Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecu... more Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (referred to as ‘PROTACs’, for PROteolysis Targeting Chimeras) that recruit a ubiquitin ligase to the target of interest, leading to ubiquitination of the target and its destruction via the ubiquitin-proteasome system. A number of PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by...
Tolerance to abiotic stresses caused by environmental conditions can prevent yield loss in crops ... more Tolerance to abiotic stresses caused by environmental conditions can prevent yield loss in crops for sustaining agricultural productivity [...]
Speciation genes are responsible for reproductive isolation between species. By directly particip... more Speciation genes are responsible for reproductive isolation between species. By directly participating in the process of speciation, the genealogies of isolating loci have been thought to more faithfully represent species trees. The unique properties of speciation genes may provide valuable evolutionary insights and help determine the true history of species divergence. Here, we formally analyze whether genealogies from loci participating in Dobzhansky-Muller (DM) incompatibilities are more likely to be concordant with the species tree under incomplete lineage sorting (ILS). Individual loci differ stochastically from the true history of divergence with a predictable frequency due to ILS, and these expectations-combined with the DM model of intrinsic reproductive isolation from epistatic interactions-can be used to examine the probability of concordance at isolating loci. Contrary to existing verbal models, we find that reproductively isolating loci that follow the DM model are often...
Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical proced... more Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient's phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions. However, due to the use of 100-300-bp fragment reads, this platform is not well powered to sensitively identify moderate to large structural variants (SV), such as insertions, deletions, inversions, and translocations. To overcome these limitations, we used next-generation mapping (NGM) to image high molecular weight double-stranded DNA molecules (megabase size) with fluorescent tags in nanochannel arrays for de novo genome assembly. We investigated the capacity of this NGM platform to identify pathogenic SV in a series of patients diagnosed with Duchenne muscular dystrophy (DMD), due to large deletions, insertion, and inversion involving the DMD gene. We identified del...
Recombination rate is a heritable quantitative trait that evolves despite the fundamentally conse... more Recombination rate is a heritable quantitative trait that evolves despite the fundamentally conserved role that recombination plays in meiosis. Differences in recombination rate can alter the landscape of the genome and the genetic diversity of populations. Yet our understanding of the genetic basis of recombination rate evolution in nature remains limited. We used wild house mice (Mus musculus domesticus) from Gough Island (GI), which diverged recently from their mainland counterparts, to characterize the genetics of recombination rate evolution. We conducted intercrosses between GI-derived mice and the wild-derived inbred strain WSB/EiJ, and quantified genome-wide autosomal recombination rates by immunofluorescence cytology in spermatocytes from 240 F2 males. We identified 4 quantitative trait loci (QTL) responsible for inter-F2 variation in this trait, the strongest of which had effects that opposed the direction of the parental trait differences. Candidate genes and mutations fo...
Genomes of ten species of Elymus, either presumed or known as tetraploid StY, were characterized ... more Genomes of ten species of Elymus, either presumed or known as tetraploid StY, were characterized using fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH). These tetraploid species could be grouped into three categories. Type I included StY genome reported species-Roegneria pendulina, R. nutans, R. glaberrima, R. ciliaris, and Elymus nevskii, and StY genome presumed species-R. sinica, R. breviglumis, and R. dura, whose genome could be separated into two sets based on different GISH intensities. Type I genome constitution was deemed as putative StY. The St genome were mainly characterized with intense hybridization with pAs1, fewer AAG sites, and linked distribution of 5S rDNA and 18S-26S rDNA, while the Y genome with less intense hybridization with pAs1, more varied AAG sites, and isolated distribution of 5S rDNA and 18S-26S rDNA. Nevertheless, further genomic variations were detected among the different StY species. Type II included E. alashanicus, wh...
... Richard Wang, Dana Butnariu, and Jennifer Rexford Princeton University; Princeton, NJ ... In ... more ... Richard Wang, Dana Butnariu, and Jennifer Rexford Princeton University; Princeton, NJ ... In addition, OpenFlow does not sup-port matching on TCP flags (eg, SYN, FIN, and RST) that would help us differentiate between new and ongo-ing connectionsimportant when our ...
Hybrids between species are often sterile or inviable. This form of reproductive isolation is tho... more Hybrids between species are often sterile or inviable. This form of reproductive isolation is thought to evolve via the accumulation of mutations that interact to reduce fitness when combined in hybrids. Mathematical formulations of this "Dobzhansky-Muller model" predict an accelerating buildup of hybrid incompatibilities with divergence time (the "snowball effect"). Although the Dobzhansky-Muller model is widely accepted, the snowball effect has only been tested in two species groups. We evaluated evidence for the snowball effect in the evolution of hybrid male sterility among subspecies of house mice, a recently diverged group that shows partial reproductive isolation. We compared the history of subspecies divergence with patterns of quantitative trait loci (QTL) detected in F2 intercrosses between two pairs of subspecies (Mus musculus domesticus with M. m. musculus and M. m. domesticus with M. m. castaneus). We used a recently developed phylogenetic comparativ...
We have isolated a homolog of the cell division gene ftsZ from the extremely halophilic archaebac... more We have isolated a homolog of the cell division gene ftsZ from the extremely halophilic archaebacterium Halobacterium salinarium. The predicted protein of 39 kDa is divergent relative to eubacterial homologs, with 32% identity to Escherichia coli FtsZ. No other eubacterial cell division gene homologs were found adjacent to H. salinarium ftsZ. Expression of the ftsZ gene region in H. salinarium induced significant morphological changes leading to the loss of rod shape. Phylogenetic analysis demonstrated that the H. salinarium FtsZ protein is more related to tubulins than are the FtsZ proteins of eubacteria, supporting the hypothesis that FtsZ may have evolved into eukaryotic tubulin.
... Quality Judgment Yeona Jang Alexander T. Ishii Richard Y. Wang Massachusetts Institute of Tec... more ... Quality Judgment Yeona Jang Alexander T. Ishii Richard Y. Wang Massachusetts Institute of Technology ... Correspondence and requests for reprints should be sent to Alexander T. Ishii, NEC C&C Research Labs, 4 Independence Way, Princeton, NJ 08540. 101 Page 2. ...
The importance of neutralizing antibodies (NtAb) in protection against hepatitis C virus (HCV) re... more The importance of neutralizing antibodies (NtAb) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06-immunoglobulin from a genotype 1a HCV-infected patient, and challenged with genotype strains efficiently neutralized by H06 in vitro. 1a-NtAb afforded no protection against 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NtAb-titers waned. However, 6a-infection was prevented. The differential in vivo neutralization patterns have implications for HCV vaccine development.
This article provides results of measurements made to characterize the effects of lowering the HE... more This article provides results of measurements made to characterize the effects of lowering the HEPA filter air velocity in a operational semiconductor facility. Reduction of HEPA filter velocity can reduce energy consumption by lowering the power consumption of recirculation fans. Data were collected for the cleanroom base HEPA velocity condition. The same data set was collected for conditions of reduced HEPA filter air velocity. Comparison of the data distinguishes changes between different operational air velocities. There is significant variation in the measured values for HEPA filter velocity attributed to technique and facility parameters. When air velocity is reduced below an optimum value, airborne particle counts and variation in the counts increase. Lowered air velocity also affects total adsorbed vapors, the drain rate of charged wafers, and electrical power consumption of recirculation air handlers. For other measured parameters, a difference can be observed but the pract...
The changing effectiveness of a treatment program for dual-diagnosis patients was evaluated over ... more The changing effectiveness of a treatment program for dual-diagnosis patients was evaluated over a 2-year period with the use of a sequential study group design. The treatment outcome of 179 consecutively enrolled patients with chronic psychotic illness and comorbid substance dependence who entered a specialized day hospital dual-diagnosis treatment program from Sept. 1, 1994, to Aug. 31, 1996, was evaluated. The 24 months were divided into four successive 6-month periods for comparing the evolving effectiveness of the program for groups of patients entering the day hospital during these four periods. Treatment attendance, hospital utilization, and twice weekly urine toxicology analyses were used as outcome measures. The initial treatment engagement rate, defined as at least 2 days of attendance in the first month, increased significantly from group 1 to group 4, more than doubling. Thirty-day and 90-day treatment retention rates also substantially increased from group 1 to group 4....
International Conference on Neural Interface and Control, CNIC, Proceedings, 2005
As software running on computer, mental activities of human brain may entry a dead loop too. Comp... more As software running on computer, mental activities of human brain may entry a dead loop too. Computer-brain interfaces give computers special channels to detect and interfere to interrupt unwanted thoughts which induce unpleasant intrusive thoughts and uncontrollable worry. In the present study, we intend to develop a noninterference and non-wake-up solution to detect and interrupt those unwanted thoughts which extend
Thin heteroepitaxial films of Si1-x-yGexC y have been grown on Si(100) substrates by rapid therma... more Thin heteroepitaxial films of Si1-x-yGexC y have been grown on Si(100) substrates by rapid thermal chemical vapor deposition (RTCVD) using C2H4 as C source. The composition and microstructure of Si1-x-yGex Cy film were characterized by Auger Electron Spectroscopy (AES), Raman spectrum and Fourier transform infrared spectroscopy (FTIR). The results exhibit that lower temperature and higher SiH4/C2H4 flow ratio are helpful to form the substitutional C and improve the crystal quality. A possible mechanism for C incorporation in Si1-x-yGexCy layer grown by RTCVD using C2H4 is also proposed
In this paper we redefine information security by extending its definition in three salient avenu... more In this paper we redefine information security by extending its definition in three salient avenues: locale (beyond the boundary of an enterprise to include partner organizations), role (beyond the information custodians' view to include information consumers' and managers' views), and resource (beyond technical dimensions to include managerial dimensions). Based on our definition, we develop a model of information security, which we call the House of Security. This model has eight constructs, Vulnerability, Accessibility, Confidentiality, IT Resources for Security, Financial Resources for Security, Business Strategy for Security, Security Policy and Procedures, and Security Culture. We have developed a questionnaire to measure the assessment and importance of information security along these eight aspects. The questionnaire covers multiple locales and questionnaire respondents cover multiple roles. Data collection is currently in process. Results from our analysis of the collected data will be ready for presentation at the conference.
Each year, new agents are added to the pharmacopoeia, ex- panding the list of possible toxicologi... more Each year, new agents are added to the pharmacopoeia, ex- panding the list of possible toxicologic reactions. In response, new antidotes are introduced, uses of more established anti- dotes evolve, and new therapeutic approaches to well-estab- lished toxicologic syndromes are developed. This brief update on critical care toxicology focuses on a few of the most impor- tant new developments. The
Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecu... more Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (referred to as ‘PROTACs’, for PROteolysis Targeting Chimeras) that recruit a ubiquitin ligase to the target of interest, leading to ubiquitination of the target and its destruction via the ubiquitin-proteasome system. A number of PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by...
Tolerance to abiotic stresses caused by environmental conditions can prevent yield loss in crops ... more Tolerance to abiotic stresses caused by environmental conditions can prevent yield loss in crops for sustaining agricultural productivity [...]
Speciation genes are responsible for reproductive isolation between species. By directly particip... more Speciation genes are responsible for reproductive isolation between species. By directly participating in the process of speciation, the genealogies of isolating loci have been thought to more faithfully represent species trees. The unique properties of speciation genes may provide valuable evolutionary insights and help determine the true history of species divergence. Here, we formally analyze whether genealogies from loci participating in Dobzhansky-Muller (DM) incompatibilities are more likely to be concordant with the species tree under incomplete lineage sorting (ILS). Individual loci differ stochastically from the true history of divergence with a predictable frequency due to ILS, and these expectations-combined with the DM model of intrinsic reproductive isolation from epistatic interactions-can be used to examine the probability of concordance at isolating loci. Contrary to existing verbal models, we find that reproductively isolating loci that follow the DM model are often...
Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical proced... more Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient's phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions. However, due to the use of 100-300-bp fragment reads, this platform is not well powered to sensitively identify moderate to large structural variants (SV), such as insertions, deletions, inversions, and translocations. To overcome these limitations, we used next-generation mapping (NGM) to image high molecular weight double-stranded DNA molecules (megabase size) with fluorescent tags in nanochannel arrays for de novo genome assembly. We investigated the capacity of this NGM platform to identify pathogenic SV in a series of patients diagnosed with Duchenne muscular dystrophy (DMD), due to large deletions, insertion, and inversion involving the DMD gene. We identified del...
Recombination rate is a heritable quantitative trait that evolves despite the fundamentally conse... more Recombination rate is a heritable quantitative trait that evolves despite the fundamentally conserved role that recombination plays in meiosis. Differences in recombination rate can alter the landscape of the genome and the genetic diversity of populations. Yet our understanding of the genetic basis of recombination rate evolution in nature remains limited. We used wild house mice (Mus musculus domesticus) from Gough Island (GI), which diverged recently from their mainland counterparts, to characterize the genetics of recombination rate evolution. We conducted intercrosses between GI-derived mice and the wild-derived inbred strain WSB/EiJ, and quantified genome-wide autosomal recombination rates by immunofluorescence cytology in spermatocytes from 240 F2 males. We identified 4 quantitative trait loci (QTL) responsible for inter-F2 variation in this trait, the strongest of which had effects that opposed the direction of the parental trait differences. Candidate genes and mutations fo...
Genomes of ten species of Elymus, either presumed or known as tetraploid StY, were characterized ... more Genomes of ten species of Elymus, either presumed or known as tetraploid StY, were characterized using fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH). These tetraploid species could be grouped into three categories. Type I included StY genome reported species-Roegneria pendulina, R. nutans, R. glaberrima, R. ciliaris, and Elymus nevskii, and StY genome presumed species-R. sinica, R. breviglumis, and R. dura, whose genome could be separated into two sets based on different GISH intensities. Type I genome constitution was deemed as putative StY. The St genome were mainly characterized with intense hybridization with pAs1, fewer AAG sites, and linked distribution of 5S rDNA and 18S-26S rDNA, while the Y genome with less intense hybridization with pAs1, more varied AAG sites, and isolated distribution of 5S rDNA and 18S-26S rDNA. Nevertheless, further genomic variations were detected among the different StY species. Type II included E. alashanicus, wh...
... Richard Wang, Dana Butnariu, and Jennifer Rexford Princeton University; Princeton, NJ ... In ... more ... Richard Wang, Dana Butnariu, and Jennifer Rexford Princeton University; Princeton, NJ ... In addition, OpenFlow does not sup-port matching on TCP flags (eg, SYN, FIN, and RST) that would help us differentiate between new and ongo-ing connectionsimportant when our ...
Hybrids between species are often sterile or inviable. This form of reproductive isolation is tho... more Hybrids between species are often sterile or inviable. This form of reproductive isolation is thought to evolve via the accumulation of mutations that interact to reduce fitness when combined in hybrids. Mathematical formulations of this "Dobzhansky-Muller model" predict an accelerating buildup of hybrid incompatibilities with divergence time (the "snowball effect"). Although the Dobzhansky-Muller model is widely accepted, the snowball effect has only been tested in two species groups. We evaluated evidence for the snowball effect in the evolution of hybrid male sterility among subspecies of house mice, a recently diverged group that shows partial reproductive isolation. We compared the history of subspecies divergence with patterns of quantitative trait loci (QTL) detected in F2 intercrosses between two pairs of subspecies (Mus musculus domesticus with M. m. musculus and M. m. domesticus with M. m. castaneus). We used a recently developed phylogenetic comparativ...
We have isolated a homolog of the cell division gene ftsZ from the extremely halophilic archaebac... more We have isolated a homolog of the cell division gene ftsZ from the extremely halophilic archaebacterium Halobacterium salinarium. The predicted protein of 39 kDa is divergent relative to eubacterial homologs, with 32% identity to Escherichia coli FtsZ. No other eubacterial cell division gene homologs were found adjacent to H. salinarium ftsZ. Expression of the ftsZ gene region in H. salinarium induced significant morphological changes leading to the loss of rod shape. Phylogenetic analysis demonstrated that the H. salinarium FtsZ protein is more related to tubulins than are the FtsZ proteins of eubacteria, supporting the hypothesis that FtsZ may have evolved into eukaryotic tubulin.
... Quality Judgment Yeona Jang Alexander T. Ishii Richard Y. Wang Massachusetts Institute of Tec... more ... Quality Judgment Yeona Jang Alexander T. Ishii Richard Y. Wang Massachusetts Institute of Technology ... Correspondence and requests for reprints should be sent to Alexander T. Ishii, NEC C&C Research Labs, 4 Independence Way, Princeton, NJ 08540. 101 Page 2. ...
The importance of neutralizing antibodies (NtAb) in protection against hepatitis C virus (HCV) re... more The importance of neutralizing antibodies (NtAb) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06-immunoglobulin from a genotype 1a HCV-infected patient, and challenged with genotype strains efficiently neutralized by H06 in vitro. 1a-NtAb afforded no protection against 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NtAb-titers waned. However, 6a-infection was prevented. The differential in vivo neutralization patterns have implications for HCV vaccine development.
This article provides results of measurements made to characterize the effects of lowering the HE... more This article provides results of measurements made to characterize the effects of lowering the HEPA filter air velocity in a operational semiconductor facility. Reduction of HEPA filter velocity can reduce energy consumption by lowering the power consumption of recirculation fans. Data were collected for the cleanroom base HEPA velocity condition. The same data set was collected for conditions of reduced HEPA filter air velocity. Comparison of the data distinguishes changes between different operational air velocities. There is significant variation in the measured values for HEPA filter velocity attributed to technique and facility parameters. When air velocity is reduced below an optimum value, airborne particle counts and variation in the counts increase. Lowered air velocity also affects total adsorbed vapors, the drain rate of charged wafers, and electrical power consumption of recirculation air handlers. For other measured parameters, a difference can be observed but the pract...
The changing effectiveness of a treatment program for dual-diagnosis patients was evaluated over ... more The changing effectiveness of a treatment program for dual-diagnosis patients was evaluated over a 2-year period with the use of a sequential study group design. The treatment outcome of 179 consecutively enrolled patients with chronic psychotic illness and comorbid substance dependence who entered a specialized day hospital dual-diagnosis treatment program from Sept. 1, 1994, to Aug. 31, 1996, was evaluated. The 24 months were divided into four successive 6-month periods for comparing the evolving effectiveness of the program for groups of patients entering the day hospital during these four periods. Treatment attendance, hospital utilization, and twice weekly urine toxicology analyses were used as outcome measures. The initial treatment engagement rate, defined as at least 2 days of attendance in the first month, increased significantly from group 1 to group 4, more than doubling. Thirty-day and 90-day treatment retention rates also substantially increased from group 1 to group 4....
International Conference on Neural Interface and Control, CNIC, Proceedings, 2005
As software running on computer, mental activities of human brain may entry a dead loop too. Comp... more As software running on computer, mental activities of human brain may entry a dead loop too. Computer-brain interfaces give computers special channels to detect and interfere to interrupt unwanted thoughts which induce unpleasant intrusive thoughts and uncontrollable worry. In the present study, we intend to develop a noninterference and non-wake-up solution to detect and interrupt those unwanted thoughts which extend
Thin heteroepitaxial films of Si1-x-yGexC y have been grown on Si(100) substrates by rapid therma... more Thin heteroepitaxial films of Si1-x-yGexC y have been grown on Si(100) substrates by rapid thermal chemical vapor deposition (RTCVD) using C2H4 as C source. The composition and microstructure of Si1-x-yGex Cy film were characterized by Auger Electron Spectroscopy (AES), Raman spectrum and Fourier transform infrared spectroscopy (FTIR). The results exhibit that lower temperature and higher SiH4/C2H4 flow ratio are helpful to form the substitutional C and improve the crystal quality. A possible mechanism for C incorporation in Si1-x-yGexCy layer grown by RTCVD using C2H4 is also proposed
In this paper we redefine information security by extending its definition in three salient avenu... more In this paper we redefine information security by extending its definition in three salient avenues: locale (beyond the boundary of an enterprise to include partner organizations), role (beyond the information custodians' view to include information consumers' and managers' views), and resource (beyond technical dimensions to include managerial dimensions). Based on our definition, we develop a model of information security, which we call the House of Security. This model has eight constructs, Vulnerability, Accessibility, Confidentiality, IT Resources for Security, Financial Resources for Security, Business Strategy for Security, Security Policy and Procedures, and Security Culture. We have developed a questionnaire to measure the assessment and importance of information security along these eight aspects. The questionnaire covers multiple locales and questionnaire respondents cover multiple roles. Data collection is currently in process. Results from our analysis of the collected data will be ready for presentation at the conference.
Each year, new agents are added to the pharmacopoeia, ex- panding the list of possible toxicologi... more Each year, new agents are added to the pharmacopoeia, ex- panding the list of possible toxicologic reactions. In response, new antidotes are introduced, uses of more established anti- dotes evolve, and new therapeutic approaches to well-estab- lished toxicologic syndromes are developed. This brief update on critical care toxicology focuses on a few of the most impor- tant new developments. The
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