Whole-exome sequencing of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), the most common malignant disorder in childhood, is typically associated with numerical chromosomal aberrations, fusion genes or small focal deletions, thought to represent important pathogenetic events in the development of the leukemia. Mutations, such as single nucleotide changes, have also been reported in childhood ALL, but these have only been studied by sequencing a small number of candidate genes. Herein, we report the first unbiased sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene (the most common genetic subtype) and corresponding normal samples. A total of 14 somatic mutations were identified, including four and seven protein-altering nucleotide substitutions in each ALL. Twelve mutations (86%) occurred in genes previously described to be mutated in other types of cancer, but none was found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. The number of single nucleotide mutations was similar to the number of copy number alterations as detected by single nucleotide polymorphism arrays. Although the true pathogenetic significance of the mutations must await future functional evaluations, this study provides a first estimate of the mutational burden at the genetic level of t(12;21)-positive childhood ALL.Leukemia advance online publication, 18 November 2011; doi:10.1038/leu.2011.333

A Fully Abstract Symbolic Semantics for Psi-Calculi

We present a symbolic transition system and bisimulation equivalence for psi-calculi, and show that it is fully abstract with respect to bisimulation congruence in the non-symbolic semantics. A psi-calculus is an extension of the pi-calculus with nominal data types for data structures and for logical assertions representing facts about data. These can be transmitted between processes and their names can be statically scoped using the standard pi-calculus mechanism to allow for scope migrations. Psi-calculi can be more general than other proposed extensions of the pi-calculus such as the applied pi-calculus, the spi-calculus, the fusion calculus, or the concurrent constraint pi-calculus. Symbolic semantics are necessary for an efficient implementation of the calculus in automated tools exploring state spaces, and the full abstraction property means the semantics of a process does not change from the original

Resolution of the type material of the Asian elephant, Elephas maximus Linnaeus, 1758 (Proboscidea, Elephantidae)

The understanding of Earth’s biodiversity depends critically on the accurate identification and nomenclature of species. Many species were described centuries ago, and in a surprising number of cases their nomenclature or type material remain unclear or inconsistent. A prime example is provided by Elephas maximus, one of the most iconic and well-known mammalian species, described and named by Linnaeus (1758) and today designating the Asian elephant. We used morphological, ancient DNA (aDNA), and high-throughput ancient proteomic analyses to demonstrate that a widely discussed syntype specimen of E. maximus, a complete foetus preserved in ethanol, is actually an African elephant, genus Loxodonta. We further discovered that an additional E. maximus syntype, mentioned in a description by John Ray (1693) cited by Linnaeus, has been preserved as an almost complete skeleton at the Natural History Museum of the University of Florence. Having confirmed its identity as an Asian elephant through both morphological and ancient DNA analyses, we designate this specimen as the lectotype of E. maximus

Psi-calculi: a framework for mobile processes with nominal data and logic

The framework of psi-calculi extends the pi-calculus with nominal datatypes for data structures and for logical assertions and conditions. These can be transmitted between processes and their names can be statically scoped as in the standard pi-calculus. Psi-calculi can capture the same phenomena as other proposed extensions of the pi-calculus such as the applied pi-calculus, the spi-calculus, the fusion calculus, the concurrent constraint pi-calculus, and calculi with polyadic communication channels or pattern matching. Psi-calculi can be even more general, for example by allowing structured channels, higher-order formalisms such as the lambda calculus for data structures, and predicate logic for assertions. We provide ample comparisons to related calculi and discuss a few significant applications. Our labelled operational semantics and definition of bisimulation is straightforward, without a structural congruence. We establish minimal requirements on the nominal data and logic in order to prove general algebraic properties of psi-calculi, all of which have been checked in the interactive theorem prover Isabelle. Expressiveness of psi-calculi significantly exceeds that of other formalisms, while the purity of the semantics is on par with the original pi-calculus.Comment: 44 page

Can work ability explain the social gradient in sickness absence: a study of a general population in Sweden

<p>Abstract</p> <p>Background</p> <p>Understanding the reasons for the social gradient in sickness absence might provide an opportunity to reduce the general rates of sickness absence. The complete explanation for this social gradient still remains unclear and there is a need for studies using randomized working population samples. The main aim of the present study was to investigate if self-reported work ability could explain the association between low socioeconomic position and belonging to a sample of new cases of sick-listed employees.</p> <p>Methods</p> <p>The two study samples consisted of a randomized working population (n = 2,763) and a sample of new cases of sick-listed employees (n = 3,044), 19-64 years old. Both samples were drawn from the same randomized general population. Socioeconomic status was measured with occupational position and physical and mental work ability was measured with two items extracted from the work ability index.</p> <p>Results</p> <p>There was an association between lower socioeconomic status and belonging to the sick-listed sample among both women and men. In men the crude Odds ratios increased for each downwards step in socioeconomic status, OR 1.32 (95% CI 0.98-1.78), OR 1.53 (1.05-2.24), OR 2.80 (2.11-3.72), and OR 2.98 (2.27-3.90). Among women this gradient was not as pronounced. Physical work ability constituted the strongest explanatory factor explaining the total association between socioeconomic status and being sick-listed in women. However, among men, the association between skilled non-manual, OR 2.07 (1.54-2.78), and non-skilled manual, OR 2.03 (1.53-2.71) positions in relation to being sick-listed remained. The explanatory effect of mental work ability was small. Surprisingly, even in the sick-listed sample most respondents had high mental and physical work ability.</p> <p>Conclusions</p> <p>These results suggest that physical work ability may be an important key in explaining the social gradient in sickness absence, particularly in women. Hence, it is possible that the factors associated with the social gradient in sickness absence may differ, to some extent, between women and men.</p

SN 2022joj: A Peculiar Type Ia Supernova Possibly Driven by an Asymmetric Helium-shell Double Detonation

We present observations of SN 2022joj, a peculiar Type Ia supernova (SN Ia) discovered by the Zwicky Transient Facility (ZTF). SN 2022joj exhibits an unusually red $g_\mathrm{ZTF}-r_\mathrm{ZTF}$ color at early times and a rapid blueward evolution afterwards. Around maximum brightness, SN 2022joj shows a high luminosity ($M_{g_\mathrm{ZTF},\mathrm{max}}\simeq-19.7$ mag), a blue broadband color ($g_\mathrm{ZTF}-r_\mathrm{ZTF}\simeq-0.2$ mag), and shallow Si II absorption lines, consistent with those of overluminous, SN 1991T-like events. The maximum-light spectrum also shows prominent absorption around 4200 \r{A}, which resembles the Ti II features in subluminous, SN 1991bg-like events. Despite the blue optical-band colors, SN 2022joj exhibits extremely red ultraviolet $-$ optical colors at maximum luminosity ($u-v\simeq1.6$ mag and $uvw1 - v\simeq4.0$ mag), suggesting a suppression of flux between $\sim$2500--4000 \r{A}. Strong C II lines are also detected at peak. We show that these unusual spectroscopic properties are broadly consistent with the helium-shell double detonation of a sub-Chandrasekhar mass ($M\simeq1\mathrm{M_\odot}$) carbon/oxygen (C/O) white dwarf (WD) from a relatively massive helium shell ($M_s\simeq0.04$--$0.1\mathrm{M_\odot}$), if observed along a line of sight roughly opposite to where the shell initially detonates. None of the existing models could quantitatively explain all the peculiarities observed in SN 2022joj. The low flux ratio of [Ni II] $\lambda$7378 to [Fe II] $\lambda$7155 emission in the late-time nebular spectra indicates a low yield of stable Ni isotopes, favoring a sub-Chandrasekhar mass progenitor. The significant blueshift measured in the [Fe II] $\lambda$7155 line is also consistent with an asymmetric chemical distribution in the ejecta, as is predicted in double-detonation models.Comment: 24 pages, 11 figures, 6 tables. Submitted to Ap

Structure and Stability of the Spinach Aquaporin SoPIP2;1 in Detergent Micelles and Lipid Membranes

Background: SoPIP2;1 constitutes one of the major integral proteins in spinach leaf plasma membranes and belongs to the aquaporin family. SoPIP2;1 is a highly permeable and selective water channel that has been successfully overexpressed and purified with high yields. In order to optimize reconstitution of the purified protein into biomimetic systems, we have here for the first time characterized the structural stability of SoPIP2;1. Methodology/Principal Finding: We have characterized the protein structural stability after purification and after reconstitution into detergent micelles and proteoliposomes using circular dichroism and fluorescence spectroscopy techniques. The structure of SoPIP2;1 was analyzed either with the protein solubilized with octyl-beta-D-glucopyranoside (OG) or reconstituted into lipid membranes formed by E. coli lipids, diphytanoylphosphatidylcholine (DPhPC), or reconstituted into lipid membranes formed from mixtures of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPE), 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE), 1-palmitoyl-2-oleoyl-phosphatidylserine (POPS), and ergosterol. Generally, SoPIP2;1 secondary structure was found to be predominantly a-helical in accordance with crystallographic data. The protein has a high thermal structural stability in detergent solutions, with an irreversible thermal unfolding occurring at a melting temperature of 58 degrees C. Incorporation of the protein into lipid membranes increases the structural stability as evidenced by an increased melting temperature of up to 70 degrees C. Conclusion/Significance: The results of this study provide insights into SoPIP2;1 stability in various host membranes and suggest suitable choices of detergent and lipid composition for reconstitution of SoPIP2;1 into biomimetic membranes for biotechnological applications

Asthmatics Exhibit Altered Oxylipin Profiles Compared to Healthy Individuals after Subway Air Exposure

Asthma is a chronic inflammatory lung disease that causes significant morbidity and mortality worldwide. Air pollutants such as particulate matter (PM) and oxidants are important factors in causing exacerbations in asthmatics, and the source and composition of pollutants greatly affects pathological implications.This randomized crossover study investigated responses of the respiratory system to Stockholm subway air in asthmatics and healthy individuals. Eicosanoids and other oxylipins were quantified in the distal lung to provide a measure of shifts in lipid mediators in association with exposure to subway air relative to ambient air.Sixty-four oxylipins representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of bronchoalveolar lavage (BAL)-fluid. Validations through immunocytochemistry staining of BAL-cells were performed for 15-LOX-1, COX-1, COX-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Multivariate statistics were employed to interrogate acquired oxylipin and immunocytochemistry data in combination with patient clinical information.Asthmatics and healthy individuals exhibited divergent oxylipin profiles following exposure to ambient and subway air. Significant changes were observed in 8 metabolites of linoleic- and α-linolenic acid synthesized via the 15-LOX pathway, and of the COX product prostaglandin E(2) (PGE(2)). Oxylipin levels were increased in healthy individuals following exposure to subway air, whereas asthmatics evidenced decreases or no change.Several of the altered oxylipins have known or suspected bronchoprotective or anti-inflammatory effects, suggesting a possible reduced anti-inflammatory response in asthmatics following exposure to subway air. These observations may have ramifications for sensitive subpopulations in urban areas

An Ancient Duplication of Exon 5 in the Snap25 Gene Is Required for Complex Neuronal Development/Function

Alternative splicing is an evolutionary innovation to create functionally diverse proteins from a limited number of genes. SNAP-25 plays a central role in neuroexocytosis by bridging synaptic vesicles to the plasma membrane during regulated exocytosis. The SNAP-25 polypeptide is encoded by a single copy gene, but in higher vertebrates a duplication of exon 5 has resulted in two mutually exclusive splice variants, SNAP-25a and SNAP-25b. To address a potential physiological difference between the two SNAP-25 proteins, we generated gene targeted SNAP-25b deficient mouse mutants by replacing the SNAP-25b specific exon with a second SNAP-25a equivalent. Elimination of SNAP-25b expression resulted in developmental defects, spontaneous seizures, and impaired short-term synaptic plasticity. In adult mutants, morphological changes in hippocampus and drastically altered neuropeptide expression were accompanied by severe impairment of spatial learning. We conclude that the ancient exon duplication in the Snap25 gene provides additional SNAP-25-function required for complex neuronal processes in higher eukaryotes