Meiotic Transmission of an In Vitro<i>–</i>Assembled Autonomous Maize Minichromosome

Autonomous chromosomes are generated in yeast (yeast artificial chromosomes) and human fibrosarcoma cells (human artificial chromosomes) by introducing purified DNA fragments that nucleate a kinetochore, replicate, and segregate to daughter cells. These autonomous minichromosomes are convenient for manipulating and delivering DNA segments containing multiple genes. In contrast, commercial production of transgenic crops relies on methods that integrate one or a few genes into host chromosomes; extensive screening to identify insertions with the desired expression level, copy number, structure, and genomic location; and long breeding programs to produce varieties that carry multiple transgenes. As a step toward improving transgenic crop production, we report the development of autonomous maize minichromosomes (MMCs). We constructed circular MMCs by combining DsRed and nptII marker genes with 7–190 kb of genomic maize DNA fragments containing satellites, retroelements, and/or other repeats commonly found in centromeres and using particle bombardment to deliver these constructs into embryogenic maize tissue. We selected transformed cells, regenerated plants, and propagated their progeny for multiple generations in the absence of selection. Fluorescent in situ hybridization and segregation analysis demonstrated that autonomous MMCs can be mitotically and meiotically maintained. The MMC described here showed meiotic segregation ratios approaching Mendelian inheritance: 93% transmission as a disome (100% expected), 39% transmission as a monosome crossed to wild type (50% expected), and 59% transmission in self crosses (75% expected). The fluorescent DsRed reporter gene on the MMC was expressed through four generations, and Southern blot analysis indicated the encoded genes were intact. This novel approach for plant transformation can facilitate crop biotechnology by (i) combining several trait genes on a single DNA fragment, (ii) arranging genes in a defined sequence context for more consistent gene expression, and (iii) providing an independent linkage group that can be rapidly introgressed into various germplasms.</p

The Role of Geography in Human Adaptation

Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme FST values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes—especially population history, migration, and drift—exert powerful influences over the fate and geographic distribution of selected alleles.</p

Magnon-mediated qubit coupling determined via dissipation measurements

Controlled interaction between localized and delocalized solid-state spin systems offers a compelling platform for on-chip quantum information processing with quantum spintronics. Hybrid quantum systems (HQSs) of localized nitrogen-vacancy (NV) centers in diamond and delocalized magnon modes in ferrimagnets—systems with naturally commensurate energies—have recently attracted significant attention, especially for interconnecting isolated spin qubits at length-scales far beyond those set by the dipolar coupling. However, despite extensive theoretical efforts, there is a lack of experimental characterization of the magnon-mediated interaction between NV centers, which is necessary to develop such hybrid quantum architectures. Here, we experimentally determine the magnon-mediated NV–NV coupling from the magnon-induced self-energy of NV centers. Our results are quantitatively consistent with a model in which the NV center is coupled to magnons by dipolar interactions. This work provides a versatile tool to characterize HQSs in the absence of strong coupling, informing future efforts to engineer entangled solid-state systems

Data Isotopes for Data Provenance in DNNs

Today, creators of data-hungry deep neural networks (DNNs) scour the Internet for training fodder, leaving users with little control over or knowledge of when their data, and in particular their images, are used to train models. To empower users to counteract unwanted use of their images, we design, implement and evaluate a practical system that enables users to detect if their data was used to train a DNN model for image classification. We show how users can create special images we call isotopes, which introduce ``spurious features'' into DNNs during training. With only query access to a model and no knowledge of the model-training process, nor control of the data labels, a user can apply statistical hypothesis testing to detect if the model learned these spurious features by training on the user's images. Isotopes can be viewed as an application of a particular type of data poisoning. In contrast to backdoors and other poisoning attacks, our purpose is not to cause misclassification but rather to create tell-tale changes in confidence scores output by the model that reveal the presence of isotopes in the training data. Isotopes thus turn DNNs' vulnerability to memorization and spurious correlations into a tool for data provenance. Our results confirm efficacy in multiple image classification settings, detecting and distinguishing between hundreds of isotopes with high accuracy. We further show that our system works on public ML-as-a-service platforms and larger models such as ImageNet, can use physical objects in images instead of digital marks, and remains robust against several adaptive countermeasures.</p

Judicial Oversight of National Security Policy in Ontologically Contested Democracies

National security governance has predominantly been organized by the elected branches of government. The executive and legislative branches, many constitutional scholars contend, are institutionally more competent and democratically more legitimate in governing national security matters than courts. However, the conventional view that courts play limited roles in overseeing national security policies is not universally supported, and this is especially the case in ontologically contested democracies, where the boundary of the state or the core interests of national security are inherently contentious due to the prolonged geopolitical tensions these democracies experience. Owing to the distinct nature of ontologically contested democracies, national security governance involves the normalization of geopolitical tensions, uneven public support for the executive’s decisive national security measures, and high-profile national security disputes. These three factors present a particular political and constitutional environment that may encourage courts to oversee national security policies in a rigorous manner. In this dissertation, I examine the oversight of national security policy by constitutional courts in three ontologically contested democracies: South Korea, Taiwan, and Lithuania. Focusing on the behavior of the three constitutional courts, I present three major research findings: First, I show that the methodologies used by the constitutional courts to handle national security disputes have been shaped by their respective international and domestic political contexts. Second, I identify three conditions which contribute to the exercise of oversight by the Constitutional Courts of South Korea, Taiwan, and Lithuania in the national security context: judicial capacity, political schism, and judicial reputation. Regarding judicial capacity, I argue that the three constitutional courts have been familiar with and thus capable of deciding on national security disputes related to civil liberties protections, mandatory military issues, and large-scale military reforms, given that the disputes within these categories have been handled by the courts regularly due to the normalization of national security concerns in these jurisdictions. Regarding political schism, I demonstrate that intense political divisions in South Korea, Taiwan, and Lithuania have given the three constitutional courts substantial leverage to mediate political elites. Finally, concerning judicial reputation, I show that the Constitutional Courts of South Korea, Taiwan, and Lithuania have rigorously exercised oversight in high-profile national security disputes. As these disputes attract widespread attention from domestic or even international audiences, judicial oversight, rather than deference, strengthens the reputation of the courts in the eyes of their target audiences. Third, I demonstrate that by exercising oversight, the Constitutional Courts of South Korea, Taiwan, and Lithuania have stimulated legal reforms, mediated political conflicts, and strengthened the doctrinal significance of national security in their respective jurisdictions. Through these methods, the three constitutional courts have rigorously established the ground rules for formulating and enforcing national security policies. With these findings, I underscore the necessity of carefully considering the nuanced dynamics and effects of the judicial politics surrounding national security law from a comparative perspective. Comparative studies of national security law can broaden and deepen our understanding of the functions of courts within diverse national contexts

Missed Opportunities: The Impact of Opportunity Zones on Small Business Development in New York City

In 2017, the Tax Cuts and Jobs Act introduced the Opportunity Zone (OZ) program to stimulate investments in low-income tracts across the United States through capital gains tax incentives. The goals of the program are to spur economic growth and job creation nationally, however, there is currently no consensus on the impact of place-based policies like OZs. Existing literature examines the impact of OZs on broad economic growth and real estate with few papers focusing on their impacts on job creation or in urban cities. Given that place-based policies like OZs are based on economic theories of agglomeration economies, OZs have unique effects on urban cities. Addressing this lacuna, this paper examines (1) the impacts of OZs on small businesses—significant sources of job creation in New York City—and (2) the impact of OZs on a high-density city like New York. A difference-in-differences regression analysis of small businesses in designated and in eligible but not designated census tracts is used to identify OZ impacts on key metrics like changes in the number of small businesses and the number of employees per census tract. Ultimately, I find that the OZ program has not had any statistically significant nor economically significant impacts on small business outcomes in New York City due to the profit-driven structure of the policy

Acquired resistance to immunotherapy and chemoradiation in MYC amplified head and neck cancer

The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC

Ultrahigh-pressure disordered eight-coordinated phase of Mg_2GeO4: Analogue for super-Earth mantles

Mg2GeO4 is important as an analog for the ultrahigh-pressure behavior of Mg2GeO4, a major component of planetary interiors. In this study, we have investigated magnesium germanate to 275 GPa and over 2,000 K using a laser-heated diamond anvil cell combined with in situ synchrotron X-ray diffraction and density functional theory (DFT) computations. The experimental results are consistent with the formation of a phase with disordered Mg and Ge, in which germanium adopts eightfold coordination with oxygen: the cubic, Th3P4-type structure. DFT computations suggest partial Mg-Ge order, resulting in a tetragonal I 4 &#xAF; 2 d structure indistinguishable from I 4 &#xAF; 3 d Th3P4 in our experiments. If applicable to silicates, the formation of this highly coordinated and intrinsically disordered phase may have important implications for the interior mineralogy of large, rocky extrasolar planets

Case-Control Study of Vitamin D, <i>dickkopf homolog 1</i> (<i>DKK1</i>) Gene Methylation, <i>VDR</i> Gene Polymorphism and the Risk of Colon Adenoma in African Americans

Background: There are sparse data on genetic, epigenetic and vitamin D exposure in African Americans (AA) with colon polyp. Consequently, we evaluated serum 25(OH) D levels, vitamin D receptor (VDR) polymorphisms and the methylation status of the tumor suppressor gene dickkopf homolog 1 (DKK1) as risk factors for colon polyp in this population.Methods: The case-control study consisted of 93 patients with colon polyp (cases) and 187 healthy individuals (controls) at Howard University Hospital. Serum levels of 25(OH)D (including D3, D2, and total) were measured by liquid chromatography-mass spectrometry. DNA analysis focused on 49 single nucleotide polymorphisms (SNPs) in the VDR gene. Promoter methylation analysis of DKK1 was also performed. The resulting data were processed in unadjusted and multivariable logistic regression analyses.Results: Cases and controls differed in vitamin D status (D33 (VDR polymorphisms and colon polyp. The promoter of the DKK1 gene was unmethylated in 96% of the samples.Conclusion: We found an inverse association between serum 25(OH)D3 and colon polyp in AAs. VDR SNPs and DKK1 methylation were not associated with colon polyp. Vitamin D levels may in part explain the higher incidence of polyp in AAs.</p

The Mu Opioid Receptor Promotes Opioid and Growth Factor-Induced Proliferation, Migration and Epithelial Mesenchymal Transition (EMT) in Human Lung Cancer

Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor (MOR) can influence cancer progression. Based on our previous observations that overexpression of MOR in human non-small cell lung cancer (NSCLC) cells increased tumor growth and metastasis, this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition (EMT) in human NSCLC cells. We utilized specific siRNA, shRNA, chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO, morphine, fentanyl, EGF or IGF. Cell function assays, immunoblot and immunoprecipitation assays were then performed. Our results indicate MOR regulates opioid and growth factor-induced EGF receptor signaling (Src, Gab-1, PI3K, Akt and STAT3 activation) which is crucial for consequent human NSCLC cell proliferation and migration. In addition, human NSCLC cells treated with opioids, growth factors or MOR overexpression exhibited an increase in snail, slug and vimentin and decrease ZO-1 and claudin-1 protein levels, results consistent with an EMT phenotype. Further, these effects were reversed with silencing (shRNA) or chemical inhibition of MOR, Src, Gab-1, PI3K, Akt and STAT3 (p<0.05). Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation, migration and EMT transition during lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings.</p