Miracle-dz/UniFAR-FTUs huggingface dataset:
Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa

Epidermolysis bullosa patient–specific iPSCs were generated from spontaneously corrected revertant keratinocytes for skin reconstitution. “Natural Gene Therapy” for Rare, Genetic Skin Disease Epidermolysis bullosa (EB) is a rare, inherited skin disorder that causes such severe blistering that patients are often relegated to a delicate life in bandages. Like a patchwork quilt, the skin of a patient with EB can consist of both mutated skin cells (which cause the disease) and spontaneously genetically corrected “normal” cells; this patchwork phenomenon is known as revertant mosaicism. In a new study, Umegaki-Arao and colleagues demonstrated that these revertant cells could be used to generate healthy skin, representing a possible cell therapy for patients with EB who have no treatment options. The authors took revertant keratinocytes (skin cells) from a patient with junctional EB, who have mutations in the gene expressing type XVII collagen. These revertant keratinocytes were used to generate induced pluripotent stem cells, which, in turn, could be differentiated into a keratinocyte lineage that created normal-looking skin layers not only in vitro but also in vivo in mice. Because the cells already expressed type XVII collagen, there was no need for genetic correction, thus avoiding many of the pitfalls that gene and cell therapies face during translation to the clinic. Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic gene mutation in a somatic cell. It has been observed in several genetic diseases, including epidermolysis bullosa (EB), a group of inherited skin disorders characterized by blistering and scarring. Induced pluripotent stem cells (iPSCs), generated from fibroblasts or keratinocytes, have been proposed as a treatment for EB. However, this requires genome editing to correct the mutations, and, in gene therapy, efficiency of targeted gene correction and deleterious genomic modifications are still limitations of translation. We demonstrate the generation of iPSCs from revertant keratinocytes of a junctional EB patient with compound heterozygous COL17A1 mutations. These revertant iPSCs were then differentiated into naturally genetically corrected keratinocytes that expressed type XVII collagen (Col17). Gene expression profiling showed a strong correlation between gene expression in revertant iPSC–derived keratinocytes and the original revertant keratinocytes, indicating the successful differentiation of iPSCs into the keratinocyte lineage. Revertant-iPSC keratinocytes were then used to create in vitro three-dimensional skin equivalents and reconstitute human skin in vivo in mice, both of which expressed Col17 in the basal layer. Therefore, revertant keratinocytes may be a viable source of spontaneously gene-corrected cells for developing iPSC-based therapeutic approaches in EB.
Perioperative stress response in the dog: effect of pre-emptive administration of medetomidine.

OBJECTIVE To determine the effect of medetomidine on the stress response induced by ovariohysterectomy in isoflurane-anesthetized dogs. STUDY DESIGN Prospective randomized study. ANIMALS Twelve healthy adult female purpose-bred dogs, weighing 16.8 to 25 kg. METHODS Two treatments were randomly administered to each of twelve dogs at weekly intervals: (1) Saline injected IM followed in 15 minutes by isoflurane anesthesia (ISO) induced by mask and maintained at an end-tidal concentration of 1.8% for 60 minutes; and (2) Medetomidine, 15 ug/lkg IM followed in 15 minutes by isoflurane anesthesia (ISO&MED) induced by mask and maintained at an end-tidal concentration of 1.0% for 60 minutes. One week after completion of these two treatments, all dogs were ovariohysterectomized. six receiving each treatment (SURG and SURG&MED). Central venous blood samples (10 mL) were obtained immediately before medetomidine or saline (baseline) and at 30, 75, and 195 minutes and 24 hours after administration of medetomidine or saline in ISO and ISO&MED. In SURG and SURG&MED, samples were obtained immediately prior to injection of medetomidine or saline (baseline) and at 30 (before skin incision), 45 (after severence of the ovarian ligament), 75 (after skin closure), 105 (30 minutes after skin closure, dog recovered and in sternal recumbency), 135, 195, 375 minutes, and 24 hours after the initial sample. Samples were analyzed for epinephrine, norepinephrine, adrenocorticotrophic hormone (ACTH), cortisol, insulin, and glucose. Data were analyzed by analysis of variance and where significant differences were found, a least significant difference test was applied. RESULTS Premedication with medetomidine prevented or delayed the stress response induced by ovariohysterectomy in isoflurane-anesthetized dogs. CONCLUSIONS The stress response induced by ovariohysterectomy, although significant, is of short duration. Medetomidine safely and effectively reduced surgically-induced stress responses. CLINICAL RELEVANCE Surgically induced stress responses can be obtunded or prevented by administration of medetomidine.
Erythropoietin Withdrawal Alters Interactions Between Young Red Blood Cells, Splenic Endothelial Cells, and Macrophages

Background We have described the rapid destruction of young red blood cells (neocytolysis) in astronauts adapting to microgravity, in polycythemic high altitude dwellers who descend to sea level, and in patients with kidney disorders. This destruction results from a decrease in erythropoietin (EPO) production. We hypothesized that such EPO withdrawal could trigger physiological changes in cells other than red cell precursors and possibly lead to the uptake and destruction of young red cells by altering endothelial cell-macrophage interactions, most likely occurring in the spleen. Methods We identified EPO receptors on human splenic endothelial cells (HSEC) and investigated the responses of these cells to EPO withdrawal. Results A monolayer of HSEC, unlike human endothelial cells from aorta, glomerulus, or umbilical vein, demonstrated an increase in permeability upon EPO withdrawal that was accompanied by unique morphological changes. When HSEC were cultured with monocyte-derived macrophages (but not when either cell type was cultured alone), EPO withdrawal induced an increased ingestion of young red cells by macrophages when compared with the constant presence or absence of EPO. Conclusions HSEC may represent a unique cell type that is able to respond to EPO withdrawal by increasing permeability and interacting with phagocytic macrophages, which leads to neocytolysis.
Outcomes of Patients Discharged to Skilled Nursing Facilities After Acute Care Hospitalizations

Objectives:To evaluate previously independent older patients discharged to skilled nursing facilities (SNFs) and identify risk factors for failure to return home and death and development of a predictive tool to determine likelihood of adverse outcome. Background:Little is known about the likelihood of return to home, and higher than expected mortality rates in SNFs have recently been described, which may represent an opportunity for quality improvement. Methods:Retrospective cohort of older hospitalized patients discharged to SNFs during 2007 to 2009 in 5 states using Centers for Medicare & Medicaid Services linked minimum data set data from SNFs. We assessed mortality, hospital readmission, discharge to home, and logistic regression models for predicting risk of each outcome. Results:Of 416,997 patients, 3.8% died during the initial SNF stay, 28.6% required readmission, and 60.5% were ultimately discharged home. Readmission to a hospital was the strongest predictor of death in the years after SNF admission (unadjusted hazard ratio, 28.2; 95% confidence interval, 27.2–29.3; P < 0.001). Among all patients discharged to SNFs, 7.8% eventually died in an SNF and overall 1-year mortality was 26.1%. Risk factors associated with mortality and failure to return home were increasing age, male sex, increasing comorbidities, decreased cognitive function, decreased functional status, parenteral nutrition, and pressure ulcers. Conclusions:A large proportion of older patients discharging to SNFs never return home. A better understanding of the natural history of patients sent to SNFs after hospitalization and risk factors for failure to return to home, readmission, and death should help identify opportunities for interventions to improved outcome.
Application of MM/PBSA colony free energy to loop decoy discrimination: Toward correlation between energy and root mean square deviation

Accurate free energy estimation is needed in many predictive tasks. The molecular mechanics/Poisson‐Boltzmann solvent accessible surface area (MM/PBSA) approach has proven to be accurate. However, the correlation between the estimated free energy and the distance (e.g., root mean square deviation [RMSD]) from the most stable conformation is hindered by the strong free energy dependence on minor conformational variations. In this paper, a protocol for MM/PBSA free energy estimation is designed and tested on several loop decoy sets. We show that further integration of MM/PBSA free energy estimator with the colony energy approach makes the correlation between the free energy and RMSD from the native structure apparent, for the test sets on which it could be applied. Our results suggest that (1) the MM/PBSA free energy estimator is able to detect native‐like structures for most decoy sets, and (2) application of the colony energy approach greatly hampers the MM/energy strong dependence on minor conformational changes.
Autoradiographic localization of cholecystokinin receptors in rodent brain

Cholecystokinin (CCK) receptor binding sites have been localized by autoradiography in the guinea pig and rat central nervous system. [125I]CCK-triacontatriapeptide labeled the sites in brain slices with an observed association constant equal to 0.041 min-1 and a dissociation constant equal to 0.008 min-1. CCK-triacontatriapeptide (CCK-33) and the C-terminal octapeptide of CCK-33 (CCK-8) potently inhibited [125I]CCK-33 binding with Ki's of 2 nM, whereas desulfated CCK-8 (CCK8-ds) and the C-terminal tetrapeptide of CCK-33 (CCK-4) were much weaker. Receptors were concentrated in the olfactory bulb, in the superficial laminae of the primary olfactory cortex, in the deep laminae of the cerebral cortex, and in the pretectal area. Substantial numbers of sites were also found in the basal ganglia, in the amygdala, and in the hippocampal formation. [125I]CCK-33 binding sites appear to be located on fibers of the optic tract and probably on olfactory tract fibers as well. These results are discussed in terms of physiological functions associated with CCK, presynaptic receptors, and axonal flow of CCK receptors.
Sca‐1 is negatively regulated by TGF‐βlin myogenic cells

Sca‐1 (stem cell antigen‐1) is a member of the Ly‐6 family of proteins and regulates cell proliferation, differentiation, and self‐renewal in multiple tissues. In skeletal muscle, Sca‐1 inhibits both proliferation and differentiation of myogenic cells. Sca‐1 expression is dynamically regulated during muscle regeneration, and mice lacking Sca‐1 display increased fibrosis following muscle injury. Here, we show that Sca‐1 expression is negatively regulated by TGF‐β1 and that this inhibition is dependent on Smad3. We demonstrate that levels of TGF‐β1 in skeletal muscle rapidly increase on injury and that the majority of this TGFβ1 is produced by infiltrating macrophages. Sca‐1 is expressed in multiple cell types, and we demonstrate that TGF‐β1 represses Sca‐1 expression in T cells and other immune cell populations derived from the spleen, indicating that regulation byTGF‐β1 is a general feature of Sca‐1 expression in multiple cell types. Elucidation of the mechanisms by which Sca‐1 expression is regulated may aid in the understanding of muscle homeostasis, potentially identifying novel therapeutic targets for muscle diseases. —Long, K. , Montano, M. , Pavlath, G. K. Sca‐1 is negatively regulated by TGF‐β1 in myogenic cells. FASEB J. 25, 1156–1165 (2011). www.fasebj. org
Implications of Streptococcus pneumoniae Penicillin Resistance and Serotype Distribution in Kuwait for Disease Treatment and Prevention

ABSTRACT Streptococcus pneumoniae causes serious infections. Treatment is difficult because of the emergence of penicillin resistance in S. pneumoniae. Pneumococcal vaccines offer the promise of control and prevention of pneumococcal infections. Serotype prevalence and penicillin susceptibility data for a country will predict the usefulness of the vaccines in that country. In Kuwait, the 23-valent polysaccharide and the 7-valent conjugate vaccines are being used without knowledge of the prevalent serotypes in the country. To obtain the necessary background information, data on penicillin susceptibility and serogroups were obtained from 397 consecutive clinical isolates collected during 2004 and 2005. Two hundred fifty-three isolates (64%) were penicillin resistant, and resistance was significantly higher in patients ≤15 years old and among the upper respiratory tract and eye isolates. The most common serotypes were 23F, 19F, 6A, 6B, 14, and 19A. Among the penicillin-resistant strains, the most common serotypes were 23F, 19F, 6B, 14, and 9A. Among the invasive strains, the most common serotypes were 14, 23F, 19A, and 9V. The polysaccharide vaccine gave 82% coverage against invasive infections in all age groups >2 years. The coverage of the 7-valent conjugate vaccine against invasive serotypes in children ≤2 years old was 55%. This moderate coverage by the conjugate vaccine against invasive infections in children necessitates a revised strategy on the use of the present conjugate vaccine and shows the need for formulation of an improved vaccine for superior coverage for Kuwait and possibly other countries of the Arabian Gulf.
Inheritance of extrachromosomal rDNA in Physarum polycephalum

In the acellular slime mold Physarum polycephalum, the several hundred genes coding for rRNA are located on linear extrachromosomal DNA molecules of a discrete size, 60 kilobases. Each molecule contains two genes that are arranged in a palindromic fashion and separated by a central spacer region. We investigated how rDNA is inherited after meiosis. Two Physarum amoebal strains, each with an rDNA recognizable by its restriction endonuclease cleavage pattern, were mated, the resulting diploid plasmodium was induced to sporulate, and haploid progeny clones were isolated from the germinated spores. The type of rDNA in each was analyzed by blotting hybridization, with cloned rDNA sequences used as probes. This analysis showed that rDNA was inherited in an all-or-nothing fashion; that is, progeny clones contained one or the other parental rDNA type, but not both. However, the rDNA did not segregate in a simple Mendelian way; one rDNA type was inherited more frequently than the other. The same rDNA type was also in excess in the diploid plasmodium before meiosis, and the relative proportions of the two rDNAs changed after continued plasmodial growth. The proportion of the two rDNA types in the population of progeny clones reflected the proportion in the parent plasmodium before meoisis. The rDNAs in many of the progeny clones contained specific deletions of some of the inverted repeat sequences at the central palindromic symmetry axis. To explain the pattern of inheritance of Physarum rDNA, we postulate that a single copy of rDNA is inserted into each spore or is selectively replicated after meiosis.
A Pilot Study to Examine the Feasibility and Potential Effectiveness of Using Smartphones to Provide Recovery Support for Adolescents

Background Smartphone applications can potentially provide recovery monitoring and support in real-time, real-life contexts. Study aims included determining feasibility of (a) adolescents completing ecological momentary assessments (EMAs) and utilizing phone-based ecological momentary interventions (EMIs); and (b) using EMA and EMI data to predict substance use in the subsequent week. Methods Twenty-nine adolescents were recruited at discharge from residential treatment, regardless of their discharge status or length of stay. During the 6-week pilot, youth were prompted to complete an EMA at 6 random times per day and were provided access to a suite of recovery support EMI. Youth completed 87% of the 5580 EMAs. Based on use in the next 7 days, EMA observations were classified into 3 risk groups: “Current Use” in the past 30 minutes (3% of observations), “Unrecognized Risk” (42%), or “Recognized Risk” (55%). All youth had observations in 2 or more risk groups and 38% in all 3. Youth accessed an EMI on average 162 times each week. Results Participants were 31% female, 48% African American, 21% Caucasian, 7% Hispanic, and 24% Mixed/Other; average age was 16.6 years. During the 90 days prior to entering treatment, youth reported using alcohol (38%), marijuana (41%), and other drugs (7%). When compared with the “Recognized Risk” group's use in the following week (31%), both the “Unrecognized Risk” (50%, odds ratio [OR] = 2.08) and “Current Use” (96%, OR = 50.30) groups reported significantly higher rates of use in the next week. When an EMI was accessed 2 or more times within the hour following an EMA, the rate of using during the next week was significantly lower than when EMIs were not accessed (32% vs. 43%, OR = 0.62). Conclusions Results demonstrate the feasibility of using smartphones for recovery monitoring and support with adolescents, with potential to reduce use.
Gene expression of amino acid transporter in pigeon (Columbia livia) intestine during post‐hatch development and its correlation with amino acid in pigeon milk

&NA; This study was conducted to evaluate gene expression of the amino acid transporter in post‐hatch pigeon small intestine and the association of pigeon milk amino acid with the above transporter's gene expression. A total of 48 pigeon breeding families were randomly allocated to 8 groups of 6 replicates of one parental pigeon pair and 2 squabs. Samples of pigeon milk and duodenum, jejunum, and ileum were collected on d 1, 2, 3, 4, 6, 8, 10, and 14 post hatch. The results showed that levels of crude protein (8.93 to 15.56%) were highest in pigeon milk on an air‐dry basis. Amino acid content in pigeon milk remained constant in the first 4 d, declined abruptly at d 6, then increased dramatically from d 8 to 14. There was a significant effect of interaction between age and intestinal segments on those amino acid transporters gene expression. mRNA abundance of ATB0'+, SNAT‐2, LAT‐4, rBAT, b0'+AT, EAAT‐3 and PAT‐1 was highest in the ileum; B0AT1, asc‐1, and IMINO were predominate in the jejunum; and CAT‐1 and y+LAT2 were greatest in the duodenum. Age‐related changes of amino acid transporter mRNA was inconsistent. mRNA levels of SNAT‐2, rBAT, y+LAT2, b0'+AT, and EAAT‐3 ascended with age, whereas that of asc‐1, CAT‐1, and IMINO diminished significantly. Levels of B0AT1 and PAT‐1 mRNA abundance were minimized at d 6. However, few correlations were found between pigeon milk amino acid and the amino acid transporter gene expressions in squab small intestine. Our findings provide a comprehensive elaboration on ontogeny of the amino acid transporter in post‐hatch pigeon intestine.
[Neuropsychological update on obsessive-compulsive disorder].

INTRODUCTION The most recent neuroscientific studies have provided evidence about the existence of structural and functional abnormalities in fronto-estriatal circuits among patients with obsessive-compulsive disorder (OCD). Those abnormalities have also been proposed as the explanation for cognitive deficits and clinical symptoms of patients with OCD. In this paper we present a review of studies that have examined the neurocognitive functioning (attention, memory and executive functions) of patients with OCD. DEVELOPMENT Studies show mixed results in terms of selective attention and processing speed. With regards to executive functions, patients with OCD display deficit to change the focus of attention, problems in response inhibition and difficulties to generate planning strategies. Studies assessing memory indicate that these patients present an evident deficiency in non-verbal memory, while is not so clear in verbal memory. This memory deficit seems to be related to the lack in the use of effective strategies, the need for excessive testing and the appearance of the doubt. CONCLUSIONS The vast heterogeneity of the disorder and the limitations of some studies, which do not control the influence of variables such as comorbidity and medication, do not allow more definitive conclusions. Anyway, executive functions deficit seems to be the more consistent neuropsychological deficit in OCD. Future studies should focus on the control of extraneous variables, as well as on the relationship between the cognitive processes and symptoms of OCD.
A Data Streaming Algorithm for Detection of Superpoints With Small Memory Consumption

A superpoint is a host that communicates with a large number of distinct destinations (sources) within a measurement period. Identifying superpoints is an important and meaningful task for network security and monitoring. To keep up with the line speed in a high-speed network, fast memory is indispensable for detecting superpoints. Moreover, the memory is also expensive and size-limited. In this letter, we propose a new data streaming algorithm for detecting superpoints, called Snare, which can work in tight memory space and yield good performance. Its accuracy and efficiency come from a new data structure snare and the compensation mechanism for the number of lost flows. Theoretical analysis and experimental results show that Snare can detect superpoints accurately and efficiently.
Genomic divergence between the migratory and stationary ecotypes of Atlantic cod

Atlantic cod displays a range of phenotypic and genotypic variations, which includes the differentiation into coastal stationary and offshore migratory types of cod that co‐occur in several parts of its distribution range and are often sympatric on the spawning grounds. Differentiation of these ecotypes may involve both historical separation and adaptation to ecologically distinct environments, the genetic basis of which is now beginning to be unravelled. Genomic analyses based on recent sequencing advances are able to document genomic divergence in more detail and may facilitate the exploration of causes and consequences of genome‐wide patterns. We examined genomic divergence between the stationary and migratory types of cod in the Northeast Atlantic, using next‐generation sequencing of pooled DNA from each of two population samples. Sequence data was mapped to the published cod genome sequence, arranged in more than 6000 scaffolds (611 Mb). We identified 25 divergent scaffolds (26 Mb) with a higher than average gene density, against a backdrop of overall moderate genomic differentiation. Previous findings of localized genomic divergence in three linkage groups were confirmed, including a large (15 Mb) genomic region, which seems to be uniquely involved in the divergence of migratory and stationary cod. The results of the pooled sequencing approach support and extend recent findings based on single‐nucleotide polymorphism markers and suggest a high degree of reproductive isolation between stationary and migratory cod in the North‐east Atlantic.