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As a result of industrialisation and the many recent advances in technology, we are being intensely subjected to non-ionised radiation sources. As such, the effect of non-ionised radiation on human tissue is now being researched. In this study, the effects of Wi-Fi waves found in some third-generation mobile phones to facilitate internet connection on the brain hippocampal dentate gyrus granule cell quantity of rats during the prenatal period was stereologically examined. During the study, mated albino rats were subjected to Wi-Fi throughout pregnancy. A month after giving birth, six rats from each group, for a total of 12 rats, was sacrificed under perfusion and anaesthesia. Their skulls were opened and brains were removed to undergo routine checks in which the granule cells were counted. Strategic sections were defined, and every 45th section couple (with a thickness of 5 µm) was taken and dyed with haematoxylin and eosin (H&E) and cresyl violet stain. The granule cells were counted using a combination of the stereological disector method and Cavalieri’s principle. Then, the results were analysed using the Mann–Whitney U test. No statistically significant difference has been observed between the groups (p > 0.05). The findings were discussed in light of the relevant literature, and it was determined that throughout pregnancy, Wi-Fi modem device did not result in any changes in the dentate gyrus granule cell count of the hippocampus of postnatal rats’ brains. © 2022 Ondokuz Mayis Universitesi. All rights reserved. 2009-TFU-U075 The authors are grateful to Yuzuncu Yil University Department of Scientific Research Projects (2009-TFU-U075).

Introduction: Ligands of adenosine A1Rs are potential candidates for the development of drugs for the treatment of paroxysmal supraventricular tachycardia, angina pectoris, hypertriglyceridemia, type 2 diabetes mellitus, neuropathic pain, and heart failure. At the same time, there is a deficiency of drugs that can regulate the functions of A1 receptors. A number of A1-antagonists are at the various stages of clinical trials; other drugs are not very selective or are characterized by an insufficient breadth of their therapeutic action. Therefore, the search for new medicinal compounds for the prevention and treatment of A1-depended diseases among nitro derivatives of tetrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine is of scientific interest. Materials and methods: The search for active compounds was carried out by in silico and in vitro methods. At the first stage, a computer forecast of A1-antagonistic activity was carried out using the Microcosm BioS software. At the second stage, the prediction results were verified in vitro in a model of isolated mouse atria. Results and discussion: Based on the results of the prediction by the method of maximum similarity to standards, the most active compounds III, VIII, and XVII were selected. After testing the prediction results by the isolated atria method, the compound VIII was characterized by A1-blocking effect in vitro at a concentration of 10 μmol/L. Conclusion: The most promising compound with A1-blocking effect in vitro was identified; it is a derivative of tetrazolo[1,5-a]pyrimidine under the code of VIII. It is of interest for us for further in-depth study of its pharmacological properties.

Pesticides, which adversely affect the critical metabolic processes of organisms, disrupt the physiological balance by specifically targeting enzymes and may lead to such consequences that may lead to death. It provides benefits in agricultural activities. The p53 protein antagonizes bcl-2, an anti-apoptotic protein character, and induces apoptosis by causing mitochondrial membrane permeability. This study aims to show the effect of acetamiprid, which is an insecticide from the neonicotinoid class, on bcl-2 and p53 immunoreactivity, which has an important place in the apoptotic mechanism in kidney tissue. A total of four groups including control and three experimental groups (the acetamiprid was administered 5, 10, and 15 mg kg−1) were formed in the study. After acetamiprid was administered via gavage for 14 days, the kidney tissues taken from the mice, which were sacrificed by cervical dislocation, were fixed in 10% formaldehyde solution for histological and immunohistochemical analyses, and as a result of routine tissue follow-up, the sections were blocked in paraffin and stained with haematoxylin–eosin and immunostaining. The histopathological examinations revealed that while the kidney tissue had a normal structure in the control group, degeneration in the distal and proximal tubules, glomerular degeneration, increase in the capsular area, glomerular atrophy, and haemorrhage were determined in the acetamiprid groups at increasing severity and frequency depending on the dose of the applied substance. In the kidney tissue, Bcl-2 and p53 immunoreactivity was observed in glomerular cells, sinusoidal epithelium, and proximal and distal tubule cells. The acetamiprid caused pathological changes in the kidneys in the dose range used. This effect also affects the expression of bcl-2 and p53 genes, which are biomarkers in the apoptotic mechanism. As acetamiprid accumulates in tissues, it increases the expression of p53 from cell death receptors, while suppressing the anti-apoptotic bcl-2 expression.

Background/aim: Hydroxychloroquine (HCQ) is an antimalarial that is widely used in the management of rheumatoid arthritis and other autoimmune diseases. In this study, we aimed to examine the vascular effects of HCQ on rat aorta (RA). Materials and methods: The RA rings were suspended in isolated organ baths and tension was recorded isometrically. HCQ-induced relaxations were tested in the presence of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME, 100 mM); the cyclooxygenase enzyme inhibitor, indomethacin (10 mM); the calcium (Ca2+) ion channel blocker, nilvadipine (10 ?M); and the K+ ion channel inhibitors, tetraethylammonium (1 mM), glibenclamide (10 mM), 4-aminopyridine (1 mM), and barium chloride (30 mM). The effect of HCQ on Ca2+ channels was examined using Ca2+-free Krebs solution, and adding calcium chloride (CaCl2, 10-5– 10-2 M) cumulatively to baths incubated with HCQ. Results: Removing the endothelium resulted in less relaxation of RA rings compared to endothelium-intact rings (p < 0.05). The effect of endothelium was supported by using L-NAME where HCQ produced-vasorelaxation was decreased (p < 0.05). The contraction of vascular rings was inhibited to a significant degree following the addition of CaCl2, PE, or KCl on HCQ-incubated RA rings (p < 0.05). The incubation of the RA rings with the Ca2+ channel blocker, the K+ channel blockers, and the COX inhibitor, indomethacin did not significantly affect vascular relaxation induced by HCQ. Conclusion: HCQ produced relaxation of RA rings. The relaxation mechanism differs according to the concentration of HCQ. At concentrations of 10-6 and 10-5 M, the relaxation is endothelium-dependent and mediated by NO. We strongly suggest that Ca2+ channel inhibition is involved at concentrations of 10-5 and 10-4 M, as well as NO. © TÜBİTAK.

La Trobe University Faculty of Science, Technology and Engineering Murray Darling Freshwater Research CentreMDFRC item.Routine microscopic examination of biomass samples from many activated sludge plants around the world reveals the presence of large numbers of both Gram positive and Gram negative coccoid cells often arranged in distinctive tetrads or sheets of tetrads. Three Gram negative tetrad cocci were successfully isolated into pure culture using micromanipulation from samples of biomass from plants in Tamworth, N.S.W., Australia, Verona, Italy and Macau. After extensive phenotypic characterisation and 16S rDNA sequence analysis, all isolates showed high overall similarity to each other, but were phylogenetically quite different to any previously sequenced bacterium. They have therefore been classified as three species of a new genus, the genus Amaricoccus in the a Proteobacteria in the domain Bacteria. None could accumulate polyphosphate granules, and production of intracellular poly-beta-hydroxybutyrate (PHB) granules depended on the carbon source used in the medium. A similar characterisation of the original isolate of the G-bacteria described by Cech and Hartman showed this organism also belonged to the same genus as the other three isolates, but as a distinct species. The practical implications of these observations are discussed.

The problem of chemo/antibiotic resistance in modern medicine remains relevant today. The sensitivity of microorganisms (MO) determines the range of drugs used, which ultimately affects the effectiveness of treatment and the prognosis for the patient. However, taking into account the adaptation process of individual strains of MO, the uncontrolled use of antibiotics will inevitably lead to the maintenance of the so-called crisis of antibiotic resistance throughout the world, as well as the formation of a vicious circle that reduces the functional and anatomical outcomes of the treatment of any inflammatory diseases, including ophthalmological ones. This article presents the process of experimental creation and certification, assessment of the physicochemical properties of quantum dots, as well as biological nanoconjugates as an option for overcoming the antibiotic resistance of certain strains of microorganisms in the treatment of infectious and inflammatory pathology in ophthalmology, in particular endophthalmitis. Also, an animal model has demonstrated the safety of using InP / ZnSe / ZnS 660 quantum dot solutions for intravitreal administration in pure form and in combination with antibiotics. © 2021 Ophthalmology Publishing Group. All rights reserved.

Review of Nathan Snaza. Animate Literacies: Literature, Affect, and the Politics of Humanism. Durham, North Carolina: Duke University Press, 2019. 232 pp. ISBN: 978-1-4780-0562-9

Background We report the results of INICC surveillance study from 2013 to 2018, in 664 intensive care units (ICUs) in 133 cities, of 45 countries, from Latin-America, Europe, Africa, Eastern-Mediterranean, Southeast-Asia, and Western-Pacific. Methods Prospective data from patients hospitalized in ICUs were collected through INICC Surveillance Online System. CDC-NHSN definitions for device-associated healthcare-associated infection (DA-HAI) were applied. Results We collected data from 428,847 patients, for an aggregate of 2,815,402 bed-days, 1,468,216 central line (CL)-days, 1,053,330 mechanical ventilator (MV)-days, 1,740,776 urinary catheter (UC)-days. We found 7,785 CL-associated bloodstream infections (CLAB), 12,085 ventilator-associated events (VAE), and 5,509 UC-associated urinary tract infections (CAUTI). Pooled DA-HAI rates were 5.91% and 9.01 DA-HAIs/1,000 bed-days. Pooled CLAB rate was 5.30/1,000 CL-days; VAE rate was 11.47/1,000 MV-days, and CAUTI rate was 3.16/1,000 UC-days. P aeruginosa was non-susceptible (NS) to imipenem in 52.72% of cases; to colistin in 10.38%; to ceftazidime in 50%; to ciprofloxacin in 40.28%; and to amikacin in 34.05%. Klebsiella spp was NS to imipenem in 49.16%; to ceftazidime in 78.01%; to ciprofloxacin in 66.26%; and to amikacin in 42.45%. coagulase-negative Staphylococci and S aureus were NS to oxacillin in 91.44% and 56.03%, respectively. Enterococcus spp was NS to vancomycin in 42.31% of the cases. Conclusions DA-HAI rates and bacterial resistance are high and continuous efforts are needed to reduce them.

There is a worrying lack of epidemiological data on the sex differential in COVID-19 fatality rates. We ex-amined the Global Health 50/50 tracks of sex-disag-gregated infection and mortality COVID-19 data from 73 countries through May 20, 2021. We compared the infection fatality rate (IFR) in men vs. women and risk of death from COVID-19 by country. Of all cases in 73 countries, 42,933,757 were in women and 40,187,894 in men;1,274,663 men and 971,899 women died. The IFR was higher in males (3.17%) than in women (2.26%). The IFR in males vs. females varied from country to country, and it was higher in men in Brazil, Yemen, Mexico, Ecuador, Scotland, Peru, Guatemala, North Macedonia and Afghanistan. Overall, men had a higher odd of death from COVID-19 (OR, 1.22;95% CI, 1.13–1.32;=0.00001) and in 49 countries, compared to women. Men in Albania and Guatemala had twice the risk of death from COVID-19. Our findings show higher fatality rates among men than among women. These rates vary widely by country, and men have a higher odd of death from COVID-19. © 2021, EDIMES Edizioni Medico Scientifiche. All rights reserved.

Methotrexate (MTX) is a folic acid antagonist that is commonly used in paediatric and adult oncology to treat a variety of malignancies. Internal organs, including the testis, are severely cytotoxic and genotoxic to MTX. Omega-3, as an antioxidant, has been shown to protect rat testis tissue from injury. The effect of fish oil (FO) on MTX-induced reproductive damage in rats was investigated in this work. The 28 animals were divided into four groups for this purpose (control, FO, MTX, and MTX-FO). On the third day, the MTX group received a single intraperitoneal injection of 20 mg/kg MTX. Furthermore, in the FO and MTX-FO groups, FO was delivered through gavage once daily for 14 days. All animals euthanized under general anaesthesia on the 15th day. TBARS, catalase, glutathione peroxidase, glutathione (GSH), superoxide dismutase levels were measured biochemically. The Cosentino grading system was utilized for histology. Germ cell thickness and caspase-3 activity were also evaluated. In addition, sperm motility rate, epididymal sperm count, aberrant sperm rate, and sperm vitality were measured to assess sperm quality. Some TBARS levels have increased, but GSH levels decreased significantly in the MTX group. FO reduced TBARS levels while considerably increasing GSH levels. All sperm quality measures were significantly lowered in the MTX group, while FO had a recovery effect. There were no notable variations in histopathology across groups except for germ cell thickness, which reduced considerably in the MTX group and recovered with FO treatment. As a result, FO has been shown to reduce testicular toxicity following MTX treatment in rats. © 2022 Wiley-VCH GmbH.

The human intestinal microbiota is composed of a complex combination of microorganisms including bacteria, virus, and eukaryotes. The microbiota plays a critical role in homeostasis through creating a mucosal barrier, providing protective responses to pathogens, and affecting the immune system and metabolism of the host. Molecules secreted by parasites can alter composition of microbiota both by acting directly on the microbial community and indirectly by affecting the host physiology. On the other hand, the microbiota composition can affect the survival, physiology, and virulence of many parasitic protozoa. Explanation of possible interactions between the microbiota, immune response, and protozoa may further clarify the underlying mechanisms of infectivity, clinical variations, and life-cycle of protozoa. © 2021, Indian Society for Parasitology.

The Red fox is the largest of the true foxes and the most abundant wild member of the carnivora. This study aimed to determine the anatomical and histological structure of the ovary and salpinx of the Red foxes. The ovary and salpinx of four Red foxes of similar ages, which could not be rescued by the Center despite all interventions, were dissected. Measurements were taken from the right-left ovary and salpinx using digital callipers. The weights of each ovary and salpinx were measured using a precision scale (min: 0.0001 g, max: 220 g). The mean length of the ovary was 13.43 ± 2.38 mm, the width was 6.28 ± 1.99 mm, the thickness was 4.89 ± 0.18 mm, and weight was 0.93 ± 0.14 g. The mean length of the salpinx was 76.22 ± 3.02 mm, the width was 1.98 ± 0.07 mm, and the weight was 0.53 ± 0.31 g. Crossman’s triple staining method was applied for histological examination of the ovary tissue. It was observed that the ovary was surrounded by germinative epithelium from the outside and consisted of the cortex with different follicles in the development stage, and the medulla layer with plenty of blood vessels and nerve plexuses inside. In conclusion, we believe that the findings of this study may be useful for further studies on foxes and surgical operations (ovariectomy, ovariohysterectomy). In addition, it is aimed to eliminate the insufficient information regarding the reproductive system of wild animals in this study. © 2021, Chartered Inst. of Building Services Engineers. All rights reserved. This research received no grant from any funding agency/sector.

This article proposes a posthumanist reading of Joyce Carol Oates’s “Poe Posthumous; or, The Light-House,” and argues that posthumanism provides human beings with a new way of living. In the story, the narrator comes to the Light-House at Viña de Mar to participate in a scientific experiment. As an “exemplary specimen of Homo sapiens,” the narrator endeavours to preserve human knowledge, which symbolises his superiority over nonhuman species. However, on becoming further involved in nature, he gradually abandons his anthropocentric thought, and learns to live with other species. The posthumanist thought finds its full expression in the symbiotic coexistence of multiple species and culminates in the narrator’s cross-species marriage to a female Cyclophagus. The juxtaposition of the decentring of anthropocentrism with the ascent of nonhuman agents highlights the posthumanist coexistence of humans and nonhumans.

Sea turtles are considered as bio-indicators for monitoring the efficiency of restoration measures to reduce marine litter impacts on health. However, the lack of extended and standardised empirical data has prevented the accurate analysis of the factors influencing litter ingestion and the relationships with individual health. Historic data collected from 1988 and standard data collected from 2016 were harmonised to enable such analyses on necropsied loggerhead turtles (Caretta caretta) in eight Mediterranean and North-East Atlantic countries. Litter was found in 69.24 % of the 1121 individuals, mostly single-use and fishing-related plastics. Spatial location, sex and life history stage explained a minor part of litter ingestion. While no relationships with health could be detected, indicating that all individuals can be integrated as bio-indicators, the mechanistic models published in literature suggest that the high proportion of plastics in the digestive contents (38.77 % per individual) could have long-term repercussions on population dynamics. © 2022

Pembrolizumab is a monoclonal antibody. Anastrozole is an infertility inhibitor of aromatase. Resveratrol is an antioxidant polyphenol in the reproductive system. This study was planned to demonstrate the protective effects of anastrozole and resveratrol against pembrolizumab-induced reproductive damage. Forty-two Sprague–Dawley rats were used in the study. Groups: The control, Pembrolizumab (PEMB), PEMB + Anastrazol (ANAST), PEMB + Resveratrol (RES), RES, and ANAST groups. At the end of the experiment, rats were euthanased under anaesthesia. Tissue samples were taken from rats for biochemical, histological, and ELISA evaluations. Tissues were subjected to routine tissue follow-up for histological analysis. Biochemically, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) levels were measured. Sperm motility, abnormal sperm rate, and epididymal sperm concentration were examined spermatologically. Serum testosterone and programmed cell death-1 (PD-1) levels were measured using the ELISA. TBARS levels were significantly increased and GSH, SOD, GPx, and CAT levels were mitigated in PEMB-treated rats. Histologically; Control, ANAST, and RES groups testis samples were observed with normal histological appearance. Histological damage was detected in seminiferous tubule structures in testicular tissue in the PEMB group. In treatment groups, this damage was decreased. In addition, PD-1 and testosterone levels were evaluated by the ELISA method. ANAST and RES have therapeutic effects against reproductive damage caused by PEMB. © 2022 Wiley-VCH GmbH.

Sea turtles are considered pollution bioindicators due to their tendency to accumulate high metal levels in their tissues during their long lifespans. In this context, we aimed to analyse the concentrations of 12 elements in liver, kidney, heart and muscle samples from green turtles (Chelonia mydas; n = 41) and loggerhead turtles (Caretta caretta; n = 14) found stranded in Northern Cyprus. The samples were collected between 2019 and 2021, stored in sterile Eppendorf tubes at ?20 °C until metal analysis, and analysed with an inductively coupled plasma mass spectrometer. With this study, we contribute to the limited number of studies on metal accumulation in heart tissue and present the first data for Mg accumulation in the heart, liver, muscle and kidney tissues of both species. We found that metal accumulation levels differed among the two study species’ tissues, with some elements in the same tissue (AlKidney, AsHeart, AsLiver, FeMuscle, FeKidney, FeHeart, MnHeart, PbHeart, ZnMuscle and ZnKidney) significantly differing between species. The observed variation likely resulted from their different feeding habits, which cause them to be exposed to different levels of metals. We also found significant associations among elements within tissues, as well as between the same element across different tissues in both species, which may indicate the differential accumulation of elements among organs due to physiological processes in turtle metabolism, bioaccumulation or excretion. © 2022 Elsevier Ltd

Cell clarification represents a major challenge for the intensification through very high cell density in the production of biopharmaceuticals such as monoclonal antibodies (mAbs). The present report proposes a solution to this challenge in a streamlined process where cell clarification and mAb capture are performed in a single step using magnetic beads coupled with protein A. Capture of mAb from non-clarified CHO cell suspension showed promising results; however, it has not been demonstrated that it can handle the challenge of very high cell density as observed in intensified fed-batch cultures. The performances of magnetic bead-based mAb capture on non-clarified cell suspension from intensified fed-batch culture were studied. Capture from a culture at density larger than 100 × 106 cells/ml provided an adsorption efficiency of 99% and an overall yield of 93% with a logarithmic host cell protein (HCP) clearance of ≈2–3 and a resulting HCP concentration ≤≈5 ppm. These results show that direct capture from very high cell density cell suspension is possible without prior processing. This technology, which brings significant benefits in terms of operational cost reduction and performance improvements such as low HCP, can be a powerful tool alleviating the challenge of process intensification. QC 20221102

Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another ?-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors. © 2021 American Chemical Society. 1R01CA244344; University of Texas MD Anderson Cancer Center; Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK: 215S008, TUBITAK-BIDEB 2214A This study was funded by The Scientific and Technological Research Council of Turkey (TUBITAK) (grant number 215S008 and TUBITAK-BIDEB 2214A program, F.C.O.) and The University of Texas-MD Anderson Cancer Center Bridge fund (B.O. and N.K.) and NIH-NCI 1R01CA244344 grants (B.O. and N.K.).

Loneliness and isolation were two factors introduced as “effective measures” during the COVID-19 crisis. The lockdown exacerbated loneliness among those already suffering from acute illnesses. In this context, a rereading of the film Lars and the Real Girl by Craig Gillespie is particularly relevant as it offers novel perspectives on loneliness. The interplay between Lars’s desire to be in a compassionate relationship and the fear of meeting and socializing is comparable to what was witnessed across the coronavirus-afflicted world. This paper explores the potential for understanding delusion caused by traumatic experiences as a form of communication rather than a mental disorder. The film explains how a silicone sex doll functions as a medium between the lonesome Lars and society in resolving the trauma. The paper focuses on the infantile nature of humans and uses infantilism in a conducive manner to understand anthropomorphism for bridging the gap between a lonely/delusional person and society while drawing examples from the film. The introduction of a nonhuman actor—an anatomically correct doll—becomes an opportunity for a traumatized person such as Lars to know himself well and gradually open up to socializing. As he moves from external to threshold en-rolling, followed by internal en-rolling, it indicates his opening up to communication as he moves from language to lalangue and creates his world with the doll. This film presents a therapeutic approach to treating schizoid personality disorder with the assistance of a nonhuman actor.

The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1–F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline. CC BY 4.0© 2023 The Author(s)Correspondence: qiaolin.deng@ki.se (Q.D.), elisabet.stener-victorin@ki.se (E.S.-V.)We thank Zhiyi Zhao, Jacob Victorin, Sonja Edström, and Sara Pilström for technical assistance during animal work and molecular analysis; TSE Systems and the Metabolic Phenotyping Center at the Strategic Research program in Diabetes at the Karolinska Institutet; and the electron microscopy unit Emil at Huddinge University Hospital at the Karolinska Institutet. This work is supported by the Swedish Medical Research Council: project nos. 2018-02435 and 2022-00550 (E.S.-V.) and 2018-02557 and 2020-00253 (Q.D.); the Knut and Alice Wallenberg Foundation: 2019.0211 (Q.D.); Distinguished Investigator Grant – Endocrinology and Metabolism, Novo Nordisk Foundation: NNF22OC0072904 (E.S.-V.); the Diabetes Foundation:DIA2021-633 (E.S.-V.); the Novo Nordisk Foundation: NNF18OC0033992 and NNF19OC0056647 (E.S.-V.); the Strategic Research Program in Diabetes at the Karolinska Institutet (E.S.-V.); the Adlerbertska Research Foundation: GU 2019/86 (E.S.-V.); Karolinska Institutet KID funding: 2020-00990 (E.S.-V.); a Karolinska Instiutet faculty funded position (Q.D.); the Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet: 20190079 (E.S.-V.); O.E. och Edla Johanssons Stiftelse 2021 (S.R.); the Karolinska Institutet China scholarship council program (Q.L.); Magnus Bergvalls Stiftelse: 2020-03808 and 2021-04329 (S.R.); the Karolinska Institutet: 2020-02026 (S.R.); the National Fund for Scientific and Technological Development (FONDECYT): project no. 1151531 (T.S.P.); the FONDECYT: project no. 1201483 (B.E.); the National Commission for Scientific and Technological Research (CONICYT) (R.F.); HKH Kronprinsessan Lovisas förening för barnasjukvård (R.F.); and Stiftelsen Axel Tielmans minnesfond (R.F.)

The phylogeny and systematics of fur seals and sea lions (Otariidae) have long been studied with diverse data types, including an increasing amount of molecular data. However, only a few phylogenetic relationships have reached acceptance because of strong gene-tree species tree discordance. Divergence times estimates in the group also vary largely between studies. These uncertainties impeded the understanding of the biogeographical history of the group, such as when and how trans-equatorial dispersal and subsequent speciation events occurred. Here, we used high-coverage genome-wide sequencing for 14 of the 15 species of Otariidae to elucidate the phylogeny of the family and its bearing on the taxonomy and biogeographical history. Despite extreme topological discordance among gene trees, we found a fully supported species tree that agrees with the few well-accepted relationships and establishes monophyly of the genus Arctocephalus. Our data support a relatively recent trans-hemispheric dispersal at the base of a southern clade, which rapidly diversified into six major lineages between 3 and 2.5 Ma. Otaria diverged first, followed by Phocarctos and then four major lineages within Arctocephalus. However, we found Zalophus to be nonmonophyletic, with California (Zalophus californianus) and Steller sea lions (Eumetopias jubatus) grouping closer than the Galapagos sea lion (Zalophus wollebaeki) with evidence for introgression between the two genera. Overall, the high degree of genealogical discordance was best explained by incomplete lineage sorting resulting from quasi-simultaneous speciation within the southern clade with introgresssion playing a subordinate role in explaining the incongruence among and within prior phylogenetic studies of the family. [Hybridization; ILS; phylogenomics; Pleistocene; Pliocene; monophyly.]

As human-caused environmental crises worsen, many young people are anxious but alienated from nature, hardly perceiving the ecosystems in which they participate. This thesis reveals that, vitally, contemporary YA fantasy novels tend to represent the senses as skills and thereby convey human participation in nature with some optimism. Human characters who learn to sense skilfully value their humanimal embodiment and interact responsively with nonhumans, participating in their environments with an embodied awareness that one might call ecoconsciousness. Drawing from a corpus of 160 novels published between 1994 and 2021, I combine ecocriticism with sensory studies to analyse common sensory motifs that, when developed, model how humans can perceive and participate in the more-than-human world ecoconsciously. Literary portrayals of sensing require critical appraisal so that authors may avoid inadvertently perpetuating human exceptionalism and ecophobia through their sensory descriptions and instead encourage skilful embodied participation in nature. The first chapter studies how focalisation can present sight as an embodied, relational skill. In J.K. Rowling’s "Harry Potter" series and Nnedi Okorafor’s "Nsibidi Scripts" trilogy, human–animal gazes define and conduct relationships, sometimes antagonistic and sometimes mutually beneficial, while the motif of magical invisibility reveals that wonder is an embodied visual skill requiring practice. Despite twentieth-century scholars’ claims that sight disembodies the perceiver and disempowers the perceived, descriptions of humans looking at animals in contemporary YA fantasy show that focalisers interact with nonhumans more skilfully when they remember their own humanimal embodiment and consider how they appear to those whom they sense. The second chapter investigates how taste descriptions encapsulate perceivers’ attitudes to their embodiment and highlight their entanglement in naturecultures that produce and consume food in certain ways. Philip Pullman’s "His Dark Materials" exemplifies a motif in which young people renew naturecultures through taste pleasure, but "The Book of Dust" explores how repressive naturecultures inhibit skilful embodied pleasure. In Frances Hardinge’s "A Face Like Glass", more-than-human taste encounters lead the protagonist to reject the unjust natureculture that produces her food. Representations of taste consistently suggest that eaters should enjoy their embodiment but must not ignore others’ suffering. The third chapter critiques persistent portrayals of smell as an alarmingly instinctive animal reaction that threatens human rationality. The "Twilight" series by Stephenie Meyer exhibits the extent to which contemporary cultures fear smell, which her work links with violence and mortality through the central motif of predatory vampires smelling their prey, and Terry Pratchett’s "Tiffany Aching" series depicts smell as too emotional to inform rational thought. Unusually, P.M. Freestone’s "Shadowscent" books model human protagonists smelling skilfully, especially in how they use cultural context to interpret the significance of scents. We need more novels depicting skilful smell to counteract cultural attitudes that shame us into loathing, fearing, and repressing our humanimal embodiment. The fourth chapter contends that a key part of skilful touch in YA fantasy is knowing when not to touch, being careful of ourselves, others, and the consequences of touching. Elizabeth Lim’s "Blood of Stars" duo extensively develops the motif of skin suffering as a punishment for human hands hubristically manipulating nature, and Natasha Ngan’s "Girls of Paper and Fire" demands respect for tactile pain, encouraging readers to trust their humanimal responses and escape painful touches rather than understanding pain as a necessary price for achieving their aims. Touch communicates across species boundaries and helps us act sensitively in the more-than-human world, sometimes by not touching. Representations of kinaesthesia in contemporary YA fantasy position humans as bodyminds whose movements flow responsively from others’ movements, as I will show in the fifth chapter. Kristin Cashore’s "Graceling" books investigate the motif of movement as thought and ultimately celebrate integrated bodyminds moving with skilful responsiveness, both in fight scenes and metaphors of the body politic. Kinaesthetic descriptions in Sarah Beth Durst’s "Queens of Renthia" series show how human and nonhuman characters influence each other’s motions and together create more-than-human places. In the final chapter, human characters (re)develop hearing skills appropriate for specific places, learning how to interpret their distinctive nonhuman voices. Garth Nix’s "Old Kingdom" series, Patrick Ness’s "Chaos Walking" trilogy, and Nicky Singer’s "Island" all depict protagonists learning almost-lost skills of listening needed to participate in certain places, partly through education by Indigenous cultures. The aural poetics of the texts reinforce these motifs and convey how hearing involves a perceiver’s bodymind in the movements that make place. YA fantasy’s imaginative adjustments to what humans sense draw attention to how we sense. Characters who sense skilfully respect nonhuman needs and enjoy their humanimal bodyminds, participating ecoconsciously in a more-than-human world. The genre does vital work modelling how our senses could help us overcome cultural alienation from nature.

Background Nanoparticles play a crucial role in nanodiagnostics, radiation therapy of cancer, and they are now widely used to effectively deliver drugs to specific sites, targeting whole organs and down to single cells, in a controlled manner. Therapeutic efficiency of nanoparticles greatly depends on their clustering distribution inside cells. Our purpose is to find the cluster density using Smoluchowski’s coagulation equation with injections. Results We obtain an exact cluster density of nanoparticles as the steady-state solution of Smoluchowski’s equation describing clustering due to the fusion of endosomes. We also analyze the unsteady cluster distribution and compare it with the experimental data for time evolution of gold nanoparticle clusters in living cells. Conclusions We show the steady cluster density is in good agreement with experimental data on gold nanoparticle distribution inside endosomes. We find that for clusters containing between 1 and 20 nanoparticles, the exact cluster density provides a better description of the existing experimental data than the well-known approximate asymptotic power-law distribution $$x^{-3/2}$$ x - 3 / 2

Purpose of Review Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. Recent Findings Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. Summary In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD.

Chronic hypoxia negatively affects male fertility by causing pathological changes in male reproductive system. However, underlying mechanisms of this damage are unknown. Chloroquine (CLQ) is an anti-inflammatory agent that is widely used in the treatment of inflammation-related diseases such as malaria and rheumatoid arthritis. This study aimed to investigate the therapeutic effects of CLQ in the hypoxia-induced testicular damage via assessment of hypoxic response, endoplasmic reticulum stress and apoptosis. For this purpose, 32 Wistar albino rats were divided into 4 groups as control (given 20%-21% O2, no treatment), CLQ (given 50 mg/kg and 20%-21% O2 for 28 days), hypoxia (HX) (given 10% O2 for 28 days) and HX + CLQ (given 50 mg/kg and 10% O2 for 28 days). After the experiment, blood samples and testicular tissues were taken. Histopathological evaluation was performed on testicular tissues and hypoxia-inducible factor 1-? (HIF1-?), heat shock proteins (HSPs) HSP70, HSP90 and growth arrest and DNA damage-inducible gene 153 (GADD153) expression levels were detected via immunohistochemistry. Moreover, apoptotic cells were detected via terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining and serum testosterone levels were determined by enzyme-linked immunosorbent assay (ELISA) assay. Histopathological changes, apoptotic cell numbers and HIF1-?, HSP70, HSP90 and GADD153 expressions significantly increased in HX group (P .05). However, CLQ exerted a strong ameliorative effect on all parameters in HX + CLQ group. According to our results, we suggested that CLQ can be considered as an alternative protective agent for eliminating the negative effects of hypoxic conditions on male fertility. © 2022 John Wiley & Sons Australia, Ltd.

Bu çalışmada 22 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19. Sanofi & Regeneron GlaxoSmithKline European Commission Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung Christine Kühne – Center for Allergy Research and Education

Rationale: Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities. Objectives: Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats. Results: (S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared with other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding. Conclusions: These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature. The authors would like to acknowledge Eurofins DiscoverX Corporation (Fremont, CA).

The therapeutic potential of the adipose tissue is also supported by a source of mesenchymal stem cells (MSCs), endothelial progenitor cells, mast cells, T- lymphocyte, B lymphocyte, and adipose-resident macrophages with repairing and regenerative ability. The purpose of this study was to compare adipose tissue derived mesenchymal stem cells (ADSCs) and stromal vascular fraction cells (SVF cells) in terms of the usage of non-enzymatic isolation, detection of cell adhesion, fibroblastoid cell formation, properties of cell population, cell culture duration until 3rd passages under in-vitro culture condition. We used 3 months old, 4 male Sprague Dawley rats (mean of live weight about 250 g) to examined the variation of the cell population, cell properties, phases of cellular formation, cell culturing time, subculturing duration, differences in confluency between SVF cells and ADSCs. In in-vitro expansion, ADSCs displayed higher rate of adhesiveness, homogenous cell population, faster proliferation and formation of fibroblast like cells compared to SVF cells. As a result, we showed that ADSCs have better adhesive ability, higher proliferative capacity in all of the 3 passages and require shorter time to reach confluency compared with SVF cells in vitro. These findings may contribute to future studies that deal with isolation and selection of stem cells from various tissues, as well as design clinical trials based on ADSCs and SVF cells. Adipoz dokusunun terapötik potansiyeli; mezenkimal kök hücreler (MKH) ile desteklenmesinin yanında endotel progenitor hücreleri, mast hücreleri, T lenfositleri ve adipoz dokusundaki makrofajların etkisi ile tedavi ve rejenerasyon potansiyeli ile de desteklenmektedir. Bu çalışmanın amacı; adipoz doku kökenli mezenkimal kök hücreler (ADMKH) ve stromal vasküler fraksiyon kökenli hücrelerin (SVF hücreleri) non enzimatik hücre izolasyonu yöntemi, hücrelerin plastik yüzeye tutunması, fibroblastoid yapının oluşumu, hücre populasyonunun özellikleri, 3. pasaja kadar in vitro kültür yönünden karşılaştırılmasıdır. Bu çalışmada, SVF hücreleri ve ADMKH'lerin arasındaki; hücre popülasyonu, hücrelerin yapısal özellikleri, hücresel gelişim fazları, hücre kültür süresi, subkültür süresi, konfluensinde bulunan farklılıkları incelemek için 3 aylık yaştaki, 4 erkek Sprague Dawley ırkı sıçan (ortalama canlı ağırlıkları yaklaşık 250 g) kullandık. İn vitro ekspansiyonda, SVF hücreleri ile karşılaştırıldıklarında ADMKH’ler; yüksek oranda hücresel tutunma, hızlıca fibrolastoid hücre yapısını oluşturma, homojen hücre populasyonu, daha hızlı proliferasyon gösterdi. Sonuç olarak, ADMKH’lerin her 3 pasajda daha fazla oranda plastik yüzeye tutunduğu, daha yüksek proliferasyon kapasitesine sahip olduğu ve in vitro kültürde SVF hücrelerinden daha kısa sürede konfluense ulaştığını gözlemledik. Bu bulgular, çeşitli dokulardan kök hücrelerin izolasyonu ve seçimi ile ilgili ileriki çalışmalara katkıda bulunmasının yanı sıra, ADMKH'ler ve SVF hücreleriyle yapılan klinik deneylerin tasarlanmasına da katkı sağlayacaktır.

In past decade, Pt-based nanomaterials as peroxidase mimics have attracted much attention for H2O2 and glucose detection. However, easy aggregation of Pt nanoparticles (Pt NPs) greatly decreases their peroxidase-like activity. In this work, novel Pt/EMT nanocomposites were prepared by uniformly loading Pt NPs (5?8 nm) onto the support of ultrasmall EMT zeolite (15?20 nm), a kind of low-silica microporous aluminosilicate material. The hybrid Pt/EMT nanomaterials could be well dispersed in water to form a homogeneous suspension, and were then utilized as a superior peroxidase-like catalyst for oxidation of 3,3?,5,5?-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). The optimal catalyst of 2.6Pt/EMT nanocomposite exhibited excellent catalytic performance toward H2O2 and TMB than natural enzyme of horseradish peroxidase (HRP) by using a steady-state kinetic analysis based on the typical Michaelis-Menten kinetics theory. The peroxidase-like catalyst showed a promising activity in a wide pH and temperature range as well as the long-term stability. A facile and reliable colorimetric assay based on the peroxidase mimic of Pt/EMT nanocomposite was constructed for precise detection of H2O2 and glucose in a wide linear range, with low limits of detection of 1.1 ?M and 13.2 ?M, respectively. Due to high selectivity to glucose against other sugars on the catalyst, the method was demonstrated to accurately measure the concentration of glucose in real samples including human blood serum and fruit juices, indicating a potential application of the Pt/EMT nanocomposites as a robust peroxidase mimic and a reliable biosensor in the fields of clinical diagnosis, pharmaceutical, food research and so on. 2020 Scopus

Increased risk of pancreatic cancer may be associated with consumption of sugar containing foods. The aim of this study was to evaluate the effect of peach nectar containing high fructose corn sirup (HFCS) consumption in a pancreatic carcinogenesis rat model induced by 7,12-Dimethyl benzanthracene (DMBA). Fifty-day-old male Sprague Dawley rats were fed with peach nectar containing HFCS + chow, peach nectar containing sucrose + chow and only chow. After 8 mo, feeding period, each group was divided into two subgroups, in which the rats were implanted with DMBA and no DMBA (sham). Histologic specimens were evaluated according to the routine tissue processing protocol. The animals withad libitumaccess to pn-HFCS, pn-sucrose and chow (only) showed significant differences in chow consumption and glucose level. Necropsy and histopathologic findings showed tumor formation in the entire group treated with DMBA. Excluding one rat in chow group, which was classified as poorly differentiated type, the others were classified as moderately differentiated pancreatic ductal adenocarcinoma (PDAC). This study demonstrated that daily intake of HFCS did not increase body weight and there was no effect of peach nectar consumption on the development of PDAC induced by DMBA in rats.

Background: Glioblastoma (GB) is the most aggressive form of brain tumor. Despite the current treatment methods, the survival rate of patients is very low. Therefore, there is a need to develop new therapeutic agents. The migration and invasion capacity of GB cells is related to mesenchymal transition (MT) mechanism. Materials and Methods: The effect of OLE on MT was determined by analysis of the Twist, Snail, Zeb1, N-cadherin and E-cadherin genes in the EMT mechanism. The effect of OLE on cell migration was determined by wound healing test. Results: 2 mg/ml OLE reduced Twist, Snail, Zeb1 and N-cadherin expression and the combination of OLE + TMZ (2 mg/ml OLE + 350 mM TMZ) increased E-cadherin and reduced Twist, Zeb1 and N-cadherin. In addition, co-treatment with OLE increased TMZ-induced anti-invasion properties thought suppressing transcription factors of MT mechanism. Conclusion: OLE can enhance the anti-MT activities of TMZ against GB and provide strong evidence that combined treatment with OLE and TMZ has the potential to be an effective alternative approach in GB therapy.

We studied the effects on the performance and intestinal health of broiler chickens who were given Macleaya cordata (M. cordata) extract alone and those given a newly developed plant extract mixture (PEM) as a natural feed additive in the diet. Total 240 Ross 308 male chicks were used in this study and divided into 4 groups of 60 chicks each. For the experimental groups, 100 ppm PEM was added to the diet of group I (PEM 100); 200 ppm PEM was added for group II (PEM 200), and 18 ppm M. cordata extract (MCE) was added for group III. Although there were no significant differences in the feed conversion ratio, carcass weight, and carcass yield, other performance variables, including body weight, body weight gain, and feed intake were significantly affected. An analysis of the data from this study showed that specified feed additives decreased the ileal inflammation score without changing the villus height in the duodenum of the chickens. In conclusion, dietary supplementation of MCE supplement alone and the effects of newly developed PEM improved the performance parameters. Moreover, it can be said that it has an intestinal inflammation-reducing effect. Thus, this supplementation may have the potential to improve intestinal health. © 2020 Istanbul University. All rights reserved. Uludağ Üniversitesi: KUAP (V)-2018/13 This study was funded by the Uludag University Scientific Research Unit Grant (Project No: KUAP (V)- 2018/13). Financial Disclosure: This study was funded by the Uludağ University Scientific Research Unit Grant (Project No: KUAP (V)-2018/13).

The major histocompatibility complex (MHC) is one of the most gene-dense regions of the mammalian genome. Multiple genes within the human MHC (HLA) show extensive polymorphism, and currently, more than 26,000 alleles divided over 39 different genes are known. Nonhuman primate (NHP) species are grouped into great and lesser apes and Old and New World monkeys, and their MHC is studied mostly because of their important role as animal models in preclinical research or in connection with conservation biology purposes. The evolutionary equivalents of many of the HLA genes are present in NHP species, and these genes may also show abundant levels of polymorphism. This review is intended to provide a comprehensive comparison relating to the organization and polymorphism of human and NHP MHC regions.

Background: Natural phenolic compounds in medicinal herbs and dietary plants are antioxidants which play therapeutic or preventive roles in different pathological situations, such as oxidative stress and inflammation. One of the most studied phenolic compounds in the last decade is chlorogenic acid (CGA), which is a potent antioxidant found in certain foods and drinks. Objective: This review focuses on the anti-inflammatory and antinociceptive bioactivities of CGA, and the putative mechanisms of action are described. Ethnopharmacological reports related to these bioactivities are also reviewed. Materials and Methods: An electronic literature search was conducted by authors up to October 2019. Original articles were selected. Results: CGA has been shown to reduce inflammation and modulate inflammatory and neuropathic pain in animal models. Conclusion: The consensus of the literature search was that systemic CGA may facilitate pain management via bolstering antioxidant defenses against inflammatory insults.

Cd14 and Alpk1 both encode pathogen recognition receptors and are known candidate genes for affecting severity in inflammatory bowel diseases. CD14 acts as a coreceptor for bacterial lipopolysaccharide (LPS), while ALPK1 senses ADP-D-glycero-beta-D-manno-heptose, a metabolic intermediate of LPS biosynthesis. Intestinal barrier integrity can be influenced by CD14, whereas to date, the role of ALPK1 in maintaining barrier function remains unknown. We used colon-derived 3D organoids, first characterised for growth, proliferation, stem cell markers, and expression of tight junction (TJ) components using qPCR and immunohistochemistry. They showed characteristic crypt stem cells, apical shedding of dead cells, and TJ formation. Afterwards, organoids of different genotypes (WT, Il10-/-, Cd14-/-, and Alpk1-/-) were then stimulated with either LPS or Escherichia coli Nissle 1917 (EcN). Gene expression and protein levels of cytokines and TJ components were analysed. WT organoids increased expression of Tnfα and tight junction components. Cd14-/- organoids expressed significantly less Tnfα and Ocln after LPS stimulation than WT organoids but reacted similarly to WT organoids after EcN stimulation. In contrast, compared to WT, Alpk1-/- organoids showed decreased expression of different TJ and cytokine genes in response to EcN but not LPS. However, Western blotting revealed an effect of ALPK1 on TJ protein levels. These findings demonstrate that Cd14, but not Alpk1, alters the response to LPS stimulation in colonic epithelial cells, whereas Alpk1 is involved in the response upon bacterial challenge.

Hydrolysis is considered the limiting step during solid waste anaerobic digestion (including co-digestion of sludge and biosolids). Mechanisms of hydrolysis are mechanistically not well understood with detrimental impact on model predictive capability. The common approach to multiple substrates is to consider simultaneous degradation of the substrates. This may not have the capacity to separate the different kinetics. Sequential degradation of substrates is theoretically supported by microbial capacity and the composite nature of substrates (bioaccessibility concept). However, this has not been experimentally assessed. Sequential chemical fractionation has been successfully used to define inputs for an anaerobic digestion model. In this paper, sequential extractions of organic substrates were evaluated in order to compare both models. By removing each fraction (from the most accessible to the least accessible fraction) from three different substrates, anaerobic incubation tests showed that for physically structured substrates, such as activated sludge and wheat straw, sequential approach could better describe experimental results, while this was less important for homogeneous materials such as pulped fruit. Following this, anaerobic incubation tests were performed on five substrates. Cumulative methane production was modelled by the simultaneous and sequential approaches. Results showed that the sequential model could fit the experimental data for all the substrates whereas simultaneous model did not work for some substrates. © 2019

Background: The objective of this study is comparing different count data models for stillbirth data. In modeling this type of data, Poisson regression or alternative models can be preferred. Methods: The poisson, negative binomial, zero-inflated poisson, zero-inflated negative binomial, poisson-logit hurdle and negative binomial-logit hurdle regressions were compared and used to examine the effects of the gender, parity and herd-year-season independent variables on stillbirth. Furthermore, the Log-Likelihood statistics, Akaike Information Criteria, Bayesian Information Criteria and rootogram graphs were used as comparison criteria for performance of the models. According to these criteria, Negative Binomial-Logit Hurdle Regression model was chosen as the best model. Result: The parameter estimates obtained by Negative Binomial-Logit Hurdle Regression model in relation to the effects of the gender, parity and herd-year-season independent variables on stillbirth were found to be significant (p, Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, TÜBİTAK, The authors wish to thank Dr. Daniel Gianola, Dr. Kent Weigel and US National Association of Animal Breeders for providing data. TUBITAK (The Scientific and Technological Research Council of Turkey) and Ege University Research Institute are gratefully acknowledged for financial support.

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone’s effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders., This work was supported by the Swiss National Science Foundation (no.176206; NCCR Synapsy grant no.185897) to C.S.; the European Research Council (ERC) advanced grant SYNEME to J.C.B.; Instituto de Salud Carlos III (ISCIII)—Fondo Europeo de Desarrollo Regional (FEDER) (PI17/00296), RETICs Oftared (RD16/0008/0014), and Generalitat de Catalunya (2017SGR737) to X.G.; Ministerio de Ciencia e Innovación (BFU2017-83317-P) to D.S.; Ministerio de Economia, Industria y Competitividad, Maria de Maeztu (MDM-2017-0729) to Institut de Neurociencies, Universitat de Barcelona; ISCIII-FEDER (PI14/01126, PI17/01019), the National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, and R01AG061566), Fundació La Marató de TV3 (20141210), and Generalitat de Catalunya (SLT006/17/00119) to J.F.; ISCIII-FEDER (PI17/00279 and PI20/0042), Fundació La Marató de TV3 (201614.31), and Generalitat de Catalunya (SLT008/18/00127) to A.J.; Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI) and FEDER (PID2019-111669RB-I00 and PID2020-115055RB-I00), CIBEREHD, the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, Generalitat de Catalunya (SGR-2017-1112), the European Cooperation in Science & Technology (COST) ACTION CA17112, FUNDACIÓN BBVA (“ER stress-mitochondrial cholesterol axis in obesity-associated insulin resistance and comorbidities”), and Red Nacional 2018-102799-T de Enfermedades Metabólicas y Cáncer and Fundació La Marató de TV3 (201916/31) to J.C.F.-C.; and ERC consolidator grant MITOSENSING (725004), ISCIII-FEDER (PI16/00963), “la Caixa” Foundation (ID100010434) under agreement LCF/PR/HR19/52160016, and CERCA Programme/Generalitat de Catalunya to M.C. D.A. is supported by ISCIII (INT19/00016) and Generalitat de Catalunya PERIS program (SLT006/17/125), A.P. is supported by Hospital Clínic de Barcelona (“Ajut Josep Font”), A.O. is supported by a Miguel Servet contract (CP19/00083) from ISCIII-FEDER, and R.H.-T. is supported by a Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF) and NEUROPREG (891247). S.R. is a recipient of Juan de la Cierva Formación (FJCI-2016-28911) and Incorporación (IJC2018-037341-I) programs from the Spanish Ministry of Science and Innovation. This work was carried out in part at Esther Koplowitz Centre.

E. coli that produce extended-spectrum β-lactamases (ESBLs) are major multidrug-resistant bacteria. In Peru, only a few reports have characterised the whole genome of ESBL enterobacteria. We aimed to confirm the identity and antimicrobial resistance (AMR) profile of two ESBL isolates from dog faeces and drinking water of rural Andean households and determine serotype, phylogroup, sequence type (ST)/clonal complex (CC), pathogenicity, virulence genes, ESBL genes, and their plasmids. To confirm the identity and AMR profiles, we used the VITEK®2 system. Whole-genome sequencing (WGS) and bioinformatics analysis were performed subsequently. Both isolates were identified as E. coli, with serotypes -:H46 and O9:H10, phylogroups E and A, and ST/CC 5259/- and 227/10, respectively. The isolates were ESBL-producing, carbapenem-resistant, and not harbouring carbapenemase-encoding genes. Isolate 1143 ST5259 harboured the astA gene, encoding the EAST1 heat-stable toxin. Both genomes carried ESBL genes (blaEC-15, blaCTX-M-8, and blaCTX-M-55). Nine plasmids were detected, namely IncR, IncFIC(FII), IncI, IncFIB(AP001918), Col(pHAD28), IncFII, IncFII(pHN7A8), IncI1, and IncFIB(AP001918). Finding these potentially pathogenic bacteria is worrisome given their sources and highlights the importance of One-Health research efforts in remote Andean communities.

Objectives: We conceptualize patient values and preferences as the relative importance of health outcomes (RIO) which are often obtained through utility elicitation research. A transparent and structured approach to present synthesized RIO evidence and the certainty of this evidence is needed. This study aims to adapt the summary of findings (SoF) table to describe the RIO. Study Design and Setting: We performed three interactive workshops with a protype version of the SoF table for RIO, evidence adapted from the SoF table for intervention effects. We then tested the new format through semi-structured interviews with professionals who interpret RIO evidence (e.g., systematic review authors and guideline developers). Results: We adapted the SoF table for the presentation of RIO evidence. This SoF table may be easy to use, but bears one risk: some participants misunderstood the utility information and the variability around the RIO. We added a visual analogue scale to clarify the concept of utilities. Conclusion: Through a multi-stage process including brainstorming sessions and interviews, we adapted the SoF table to present RIO evidence. This table may enhance understanding of evidence synthesis of values and preferences, facilitating the incorporation of this type of evidence in decision-making. © 2022

Background: Knowing how long SARS-CoV-2-positive individuals can remain infective is crucial for the design of infection prevention and control strategies. Viral culture is the gold standard for detecting an active-replicative virus and evaluating its infectious potential. Objective: To assess the correlation of SARS-CoV-2 infectivity with the number of days from symptom onset and the Ct value, using culture as a reference method. Also, to describe a detailed protocol for SARS-CoV-2 culture and immunofluorescence confirmation based on our experience with other respiratory viruses. Study design: 100 consecutive respiratory samples positive for SARS-CoV-2 by RT-PCR from different subjects were inoculated into VERO E6 cells. Results: Viral isolation was successful in 58% of samples. The median number of days from symptom onset for culture-positive samples was 2, and 15 for culture-negative samples. Six positive cultures were obtained in patients =14 days after symptom onset, all of whom were immunocompromised or with severe COVID-19. The mean Ct value was 12.64 units higher in culture-negative than in culture-positive samples. The probability of successfully isolating SARS-CoV-2 in samples with a Ct value 27. Conclusions: Our findings show a significant positive correlation between the probability of isolating SARS-CoV-2 in culture, fewer days of symptoms and a lower RT-PCR Ct value. SARS-CoV-2 infectivity lasts no more than 14 days from symptom onset in immunocompetent individuals. In contrast, in immunocompromised patients or those with severe COVID-19 infectivity may remain after 14 days. Ct value

BackgroundIbrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis.ObjectiveThe aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida.MethodsIbrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated.ResultsIbrexafungerp MICs ranged from 0.016 to ≥8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016–0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06–≥8 mg/L). Modal MICs/MIC50s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis.ConclusionIbrexafungerp showed a potent in vitro activity against Candida.

Background and aim: Aging is one of the causes of male infertility, and abnormal global DNA methylation and imprinting defects have been characterized in testis during biological aging. One of the important emerging approaches aims to take advantage of the healing properties of young blood plasma to limit the progression of aging in various organs in the body. We aimed to show whether blood plasma transfer has an effect on DNA methylation and spermatogenetic cell development. In addition, we aimed to show whether the young plasma transfer to old mice has an effect on the rejuvenation of the old and whether the impaired DNA methylation and PCNA expression in old age can be restored. Methods: Groups were (i) young control, (ii) young plasma transfer to aged, (iii) aged control, (iv) aged plasma transfer to young. We utilized IHC and WB in protein level of Dnmts. For the global DNA methylation level, we used 5-methylcytosine staining. We also analyzed PCNA protein expressions in all groups by IHC. Results: We found that transfusion of young plasma into the old animal restored DNA methylation and PCNA expression as it did in the young animal. Most importantly, we observed an increase in spermatogonia and spermatid counts in older animals after young blood plasma transfer. Conclusions: Our findings show that young plasma transfer can restore epigenetic disorders that occur with aging and solve infertility problems by increasing the sperm count that decreases. It needs to be supported by different studies, especially human studies. © 2022 The Authors We would like to thank all authors who provided published data.

We estimated the impact of the Zika virus outbreak on birth rates and demand for health care services in Colombia. Our analysis exploits the variation in the level of natural protection against mosquito-transmitted diseases across the country. This characteristic induced exogenous variation in Zika incidence, which allows us to construct a control group of municipalities with similar historical fertility trends but with differential exposure to the Zika crisis. We implemented a difference-in-differences model after matching, as well as synthetic control. We found a decrease in birth rates of approx. 10% in the last two quarters of 2019. The impact of the virus was similar irrespective of the women's education level, and we found no discernible impact on teenage pregnancy. © 2019 Elsevier B.V.

Background Recently it was shown that production of recombinant proteins in E. coli BL21(DE3) using pET based expression vectors leads to metabolic stress comparable to a carbon overfeeding response. Opposite to original expectations generation of energy as well as catabolic provision of precursor metabolites were excluded as limiting factors for growth and protein production. On the contrary, accumulation of ATP and precursor metabolites revealed their ample formation but insufficient withdrawal as a result of protein production mediated constraints in anabolic pathways. Thus, not limitation but excess of energy and precursor metabolites were identified as being connected to the protein production associated metabolic burden. Results Here we show that the protein production associated accumulation of energy and catabolic precursor metabolites is not unique to E. coli BL21(DE3) but also occurs in E. coli K12. Most notably, it was demonstrated that the IPTG-induced production of hFGF-2 using a tac-promoter based expression vector in the E. coli K12 strain TG1 was leading to persistent accumulation of key regulatory molecules such as ATP, fructose-1,6-bisphosphate and pyruvate. Conclusions Excessive energy generation, respectively, accumulation of ATP during recombinant protein production is not unique to the BL21(DE3)/T7 promoter based expression system but also observed in the E. coli K12 strain TG1 using another promoter/vector combination. These findings confirm that energy is not a limiting factor for recombinant protein production. Moreover, the data also show that an accelerated glycolytic pathway flux aggravates the protein production associated “metabolic burden”. Under conditions of compromised anabolic capacities cells are not able to reorganize their metabolic enzyme repertoire as required for reduced carbon processing.

The role of domestic cats in the dynamics of SARS-CoV-2 remains poorly characterized, especially in epidemiologic contexts of countries with high viral transmission. Here, we report the first evidence of SARS-CoV-2 Lambda variant of interest in symptomatic domestic cats whose owners were diagnosed with COVID-19 in Lima, Peru, providing evidence that transmission of this new variant in domestic cats is occurring. More epidemiological studies are required to further characterize the role of domestic animals in the transmission dynamics of SARS-CoV-2.

A simple method was employed for the synthesis of dihydropyrano[3, 2-b]chromenedione derivatives (4a-o) in high yields by condensation of 5, 5-dimethylcyclohexane-1, 3-dione(1), different aromatic aldehydes (2a-o), and 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one(3), using meglumine as a stable and reusable catalyst. Meglumine, an amino sugar, was employed as an environmentally benign catalyst, due to its splendid properties such as being inexpensive, recyclable, and biodegradable. The accomplished protocol employs low catalyst loading and easy work-up for the synthesis of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one derivatives. A great asset is that without any significant loss, the catalyst could be recovered and reused for extended synthetic steps. This offer huge advantage to overcome recyclability issues. Our synthesized compounds were analyzed by IR, 1H, 13C NMR, mass spectra and evaluated for their antioxidant properties by 1, 1-diphenyl-2-picryl hydrazyl radical (DPPH), hydrogen peroxide(H2O2), and nitric oxide (NO) scavenging methods. The correlation in exhibition of antioxidant activity was effective at all doses. The binding interactions and molecular docking studies for entitled compounds were studied against 3MNG protein; 4k exhibited marked binding affinity with excellent docking score of −7.6 Kcal/mol and emerged as a lead compound. © 2019 Wiley Periodicals, Inc. Ural Federal University, UrFU The authors G. Sravya and N. Bakthavatchala Reddy are thankful to Ural Federal University, Yekaterinburg, Russia, for postdoctoral fellowship.

Objective: The aim of this study was to examine pancreatic pathology and the prophylactic effects of pregabalin in lipopolysaccharide (LPS) induced sepsis model in aged rats. Methods: Twenty-four female, one-year-old, Wistar Albino rats were assigned to three groups; Group I (control), Group II (study group: 5mg/kg LPS intraperitoneal, single dose) and Group III(treatment group: 5mg/kg LPS+30 mg/kg oral pregabalin one hour before LPS). Animals were sacrificed by exsanguination 6 hours after LPS administration. Blood and pancreatic tissue samples were collected for biochemical, pathological, and immunohistochemical analyses. Results: LPS caused increases in serum amylase and lipase level but led to a reduction in glucose levels. Following histopathological analysis, numerous neutrophil leucocyte infiltrations were observed in vessels and pancreatic tissues. Increased caspase-3 expression was observed in both the endocrine and exocrine pancreas in the LPS group. Similarly, IL-6, caspase-3 (Cas-3), inducible nitric oxide synthase (iNOS), granulocyte colony-stimulating factor (G-CSF) and serum amyloid-A (SAA) expressions were increased by LPS. Pregabalin improved biochemical, histopathological, and immunohistochemical findings. Conclusion: This study showed that LPS causes pathological findings in the pancreas, but pregabalin has ameliorative effects in aged rats with sepsis. Cas-3, IL-6, iNOS, G-CSF, and SAA all play pivotal roles in the pathogenesis of LPS-induced pancreatic damage.

Filamentous fungi have been used for more than a century as versatile and highly productive cell factories. They are used to produce enzymes and small molecule compounds such as antibiotics and organic acids. Filamentous fungi are now also being explored for the production of sustainable materials that can for instance replace plastics. Mutagenesis and genetic modification are used to improve performance of production strains. Single cell technologies and bulk sample analysis are novel strategies to identify genes that can be used for genetic modification of production strains. Such genes may for instance be involved in fungal reproduction and hyphal heterogeneity. These differentiation processes have recently been implicated to affect production of enzymes and small molecule compounds. Finally, use of mixed cultures instead of monocultures can be a strategy to improve production processes.

Cytogenetic studies in the subfamily Potamotrygoninae have provided valuable insights into the understanding of the evolution and diversification of its species. In the present study, the chromosomal features of seven nominal potamotrygonin species are provided: Plesiotrygon iwamae (2n=74, FN=120), Potamotrygon amazona (2n=66, FN=107), P. constellata (2n=66, FN=110), P. leopoldi (2n=64, FN=102), P. motoro (2n=66, FN=106) from four different localities, and P. orbignyi (2n=66, FN=106), P. scobina (2n=66, FN=104), from Central Amazon. Additionally, we found a new karyomorph in P. wallacei. We considered the localization of Nucleolus Organizer Regions (NORs), as well as the pattern of constitutive heterochromatin, as species-specific characters. We found an XX/XY sex chromosome system in P. orbignyi, and we suggest that P. scobina and P. amazona also possess the same sex chromosome system. Overall, the chromosomal evolution in this group appears to have progressed towards a reduction in diploid number, with a concomitant increase in the number of bi-armed and nucleolar chromosomes. © 2019, Brazilian Journal of Genetics. All rights reserved.