Miracle-dz/UniFAR-FTUs huggingface dataset:
Survival of carbapenem-resistant Acinetobacter baumannii bacteremia: colistin monotherapy versus colistin plus meropenem

Objective The aim of this study was to compare clinical outcomes between patients with carbapenem-resistant Acinetobacter baumannii (CRAB) bacteremia treated with colistin monotherapy and those treated with colistin plus meropenem. Methods We retrospectively evaluated data from 71 patients with CRAB bacteremia treated from November 2006 to February 2018. Predictors of 14-day mortality were determined through logistic regression analysis. Results Our study cohort included 40 bacteremia patients (44.6 %) treated with colistin monotherapy and 31 (55.4 %) treated with colistin plus meropenem. Overall 14-day mortality tended to be higher with monotherapy rather than combination therapy (47.5% vs 25.8%). The latter also showed a tendency for higher clinical success rate compared with monotherapy (61.3% vs 40.0%). Logistic regression analysis showed that Pitt bacteremia score, pneumonia, and combination therapy were significantly associated with mortality. In patients with higher Pitt bacteremia score (≥4), mortality was significantly higher with monotherapy compared with combination therapy (66.7% vs 27.8%). In patients with lower Pitt bacteremia score (≤3), mortality was similar between the two treatment groups (26.3% vs 23.1%). Conclusion Treatment with colistin plus meropenem improves survival in critically-ill patients with CRAB.
Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1-Nrf2 Interaction.

Macrocyclic peptides have proven highly effective inhibitors of protein-protein interactions, but generally lack cell permeability to access intracellular targets. We show herein that macrocyclic peptides may be rendered highly cell-permeable and biologically active by conjugating with a cyclic cell-penetrating peptide (CPP). A previously reported cyclic peptidyl inhibitor against the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 (Nrf2) interaction (KD = 18 nM) was covalently attached to a cyclic CPP through a flexible linker. The resulting bicyclic peptide retained the Keap1-binding activity, resisted proteolytic degradation, readily entered mammalian cells, and activated the transcriptional activity of Nrf2 at nanomolar to low micromolar concentrations in cell culture. The inhibitor provides a useful tool for investigating the biological function of Keap1-Nrf2 and a potential lead for further development into a novel class of anti-inflammatory and anticancer agents. Our data suggest that other membrane-impermeable cyclic peptides may be similarly rendered cell-permeable by conjugation with a cyclic CPP.
The Arctic Cylindrocystis (Zygnematophyceae, Streptophyta) Green Algae are Genetically and Morphologically Diverse and Exhibit Effective Accumulation of Polyphosphate

The green algal genus Cylindrocystis is widespread in various types of environments, including extreme habitats. However, very little is known about its diversity, especially in polar regions. In the present study, we isolated seven new Cylindrocystis‐like strains from terrestrial and freshwater habitats in Svalbard (High Arctic). We aimed to compare the new isolates on a molecular (rbcL and 18S rDNA), morphological (light and confocal laser scanning microscopy), and cytological (Raman microscopy) basis. Our results demonstrated that the Arctic Cylindrocystis were not of a monophyletic origin and that the studied strains clustered within two clades (tentatively named the soil and freshwater/glacier clades) and four separate lineages. Morphological data (cell size, shape, and chloroplast morphology) supported the presence of several distinct taxa among the new isolates. Moreover, the results showed that the Arctic Cylindrocystis strains were closely related to strains originating from the temperate zone, indicating high ecological versatility and successful long‐distance dispersal of the genus. Large amounts of inorganic polyphosphate (polyP) grains were detected within the chloroplasts of the cultured Arctic Cylindrocystis strains, suggesting effective luxury uptake of phosphorus. Additionally, various intracellular structures were identified using Raman microscopy and cytochemical and fluorescent staining. This study represents the first attempt to combine molecular, morphological, ecological, and biogeographical data for Arctic Cylindrocystis. Our novel cytological observations partially explain the success of Cylindrocystis‐like microalgae in polar regions.
Attractive male sticklebacks carry more oxidative DNA damage in the soma and germline

Trade‐offs between the expression of sexual signals and the maintenance of somatic and germline tissues are expected when these depend upon the same resources. Despite the importance of sperm DNA integrity, its trade‐off with sexual signalling has rarely been explored. We experimentally tested the trade‐off between carotenoid‐based sexual coloration and oxidative DNA damage in skeletal muscle, testis and sperm by manipulating reproductive schedule (early vs. late onset of breeding) in male three‐spined sticklebacks. Oxidative DNA damage was measured as the amount of 8‐hydroxy‐2‐deoxyguanosine in genomic DNA. Irrespective of the experimentally manipulated reproductive schedule, individuals investing more in red coloration showed higher levels of oxidative DNA damage in muscle, testis and sperm during the peak breeding season. Our results show that the expression of red coloration traded off against the level of oxidative DNA damage possibly due to the competing functions of carotenoids as colorants and antioxidants. Thus, female sticklebacks may risk fertility and viability of offspring by choosing redder, more deteriorated partners with decreased sperm DNA integrity. The evolution of sexual signal may be constrained by oxidative DNA damage in the soma and germline.
Clinical Toxicology of Commercial Products, Acute Poisoning

The third edition of Gleason, Gosselin, and Hodge remains an essential volume for any Pediatric Emergency Service or for any doctor dealing at all commonly with poisonings. With the addition of one more author, Roger P. Smith, PhD, and a change in cover color to bright blue, this new volume should be placed alongside the two prior editions rather than replace them since some of the previously listed products have been dropped as obsolete and yet, still may exist to cause a rare poisoning. Basically, the third edition is unchanged as to format; the same seven sections: (1) first aid and general treatment, (2) ingredient index and toxicity ratings, (3) therapeutic discussions of specific poisons, (4) supportive treatment, (5) trade name product index and contents, (6) general formulations of common classes of commercial products such as drainpipe cleaners or hair sprays, and (7) index of manufacturers with addresses. Much of
Cognitive training increases dendritic arborization in the dorsal hippocampal CA1 and CA3 neurons of female and male Long–Evans rats

Experiences influence the development of the central nervous system. Cognitive training promotes changes in the structure of the brain, such as in its weight and number of cells, as well as ability to perform dendritic remodeling. The present study was designed to detect possible differences in the neuronal morphology of the dorsal hippocampus between female and male Long–Evans rats after cognitive training (CT). CT was promoted through three learning and memory tests: the Morris water maze, the Barnes circular maze, and Novel object recognition tests. Our data revealed no differences in learning or memory capacities between female and male rats; rats of the two sexes solved the behavioral test with equal efficiency. CT caused an increase in the basilar and apical dendritic arborization of CA1 neurons in male rats, whereas female rats that underwent CT presented only remodeling in the apical arbors of CA1 neurons. The basilar arbors of CA3 neurons of female rats showed an increase in arborization, but their apical arbors were not modified; the arbors of CA3 neurons of male rats submitted to CT were not modified. Total dendritic length was modified by CT in the apical arbors of CA1 neurons of female and male rats and in the basilar CA1 arbors of male rats. There was a significant increase in dendritic spine density in all arbors of CA1 and CA3 neurons of females and males subjected to CT. These results suggest that dendritic remodeling after CT is similar between female and male rats.
Corneal Epithelial Thickness Mapping After Photorefractive Keratectomy for Myopia.

PURPOSE To evaluate the longitudinal changes in epithelial thickness after photorefractive keratectomy (PRK) and correlate these with refractive changes. METHODS This prospective study included 52 eyes of 52 candidates for myopic PRK. Along with standard ophthalmic examinations, corneal epithelial thickness mapping by anterior segment optical coherence tomography was performed. Epithelial thickness maps of 9-mm diameter were divided into 25 sectors, including a central 2-mm zone and eight octants within para-central (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) annular zones. All PRK treatments were performed using the Technolas Teneo 317 model 2 excimer laser (Bausch & Lomb, Rochester, NY) and an aspheric profile with a 6-mm diameter optical zone. Follow-up was at 1, 3, and 6 months. RESULTS Repeated thickness measures before and after PRK at different follow-up times showed a significant difference in thickness separately in various zones (P < .001). A significant decrease in thickness was seen 1 month after PRK in all zones. Afterward, epithelial thickening continued in all zones and reached the preoperative thickness in the midperipheral and peripheral zones 6 months later, whereas the thickness in the central 5-mm zone was significantly thicker than before surgery. There was also a significant correlation between changes in spherical equivalent and epithelial thickness from before to 6 months postoperatively in the paracentral and peripheral zones. CONCLUSIONS There was a marked decrease in the epithelial thickening pattern at 1 month after PRK, with gradual thickening at 3 and 6 months. Changes in epithelial thickness and spherical equivalent were significant only for the para-central peripheral zone. [J Refract Surg. 2019;35(10):632-641. ].
Inter-assay variability in automated serum free light chain assays and their use in the clinical laboratory

Abstract Serum κ and λ free light chain levels are markers of plasma cell proliferation, and their measurements have been included in recent guidelines by the International Myeloma Working Group for the management of patients with plasma cellular dyscrasias. Five in vitro diagnostic methods for the immunochemical quantification of serum free light chains (FLC) are available, three based on polyclonal antibodies (Freelite®, The Binding Site; FLC ELISA κ and λ, Sebia; human κ and λ FLC, Diazyme Laboratories) and two on monoclonal antibodies (N Latex FLC, Siemens Healthineers; Seralite®, Sebia). Several studies have shown that these methods cannot be used interchangeably for the follow-up of patients because measured κ and λ FLC concentrations may differ significantly, especially at high levels. Because no international reference material for the measurement of FLC is available, it is not possible to establish which method is the most accurate. For this reason, knowledge about the analytical and diagnostic performances of the assays used is important. The aim of this review is to describe the main analytical features of the κ and λ FLC assays and how they may influence the clinical use of these parameters.
Enhanced detection of infectious pancreatic necrosis virus via lateral flow chip and fluorometric biosensors based on self-assembled protein nanoprobes.

Salmon fish farmers face remarkable problems in fish rearing and handling due to the spread of disease by infectious pancreatic necrosis virus (IPNV). Therefore, we developed a straightforward and sensitive technique to detect IPNV based on recombinant human apoferritin heavy chain (hAFN-H) protein nanoparticles. In this study, the 24 subunits of the hAFN-H were genetically modified to express 6×His-tag and protein-G at their C-terminal site, using Escherichia coli. We thus achieved a two-step signal amplifying strategy that utilizes a recombinant hAFN-H nanoprobe having a protein-G-binding site that targets the Fc region of monoclonal antibodies, and a 6×His-tag that actively interacts with the functionalized Ni-NTA derivatives. In this study, we report a considerable advancement in magnetic bead-based detection systems that use Ni-NTA-atto 550, reliably exhibiting detection limits of 1.02 TCID50/mL (50 % tissue culture infective dose). Additionally, we propose a lateral flow chip-based detection method that uses the hAFN-H surface functionalized with 5 nm of the Ni-NTA-nanogold complex as a nanoprobe; the limit of detection towards IPNV was 0.88 TCID50/mL. The detection of IPNV by this recombinant hAFN-H nanoprobe was linear to virus titers in the range of 101-103 TCID50/mL.
Bacterial survival in microscopic surface wetness

Plant leaves constitute a huge microbial habitat of global importance. How microorganisms survive the dry daytime on leaves and avoid desiccation is not well understood. There is evidence that microscopic surface wetness in the form of thin films and micrometer-sized droplets, invisible to the naked eye, persists on leaves during daytime due to deliquescence – the absorption of water until dissolution – of hygroscopic aerosols. Here, we study how such microscopic wetness affects cell survival. We show that, on surfaces drying under moderate humidity, stable microdroplets form around bacterial aggregates due to capillary pinning and deliquescence. Notably, droplet-size increases with aggregate-size, and cell survival is higher the larger the droplet. This phenomenon was observed for 13 bacterial species, two of which – Pseudomonas fluorescens and P. putida – were studied in depth. Microdroplet formation around aggregates is likely key to bacterial survival in a variety of unsaturated microbial habitats, including leaf surfaces.
Global sensitivity analysis of skeletal muscle dMRI metrics: Effects of microstructural and pulse parameters

Estimating microstructural parameters of skeletal muscle from diffusion MRI (dMRI) signal requires understanding the relative importance of both microstructural and dMRI sequence parameters on the signal. This study seeks to determine the sensitivity of dMRI signal to variations in microstructural and dMRI sequence parameters, as well as assess the effect of noise on sensitivity.
Alliance of Efflux Pumps with β-Lactamases in Multidrug-Resistant Klebsiella pneumoniae Isolates

Nosocomial infections caused by Klebsiella pneumoniae are primarily characterized by a high prevalence of extended-spectrum β-lactamases (ESBL's) and a soaring pace of carbapenemase dissemination. Availability of limited antimicrobial agents as a therapeutic option for multidrug-resistant bacteria raises an alarming concern. This study aimed at the molecular characterization of multidrug-resistant K. pneumoniae clinical isolates and studied the role of efflux pumps in β-lactam resistance. Thirty-three isolates confirmed as ESBL-positive K. pneumoniae that harbored resistance genes to major classes of antibiotics. The results showed that CTX-M15 was the preeminent β-lactamase along with carbapenemases in ESBL-positive isolates. However, the efficacy of different antibiotics varied in the presence of lactamase inhibitors and efflux pump inhibitors (EPIs). Those showing increased efficacy of antibiotics with EPI were further explored for the expression of efflux pump genes and expressed a significantly different level of efflux pumps. We found that an isolate had higher expression of kpnF (SMR family) and kdeA (MATE family) pump genes relative to RND family pump genes. No mutations were observed in the genes for porins. Together, the findings suggest that β-lactamases are not the only single factor responsible for providing resistance against the existing β-lactam drugs. Resistance may increase many folds by simultaneous expression of RND family (the most prominent family in Gram-negative bacteria) and other efflux pump family.
Cystine import is a valuable but risky process whose hazards Escherichia coli minimizes by inducing a cysteine exporter

The structure of free cysteine makes it vulnerable to oxidation by molecular oxygen; consequently, organisms that live in oxic habitats have acquired the ability to import cystine as a sulfur source. We show that cystine imported into Escherichia coli can transfer disulfide bonds to cytoplasmic proteins. To minimize this problem, the imported cystine is rapidly reduced. However, this conversion of cystine to cysteine precludes product inhibition of the importer, so cystine import continues into cells that are already sated with cysteine. The burgeoning cysteine pool is itself hazardous, as cysteine promotes the formation of reactive oxygen species, triggers sulfide production and competitively inhibits a key enzyme in the isoleucine biosynthetic pathway. The Lrp transcription factor senses the excess cysteine and induces AlaE, an export protein that pumps cysteine back out of the cell until transcriptional controls succeed in lowering the amount of the importer. While it lasts, the overall phenomenon roughly doubles the NADPH demand of the cell. It comprises another example of the incompatibility of the reduced cytoplasms of microbes with the oxic world in which they dwell. It also reveals one natural source of cytoplasmic disulfide stress and sheds light on a role for broad‐spectrum amino acid exporters.
Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV‐mediated effects of osteotropic breast cancer cells (MDA‐MB‐231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA‐MB‐231 (MDA) cells promoted pro‐osteoclastogenic and pro‐angiogenic effects by osteoblast EVs (OB‐EVs), as well as an increase of RANKL‐positive OB‐EVs. Moreover, when treating osteoblasts with MDA‐EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA‐EVs also reduced transcription of Cyclin D1 and of the osteoblast‐differentiating genes, while enhancing the expression of the pro‐osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA‐EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA‐EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF‐BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA‐EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA‐EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast‐derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research.
Generation of Human‐Induced Pluripotent Stem Cells From Anterior Cruciate Ligament

Human‐induced pluripotent stem cells (hiPSCs) are reprogrammed somatic cells and are an excellent cell source for tissue engineering applications, disease modeling, and for understanding human development. HiPSC lines have now been generated from a diverse range of somatic cell types and have been reported to retain an epigenetic memory of their somatic origin. To date, the reprogramming of a true ligament has not been reported. The aim of this study is to generate iPSCs from human anterior cruciate ligament (ACL) cells. ACL cells from three above‐knee amputation donors, with donor matched dermal fibroblasts (DFs) were tested for reprogramming using an existing DF reprogramming protocol. ACL cells were, however, more sensitive than donor matched DF to transforming growth factor‐β (TGF‐β); displaying marked contraction, increased proliferation and increased TNC and COMP expression in vitro, which hindered reprogramming to iPSCs. Modification of the protocol by scoring the cell monolayer or by removal of TGF‐β during ACL reprogramming resulted in emerging colonies being easier to identify and extract, increasing reprogramming efficiency. Following 30 passages in culture, the generated ACL derived iPSCs displayed pluripotency markers, normal karyotype and can successfully differentiate to cells of the three embryonic germ layers. This study illustrates it is possible to generate hiPSCs from ligament and identifies optimized ligament reprogramming conditions. ACL derived iPSCs may provide a promising cell source for ligament and related tissue engineering applications. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:92–104, 2020
The Effect of CASA on Child Welfare Permanency Outcomes

The present study is the largest and most rigorous study to date on the effects of being appointed a Court Appointed Special Advocate (CASA) on permanency outcomes of children in foster care. The intent-to-treat study accounts for selection bias by applying inverse probability weighting to logistic and sequential logistic regressions in a large sample of children in foster care in the state of Texas (N = 31,754). Overall, children appointed a CASA have significantly lower odds than children without a CASA of achieving permanency. They have lower odds of being reunified, greater odds of being adopted (if not reunified), and lower odds of being placed in permanent kin guardianship (if not reunified or adopted) than children who are not appointed CASA. This study makes an additional contribution by looking beyond the aggregate effect of CASA on permanency by examining the effect of CASA for different age groups and different types of first placement after removal.
Staphylococcus aureus exhibits heterogeneous siderophore production within the vertebrate host

Siderophores, iron-scavenging small molecules, are fundamental to bacterial nutrient metal acquisition and enable pathogens to overcome challenges imposed by nutritional immunity. Multimodal imaging mass spectrometry allows visualization of host−pathogen iron competition, by mapping siderophores within infected tissue. We have observed heterogeneous distributions of Staphylococcus aureus siderophores across infectious foci, challenging the paradigm that the vertebrate host is a uniformly iron-depleted environment to invading microbes.