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This paper develops a framework for TAG (Tree Adjoining Grammar) semantics that brings together ideas from different recent approaches.Then, within this framework, an analysis of scope is proposed that accounts for the different scopal properties of quantifiers, adverbs, raising verbs and attitude verbs. Finally, including situation variables in the semantics, different situation binding possibilities are derived for different types of quantificational elements.
LTAG semantics for questions
(2004)
This papers presents a compositional semantic analysis of interrogatives clauses in LTAG (Lexicalized Tree Adjoining Grammar) that captures the scopal properties of wh- and nonwh-quantificational elements. It is shown that the present approach derives the correct semantics for examples claimed to be problematic for LTAG semantic approaches based on the derivation tree. The paper further provides an LTAG semantics for embedded interrogatives.
MAPK6/ERK3 is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary disfunction and by defects in function, activation and positive selection of T cells. To study the role of ERK3 in vivo, we generated mice carrying a conditional Erk3 allele with exon3 flanked by LoxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)-cre and a clear reduction of the protein kinase MK5 is detected, providing first evidence for the existence of the ERK3/MK5 signaling complex in vivo. In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile, do not display pulmonary hypoplasia, acute respiratory failure, abnormal T cell development, reduction of thymocyte numbers or altered T cells selection. Hence, ERK3 is dispensable for pulmonary and T-cell functions. The perinatal lethality, lung and T-cell defects of the previous ERK3 knockout mice are likely due to ERK3-unrelated effects of the inserted lacZ-neomycin-resistance-cassette. The knockout mouse of the closely related atypical MAPK ERK4/MAPK4 is also normal suggesting redundant functions of both protein kinases.
The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1 had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineage-specific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.
Incidence of an intracellular multiplication niche amongst Acinetobacter baumannii clinical isolates
(2021)
The spread of antibiotic resistant Acinetobacter baumannii poses a significant threat to public health worldwide. This nosocomial bacterial pathogen can be associated with life-threatening infections, particularly in intensive care units. A. baumannii is mainly described as an extracellular pathogen with restricted survival within cells. This study shows that a subset of A. baumannii clinical isolates extensively multiply within non-phagocytic immortalized and primary cells, without the induction of apoptosis, and with bacterial clusters visible up to 48 hours after infection. This phenotype was observed for the A. baumannii C4 strain associated with high mortality in a hospital outbreak, and the A. baumannii ABC141 strain which wasn’t isolated from an infection site but was found to be hyperinvasive. Intracellular multiplication of these A. baumannii strains occurred within spacious single membrane-bound vacuoles, labeled with the lysosomal associate membrane protein (LAMP1). However, these compartments excluded lysotracker, an indicator of acidic pH, suggesting that A. baumannii can divert its trafficking away from the lysosomal degradative pathway. These compartments were also devoid of autophagy features. A high-content microscopy screen of 43 additional A. baumannii clinical strains highlighted various phenotypes: (1) the majority of strains remained extracellular, (2) a significant proportion was capable of invasion and limited persistence, and (3) two strains efficiently multiplied within LAMP1-positive vacuoles, one of which was also hyperinvasive. These data identify an intracellular niche for specific A. baumannii clinical strains that enables extensive multiplication in an environment protected from host immune responses and out of reach from many antibiotics.
Importance Multidrug resistant Acinetobacter baumannii strains are associated with significant morbidity and mortality in hospitals world-wide. Understanding their pathogenicity is critical for improving therapeutics. Although A. baumannii can steadily adhere to surfaces and host cells, most bacteria remain extracellular. Recent studies have shown that a small proportion of bacteria can invade cells but present limited survival. We have found that some A. baumannii clinical isolates can establish a specialized intracellular niche that sustains extensive intracellular multiplication for a prolonged time without induction of cell death. We propose that this intracellular compartment allows A. baumannii to escape the cell’s normal degradative pathway, protecting bacteria from host immune responses and potentially hindering antibiotic accessibility. This may contribute to A. baumannii persistence, relapsing infections and enhanced mortality in susceptible patients. A high-content microscopy-based screen confirmed this pathogenicity trait is present in other clinical isolates. There is an urgent need for new antibiotics or alternative antimicrobial approaches, particularly to combat carbapenem-resistant A. baumannii. The discovery of an intracellular niche for this pathogen as well as hyperinvasive isolates may help guide the development of antimicrobial therapies and diagnostics in the future.
A medium modified gluon propagator is used to evaluate the scattering cross section for the process gg - gg in the QCD medium by performing an ex- plicit sum over the polarizations of the gluons. We incorporate a magnetic sreening mass from a non - perturbative study. It is shown that the medium modified cross section is finite, divergence free, and is independent of any ad-hoc momentum transfer cut-off parameters. The medium modified finite cross sections are necessary for a realistic investigation of the production and equilibration of the minijet plasma expected at RHIC and LHC PACS: 12.38.Mh; 14.70.Dj; 12.38.Bx; 11.10.Wx
Within the ADD-model, we elaborate an idea by Vacavant and Hinchliffe and show quantitatively how to determine the fundamental scale of TeV-gravity and the number of compactified extra dimensions from data at LHC. We demonstrate that the ADD-model leads to strong correlations between the missing E_T in gravitons at different center of mass energies. This correlation puts strong constraints on this model for extra dimensions, if probed at sqr s=5.5 TeV and sqrt s=14 TeV at LHC.
Improved integration of single cell transcriptome data demonstrated on heart failure in mice and men
(2023)
Biomedical research frequently uses murine models to study disease mechanisms. However, the translation of these findings to human disease remains a significant challenge. In order to improve the comparability of mouse and human data, we present a cross-species integration pipeline for single-cell transcriptomic assays.
The pipeline merges expression matrices and assigns clear orthologous relationships. Starting from Ensembl ortholog assignments, we allocated 82% of mouse genes to unique orthologs by using additional publicly available resources such as Uniprot, and NCBI databases. For genes with multiple matches, we employed the Needleman-Wunsch global alignment based on either amino acid or nucleotide sequence to identify the ortholog with the highest degree of similarity.
The workflow was tested for its functionality and efficiency by integrating scRNA-seq datasets from heart failure patients with the corresponding mouse model. We were able to assign unique human orthologs to up to 80% of the mouse genes, utilizing the known 17,492 orthologous pairs. Curiously, the integration process enabled the identification of both common and unique regulatory pathways between species in heart failure.
In conclusion, our pipeline streamlines the integration process, enhances gene nomenclature alignment and simplifies the translation of mouse models to human disease. We have made the OrthoIntegrate R-package accessible on GitHub (https://github.com/MarianoRuzJurado/OrthoIntegrate), which includes the assignment of ortholog definitions for human and mouse, as well as the pipeline for integrating single cells.
System size dependence of multiplicity fluctuations of charged particles produced in nuclear collisions at 158 A GeV was studied in the NA49 CERN experiment. Results indicate a non-monotonic dependence of the scaled variance of the multiplicity distribution with a maximum for semi-peripheral Pb+Pb interactions with number of projectile participants of about 35. This effect is not observed in a string-hadronic model of nuclear collision HIJING.
We call a vector x/spl isin/R/sup n/ highly regular if it satisfies =0 for some short, non-zero integer vector m where <...> is the inner product. We present an algorithm which given x/spl isin/R/sup n/ and /spl alpha//spl isin/N finds a highly regular nearby point x' and a short integer relation m for x'. The nearby point x' is 'good' in the sense that no short relation m~ of length less than /spl alpha//2 exists for points x~ within half the x'-distance from x. The integer relation m for x' is for random x up to an average factor 2/sup /spl alpha//2/ a shortest integer relation for x'. Our algorithm uses, for arbitrary real input x, at most O(n/sup 4/(n+log A)) many arithmetical operations on real numbers. If a is rational the algorithm operates on integers having at most O(n/sup 5/+n/sup 3/(log /spl alpha/)/sup 2/+log(/spl par/qx/spl par//sup 2/)) many bits where q is the common denominator for x.