Miracle-dz/UniFAR-FTUs huggingface dataset:
Focal Energy Deprivation Underlies Arrhythmia Susceptibility in Mice With Calcium-Sensitized Myofilaments

Rationale: The Ca2+ sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca2+ sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown. Objective: To investigate how myofilament Ca2+ sensitization creates reentrant arrhythmia susceptibility. Methods and Results: Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca2+ sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca2+ sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca2+-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca2+ desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias. Conclusions: Myofilament Ca2+ sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca2+ sensitivity.
Stochastic resonance induced by exogenous noise in a model of a neuronal network

This study investigates the possibility of using exogenous noise to restore the processing performances of neuronal systems where the endogenous noise is reduced due to the ageing or to degenerative diseases. This idea is based on the assumption, supported by theoretical studies, that the endogenous noise has a positive role in neuronal signal detection and that its reduction impairs the system function. Results, obtained on a two-layers feedforward network, show the onset of the Stochastic Resonance (SR) behavior, as long as the exogenous noise is properly tailored and filtered. The amount of noise to be furnished from the outside to optimize the system performance depends on the residual level of endogenous noise, indicating that both kinds of noise cooperate to the signal detection. These results support potentially new bioengineering applications where exogenous noise is furnished to enhance signal detectability.
Anaesthesia for oncological surgery – can it really influence cancer recurrence?

Surgical resection is the mainstay of treatment for most solid malignancies. Given the high incidence of cancer recurrence in postoperative patients [1], the influence of perioperative factors, including anaesthetic techniques, on residual tumour cell survival and ‘metastatic potential’-phenotypic characteristics that govern whether these cells go on to cause cancer recurrence and metastasis postoperatively, is an area of intense research [2–4]. Although controversial, mounting retrospective and preclinical data have implicated inhalational anaesthesia and opioid analgesia as independent risk factors for disease recurrence and, conversely, local-regional anaesthesia and propofol-based total intravenous anaesthesia as having potential ‘chemopreventative’ effects.
How patterned neural connections can be set up by self-organization

An important problem in biology is to explain how patterned neural connections are set up during ontogenesis. Topographically ordered mappings, found widely in nervous systems, are those in which neighbouring elements in one sheet of cells project to neighbouring elements in a second sheet. Exploiting this neighbourhood property leads to a new theory for the establishment of topographical mappings, in which the distance between two cells is expressed in terms of their similarity with respect to certain physical properties assigned to them. This topographical code can be realized in a model employing either synchronization of nervous activity or exchange of specific molecules between neighbouring cells. By means of modifiable synapses the code is used to set up a topographical mapping between two sheets with the same internal structure. We have investigated the neural activity version. Without needing to make any elaborate assumptions about its structure or about the operations its elements are to carry out we have shown that the mappings are set up in a system-to-system rather than a cell-to-cell fashion. The pattern of connections develops in a step-by-step and orderly fashion, the orientation of the mappings being laid down in the earliest stages of development.
Prevalence of Pulmonary Embolism in Patients With Suspected Cardioembolic Ischemic Stroke

Purpose Venous thromboemboli can cause both pulmonary embolism (PE) and paradoxical embolism in the presence of a cardiac right-to-left shunt. Our aim was to prospectively assess the prevalence of PE in patients with ischemic stroke with suspected cardiogenic etiology and thereby to clarify the possible role of paradoxical embolism as a cause of ischemic stroke. Materials and Methods Consecutive patients with suspected cardiogenic ischemic stroke (n=113, male/female=76/37, mean age 62±11 y) underwent computed tomography angiography of the pulmonary arteries to assess for the presence of PE as an adjunct to routine computed tomography angiography of the cervicocranial arteries. Transthoracic and transesophageal echocardiography were used to evaluate for patent foramen ovale (PFO) and cardiac defects. Results PE was found in 4 patients (3.5%). Only 1 patient with PE had symptoms or signs suggestive of PE. None of the patients with PE had intracardiac defects or PFO. In the entire study population, atrial septal defect was detected in 5 (4%) patients and PFO in 13 (12%) patients. Conclusions The prevalence of PE in patients with ischemic stroke with suspected cardiogenic etiology is low. This study does not support a significant association between PE and cardiogenic ischemic stroke.
Boosting Antimicrobial Peptides by Hydrophobic Oligopeptide End Tags*

A novel approach for boosting antimicrobial peptides through end tagging with hydrophobic oligopeptide stretches is demonstrated. Focusing on two peptides derived from kininogen, GKHKNKGKKNGKHNGWK (GKH17) and HKHGHGHGKHKNKGKKN (HKH17), tagging resulted in enhanced killing of Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli, and fungal Candida albicans. Microbicidal potency increased with tag length, also in plasma, and was larger for Trp and Phe stretches than for aliphatic ones. The enhanced microbicidal effects correlated to a higher degree of bacterial wall rupture. Analogously, tagging promoted peptide binding to model phospholipid membranes and liposome rupture, particularly for anionic and cholesterol-void membranes. Tagged peptides displayed low toxicity, particularly in the presence of serum, and resisted degradation by human leukocyte elastase and by staphylococcal aureolysin and V8 proteinase. The biological relevance of these findings was demonstrated ex vivo and in vivo in porcine S. aureus skin infection models. The generality of end tagging for facile boosting of antimicrobial peptides without the need for post-synthesis modification was also demonstrated.
Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.

IMPORTANCE A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). INTERVENTIONS Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. MAIN OUTCOMES AND MEASURES Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. RESULTS Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab. CONCLUSIONS AND RELEVANCE Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (≥2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00045032.
Assembling the 20 Gb white spruce (Picea glauca) genome from whole-genome shotgun sequencing data

White spruce (Picea glauca) is a dominant conifer of the boreal forests of North America, and providing genomics resources for this commercially valuable tree will help improve forest management and conservation efforts. Sequencing and assembling the large and highly repetitive spruce genome though pushes the boundaries of the current technology. Here, we describe a whole-genome shotgun sequencing strategy using two Illumina sequencing platforms and an assembly approach using the ABySS software. We report a 20.8 giga base pairs draft genome in 4.9 million scaffolds, with a scaffold N50 of 20 356 bp. We demonstrate how recent improvements in the sequencing technology, especially increasing read lengths and paired end reads from longer fragments have a major impact on the assembly contiguity. We also note that scalable bioinformatics tools are instrumental in providing rapid draft assemblies. Availability: The Picea glauca genome sequencing and assembly data are available through NCBI (Accession#: ALWZ0100000000 PID: PRJNA83435). http://www.ncbi. nlm.nih. gov/bioproject/83435. Contact: ibirol@bcgsc.ca Supplementary information: Supplementary data are available at Bioinformatics online.
miR‐21 expression is related to particle‐induced osteolysis pathogenesis

Previous studies have found that microRNA‐21 (miR‐21) is an important functional factor during osteoclast differentiation. Abnormal osteoclastogenesis induced by wear particles is the main cause of aseptic loosening in joint replacements. The aim of the present study is to investigate the possible role of miR‐21 in the pathogenesis of particle‐induced osteolysis (PIO). miR‐21 expression was examined in a PIO mouse model using real‐time (RT‐PCR). Osteoclastogenesis was determined by a tartrate resistant acid phosphatase (TRAP) quantification method. A toluidine blue staining assay was used to examine calvarial osteolysis. The results demonstrated that miR‐21 was significantly upregulated in the PIO animal model. Knocking out miR‐21 in the particle‐stimulated tissue could ameliorate osteolysis symptoms. Additionally, through our analysis of PDCD4 and AP‐1 expression, we suggest that the feedback loop of AP‐1, miR‐21, and PDCD4 might have an important influence on the development of PIO and that miR‐21 is a potential target for implant loosening therapies. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1837–1842, 2012
Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis.

UNLABELLED Postoperative nausea and vomiting are important causes of morbidity after anesthesia and surgery. We performed a meta-analysis of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for the prevention of postoperative nausea and vomiting. We performed a literature search of English references using both the MEDLINE database and a manual search. Double-blinded, randomized, controlled trials comparing the efficiency of the prophylactic administration of ondansetron, droperidol, and/or metoclopramide therapy during general anesthesia were included. A total of 58 studies were identified, of which 4 were excluded for methodological concerns. For each comparison of drugs, a pooled odds ratio (OR) with a 95% CI was calculated using a random effects model. Ondansetron (pooled OR 0.43, 95% CI 0.31, 0.61; P < 0.001) and droperidol (pooled OR 0.68, 95% CI 0.54, 0.85; P < 0.001) were more effective than metoclopramide in preventing vomiting. Ondansetron was more effective than droperidol in preventing vomiting in children (pooled OR 0.49; P = 0.004), but they were equally effective in adults (pooled OR 0.87; P = 0.45). The overall risk of adverse effects was not different among drug combinations. We conclude that ondansetron and droperidol are more effective than metoclopramide in reducing postoperative vomiting. IMPLICATIONS We performed a systematic review of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting. Ondansetron and droperidol were more effective than metoclopramide in reducing postoperative vomiting. The overall risk of adverse effects did not differ.
Evaluation of protective effect of a water-in-oil microemulsion incorporating quercetin against UVB-induced damage in hairless mice skin.

PURPOSE In the present study, histological aspects were considered in order to evaluate the in vivo photoprotective effect of a w/o microemulsion containing quercetin against UVB irradiation-induced dermal damages. The toxicity in cell culture and the potential skin irritation resulting from topical application of this formulation were also investigated. METHODS Mouse dorsal surfaces were treated topically with 300 mg of the unloaded and quercetin-loaded (0.3%, w/w) microemulsions before and after exposure to UVB (2.87 J/cm2) irradiation. The untreated control groups irradiated and non-irradiated were also evaluated. UVB-induced histopathological changes as well as the photoprotective effect of this formulation were evaluated considering the parameters of infiltration of inflammatory cells, epidermis thickening (basale and spinosum layers) and collagen and elastic fiber contents. The cytotoxicity of the reported formulation was evaluated in L929 mice fibroblasts by MTT assay and the skin irritation was investigated after topical application of both unloaded and quercetin-loaded microemulsions once a day for 15 days. RESULTS The results demonstrated that the w/o microemulsion containing quercetin reduced the incidence of histological skin alterations, mainly the connective-tissue damage, induced by exposure to UVB irradiation, this allows the suggestion that protective effects of this formulation against UV-induced responses are not secondary to the interference of UV transmission (i.e., blocking the UVB radiation from being absorbed by the skin), as is usually done with UVB absorbers and sunscreens, but is instead due to different biological effects of this flavonoid. Furthermore, by evaluating the cytotoxic effect on L929 cells and histological aspects such as infiltration of inflammatory cells and epidermis thickness of hairless mice, the present study also demonstrated no toxicity of the proposed system. CONCLUSIONS Therefore, based on these mouse models, a detailed characterization of the w/o microemulsion incorporating quercetin effects as a photochemoprotective agent on human skin is thus indicated.
Dipicolinic Acid Synthesis in Penicillium citreo-viride

Hodson, Phillip H. (University of Texas, Austin), and J. W. Foster. Dipicolinic acid synthesis in Penicillium citreo-viride. J. Bacteriol. 91:562–569. 1966. —Dipicolinic acid (DPA) accumulation in culture filtrates of the mold Penicillium citreo-viride was studied in surface and submerged cultures. Good DPA yields were obtained in suspensions of washed, submerged mycelium in the presence of a carbon and a nitrogen source but in the absence of other minerals essential for growth. Fumaric acid was the only other acid formed in significant amounts. Glucose and glycerol were superior to various salts of organic acids as carbon sources, and certain amino acids were excellent nitrogen sources. l-Leucine, l-norvaline, l-tyrosine, and l-histidine were superior to urea, NH4Cl, or NaNO3 as nitrogen precursors for DPA production. d-Norvaline was useless for DPA production. Glycerol-2-C14 and -1-C14, C14O2, and l-leucine-C14, l-tyrosine-C14, and l-histidine-C14 were tested as precursors in conjunction with suitable carbon and nitrogen sources. The DPA was decarboxylated chemically, and the distribution of C14 was determined in the pyridine-C and in the carboxyl-C. The data are consistent with Martin and Foster's suggestion for bacteria that the DPA molecule is formed by a condensation of C3 plus C4 precursors, the resulting 2-keto, 6-aminopimelic acid derivate undergoing ring closure to form a heterocyclic precursor of DPA. The C14O2 experiments indicate that oxaloacetate is formed by β-carboxylation of pyruvate, this in turn probably becoming aspartic acid β-semialdehyde, the C4 compound which condenses with a second pyruvate. The enhancement of DPA formation by l-norvaline, l-leucine, and l-histidine is not ascribable to their functioning either as a source of nitrogen or carbon. l-Tyrosine, in a glycerol medium, contributed nearly 40% of the DPA carbon. The mechanism of biosynthesis of C7 straight-chain and cyclic compounds is discussed.
Estimating Leaf Area Index in Southeast Alaska: A Comparison of Two Techniques

The relationship between canopy structure and light transmission to the forest floor is of particular interest for studying the effects of succession, timber harvest, and silviculture prescriptions on understory plants and trees. Indirect measurements of leaf area index (LAI) estimated using gap fraction analysis with linear and hemispheric sensors have been commonly used to assess radiation interception by the canopy, although the two methods often yield inconsistent results. We compared simultaneously obtained measurements of LAI from a linear ceptometer and digital hemispheric photography in 21 forest stands on Prince of Wales Island, Alaska. We assessed the relationship between these estimates and allometric LAI based on tree diameter at breast height (LAIDBH). LAI values measured at 79 stations in thinned, un-thinned controls, old-growth and clearcut stands were highly correlated between the linear sensor (AccuPAR) and hemispheric photography, but the latter was more negatively biased compared to LAIDBH. In contrast, AccuPAR values were more similar to LAIDBH in all stands with basal area less than 30 m2ha−1. Values produced by integrating hemispheric photographs over the zenith angles 0–75° (Ring 5) were highly correlated with those integrated over the zenith angles 0–60° (Ring 4), although the discrepancies between the two measures were significant. On average, the AccuPAR estimates were 53% higher than those derived from Ring 5, with most of the differences in closed canopy stands (unthinned controls and old-growth) and less so in clearcuts. Following typical patterns of canopy closure, AccuPAR LAI values were higher in dense control stands than in old-growth, whereas the opposite was derived from Ring 5 analyses. Based on our results we advocate the preferential use of linear sensors where canopy openness is low, canopies are tall, and leaf distributions are clumped and angles are variable, as is common in the conifer forests of coastal Alaska.
Stable polymers of the axonal cytoskeleton: the axoplasmic ghost

We have examined the monomer-polymer equilibria which form the cytoskeletal polymers in squid axoplasm by extracting protein at low concentrations of monomer. The solution conditions inside the axon were matched as closely as possible by the extraction buffer (buffer P) to preserve the types of protein associations that occur in axoplasm. Upon extraction in buffer P, all of the neurofilament proteins in axoplasm remain polymerized as part of the stable neurofilament network. In contrast, most of the polymerized tubulin and actin in axoplasm is soluble although a fraction of these proteins also exists as a stable polymer. Thus, the axoplasmic cytoskeleton contains both stable polymers and soluble polymers. We propose that stable polymers, such as neurofilaments, conserve cytoskeletal organization because they tend to remain polymerized, whereas soluble polymers increase the plasticity of the cytoskeleton because they permit rapid and reversible changes in cytoskeletal organization.
The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose

Treatment of hypotension caused by calcium channel blocker overdose (CCB) remains a challenge. We describe the successful use of vasopressin in two patients with massive CCB overdoses in whom hypotension was unresponsive to calcium, glucagon, insulin, and conventional vasopressor therapies. While various modes of treatments have been used to treat the hypotension of CCB overdose, this is the first report to our knowledge of the successful use of vasopressin in this clinical setting.