis, Macrolampis sp2; Cratomorphini: Cratomorphus distinctus), Photurinae (Photuris pennsylvanica), Luciolinae (Luciola cruciata, L. lateralis, L. mingrelica, L. italica, Hotaria parvula), and Amydetinae (Amydetes vivianii) occurring in different parts of the world. The largest number has been cloned from fireflies occurring in Brazilian biomes. Taking advantage of the large biodiversity of fireflies occurring in the Brazilian Atlantic rainforest, here we report the cloning and characterization of a novel luciferase cDNA from the Photurinae subfamily, Bicellonycha lividipennis, which is a very common firefly in marshlands in Brazil. As expected, multialignements and phylogenetic analysis show that this luciferase clusters with Photuris pennsylvanica adult isozyme, and with other adult lantern firefly luciferases, in reasonable agreement with traditional phylogenetic analysis. The luciferase elicits light emission in the yellow-green region, has kinetics properties similar to other adult lantern firefly luciferases, including pH- and metal sensitivities, but displays a lower sensitivity to nickel, which is suggested to be caused by the natural substitution of H310Y.

Multiple biomechanical shoulder simulators have been described in the literature, with a trend toward increasing complexity to better simulate clinical scenarios. Our objective was to develop an advanced, novel shoulder joint simulator and compare outcomes at two separate institutions, for a typical shoulder joint motion simulation. Identical shoulder simulators were developed & deployed at both institutions. Eight cadaveric upper extremities were tested by simulating actively controlled, arm elevation in the plane of the scapula for two sequential test conditions (intact and nondestructive simulated cuff-tear), each repeated for a total of five trials. Muscle forces and joint translations were recorded for both conditions. The intact condition was repeated following simulated cuff-tear to assess effect of testing order. Statistical analyses were aimed at assessing repeatability and reproducibility of results within specimens, between specimens, and between institutions. The highest average forces were observed for the middle deltoid (233N or 32.5% body weight (BW)), followed by infraspinatus (99.0N), and posterior deltoid (93.7N) muscles. Differentiation between test conditions was unhindered by variability between repeated trials. Data from testing repeated over time, and between the two institutions were not significantly different. The novel shoulder simulator produced repeatable results with low trial-to-trial variation and outcomes were comparable between the two institutions. The results demonstrated a consistent response in muscle forces and humeral translation for the simulated rotator cuff tear condition. Such advanced shoulder simulators could thus be used for evaluating and optimizing surgical interventions and implant strategies.

Belle-II DEPFET and PXD Collaboration: et al., The Belle II experiment at the SuperKEKB accelerator has started its physics data taking with the full detector setup in March 2019. It aims to collect 40 times more e+ e- collision data compared with its predecessor Belle experiment. The Belle II pixel detector (PXD) is based on the Depleted P-channel Field Effect Transistor (DEPFET) technology. The PXD plays an important role in the tracking and vertexing of the Belle II detector. Its two layers are arranged at radii of 14 mm and 22 mm around the interaction point. The sensors are thinned down to 75 m to minimize multiple scattering, and each module has interconnects and ASICs integrated on the sensor with silicon frames for mechanical support. PXD showed good performance during data taking. It also faces several operational challenges due to the high background level from the SuperKEKB accelerator, such as the damage from beam loss events, the drift in the HV working point due to radiation effect, and the impact of the high background., This work is supported by MEXT, WPI, and JSPS (Japan); MSMT, GAUK 404316 (Czech Republic), MSCA-RISE project JENNIFER-2 (EU grant 822070); Federal Ministry of Education and Research (BMBF, Germany); CIDEGENT/2018/020 of Generalitat Valenciana (Spain); National Natural Science Foundation of China (No. 11435013); and research grants S-1440-0321, S-0256-1438, and S-0280-1439 (University of Tabuk, KSA, Saudi Arabia ).

Metabolic health is a crucial area of current research, and is an outcome of innate physiology, and interactions with the environment. Environmental cues, such as the Earth's day-night rhythm, partly regulate diurnal hormones and metabolites. Circadian physiology consists of highly conserved biological processes over ∼24-hour cycles, which are influenced by external cues (Zeitgebers - "time-keepers"). Skeletal muscle has diurnal variations of a large magnitude, owing in part to the strong nature of physical activity throughout the day and other external Zeitgebers. The orchestration of whole-body, and skeletal muscle metabolism is a complex, finely-tuned process, and molecular diurnal variations are regulated by a transcription-translation feedback loop controlled by the molecular clock, as well as non-transcriptional metabolic processes. The mitochondrion may play an important role in regulating diurnal metabolites within skeletal muscle, given its central role in the regulation of NAD+ /NADH, O2, reactive oxygen species and redox metabolism. These molecular pathways display diurnal variation and illustrate the complex orchestration of circadian metabolism in skeletal muscle. Probably the most robust Zeitgeber of skeletal muscle is exercise, which alters glucose metabolism and flux, in addition to a range of other diurnal metabolic pathways. Indeed, performing exercise at different times of the day may alter metabolism and health outcomes in some cohorts. The objective of this Symposium Review is to briefly cover the current literature, and to speculate regarding future areas of research. Thus, we postulate that metabolic health may be optimized by altering the timing of external cues such as diet and exercise. This article is protected by copyright. All rights reserved.

Ammonia oxidation is the rate-limiting first step of nitrification and a key process in the nitrogen cycle that results in the formation of nitrite (NO2–), which can be further oxidized to nitrate (NO3–). In the Amazonian floodplains, soils are subjected to extended seasons of flooding during the rainy season, in which they can become anoxic and produce a significant amount of methane (CH4). Various microorganisms in this anoxic environment can couple the reduction of different ions, such as NO2– and NO3–, with the oxidation of CH4 for energy production and effectively link the carbon and nitrogen cycle. Here, we addressed the composition of ammonium (NH4+) and NO3–—and NO2–—dependent CH4-oxidizing microbial communities in an Amazonian floodplain. In addition, we analyzed the influence of environmental and geochemical factors on these microbial communities. Soil samples were collected from different layers of forest and agroforest land-use systems during the flood and non-flood seasons in the floodplain of the Tocantins River, and next-generation sequencing of archaeal and bacterial 16S rRNA amplicons was performed, coupled with chemical characterization of the soils. We found that ammonia-oxidizing archaea (AOA) were more abundant than ammonia-oxidizing bacteria (AOB) during both flood and non-flood seasons. Nitrogen-dependent anaerobic methane oxidizers (N-DAMO) from both the archaeal and bacterial domains were also found in both seasons, with higher abundance in the flood season. The different seasons, land uses, and depths analyzed had a significant influence on the soil chemical factors and also affected the abundance and composition of AOA, AOB, and N-DAMO. During the flood season, there was a significant correlation between ammonia oxidizers and N-DAMO, indicating the possible role of these oxidizers in providing oxidized nitrogen species for methanotrophy under anaerobic conditions, which is essential for nitrogen removal in these soils.

ObjectiveSight-threatening infections can be caused by pathogenic micro-organisms colonising the cornea, leading to microbial keratitis (MK). These micro-organisms can be introduced to the eye via improper contact lens use and care. MK can also result from ineffective contact lens care solutions (CLCs), even if the patient is following best practice guidelines. Therefore, it is critical to understand the differences between the effectiveness of popular CLCs on the global market.Methods and analysisFollowing the International Standards Organisation standards 14 729 and 18259, bacteria (Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus), fungi (Candida albicans, Fusarium strains) and Acanthamoeba strains were inoculated into each CLC with and without contact lenses, and held for the manufacturer’s stated disinfection time. Plate counts were conducted to determine the number of surviving micro-organisms.ResultsAll CLCs examined met the primary log reduction criteria during stand-alone testing for Pseudomonas, Staphylococcus, Candida and Fusarium. renu Multiplus, All Clean Soft, and Kombilösung Super did not meet the primary criteria when challenged with Serratia. Only OPTI-FREE Express exceeded 4 log reduction for both strains of Acanthamoeba tested. We noted a substantial reduction in disinfection efficacy when CLCs were challenged with Fusarium in the presence of lenses and cases versus stand-alone testing. OPTI-FREE Express demonstrated significantly less net log reduction loss than the other four CLCs tested.ConclusionOf the popular CLCs on the global market, the product which relies on dual biocides polyquaternium-1 and myristamidopropyl dimethylamine demonstrated the highest disinfection efficacy in microbial disinfection challenges in the absence and presence of contact lenses.