## Hotspot

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### H S Udaykumar - One of the best experts on this subject based on the ideXlab platform.

• ##### Modeling mesoscale energy localization in shocked HMX, Part II: training machine-learned surrogate models for void shape and void–void interaction effects
Shock Waves, 2020
Co-Authors: S Roy, Nirmal Kumar Rai, Oishik Sen, D B Hardin, A. S. Diggs, H S Udaykumar
Abstract:

Surrogate models for Hotspot ignition and growth rates were presented in Part I (Nassar et al., Shock Waves 29(4):537–558, 2018 ), where the Hotspots were formed by the collapse of single cylindrical voids. Such isolated cylindrical voids are idealizations of the void morphology in real meso-structures. This paper therefore investigates the effect of non-cylindrical void shapes and void–void interactions on Hotspot ignition and growth. Surrogate models capturing these effects are constructed using a Bayesian Kriging approach. The training data for machine learning the surrogates are derived from reactive void collapse simulations spanning the parameter space of void aspect ratio, void orientation $$(\theta )$$ ( θ ) , and void fraction $$(\phi )$$ ( ϕ ) . The resulting surrogate models portray strong dependence of the ignition and growth rates on void aspect ratio and orientation, particularly when they are oriented at acute angles with respect to the imposed shock. The surrogate models for void interaction effects show significant changes in Hotspot ignition and growth rates as the void fraction increases. The paper elucidates the physics of Hotspot evolution in void fields due to the creation and interaction of multiple Hotspots. The results from this work will be useful not only for constructing meso-informed macroscale models of HMX, but also for understanding the physics of void–void interactions and sensitivity due to void shape and orientation.

• ##### modeling meso scale energy localization in shocked hmx part ii training machine learned surrogate models for void shape and void void interaction effects
arXiv: Computational Physics, 2019
Co-Authors: S Roy, Nirmal Kumar Rai, Oishik Sen, D B Hardin, Angela Diggs, H S Udaykumar
Abstract:

Surrogate models for Hotspot ignition and growth rates were presented in Part I, where the Hotspots were formed by the collapse of single cylindrical voids. Such isolated cylindrical voids are idealizations of the void morphology in real meso-structures. This paper therefore investigates the effect of non-cylindrical void shapes and void-void interactions on Hotspot ignition and growth. Surrogate models capturing these effects are constructed using a Bayesian Kriging approach. The training data for machine learning the surrogates are derived from reactive void collapse simulations spanning the parameter space of void aspect ratio (AR), void orientation ($\theta$), and void fraction ($\phi$). The resulting surrogate models portray strong dependence of the ignition and growth rates on void aspect ratio and orientation, particularly when they are oriented at acute angles with respect to the imposed shock. The surrogate models for void interaction effects show significant changes in Hotspot ignition and growth rates as the void fraction increases. The paper elucidates the physics of Hotspot evolution in void fields due to the creation and interaction of multiple Hotspots. The results from this work will be useful not only for constructing meso-informed macro-scale models of HMX, but also for understanding the physics of void-void interactions and sensitivity due to void shape and orientation.

### Sharmistha Mishra - One of the best experts on this subject based on the ideXlab platform.

• ##### venue based hiv testing at sex work Hotspots to reach adolescent girls and young women living with hiv a cross sectional study in mombasa kenya
Journal of Acquired Immune Deficiency Syndromes, 2020
Co-Authors: Linwei Wang, Peter Gichangi, Vernon Mochache, Griffins Manguro, Helgar Musyoki, Parinita Bhattacharjee, Francois Cholette, Paul Sandstrom, Marissa Becker, Sharmistha Mishra
Abstract:

Background We estimated the potential number of newly diagnosed HIV infections among adolescent girls and young women (AGYW) using a venue-based approach to HIV testing at sex work Hotspots. Methods We used Hotspot enumeration and cross-sectional biobehavioral survey data from the 2015 Transition Study of AGYW aged 14-24 years who frequented Hotspots in Mombasa, Kenya. We described the HIV cascade among young females who sell sex (YFSS) (N = 408) versus those young females who do not sell sex (YFNS) (N = 891) and triangulated the potential (100% test acceptance and accuracy) and feasible (accounting for test acceptance and sensitivity) number of AGYW that could be newly diagnosed through Hotspot-based HIV rapid testing in Mombasa. We identified the profile of AGYW with an HIV in the past year using generalized linear mixed regression models. Results N = 37/365 (10.1%) YFSS and N = 30/828 (3.6%) YFNS were living with HIV, of whom 27.0% (N = 10/37) and 30.0% (N = 9/30) were diagnosed and aware (P = 0.79). Rapid test acceptance was 89.3%, and sensitivity was 80.4%. There were an estimated 15,635 (range: 12,172-19,097) AGYW at Hotspots. The potential and feasible number of new diagnosis was 627 (310-1081), and 450 (223-776), respectively. Thus, Hotspot-based testing could feasibly reduce the undiagnosed fraction from 71.6% to 20.2%. The profile of AGYW who recently tested was similar among YFSS and YFNS. YFSS were 2-fold more likely to report a recent HIV test after adjusting for other determinants [odds ratio (95% confidence interval): 2.2 (1.5 to 3.1)]. Conclusion Reaching AGYW through Hotspot-based HIV testing could fill gaps left by traditional, clinic-based HIV testing services.

• ##### venue based hiv testing at sex work Hotspots to reach adolescent girls and young women living with hiv a cross sectional study in mombasa kenya
arXiv: Other Quantitative Biology, 2019
Co-Authors: Linwei Wang, Peter Gichangi, Vernon Mochache, Griffins Manguro, Helgar Musyoki, Parinita Bhattacharjee, Francois Cholette, Paul Sandstrom, Marissa Becker, Sharmistha Mishra
Abstract:

Background: We estimated the potential number of newly diagnosed HIV infections among adolescent girls and young women (AGYW) using a venue-based approach to HIV testing at sex work Hotspots. Methods: We used Hotspot enumeration and cross-sectional bio-behavioural survey data from the 2015 Transitions Study of AGYW aged 14-24 years who frequented Hotspots in Mombasa, Kenya. We compared the HIV cascade among AGYW who sell sex (YSW, N=408) versus those who do not (NSW, N=891); and triangulated the potential (100% test acceptance and accuracy) and feasible (accounting for test acceptance and sensitivity) number of AGYW that could be newly diagnosed via Hotspot-based HIV rapid testing in Mombasa. We identified the profile of AGYW recently tested for HIV (in the past year) using multivariable logistic regression. Results: N=37/365 (10.1%) YSW and N=30/828 (3.6%) NSW were living with HIV, of whom 27.0% (N=10/37) and 30.0% (N=9/30) were diagnosed and aware (p=0.79). Rapid test acceptance was 89.3% and sensitivity was 80.4%. Hotspot enumeration estimated 15,635 (range: 12,172-19,097) AGYW in Hotspots in Mombasa. The potential and feasible number of new diagnosis were 627 (310-1,081), and 450 (223-776), respectively. Thus, Hotspot-based testing could feasibly reduce the undiagnosed fraction from 71.6% to 20.2%. The profile of AGYW who recently tested was similar among YSW and NSW. YSW were two-fold more likely to report a recent HIV test after adjusting for other determinants [odds ratio (95% CI): 2.1 (1.6-3.1)]. Conclusion: Reaching AGYW via Hotspot-based HIV testing could fill gaps left by traditional, clinic-based HIV prevention and testing services.

### S Roy - One of the best experts on this subject based on the ideXlab platform.

• ##### Modeling mesoscale energy localization in shocked HMX, Part II: training machine-learned surrogate models for void shape and void–void interaction effects
Shock Waves, 2020
Co-Authors: S Roy, Nirmal Kumar Rai, Oishik Sen, D B Hardin, A. S. Diggs, H S Udaykumar
Abstract:

Surrogate models for Hotspot ignition and growth rates were presented in Part I (Nassar et al., Shock Waves 29(4):537–558, 2018 ), where the Hotspots were formed by the collapse of single cylindrical voids. Such isolated cylindrical voids are idealizations of the void morphology in real meso-structures. This paper therefore investigates the effect of non-cylindrical void shapes and void–void interactions on Hotspot ignition and growth. Surrogate models capturing these effects are constructed using a Bayesian Kriging approach. The training data for machine learning the surrogates are derived from reactive void collapse simulations spanning the parameter space of void aspect ratio, void orientation $$(\theta )$$ ( θ ) , and void fraction $$(\phi )$$ ( ϕ ) . The resulting surrogate models portray strong dependence of the ignition and growth rates on void aspect ratio and orientation, particularly when they are oriented at acute angles with respect to the imposed shock. The surrogate models for void interaction effects show significant changes in Hotspot ignition and growth rates as the void fraction increases. The paper elucidates the physics of Hotspot evolution in void fields due to the creation and interaction of multiple Hotspots. The results from this work will be useful not only for constructing meso-informed macroscale models of HMX, but also for understanding the physics of void–void interactions and sensitivity due to void shape and orientation.

• ##### modeling meso scale energy localization in shocked hmx part ii training machine learned surrogate models for void shape and void void interaction effects
arXiv: Computational Physics, 2019
Co-Authors: S Roy, Nirmal Kumar Rai, Oishik Sen, D B Hardin, Angela Diggs, H S Udaykumar
Abstract:

Surrogate models for Hotspot ignition and growth rates were presented in Part I, where the Hotspots were formed by the collapse of single cylindrical voids. Such isolated cylindrical voids are idealizations of the void morphology in real meso-structures. This paper therefore investigates the effect of non-cylindrical void shapes and void-void interactions on Hotspot ignition and growth. Surrogate models capturing these effects are constructed using a Bayesian Kriging approach. The training data for machine learning the surrogates are derived from reactive void collapse simulations spanning the parameter space of void aspect ratio (AR), void orientation ($\theta$), and void fraction ($\phi$). The resulting surrogate models portray strong dependence of the ignition and growth rates on void aspect ratio and orientation, particularly when they are oriented at acute angles with respect to the imposed shock. The surrogate models for void interaction effects show significant changes in Hotspot ignition and growth rates as the void fraction increases. The paper elucidates the physics of Hotspot evolution in void fields due to the creation and interaction of multiple Hotspots. The results from this work will be useful not only for constructing meso-informed macro-scale models of HMX, but also for understanding the physics of void-void interactions and sensitivity due to void shape and orientation.

### Alec J Jeffreys - One of the best experts on this subject based on the ideXlab platform.

• ##### variants of the protein prdm9 differentially regulate a set of human meiotic recombination Hotspots highly active in african populations
Proceedings of the National Academy of Sciences of the United States of America, 2011
Co-Authors: Ingrid L Berg, Rita Neumann, Shriparna Sarbajna, Linda Odenthalhesse, Nicola J Butler, Alec J Jeffreys
Abstract:

PRDM9 is a major specifier of human meiotic recombination Hotspots, probably via binding of its zinc-finger repeat array to a DNA sequence motif associated with Hotspots. However, our view of PRDM9 regulation, in terms of motifs defined and Hotspots studied, has a strong bias toward the PRDM9 A variant particularly common in Europeans. We show that population diversity can reveal a second class of Hotspots specifically activated by PRDM9 variants common in Africans but rare in Europeans. These African-enhanced Hotspots nevertheless share very similar properties with their counterparts activated by the A variant. The specificity of Hotspot activation is such that individuals with differing PRDM9 genotypes, even within the same population, can use substantially if not completely different sets of Hotspots. Each African-enhanced Hotspot is activated by a distinct spectrum of PRDM9 variants, despite the fact that all are predicted to bind the same sequence motif. This differential activation points to complex interactions between the zinc-finger array and Hotspots and identifies features of the array that might be important in controlling Hotspot activity.

• ##### polymorphism in the activity of human crossover Hotspots independent of local dna sequence variation
Human Molecular Genetics, 2006
Co-Authors: Rita Neumann, Alec J Jeffreys
Abstract:

Meiotic crossovers in the human genome cluster into highly localized Hotspots identifiable indirectly from patterns of DNA diversity and directly by high-resolution sperm typing. Little is known about factors that control Hotspot activity and the apparently rapid turnover of Hotspots during recent evolution. Clues can, however, be gained by characterizing variation in sperm crossover activity between men. Previous studies have identified single nucleotide polymorphisms within Hotspots that appear to suppress crossover activity and which may be involved in Hotspot attenuation/extinction. We now analyse a closely spaced pair of Hotspots (MSTM1a, MSTM1b) on chromosome 1q42.3, the former being a candidate for a young Hotspot that has failed to leave a significant mark on haplotype diversity. Extensive surveys of different men revealed substantial polymorphism in sperm crossover frequencies at both Hotspots, but with very different patterns of variation. Hotspot MSTM1b was active in all men tested but with widely differing crossover frequencies. In contrast, MSTM1a was active in only a few men and appeared to be recombinationally inert in the remainder, providing the first example of presence/absence polymorphism of a human Hotspot. Haplotype analysis around both Hotspots identified active and suppressed men sharing identical haplotypes, establishing that these major variations in the presence/absence of a Hotspot and in quantitative activity are not caused by local DNA sequence variation. These findings suggest a role for distal regulators or epigenetic factors in Hotspot activity and provide the first direct evidence for the rapid evolution of recombination Hotspots in humans.

• ##### factors influencing recombination frequency and distribution in a human meiotic crossover Hotspot
Human Molecular Genetics, 2005
Co-Authors: Alec J Jeffreys, Rita Neumann
Abstract:

Little is known about the factors that influence the frequency and distribution of meiotic recombination events within human crossover Hotspots. We now describe the detailed analysis of sperm recombination in the NID1 Hotspot. Like the neighbouring MS32 Hotspot, the NID1 Hotspot is associated with a minisatellite, suggesting that Hotspots predispose DNA to tandem repetition. Unlike MS32, crossover resolution breakpoints in NID1 avoid the minisatellite, producing a cold spot within the Hotspot. This avoidance may be related to the palindromic nature of the minisatellite interfering with the generation and/or processing of recombination intermediates. The NID1 Hotspot also contains a single nucleotide polymorphism (SNP) close to the centre, which appears to directly influence the frequency of crossover initiation. Quantitative gene conversion assays show that this SNP affects the frequency of gene conversion and crossover to a very similar extent, providing evidence that conversions and crossovers are triggered by the same recombination initiating events. The recombination-suppressing allele is over-transmitted to recombinant progeny, and provides the most dramatic example to date of recombination-mediated meiotic drive, of a magnitude sufficient to virtually guarantee that the recombination suppressor will eventually replace the more active allele in human populations.

• ##### high resolution analysis of haplotype diversity and meiotic crossover in the human tap2 recombination Hotspot
Web Science, 2000
Co-Authors: Alec J Jeffreys, Alistair Ritchie, Rita Neumann
Abstract:

Little is known about the nature of recombination Hotspots in the human genome and the relationship between crossover activity and patterns of linkage disequilibrium. We have therefore used both haplotype analysis and direct detection of crossovers in sperm to characterize a putative recombination Hotspot in the TAP2 gene within the class II region of the MHC. Haplotype diversity provided evidence for a localized Hotspot within intron 2 of this gene. Sperm DNA typing using allele-specific PCR primers to selectively amplify recombinant TAP2 molecules revealed a highly localized meiotic crossover Hotspot approximately 1.2 kb long, unusually abundant in sequence polymorphisms and flanked by DNA much less active in recombination. Sperm crossover appeared to be fully reciprocal, and almost all crossover products were simple, involving a single exchange between adjacent heterozygous markers. This Hotspot appears to be much more active in female than male meiosis. No primary sequence similarities could be found between any of the very few well defined crossover Hotspots in the human genome, all of which show recombinationally active domains 1-2 kb long. Direct comparison of recombination frequency and haplotype diversity in TAP2 showed that linkage disequilibrium measures were a poor predictor of crossover frequency in this region, with non-recombining markers sometimes in free association and with examples of pairs of markers spanning the recombination Hotspot showing substantial or even absolute linkage disequilibrium.

### Rita Neumann - One of the best experts on this subject based on the ideXlab platform.

• ##### variants of the protein prdm9 differentially regulate a set of human meiotic recombination Hotspots highly active in african populations
Proceedings of the National Academy of Sciences of the United States of America, 2011
Co-Authors: Ingrid L Berg, Rita Neumann, Shriparna Sarbajna, Linda Odenthalhesse, Nicola J Butler, Alec J Jeffreys
Abstract:

PRDM9 is a major specifier of human meiotic recombination Hotspots, probably via binding of its zinc-finger repeat array to a DNA sequence motif associated with Hotspots. However, our view of PRDM9 regulation, in terms of motifs defined and Hotspots studied, has a strong bias toward the PRDM9 A variant particularly common in Europeans. We show that population diversity can reveal a second class of Hotspots specifically activated by PRDM9 variants common in Africans but rare in Europeans. These African-enhanced Hotspots nevertheless share very similar properties with their counterparts activated by the A variant. The specificity of Hotspot activation is such that individuals with differing PRDM9 genotypes, even within the same population, can use substantially if not completely different sets of Hotspots. Each African-enhanced Hotspot is activated by a distinct spectrum of PRDM9 variants, despite the fact that all are predicted to bind the same sequence motif. This differential activation points to complex interactions between the zinc-finger array and Hotspots and identifies features of the array that might be important in controlling Hotspot activity.

• ##### polymorphism in the activity of human crossover Hotspots independent of local dna sequence variation
Human Molecular Genetics, 2006
Co-Authors: Rita Neumann, Alec J Jeffreys
Abstract:

Meiotic crossovers in the human genome cluster into highly localized Hotspots identifiable indirectly from patterns of DNA diversity and directly by high-resolution sperm typing. Little is known about factors that control Hotspot activity and the apparently rapid turnover of Hotspots during recent evolution. Clues can, however, be gained by characterizing variation in sperm crossover activity between men. Previous studies have identified single nucleotide polymorphisms within Hotspots that appear to suppress crossover activity and which may be involved in Hotspot attenuation/extinction. We now analyse a closely spaced pair of Hotspots (MSTM1a, MSTM1b) on chromosome 1q42.3, the former being a candidate for a young Hotspot that has failed to leave a significant mark on haplotype diversity. Extensive surveys of different men revealed substantial polymorphism in sperm crossover frequencies at both Hotspots, but with very different patterns of variation. Hotspot MSTM1b was active in all men tested but with widely differing crossover frequencies. In contrast, MSTM1a was active in only a few men and appeared to be recombinationally inert in the remainder, providing the first example of presence/absence polymorphism of a human Hotspot. Haplotype analysis around both Hotspots identified active and suppressed men sharing identical haplotypes, establishing that these major variations in the presence/absence of a Hotspot and in quantitative activity are not caused by local DNA sequence variation. These findings suggest a role for distal regulators or epigenetic factors in Hotspot activity and provide the first direct evidence for the rapid evolution of recombination Hotspots in humans.

• ##### factors influencing recombination frequency and distribution in a human meiotic crossover Hotspot
Human Molecular Genetics, 2005
Co-Authors: Alec J Jeffreys, Rita Neumann
Abstract:

Little is known about the factors that influence the frequency and distribution of meiotic recombination events within human crossover Hotspots. We now describe the detailed analysis of sperm recombination in the NID1 Hotspot. Like the neighbouring MS32 Hotspot, the NID1 Hotspot is associated with a minisatellite, suggesting that Hotspots predispose DNA to tandem repetition. Unlike MS32, crossover resolution breakpoints in NID1 avoid the minisatellite, producing a cold spot within the Hotspot. This avoidance may be related to the palindromic nature of the minisatellite interfering with the generation and/or processing of recombination intermediates. The NID1 Hotspot also contains a single nucleotide polymorphism (SNP) close to the centre, which appears to directly influence the frequency of crossover initiation. Quantitative gene conversion assays show that this SNP affects the frequency of gene conversion and crossover to a very similar extent, providing evidence that conversions and crossovers are triggered by the same recombination initiating events. The recombination-suppressing allele is over-transmitted to recombinant progeny, and provides the most dramatic example to date of recombination-mediated meiotic drive, of a magnitude sufficient to virtually guarantee that the recombination suppressor will eventually replace the more active allele in human populations.

• ##### high resolution analysis of haplotype diversity and meiotic crossover in the human tap2 recombination Hotspot
Web Science, 2000
Co-Authors: Alec J Jeffreys, Alistair Ritchie, Rita Neumann
Abstract:

Little is known about the nature of recombination Hotspots in the human genome and the relationship between crossover activity and patterns of linkage disequilibrium. We have therefore used both haplotype analysis and direct detection of crossovers in sperm to characterize a putative recombination Hotspot in the TAP2 gene within the class II region of the MHC. Haplotype diversity provided evidence for a localized Hotspot within intron 2 of this gene. Sperm DNA typing using allele-specific PCR primers to selectively amplify recombinant TAP2 molecules revealed a highly localized meiotic crossover Hotspot approximately 1.2 kb long, unusually abundant in sequence polymorphisms and flanked by DNA much less active in recombination. Sperm crossover appeared to be fully reciprocal, and almost all crossover products were simple, involving a single exchange between adjacent heterozygous markers. This Hotspot appears to be much more active in female than male meiosis. No primary sequence similarities could be found between any of the very few well defined crossover Hotspots in the human genome, all of which show recombinationally active domains 1-2 kb long. Direct comparison of recombination frequency and haplotype diversity in TAP2 showed that linkage disequilibrium measures were a poor predictor of crossover frequency in this region, with non-recombining markers sometimes in free association and with examples of pairs of markers spanning the recombination Hotspot showing substantial or even absolute linkage disequilibrium.