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

Peculiarities of Electron Transfer in Chiral Linked Systems

Electron transfer (ET) is one of the most universal reactions in chemistry and biology. Recent studies conducted on the examples of photoinduced ET (PET) in chiral linked systems (dyads) have shown several important features indicative for ET in chiral systems. The peculiarity of processes with PET in such systems is primarily the stereoselectivity; there is difference in ET rates and fluorescence quantum yields in dyad diastereomers. The next feature is the spin selectivity of back ET in the biradical-zwitterions (BZs) that are formed under the dyad diastereomer UV irradiation. This is the difference in the enhancement coefficients of chemically induced dynamic nuclear polarization (CIDNP) originated in BZs. The probable cause of this effect is the variation in the spin density values, resulting from difference in the spatial structure of BZ in (R,S)- and (S,S)-configurations. The latter, in turn, is due to the fact that these dyads react in the form of associates—dimers. The impact of dimerization on the effectiveness of ET in chiral systems is an example of the chiral catalysis. The study of ET in chiral linked systems reveals reasons for the various reactivities of chiral molecules, including the difference in therapeutic activity of drug enantiomers

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

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

Federated Learning For Cyber Security: SOC Collaboration For Malicious URL Detection

Managed security service providers increasingly rely on machine-learning methods to exceed traditional, signature- based threat detection and classification methods. As machine- learning often improves with more data available, smaller orga- nizations and clients find themselves at a disadvantage: Without the ability to share their data and others willing to collaborate, their machine-learned threat detection will perform worse than the same model in a larger organization. We show that Feder- ated Learning, i.e. collaborative learning without data sharing, successfully helps to overcome this problem. Our experiments focus on a common task in cyber security, the detection of unwanted URLs in network traffic seen by security-as-a-service providers. Our experiments show that i) Smaller participants benefit from larger participants ii) Participants seeing different types of malicious traffic can generalize better to unseen types of attacks, increasing performance by 8% to 15% on average, and up to 27% in the extreme case. iii) Participating in Federated training never harms the performance of the locally trained model. In our experiment modeling a security-as-a service setting, Federated Learning increased detection up to 30% for some participants in the scheme. This clearly shows that Federated Learning is a viable approach to address issues of data sharing in common cyber security settings

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