Practice with Graph-based ANN Algorithms on Sparse Data: Chi-square Two-tower model, HNSW, Sign Cauchy Projections

Sparse data are common. The traditional ``handcrafted'' features are often sparse. Embedding vectors from trained models can also be very sparse, for example, embeddings trained via the ``ReLu'' activation function. In this paper, we report our exploration of efficient search in sparse data with graph-based ANN algorithms (e.g., HNSW, or SONG which is the GPU version of HNSW), which are popular in industrial practice, e.g., search and ads (advertising). We experiment with the proprietary ads targeting application, as well as benchmark public datasets. For ads targeting, we train embeddings with the standard ``cosine two-tower'' model and we also develop the ``chi-square two-tower'' model. Both models produce (highly) sparse embeddings when they are integrated with the ``ReLu'' activation function. In EBR (embedding-based retrieval) applications, after we the embeddings are trained, the next crucial task is the approximate near neighbor (ANN) search for serving. While there are many ANN algorithms we can choose from, in this study, we focus on the graph-based ANN algorithm (e.g., HNSW-type). Sparse embeddings should help improve the efficiency of EBR. One benefit is the reduced memory cost for the embeddings. The other obvious benefit is the reduced computational time for evaluating similarities, because, for graph-based ANN algorithms such as HNSW, computing similarities is often the dominating cost. In addition to the effort on leveraging data sparsity for storage and computation, we also integrate ``sign cauchy random projections'' (SignCRP) to hash vectors to bits, to further reduce the memory cost and speed up the ANN search. In NIPS'13, SignCRP was proposed to hash the chi-square similarity, which is a well-adopted nonlinear kernel in NLP and computer vision. Therefore, the chi-square two-tower model, SignCRP, and HNSW are now tightly integrated

Compton Scattering in Ultra-Strong Magnetic Fields: Numerical and Analytical Behavior in the Relativistic Regime

This paper explores the effects of strong magnetic fields on the Compton scattering of relativistic electrons. Recent studies of upscattering and energy loss by relativistic electrons that have used the non-relativistic, magnetic Thomson cross section for resonant scattering or the Klein-Nishina cross section for non-resonant scattering do not account for the relativistic quantum effects of strong fields ($> 4 \times 10^{12}$ G). We have derived a simplified expression for the exact QED scattering cross section for the broadly-applicable case where relativistic electrons move along the magnetic field. To facilitate applications to astrophysical models, we have also developed compact approximate expressions for both the differential and total polarization-dependent cross sections, with the latter representing well the exact total QED cross section even at the high fields believed to be present in environments near the stellar surfaces of Soft Gamma-Ray Repeaters and Anomalous X-Ray Pulsars. We find that strong magnetic fields significantly lower the Compton scattering cross section below and at the resonance, when the incident photon energy exceeds $m_ec^2$ in the electron rest frame. The cross section is strongly dependent on the polarization of the final scattered photon. Below the cyclotron fundamental, mostly photons of perpendicular polarization are produced in scatterings, a situation that also arises above this resonance for sub-critical fields. However, an interesting discovery is that for super-critical fields, a preponderance of photons of parallel polarization results from scatterings above the cyclotron fundamental. This characteristic is both a relativistic and magnetic effect not present in the Thomson or Klein-Nishina limits.Comment: AASTeX format, 31 pages included 7 embedded figures, accepted for publication in The Astrophysical Journa

Rapid profiling of DNA replication dynamics using mass spectrometry-based analysis of nascent DNA

The primary method for probing DNA replication dynamics is DNA fiber analysis, which utilizes thymidine analog incorporation into nascent DNA, followed by immunofluorescent microscopy of DNA fibers. Besides being time-consuming and prone to experimenter bias, it is not suitable for studying DNA replication dynamics in mitochondria or bacteria, nor is it adaptable for higher-throughput analysis. Here, we present mass spectrometry-based analysis of nascent DNA (MS-BAND) as a rapid, unbiased, quantitative alternative to DNA fiber analysis. In this method, incorporation of thymidine analogs is quantified from DNA using triple quadrupole tandem mass spectrometry. MS-BAND accurately detects DNA replication alterations in both the nucleus and mitochondria of human cells, as well as bacteria. The high-throughput capability of MS-BAND captured replication alterations in an E. coli DNA damage-inducing gene library. Therefore, MS-BAND may serve as an alternative to the DNA fiber technique, with potential for high-throughput analysis of replication dynamics in diverse model systems

Full polar cap cascade scenario: γ\gamma-ray and X-ray luminosities from spin-powered pulsars

We modify polar cap cascade picture to include the ICS of the higher generation pairs. In such a ``full-cascade'' scenario, not only the perpendicular portion of the energy of the pairs goes to high energy radiation via SR, but the parallel portion of the energy of the pairs can also contribute to high energy emission via ICS with the soft thermal photons from either the full neutron star surface or the hot polar cap. An important output of such a scenario is that the soft tail of the ICS spectrum can naturally result in a non-thermal X-ray component which can contribute to the luminosities observed by ROSAT and ASCA. Here we present an analytic description of such a full polar cap cascade scenario within the framework of Harding & Muslimov acceleration model. We present the theoretical predictions of the $\gamma$-ray luminosities, the thermal and non-thermal X-ray luminosities for the known spin-powered X-ray pulsars. Our results show that the observed different dependences of the high energy luminosities on the pulsar spin-down luminosities, i.e., $L_\gamma \propto (L_{\rm sd})^{1/2}$ and $L_x \sim 10^{-3} L_{\rm sd}$, are well reproduced. Our model predicts that the {\em pulsed} soft X-rays in the ROSAT band from most of the millisecond pulsars might be of thermal origin if there is no strong multipole field components near the surfaces of these pulsars.Comment: 23 pages, emulateapj style, final version to appear in the Astrophysical Journa

Unique, Gender-Dependent Serum microRNA Profile inPLS3 Gene-Related Osteoporosis

Plastin 3 (PLS3), encoded byPLS3, is a newly recognized regulator of bone metabolism, and mutations in the encoding gene result in severe childhood-onset osteoporosis. Because it is an X chromosomal gene,PLS3mutation-positive males are typically more severely affected whereas females portray normal to increased skeletal fragility. Despite the severe skeletal pathology, conventional metabolic bone markers tend to be normal and are thus insufficient for diagnosing or monitoring patients. Our study aimed to explore serum microRNA (miRNA) concentrations in subjects with defective PLS3 function to identify novel markers that could differentiate subjects according to mutation status and give insight into the molecular mechanisms by which PLS3 regulates skeletal health. We analyzed fasting serum samples for a custom-designed panel comprising 192 miRNAs in 15 mutation-positive (five males, age range 8-76 years, median 41 years) and 14 mutation-negative (six males, age range 8-69 years, median 40 years) subjects from four Finnish families with differentPLS3mutations. We identified a unique miRNA expression profile in the mutation-positive subjects with seven significantly upregulated or downregulated miRNAs (miR-93-3p, miR-532-3p, miR-133a-3p, miR-301b-3p, miR-181c-5p, miR-203a-3p, and miR-590-3p;pvalues, range .004-.044). Surprisingly, gender subgroup analysis revealed the difference to be even more distinct in female mutation-positive subjects (congruentpvalues, range .007-.086) than in males (pvalues, range .127-.843) in comparison to corresponding mutation-negative subjects. Although the seven identified miRNAs have all been linked to bone metabolism and two of them (miR-181c-5p and miR-203a-3p) have bioinformatically predicted targets in thePLS33 ' untranslated region (3 '-UTR), none have previously been reported to associate with PLS3. Our results indicate thatPLS3mutations are reflected in altered serum miRNA levels and suggest there is crosstalk between PLS3 and these miRNAs in bone metabolism. These provide new understanding of the pathomechanisms by which mutations inPLS3lead to skeletal disease and may provide novel avenues for exploring miRNAs as biomarkers in PLS3 osteoporosis or as target molecules in future therapeutic applications. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by American Society for Bone and Mineral Research.Peer reviewe

L-Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

Background and Purpose Preeclampsia, characterized by hypertension, proteinuria and restriction of fetal growth, is one of the leading causes of maternal and perinatal mortality. So far, there is no effective pharmacological therapy for preeclampsia. The present study was conducted to investigate the effects of supplementation with l-citrulline in Dahl salt-sensitive rats, a model of superimposed preeclampsia. Experimental Approach Parental Dahl salt-sensitive rats were treated with l-citrulline (2.5 g·L−1 in drinking water) from the day of mating to the end of lactation period. Blood pressure was monitored throughout pregnancy and markers of preeclampsia were assessed. Endothelial function of the pregnant Dahl salt-sensitive rats was assessed by wire myograph. Key Results In Dahl salt-sensitive rats, l-citrulline supplementation significantly reduced maternal blood pressure, proteinuria and levels of circulating soluble fms-like tyrosine kinase 1. l-Citrulline improved maternal endothelial function by augmenting the production of nitric oxide in the aorta and improving endothelium-derived hyperpolarizing factor-mediated vasorelaxation in resistance arteries. l-Citrulline supplementation improved placental insufficiency and fetal growth, which were associated with an enhancement of angiogenesis and reduction of fibrosis and senescence in the placentas. In addition, l-citrulline down-regulated genes involved in the TLR4 and NF-κB signalling pathways. Conclusion and Implications This study shows that l-citrulline supplementation reduced gestational hypertension and improved placentation and fetal growth in a rat model of superimposed preeclampsia. l-Citrulline supplementation may provide an effective and safe therapeutic strategy for preeclampsia that benefits both the mother and the fetus

Exome Sequencing Reveals a Phenotype Modifying Variant inZNF528in Primary Osteoporosis With aCOL1A2Deletion

We studied a family with severe primary osteoporosis carrying a heterozygous p.Arg8Phefs*14 deletion in COL1A2, leading to haploinsufficiency. Three affected individuals carried the mutation and presented nearly identical spinal fractures but lacked other typical features of either osteogenesis imperfecta or Ehlers-Danlos syndrome. Although mutations leading to haploinsufficiency in COL1A2 are rare, mutations in COL1A1 that lead to less protein typically result in a milder phenotype. We hypothesized that other genetic factors may contribute to the severe phenotype in this family. We performed whole-exome sequencing in five family members and identified in all three affected individuals a rare nonsense variant (c.1282C > T/p.Arg428*, rs150257846) in ZNF528. We studied the effect of the variant using qPCR and Western blot and its subcellular localization with immunofluorescence. Our results indicate production of a truncated ZNF528 protein that locates in the cell nucleus as per the wild-type protein. ChIP and RNA sequencing analyses on ZNF528 and ZNF528-c.1282C > T indicated that ZNF528 binding sites are linked to pathways and genes regulating bone morphology. Compared with the wild type, ZNF528-c.1282C > T showed a global shift in genomic binding profile and pathway enrichment, possibly contributing to the pathophysiology of primary osteoporosis. We identified five putative target genes for ZNF528 and showed that the expression of these genes is altered in patient cells. In conclusion, the variant leads to expression of truncated ZNF528 and a global change of its genomic occupancy, which in turn may lead to altered expression of target genes. ZNF528 is a novel candidate gene for bone disorders and may function as a transcriptional regulator in pathways affecting bone morphology and contribute to the phenotype of primary osteoporosis in this family together with the COL1A2 deletion. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Peer reviewe

Orexinergic Input to Dopaminergic Neurons of the Human Ventral Tegmental Area

The mesolimbic reward pathway arising from dopaminergic (DA) neurons of the ventral tegmental area (VTA) has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN) were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR) axons apposed to tyrosine hydroxylase (TH)-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.062.8% of TH-IR perikarya in humans and 3.260.3% in rats received orexin B-IR afferent contacts. On average, 0.2460.05 and 0.0560.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority(86–88%) of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavierorexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents