32 research outputs found
Selecting which Dense Retriever to use for Zero-Shot Search
We propose the new problem of choosing which dense retrieval model to use
when searching on a new collection for which no labels are available, i.e. in a
zero-shot setting. Many dense retrieval models are readily available. Each
model however is characterized by very differing search effectiveness -- not
just on the test portion of the datasets in which the dense representations
have been learned but, importantly, also across different datasets for which
data was not used to learn the dense representations. This is because dense
retrievers typically require training on a large amount of labeled data to
achieve satisfactory search effectiveness in a specific dataset or domain.
Moreover, effectiveness gains obtained by dense retrievers on datasets for
which they are able to observe labels during training, do not necessarily
generalise to datasets that have not been observed during training. This is
however a hard problem: through empirical experimentation we show that methods
inspired by recent work in unsupervised performance evaluation with the
presence of domain shift in the area of computer vision and machine learning
are not effective for choosing highly performing dense retrievers in our setup.
The availability of reliable methods for the selection of dense retrieval
models in zero-shot settings that do not require the collection of labels for
evaluation would allow to streamline the widespread adoption of dense
retrieval. This is therefore an important new problem we believe the
information retrieval community should consider. Implementation of methods,
along with raw result files and analysis scripts are made publicly available at
https://www.github.com/anonymized
The impact of sex on gene expression across human tissues
Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation
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The impact of sex on gene expression across human tissues
Many complex human phenotypes exhibit sex-differentiated characteristics, however the underlying molecular mechanisms of these differences remain largely unknown. Here, we present an extensive catalog of both sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by GTEx (v8 release). We demonstrate that sex strongly influences gene expression levels and cellular composition of tissue samples across the human body. The effect of sex on gene expression is widespread, with a total of 37% of all genes exhibiting sex-biased expression in at least one tissue. This suggests that many if not most biological processes, and thus complex traits and diseases, are impacted by sex effects on the transciptome. We expand the identification of cis-eQTLs with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation in a single sex, including novel associations not detected with sex-agnostic approaches. Altogether we provide the most comprehensive characterization of sex differences in the human transcriptome and its regulation to date.Peer ReviewedPreprin
Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe
Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones
The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides
4-Benzoyl-2-(4-bromophenyl)-1-(4-methoxyphenyl)-1,2-dihydropyrimidino[4,3-c][1,4]benzoxazine-3,5-dione
The reaction of 3-benzoylpyrrolo[2,1-c][1,4]benzoxazin-1,2,4-trione with N-(4-bromophenyl)-1-(4-methoxyphenyl)methanimine under thermolytical conditions afforded 4-benzoyl-2-(4-bromophenyl)-1-(4-methoxyphenyl)-1,2-dihydropyrimidino[4,3-c][1,4]benzoxazine-3,5-dione in a good yield. The reaction proceeded via in situ generation of a reactive intermediate, acyl(imidoyl)ketene. The compound was fully characterized
Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2<i>H</i>-pyrrol-2-ones
The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides
3-(1-Cyclohexyl-2-(cyclohexylamino)-4-(4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl)-1-methylquinoxalin-2(1<i>H</i>)-one
The reaction of 3-cyclohexyl-2-(cyclohexylimino)-6-(4-ethoxyphenyl)-5-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-one with ammonium acetate afforded 3-(1-cyclohexyl-2-(cyclohexylamino)-4-(4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl)-1-methylquinoxalin-2(1H)-one in a good yield. The compound was fully characterized