Miracle-dz/UniFAR-FTUs huggingface dataset:
LMA Supreme™ vs i‐gel™– a comparison of insertion success in novices

Two new supraglottic airway devices, the LMA Supreme™ (LMA) and the i‐gel™, offer potential benefits when inserted by inexperienced operators. This study compared the insertion success rate and ventilation profile between the LMA Supreme and the i‐gel when inserted by operators without previous airway management expertise. Following a short lecture and manikin training, airway novices were randomly allocated to insert either the LMA Supreme or the i‐gel into 80 patients undergoing breast surgery. The primary outcome was first‐time success rate, and secondary outcomes were overall success rate, insertion time, airway leak pressure, tidal volume during pressure controlled ventilation at 17 cmH2O, and adverse events. First‐time insertion success rate was significantly higher for the LMA Supreme than the i‐gel (30/39 (77%) vs 22/41 (54%); p = 0.029). Significantly more placement failures occurred with the i‐gel (6 vs 0, p = 0.025). Mean (SD) leak pressure (29 (8) vs 23 (11) cmH2O, p = 0.007) and expired tidal volume (PCV 17 cmH2O) (785 (198) vs 654 (91), p = 0.001) were significantly greater with the LMA Supreme than with the i‐gel, respectively. More patients complained of pharyngolaryngeal pain with the LMA Supreme than with the i‐gel (17/39 (44%) vs 8/41 (20%); p = 0.053). We found better first time success rate, fewer failures, and a better seal with the LMA Supreme compared with the i‐gel, indicating that the LMA Supreme may be preferable for emergency airway use by novices.
Conservation and canalization of gene expression during angiosperm diversification accompany the origin and evolution of the flower

The origin and rapid diversification of the angiosperms (Darwin's “Abominable Mystery”) has engaged generations of researchers. Here, we examine the floral genetic programs of phylogenetically pivotal angiosperms (water lily, avocado, California poppy, and Arabidopsis) and a nonflowering seed plant (a cycad) to obtain insight into the origin and subsequent evolution of the flower. Transcriptional cascades with broadly overlapping spatial domains, resembling the hypothesized ancestral gymnosperm program, are deployed across morphologically intergrading organs in water lily and avocado flowers. In contrast, spatially discrete transcriptional programs in distinct floral organs characterize the more recently derived angiosperm lineages represented by California poppy and Arabidopsis. Deep evolutionary conservation in the genetic programs of putatively homologous floral organs traces to those operating in gymnosperm reproductive cones. Female gymnosperm cones and angiosperm carpels share conserved genetic features, which may be associated with the ovule developmental program common to both organs. However, male gymnosperm cones share genetic features with both perianth (sterile attractive and protective) organs and stamens, supporting the evolutionary origin of the floral perianth from the male genetic program of seed plants.
Human tumor virus utilizes exosomes for intercellular communication

The Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) is expressed in multiple human malignancies and has potent effects on cell growth. It has been detected in exosomes and shown to inhibit immune function. Exosomes are small secreted cellular vesicles that contain proteins, mRNAs, and microRNAs (miRNAs). When produced by malignant cells, they can promote angiogenesis, cell proliferation, tumor-cell invasion, and immune evasion. In this study, exosomes released from nasopharyngeal carcinoma (NPC) cells harboring latent EBV were shown to contain LMP1, signal transduction molecules, and virus-encoded miRNAs. Exposure to these NPC exosomes activated the ERK and AKT signaling pathways in the recipient cells. Interestingly, NPC exosomes also contained viral miRNAs, several of which were enriched in comparison with their intracellular levels. LMP1 induces expression of the EGF receptor in an EBV-negative epithelial cell line, and exosomes produced by these cells also contain high levels of EGF receptor in exosomes. These findings suggest that the effects of EBV and LMP1 on cellular expression also modulate exosome content and properties. The exosomes may manipulate the tumor microenvironment to influence the growth of neighboring cells through the intercellular transfer of LMP1, signaling molecules, and viral miRNAs.
Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers

Inositol polyphosphate 4-phosphatase-II (INPP4B) is a regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway and is implicated as a tumor suppressor in epithelial carcinomas. INPP4B loss of heterozygosity (LOH) is detected in some human breast cancers; however, the expression of INPP4B protein in breast cancer subtypes and the normal breast is unknown. We report here that INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast, and in ER-positive, but not negative, breast cancer cell lines. INPP4B knockdown in ER-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth. Conversely, reconstitution of INPP4B expression in ER-negative, INPP4B-null human breast cancer cells reduced Akt activation and anchorage-independent growth. INPP4B protein expression was frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and was lost most commonly in aggressive basal-like breast carcinomas. INPP4B protein loss was also frequently observed in phosphatase and tensin homolog (PTEN)-null tumors. These studies provide evidence that INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas.
Replication error deficient and proficient colorectal cancer gene expression differences caused by 3′UTR polyT sequence deletions

Replication error deficient (RER+) colorectal cancers are a distinct subset of colorectal cancers, characterized by inactivation of the DNA mismatch repair system. These cancers are typically pseudodiploid, accumulate mutations in repetitive sequences as a result of their mismatch repair deficiency, and have distinct pathologies. Regulatory sequences controlling all aspects of mRNA processing, especially including message stability, are found in the 3′UTR sequence of most genes. The relevant sequences are typically A/U-rich elements or U repeats. Microarray analysis of 14 RER+ (deficient) and 16 RER− (proficient) colorectal cancer cell lines confirms a striking difference in expression profiles. Analysis of the incidence of mononucleotide repeat sequences in the 3′UTRs, 5′UTRs, and coding sequences of those genes most differentially expressed in RER+ versus RER− cell lines has shown that much of this differential expression can be explained by the occurrence of a massive enrichment of genes with 3′UTR T repeats longer than 11 base pairs in the most differentially expressed genes. This enrichment was confirmed by analysis of two published consensus sets of RER differentially expressed probesets for a large number of primary colorectal cancers. Sequence analysis of the 3′UTRs of a selection of the most differentially expressed genes shows that they all contain deletions in these repeats in all RER+ cell lines studied. These data strongly imply that deregulation of mRNA stability through accumulation of mutations in repetitive regulatory 3′UTR sequences underlies the striking difference in expression profiles between RER+ and RER− colorectal cancers.
Comparison of the early stages of forced unfolding for fibronectin type III modules

The structural changes accompanying stretch-induced early unfolding events were investigated for the four type III fibronectin (FN-III) modules, FN-III7, FN-III8, FN-III9, and FN-III10 by using steered molecular dynamics. Simulations revealed that two main energy barriers, I and II, have to be overcome to initiate unraveling of FN-III's tertiary structure. In crossing the first barrier, the two opposing β-sheets of FN-III are rotated against each other such that the β-strands of both β-sheets align parallel to the force vector (aligned state). All further events in the unfolding pathway proceed from this intermediate state. A second energy barrier has to be overcome to break the first major cluster of hydrogen bonds between adjacent β-strands. Simulations revealed that the height of barrier I varied significantly among the four modules studied, being largest for FN-III7 and lowest for FN-III10, whereas the height of barrier II showed little variation. Key residues affecting the mechanical stability of FN-III modules were identified. These results suggest that FN-III modules can be prestretched into an intermediate state with only minor changes to their tertiary structures. FN-III10, for example, extends 12 Å from the native “twisted” to the intermediate aligned state, and an additional 10 Å from the aligned state to further unfolding where the first β-strand is peeled away. The implications of the existence of intermediate states regarding the elasticity of fibrillar fibers and the stretch-induced exposure of cryptic sites are discussed.
Respiratory arrest with remifentanil PCA

[7]. We constructed 50% limits assuming the underlying distribution of CVs in each article was normal, which we expected would be conservative, and would underestimate the number of CVs expected to be outside the limits. As evidence of fraud, small p values will never be as jazzy as, for example, obviously doctored photographs, but well-conducted statistical analyses may be the only way to uncover many types of fraudulent scientific evidence. Dr Yentis, the Editor-in-Chief of this journal, and others, particularly Dr Shafer, Editor-in-Chief of Anesthesia and Analgesia, are to be congratulated for highlighting this important problem and spending what must be endless hours to promote awareness and encourage analyses that can convincingly uncover such cases. J. C. McCann M. L. Hudes B. N. Ames Children’s Hospital Oakland Research Institute Oakland, USA Email: jmccann@chori.org No external funding and no competing interests declared. Previously posted at the Anaesthesia Correspondence website: http://www. anaesthesiacorrespondence.com.
Demonstration of the benefits of SOI for high temperature operation

Summary form only given. To evaluate the performance of SOI circuits at high temperatures, CMOS 4K SRAMs were fabricated on SIMOX (separation by implantation of oxygen) and bulk starting material. Four varieties were included in this study: bulk (5 mu m epi on n/sup +/), and SIMOX/SOI with three silicon-layer thicknesses (0.5 mu m, 0.75 mu m, and 1.0 mu m). This combination allows the assessment of three device structures: standard bulk devices, standard SOI devices (S/D contacting the buried oxide), and semi-bulk SOI devices which operate like bulk devices but are dielectrically isolated. All the SOI SRAMs were functional to the maximum temperature available, 300 degrees C. The bulk circuits also functioned at elevated temperatures, but lost functionality between 250 degrees C and 275 degrees C due to the rapidly increasing leakage current associated with the well junction. The synchronous access time increased approximately linearly with temperature for all devices, and was nearly twice the measured room-temperature value at 300 degrees C. Leakage current increased strongly with temperature for all devices, with the thin SOI devices having the least static current at the highest temperatures. <<ETX>>
Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Mycolactone is a macrolide produced by Mycobacterium ulcerans with immunomodulatory properties. Here, we describe that in mouse, mycolactone injection led to a massive T-cell depletion in peripheral lymph nodes (PLNs) that was associated with defective expression of L-selectin (CD62-L). Importantly, preexposure to mycolactone impaired the capacity of T cells to reach PLNs after adoptive transfer, respond to chemotactic signals, and expand upon antigenic stimulation in vivo. We found that mycolactone-induced suppression of CD62-L expression by human primary T cells was induced rapidly at both the mRNA and protein levels and correlated with the reduced expression of one miRNA: let-7b. Notably, silencing of let-7b was sufficient to inhibit CD62-L gene expression. Conversely, its overexpression tended to up-regulate CD62-L and counteract the effects of mycolactone. Our results identify T-cell homing as a biological process targeted by mycolactone. Moreover, they reveal a mechanism of control of CD62-L expression involving the miRNA let-7b.
25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine

Hydrogels are hydrophilic polymer‐based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three‐dimensional (3D) matrices for tissue engineering, drug‐delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light‐sensitive, composite, and shape‐memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life.
Mechanistic alternatives for peptide bond formation on the ribosome

Abstract The peptidyl transfer reaction on the large ribosomal subunit depends on the protonation state of the amine nucleophile and exhibits a large kinetic solvent isotope effect (KSIE ∼8). In contrast, the related peptidyl-tRNA hydrolysis reaction involved in termination shows a KSIE of ∼4 and a pH-rate profile indicative of base catalysis. It is, however, unclear why these reactions should proceed with different mechanisms, as the experimental data suggests. One explanation is that two competing mechanisms may be operational in the peptidyl transferase center (PTC). Herein, we explored this possibility by re-examining the previously proposed proton shuttle mechanism and testing the feasibility of general base catalysis also for peptide bond formation. We employed a large cluster model of the active site and different reaction mechanisms were evaluated by density functional theory calculations. In these calculations, the proton shuttle and general base mechanisms both yield activation energies comparable to the experimental values. However, only the proton shuttle mechanism is found to be consistent with the experimentally observed pH-rate profile and the KSIE. This suggests that the PTC promotes the proton shuttle mechanism for peptide bond formation, while prohibiting general base catalysis, although the detailed mechanism by which general base catalysis is excluded remains unclear.
The long shadow cast by childhood physical and mental problems on adult life

In this article we assess and compare long-term adult socioeconomic status impacts from having experienced psychological and physical health problems in childhood. To do so, we use unique prospective data from the British National Child Development Study, a continuing panel study of a cohort of 17,634 children born in Great Britain during a single week in March 1958. To date there have been nine waves for this birth cohort to monitor their physical, educational, and social development, during childhood (at birth and 7, 11, and 16 y) and adulthood (age 23, 33, 42, 46, and 50 y). Excellent contemporaneous information exists throughout childhood on physical and psychological health, captured by doctor and nurse-led medical examinations and detailed parental and teacher questionnaires. This information is combined with a wealth of contemporaneous information on adult health and economic experiences collected from cohort members. Information includes their economic circumstances (earnings, labor supply, and other sources of family income), physical and psychological health, and relationship status. Large effects are found due to childhood psychological problems on the ability of affected children to work and earn as adults and on intergenerational and within-generation social mobility. Adult family incomes are reduced by 28% by age 50 y, with sustained impacts on labor supply, marriage stability, and the conscientiousness and agreeableness components of the “Big Five” personality traits. Effects of psychological health disorders during childhood are far more important over a lifetime than physical health problems.
Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes

For most intracellular structures with larger than molecular dimensions, little is known about the connection between underlying molecular activities and higher order organization such as size and shape. Here, we show that both the size and shape of the amphibian oocyte nucleolus ultimately arise because nucleoli behave as liquid-like droplets of RNA and protein, exhibiting characteristic viscous fluid dynamics even on timescales of < 1 min. We use these dynamics to determine an apparent nucleolar viscosity, and we show that this viscosity is ATP-dependent, suggesting a role for active processes in fluidizing internal contents. Nucleolar surface tension and fluidity cause their restructuring into spherical droplets upon imposed mechanical deformations. Nucleoli exhibit a broad distribution of sizes with a characteristic power law, which we show is a consequence of spontaneous coalescence events. These results have implications for the function of nucleoli in ribosome subunit processing and provide a physical link between activity within a macromolecular assembly and its physical properties on larger length scales.
Polarity proteins Bem1 and Cdc24 are components of the filamentous fungal NADPH oxidase complex

Regulated synthesis of reactive oxygen species (ROS) by membrane-bound fungal NADPH oxidases (Nox) plays a key role in fungal morphogenesis, growth, and development. Generation of reactive oxygen species (ROS) by the plant symbiotic fungus, Epichloë festucae, requires functional assembly of a multisubunit complex composed of NoxA, a regulatory component, NoxR, and the small GTPase RacA. However, the mechanism for assembly and activation of this complex at the plasma membrane is unknown. We found by yeast two-hybrid and coimmunoprecipitation assays that E. festucae NoxR interacts with homologs of the yeast polarity proteins, Bem1 and Cdc24, and that the Phox and Bem1 (PB1) protein domains found in these proteins are essential for these interactions. GFP fusions of BemA, Cdc24, and NoxR preferentially localized to actively growing hyphal tips and to septa. These proteins interact with each other in vivo at these same cellular sites as shown by bimolecular fluorescent complementation assays. The PB1 domain of NoxR is essential for localization to the hyphal tip. An E. festucae ΔbemA mutant was defective in hyphal morphogenesis and growth in culture and in planta. The changes in fungal growth in planta resulted in a defective symbiotic interaction phenotype. Our inability to isolate a Δcdc24 mutant suggests this gene is essential. These results demonstrate that BemA and Cdc24 play a critical role in localizing NoxR protein to sites of fungal hyphal morphogenesis and growth. Our findings identify a potential shared ancestral link between the protein machinery required for fungal polarity establishment and the Nox complex controlling cellular differentiation.
E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6

In ubiquitin conjugation, different combinations of E2 and E3 enzymes catalyse either monoubiquitination or ubiquitin chain formation. The E2/E3 complex Rad6/Rad18 exclusively monoubiquitinates the proliferating cell nuclear antigen (PCNA) to signal for “error prone” DNA damage tolerance, whereas a different set of conjugation enzymes is required for ubiquitin chain formation on PCNA. Here we show that human E2 enzyme Rad6b is intrinsically capable of catalyzing ubiquitin chain formation. This activity is prevented during PCNA ubiquitination by the interaction of Rad6 with E3 enzyme Rad18. Using NMR and X-ray crystallography we show that the R6BD of Rad18 inhibits this activity by competing with ubiquitin for a noncovalent “backside” binding site on Rad6. Our findings provide mechanistic insights into how E3 enzymes can regulate the ubiquitin conjugation process.
Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase II

The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1–deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca2+/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.