Miracle-dz/UniFAR-FTUs huggingface dataset:
Protective effect of a caspase inhibitor in models for cerebral ischemia in vitro and in vivo.

In primary neuronal-astrocyte cultures from mouse brain, ischemic conditions were simulated by combined oxygen-glucose deprival (OGD) for 2 hrs. This treatment resulted in near complete neuronal damage 24 hrs. later and was accompanied by DNA degradation and apoptotic nuclear morphology. Since caspases are key enzymes in the propagation and execution of programmed cell death, we evaluated the effect of the caspase inhibitor z-VAD-fmk. Damage following 2 hrs. OGD could be reduced by up to 56% with z-VAD-fmk (p<0.05). DNA-fragmentation and caspase activation has been also reported in an in vivo model of cerebral ischemia imitating human stroke. In this model the middle cerebral artery (MCA) is permanently occluded resulting in focal cerebral ischemia and subsequent infarction. Since z-VAD.fmk does not penetrate the blood-brain barrier it was applied intraventricularly as a bolus injection given 30 min. before MCA occlusion which was followed by 24 hrs. of infusion. Infarct volume was determined 48 hrs. after MCA occlusion by means of in vivo magnetic resonance imaging. Z-VAD.fmk dose dependently reduced infarct volume reaching a significant decrease of the cortical infarct by 45% when given as a 120 ng bolus followed by 40 ng/hr. infusion (p<0.05). In summary, our study supports the concept that caspase inhibitors are beneficial in brain ischemia.
Cranial mechanics and feeding in Tyrannosaurus rex

It has been suggested that the large theropod dinosaur Tyrannosaurus rex was capable of producing extremely powerful bite forces and resisting multi–directional loading generated during feeding. Contrary to this suggestion is the observation that the cranium is composed of often loosely articulated facial bones, although these bones may have performed a shock–absorption role. The structural analysis technique finite element analysis (FEA) is employed here to investigate the functional morphology and cranial mechanics of the T. rex skull. In particular, I test whether the skull is optimized for the resistance of large bi–directional feeding loads, whether mobile joints are adapted for the localized resistance of feeding–induced stress and strain, and whether mobile joints act to weaken or strengthen the skull overall. The results demonstrate that the cranium is equally adapted to resist biting or tearing forces and therefore the‘puncture–pul’ feeding hypothesis is well supported. Finite–element–generated stress–strain patterns are consistent with T. rex cranial morphology: the maxilla–jugal suture provides a tensile shock–absorbing function that reduces localized tension yet ‘weakens’ the skull overall. Furthermore, peak compressive and shear stresses localize in the nasals rather than the fronto–parietal region as seen in Allosaurus, offering a reason why robusticity is commonplace in tyrannosaurid nasals.
Biology and treatment of the 5q- syndrome

The 5q- syndrome is a unique subtype of myelodysplastic syndromes typified by a relatively indolent course and responsiveness to lenalidomide. Here, we review the salient biologic features of this disease. Hemizygous deletion of a segment of chromosome 5q is believed to be the disease-initiating event. Recent molecular techniques have isolated the common deleted region and characterized key candidate genes contributing to the disease phenotype. Gene-specific RNA interference strategies revealed that haplo-insufficiency for the RPS14 gene, which encodes a ribosomal protein, is a critical effector of the p53-dependent erythroid hypoplasia and apoptotic loss of erythroid precursors. Disease-specific sensitivity to lenalidomide results from the drug’s inhibitory effect on two haplodeficient phosphatases, PP2Acα and CDC25c, which are coregulators of the G2/M checkpoint. Hyperphosphorylation of MDM2, as a result of inhibition of PP2A phosphatase activity, stabilizes MDM2, permitting p53 degradation and transition to G2 arrest and clonal suppression. With the emerging data elucidating the pathogenesis of the 5q- syndrome and the success of clinical trials, a cohesive story connecting the biology and pharmacology associated with this subtype of myelodysplastic syndromes has emerged.
Self Injurious Behavior in Adolescent Girls with Eating Disorders

Self-injurious behaviour (SIB), repetitive intentional hurting, bruising, cutting, burning, selfpoisoning etc. with the intent to cause pain and tissue damage, is observed as comorbid condition in various psychiatric disorders. SIB is frequently but not exclusively encountered in patients with borderline personality, posttraumatic stress, and eating disorders, but it may also occur in otherwise “healthy” persons, and it may be “learned” from peers, especially in the hospital environment (Ohmann et al., 2008). SIB aims at instantaneously reducing inner tensions resulting from anxiety, depression, stress, self-discontentedness etc., at (re)gaining self-control and escaping from numbness and dissociative states, it may serve to fulfil wishes for self-punishment, and there may (rarely) be appellative aspects alerting other people about ones poor psychical state (Favaro & Santonastaso, 1999). SIB is socially not well accepted and must be differentiated from occasional or psychotic self-mutilation and socially accepted habits like piercing and tattooing. SIB does not necessarily imply death wishes (Simeon et al., 1995) and has clearly to be differentiated from (attempted) suicide or parasuicidal gestures (Eberly, 2005). The relationship between SIB and suicidal behaviour is, however, complex.
High‐solids biphasic CO2–H2O pretreatment of lignocellulosic biomass

A high pressure (200 bar) CO2–H2O process was developed for pretreating lignocellulosic biomass at high‐solid contents, while minimizing chemical inputs. Hardwood was pretreated at 20 and 40 (wt.%) solids. Switchgrass, corn stover, big bluestem, and mixed perennial grasses (a co‐culture of big bluestem and switchgrass) were pretreated at 40 (wt.%) solids. Operating temperatures ranged from 150 to 250°C, and residence times from 20 s to 60 min. At these conditions a biphasic mixture of an H2O‐rich liquid (hydrothermal) phase and a CO2‐rich supercritical phase coexist. Following pretreatment, samples were then enzymatically hydrolyzed. Total yields, defined as the fraction of the theoretical maximum, were determined for glucose, hemicellulose sugars, and two degradation products: furfural and 5‐hydroxymethylfurfural. Response surfaces of yield as a function of temperature and residence time were compared for different moisture contents and biomass species. Pretreatment at 170°C for 60 min gave glucose yields of 77%, 73%, and 68% for 20 and 40 (wt.%) solids mixed hardwood and mixed perennial grasses, respectively. Pretreatment at 160°C for 60 min gave glucan to glucose yields of 81% for switchgrass and 85% for corn stover. Biotechnol. Bioeng. 2010;107: 451–460. © 2010 Wiley Periodicals, Inc.
Peritoneal mesothelial cell injury factors in rat cancerous ascites.

To elucidate the mechanism of the peritoneal dissemination of cancer, the influence of cancerous ascites on peritoneal mesothelial cells was studied by scanning electron microscopy and light microscopy. We inoculated normal Donryu rats with AH100B ascites hepatoma cells and studied the influence of the supernatant from cancerous ascites on the normal rat peritoneal surface by i.p. injection. The mesothelial cells were damaged and exfoliated markedly, which is supposed to be a profitable condition for cancer cells to proliferate on the peritoneal surface. Therefore, the presence of mesothelial cell injury factors was noted. Subsequently, we divided the supernatant from rat cancerous ascites into four fractions by gel filtration and revealed the distribution of mesothelial cell injury factors by studying the influence of each fraction on the normal rat peritoneal surface. Although Fraction I (fibrin fraction) and Fraction II (IgG fraction) made no changes on the peritoneal surface, Fraction III (albumin fraction) and Fraction IV provoked damages on the mesothelial cells. We found that the mesothelial cell injury factors are present in the albumin fraction and in the fraction containing low-molecular-weight substances.
Periplasmic Electron Transfer via the c-Type Cytochromes MtrA and FccA of Shewanella oneidensis MR-1

ABSTRACT Dissimilatory microbial reduction of insoluble Fe(III) oxides is a geochemically and ecologically important process which involves the transfer of cellular, respiratory electrons from the cytoplasmic membrane to insoluble, extracellular, mineral-phase electron acceptors. In this paper evidence is provided for the function of the periplasmic fumarate reductase FccA and the decaheme c-type cytochrome MtrA in periplasmic electron transfer reactions in the gammaproteobacterium Shewanella oneidensis. Both proteins are abundant in the periplasm of ferric citrate-reducing S. oneidensis cells. In vitro fumarate reductase FccA and c-type cytochrome MtrA were reduced by the cytoplasmic membrane-bound protein CymA. Electron transfer between CymA and MtrA was 1.4-fold faster than the CymA-catalyzed reduction of FccA. Further experiments showing a bidirectional electron transfer between FccA and MtrA provided evidence for an electron transfer network in the periplasmic space of S. oneidensis. Hence, FccA could function in both the electron transport to fumarate and via MtrA to mineral-phase Fe(III). Growth experiments with a ΔfccA deletion mutant suggest a role of FccA as a transient electron storage protein.
Gender and the Medical Curriculum: A Rural Case Study

SUMMARY In Australia, half the medical students are women. There is increasing evidence that women engage with medicine differently from men, and medical workforce planners are being required to consider the implications of this change, particularly in areas of medical need. Between 1996–2001, the Australian government provided funding for teaching about issues for female rural doctors to encourage female students to consider rural medical practice. This was extended to include teaching about gender issues for doctors. Introducing this teaching has required building credibility for the topic among funders, faculty and students, training tutors, and meeting the need of students for an intellectual framework within which to think about gender and medicine. Teaching about gender requires conscious leadership by senior academic women. This paper describes an initiative in the rural curriculum for medical students.
Ultrastructural modifications in bovine oocytes maintained in meiotic arrest in vitro using roscovitine or butyrolactone

Butyrolactone‐I (BL‐I) and roscovitine (ROSC) are selective inhibitors of the cyclin‐dependent kinases, and both have been shown to reversibly inhibit meiotic resumption in cattle oocytes for 24 hr without having a negative affect on subsequent development to the blastocyst stage. The aim of the present study was to describe the morphological changes occurring in fully grown immature and in vitro matured bovine oocytes following exposure to either BL‐I or ROSC for 24 hr at concentrations known to be consistent with normal development. Immature bovine cumulus oocyte complexes, recovered from the ovaries of slaughtered heifers, were incubated for 24 hr in the presence of one of the inhibitors. They were then either fixed immediately and processed for transmission electron microscopy (TEM), or cultured for a further 24 hr in the absence of the inhibitor, in conditions permissive to maturation, and subsequently processed for TEM. A control group of oocytes were processed for TEM immediately upon recovery (0 hr) or following in vitro maturation (IVM) for 24 hr. In general, incubation with either inhibitor disrupted the integrity of the surrounding cumulus cells and affected their subsequent expansion during IVM. Within the oocyte cytoplasm, swelling of the mitochondrial cristae was immediately noticeable following meiotic inhibition in the presence of ROSC, while an increased population of pleomorphic mitochondria and mitochondria with electron lucent matrices following BL‐I treatment was not observed until after the subsequent IVM period. Both inhibitors caused degeneration of the cortical granules, effectively reducing the population, most noticeably following IVM. At the level of the nucleus, both inhibitory treatments caused convolution of the nuclear membrane, furthermore, aberrant structures were observed within the nucleoplasm of ROSC‐treated cumulus oocyte complexes (COCs). In conclusion, while it has been shown that inhibition of meiotic resumption using specific cdk inhibitors is possible and that such oocytes are capable of undergoing maturation, fertilization, and early embryo development, there is as yet no definitive proof that oocytes treated in this way can ultimately give rise to normal offspring. We have shown here that some modifications are induced in the oocytes at the ultrastructural level. Whether or not these modifications are compatible with normal gestation and the birth of a live calf remain to be elucidated. Mol. Reprod. Dev. 64: 369–378, 2003. © 2003 Wiley‐Liss, Inc.
Factors affecting the results of serum cholesterol determinations: an interlaboratory evaluation.

We present results of an interlaboratory survey of cholesterol assays in which methodology, standardization technique, type of standard, reagent source, and control sera used are considered. Each of these factors is evaluated, on both clear and icteric sera, with respect to accuracy, interlaboratory precision, and associated random error. We find that most participants use direct techniques, that these laboratories do not use correction procedures where these are needed, and that not all extractants effectively prevent bilirubin interference. Our data illustrate that precision on clear sera is best by direct procedures, but not in the presence of bilirubin. Participants uniformly exhibit better intralaboratory precision than interlaboratory agreement, regardless of the variable being studied. It is appropriate to consider the interactions of variables if a technique is to be properly evaluated.
Identification of Exon-Deleted Progesterone Receptor mRNAs in Human Uterine Endometrial Cancers

We demonstrated the expression of various exon-deleted progesterone receptor (PR) variant mRNAs in human uterine endometrial cancers using the reverse transcription-polymerase chain reaction-DNA sequencing analyses. In addition to PR wild-type mRNA, exon 4-deleted, exon 6-deleted, exon 3,4-deleted, exon 5,6-deleted, exon 4,5,6-deleted and exon 3,4,5,6-deleted PR variant mRNAs were identified. The exon 6-deleted and exon 5,6-deleted PR variant mRNAs lacked encoding for the steroid-binding domain. The exon 4-deleted, exon 3,4-deleted, exon 4,5,6-deleted and exon 3,4,5,6-deleted PR variant mRNAs lacked encoding for the DNA-binding domain in addition to encoding for the steroid-binding domain. While the exon 4-deleted, exon 6-deleted and exon 3,4-deleted PR variant mRNAs were observed in all samples analyzed, the exon 5,6-deleted, exon 4,5,6-deleted and/or exon 3,4,5,6-deleted PR variant mRNAs could not be detected in some cases, especially in poorly differentiated adenocarcinoma as compared with well-differentiated and moderately differentiated adenocarcinomas. The present study demonstrates the coexpression of PR exon-deleted variant mRNAs with the wild-type in uterine endometrial cancers. All translated variant proteins might possess functional diversity and might modify the progestational action of wild-type PR, and the expression of some PR variant mRNAs may be lost as endometrial cancer cells undergo dedifferentiation.
Single nucleotide polymorphism detection: allelic discrimination using TaqMan.

Candidate gene studies are one of the most widely used approaches in the dissection of the genetic basis of disease. High-throughput methods for genotyping single nucleotide polymorphisms (SNPs) are necessary to perform large-scale association studies. We describe the use of the TaqMan or 5' nuclease allelic discrimination assay for genotyping polymorphisms of the collagen I alpha 1 (COLIA1) and vitamin D receptor (VDR) genes. The basis for the assay is an allele specific oligonucleotide probe, labelled with a fluorescent reporter dye and a quencher dye, which is cleaved during the amplification process generating an increase in the intensity of fluorescence related to the accumulation of PCR product which is measured directly in the reaction well. Suitable for the discrimination of alleles differing by a single base change, this technique is robust, accurate, cost effective, and sufficiently high-throughput for a medium sized laboratory performing association analyses.
SUFFICIENT OPTIMALITY CONDITIONS FOR THE MOREAU-YOSIDA-TYPE REGULARIZATION CONCEPT APPLIED TO SEMILINEAR ELLIPTIC OPTIMAL CONTROL PROBLEMS WITH POINTWISE STATE CONSTRAINTS

We develop sucient optimality conditions for a Moreau-Yosida regularized optimal control problem governed by a semilinear elliptic PDE with pointwise constraints on the state and the control. We make use of the equivalence of a setting of Moreau-Yosida regularization to a special setting of the virtual control concept, for which standard second order sucient conditions have been shown. Moreover, we present a numerical example, solving a Moreau-Yosida regularized model problem with an SQP method.
Ternary Kv4.2 channels recapitulate voltage‐dependent inactivation kinetics of A‐type K+ channels in cerebellar granule neurons

Kv4 channels mediate most of the somatodendritic subthreshold operating A‐type current (ISA) in neurons. This current plays essential roles in the regulation of spike timing, repetitive firing, dendritic integration and plasticity. Neuronal Kv4 channels are thought to be ternary complexes of Kv4 pore‐forming subunits and two types of accessory proteins, Kv channel interacting proteins (KChIPs) and the dipeptidyl‐peptidase‐like proteins (DPPLs) DPPX (DPP6) and DPP10. In heterologous cells, ternary Kv4 channels exhibit inactivation that slows down with increasing depolarization. Here, we compared the voltage dependence of the inactivation rate of channels expressed in heterologous mammalian cells by Kv4.2 proteins with that of channels containing Kv4.2 and KChIP1, Kv4.2 and DPPX‐S, or Kv4.2, KChIP1 and DPPX‐S, and found that the relation between inactivation rate and membrane potential is distinct for these four conditions. Moreover, recordings from native neurons showed that the inactivation kinetics of the ISA in cerebellar granule neurons has voltage dependence that is remarkably similar to that of ternary Kv4 channels containing KChIP1 and DPPX‐S proteins in heterologous cells. The fact that this complex and unique behaviour (among A‐type K+ currents) is observed in both the native current and the current expressed in heterologous cells by the ternary complex containing Kv4, DPPX and KChIP proteins supports the hypothesis that somatically recorded native Kv4 channels in neurons include both types of accessory protein. Furthermore, quantitative global kinetic modelling showed that preferential closed‐state inactivation and a weakly voltage‐dependent opening step can explain the slowing of the inactivation rate with increasing depolarization. Therefore, it is likely that preferential closed‐state inactivation is the physiological mechanism that regulates the activity of both ternary Kv4 channel complexes and native ISA‐mediating channels.
Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study.

OBJECTIVE To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. DESIGN Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. SETTING Ten clinical centers in the United States and Canada. PARTICIPANTS A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. INTERVENTIONS Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. MAIN OUTCOME MEASURES Rate of change and cumulative change in FEV1 over a 5-year period. RESULTS Participants in the two smoking intervention groups showed significantly smaller declines in FEV1 than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. CONCLUSIONS An aggressive smoking intervention program significantly reduces the age-related decline in FEV1 in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1 that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1.
SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high‐affinity binding site for SH2 domains of phospholipase C gamma.

Several cytoplasmic tyrosine kinases contain a conserved, non‐catalytic stretch of approximately 100 amino acids called the src homology 2 (SH2) domain, and a region of approximately 50 amino acids called the SH3 domain. SH2/SH3 domains are also found in several other proteins, including phospholipase C‐gamma (PLC gamma). Recent studies indicate that SH2 domains promote association between autophosphorylated growth factor receptors such as the epidermal growth factor (EGF) receptor and signal transducing molecules such as PLC gamma. Because SH2 domains bind specifically to protein sequences containing phosphotyrosine, we examined their capacity to prevent tyrosine dephosphorylation of the EGF and other receptors with tyrosine kinase activity. For this purpose, various SH2/SH3 constructs of PLC gamma were expressed in Escherichia coli as glutathione‐S‐transferase fusion proteins. Our results show that purified SH2 domains of PLC gamma are able to prevent tyrosine dephosphorylation of the EGF receptor and other receptors with tyrosine activity. The inhibition of tyrosine dephosphorylation paralleled the capacity of various SH2‐containing constructs to bind to the EGF receptor, suggesting that the tyrosine phosphatase and the SH2 domain compete for the same tyrosine phosphorylation sites in the carboxy‐terminal tail of the EGF receptor. Analysis of the phosphorylation sites protected from dephosphorylation by PLC gamma‐SH2 revealed substantial inhibition of dephosphorylation of Tyr992 at 1 microM SH2. This indicates that Tyr992 and its flanking sequence is the high‐affinity binding site for SH2 domains of PLC gamma. (ABSTRACT TRUNCATED AT 250 WORDS)