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Abstract: Background: Falls from heights are common in urban areas in the United States. This study describes the epidemiology of balcony fall–related injuries requiring emergency department (ED) treatment among children and adults in the United States from 1990 through 2006. Methods: In 2009, a retrospective analysis of data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission was conducted to describe the epidemiology of balcony fall–related injuries. Results: An estimated 86 500 (95% confidence interval [CI], 68 400-104 600) balcony fall–related injuries were treated in US hospital EDs from 1990 through 2006; 70% of cases were male; 63% were adults (≥18 years old); 94% of injury events occurred at home; 24% of patients were hospitalized; and 8 patients died. The rate of balcony fall–related injuries among children decreased significantly during 1990 to 2006 and was similar to that of adults by the end of the study period. Fall heights ranged from 5 to 87.5 ft. Structural failure of the balcony was involved in an estimated 5600 cases. Patients younger than 18 years were more likely to sustain a concussion/closed head injury (relative risk, 2.42; 95% CI, 1.84-3.18) or skull fracture (relative risk, 5.86; 95% CI, 2.58-13.30) than adults. Conclusions: This is the first study of balcony fall–related injuries requiring emergency treatment using a nationally representative sample. Balcony falls are an important cause of injury in the United States. Age, male sex, and warm months of the year were associated with balcony fall–related injuries in our study population. [ABSTRACT FROM AUTHOR]

Background: Injuries and medical emergencies associated with snow shovel use are common in the United States. Methods: This is a retrospective analysis of data from the National Electronic Injury Surveillance System. This study analyzes the epidemiologic features of snow shovel–related injuries and medical emergencies treated in US emergency departments (EDs) from 1990 to 2006. Results: An estimated 195 100 individuals (95% confidence interval, 140 400-249 800) were treated in US EDs for snow shovel–related incidents during the 17-year study period, averaging 11 500 individuals annually (SD, 5300). The average annual rate of snow shovel–related injuries and medical emergencies was 4.15 per 100 000 population. Approximately two thirds (67.5%) of these incidents occurred among males. Children younger than 18 years comprised 15.3% of the cases, whereas older adults (55 years and older) accounted for 21.8%. The most common diagnosis was soft tissue injury (54.7%). Injuries to the lower back accounted for 34.3% of the cases. The most common mechanism of injury/nature of medical emergency was acute musculoskeletal exertion (53.9%) followed by slips and falls (20.0%) and being struck by a snow shovel (15.0%). Cardiac-related ED visits accounted for 6.7% of the cases, including all of the 1647 deaths in the study. Patients required hospitalization in 5.8% of the cases. Most snow shovel–related incidents (95.6%) occurred in and around the home. Conclusions: This is the first study to comprehensively examine snow shovel–related injuries and medical emergencies in the United States using a nationally representative sample. There are an estimated 11 500 snow shovel–related injuries and medical emergencies treated annually in US EDs. [ABSTRACT FROM AUTHOR]

Our goal was to determine if age, combined with estimated IQ, is an accurate predictor of a child's successful use of a visual analogue scale (VAS) in a nonclinical situation versus an acute, clinically emergent situation. For children 5 to 11 years old, we found that the VAS is used most accurately in a nonclinical environment by children 7 years of age and older who can perform a seriation task. Estimated IQ and correct performance of a seriation task were the best predictors of 5- and 6-year-old children's ability to use a VAS. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We describe the epidemiology of escalator-related injuries among children 0 to 19 years of age in the United States, with a focus on the pediatric population that is younger than 5 years. METHODS: We conducted a retrospective analysis of data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission. Reported cases were used to project national estimates and rates of escalator-related injuries in the United States. The analysis included all patients who were 0 to 19 years of age in the National Electronic Injury Surveillance System database and were seen in an emergency department for an escalator-related injury during the 13-year period 1990-2002. RESULTS: There were an estimated 26000 escalator-related injuries among children who were 0 to 19 years of age in the United States during 1990-2002, yielding an average of 2000 of these injuries annually (rate = 2.6 per 100,000 population per year). The mean age was 6.5 years at the time of injury, and 53.4% of the patients were male. When comparing cases by 5-year age groups, children who were younger than 5 years had the highest estimated number of injuries (12000), as well as the highest annual escalator-related injury rate (4.8 per 100000). The most common mechanism of injury for all age groups was a fall, accounting for 13000 (51.0%) injuries. Entrapment accounted for 29.3% of all injuries and 36.5% of injuries among children who were younger than 5 years. Six percent (723) of injuries to children who were younger than 5 years involved a stroller, with most injuries occurring when a child fell out of the stroller while on the escalator. The most common body part injured for all ages was the leg, accounting for 27.7% of all injuries. Among children who were younger than 5 years, the hand was the most common injury site (40.6%), with hand injuries frequently occurring as a result of entrapment (72.4%). A laceration was the most common type of injury, accounting for 47.4% of escalator-related injuries. Amputations and avulsions were uncommon; however, 71.4% (595 of 833) occurred among children who were younger than 5 years. CONCLUSIONS: There was a disproportionate number of escalator-related injuries among children who were younger than 5 years. Entrapment occurred more frequently among children who were younger than 5 years than in any other age group, which may explain the increased number of hand injuries in this age group. Escalator designs that reduce the gap between the steps and sidewall or shield against access to the gap may decrease entrapment risk. Young children should be supervised properly and should not be transported in a stroller while riding on an escalator. All passengers should use caution and remain alert when riding an escalator to avoid injuries related to falls or entrapment. Additional research is needed to determine the relationship among passenger behavior, escalator design, and escalator-related injury. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Here we describe the epidemiologic characteristics and secular trends of infant walker-related injuries among children who are younger than 15 months in the United States. METHODS: A retrospective analysis was conducted of data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission, 1990-2001. Sample weights that were provided by the National Electronic Injury Surveillance System were used in all analyses to adjust for the inverse probability of case selection and make national projections regarding infant walker-related injuries. RESULTS: An estimated 197200 infant walker-related injuries occurred among children who were younger than 15 months and treated in US emergency departments from 1990 through 2001. Five percent of these children required admission to the hospital. The number of infant walker-related injuries remained relatively constant from 1990 through 1994, averaging 23,000 cases per year. After the introduction in 1994 of stationary activity centers as an alternative to mobile infant walkers and the implementation of the revised American Society for Testing and Materials F977 voluntary infant walker standard in 1997, there was a marked decrease in the number of infant walker-related injuries. Overall, there was a 76% decrease in the number of injuries from 1990 to 2001 from 20,900 injuries in 1990 to 5100 in 2001. Soft tissue injuries and lacerations represented 63% of the injuries. Trauma to the head region occurred in 91% of cases. Skull fractures were the most common (62%) type of fracture. Falls down stairs was the mechanism of injury in 74% of cases. CONCLUSIONS: The adoption of passive injury-prevention strategies, such as use of stationary activity centers as alternatives to mobile infant walkers and redesign of infant walkers to prevent falls down stairs, were associated with a marked decrease in the number of infant walker-related injuries. [ABSTRACT FROM AUTHOR]

Reaction conditions that are generally applicable to a wide variety of substrates are highly desired, especially in the pharmaceutical and chemical industries 1-6 . Although many approaches are available to evaluate the general applicability of developed conditions, a universal approach to efficiently discover these conditions during optimizations is rare. Here we report the design, implementation and application of reinforcement learning bandit optimization models 7-10 to identify generally applicable conditions by efficient condition sampling and evaluation of experimental feedback. Performance benchmarking on existing datasets statistically showed high accuracies for identifying general conditions, with up to 31% improvement over baselines that mimic state-of-the-art optimization approaches. A palladium-catalysed imidazole C-H arylation reaction, an aniline amide coupling reaction and a phenol alkylation reaction were investigated experimentally to evaluate use cases and functionalities of the bandit optimization model in practice. In all three cases, the reaction conditions that were most generally applicable yet not well studied for the respective reaction were identified after surveying less than 15% of the expert-designed reaction space., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The negatively charged silicon vacancy center (SiV - ) in diamond is a promising, yet underexplored candidate for single-spin quantum sensing at sub-kelvin temperatures and tesla-range magnetic fields. A key ingredient for such applications is the ability to perform all-optical, coherent addressing of the electronic spin of near-surface SiV - centers. We present a robust and scalable approach for creating individual, ∼50 nm deep SiV - with lifetime-limited optical linewidths in diamond nanopillars through an easy-to-realize and persistent optical charge-stabilization scheme. The latter is based on single, prolonged 445 nm laser illumination that enables continuous photoluminescence excitation spectroscopy without the need for any further charge stabilization or repumping. Our results constitute a key step toward the use of near-surface, optically coherent SiV - for sensing under extreme conditions, and offer a powerful approach for stabilizing the charge-environment of diamond color centers for quantum technology applications.

Neutral silicon vacancy centers (SiV^{0}) in diamond are promising candidates for quantum applications; however, stabilizing SiV^{0} requires high-purity, boron-doped diamond, which is not a readily available material. Here, we demonstrate an alternative approach via chemical control of the diamond surface. We use low-damage chemical processing and annealing in a hydrogen environment to realize reversible and highly stable charge state tuning in undoped diamond. The resulting SiV^{0} centers display optically detected magnetic resonance and bulklike optical properties. Controlling the charge state tuning via surface termination offers a route for scalable technologies based on SiV^{0} centers, as well as charge state engineering of other defects.

Antiferromagnetic insulators are a prospective materials platform for magnonics, spin superfluidity, THz spintronics, and non-volatile data storage. A magnetomechanical coupling in antiferromagnets offers vast advantages in the control and manipulation of the primary order parameter yet remains largely unexplored. Here, we discover a new member in the family of flexoeffects in thin films of Cr 2 O 3 . We demonstrate that a gradient of mechanical strain can impact the magnetic phase transition resulting in the distribution of the Néel temperature along the thickness of a 50-nm-thick film. The inhomogeneous reduction of the antiferromagnetic order parameter induces a flexomagnetic coefficient of about 15 μ B  nm -2 . The antiferromagnetic ordering in the inhomogeneously strained films can persist up to 100 °C, rendering Cr 2 O 3 relevant for industrial electronics applications. Strain gradient in Cr 2 O 3 thin films enables fundamental research on magnetomechanics and thermodynamics of antiferromagnetic solitons, spin waves and artificial spin ice systems in magnetic materials with continuously graded parameters., (© 2022. The Author(s).)

The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Numerous disciplines, such as image recognition and language translation, have been revolutionized by using machine learning (ML) to leverage big data. In organic synthesis, providing accurate chemical reactivity predictions with supervised ML could assist chemists with reaction prediction, optimization, and mechanistic interrogation.To apply supervised ML to chemical reactions, one needs to define the object of prediction (e.g., yield, enantioselectivity, solubility, or a recommendation) and represent reactions with descriptive data. Our group's effort has focused on representing chemical reactions using DFT-derived physical features of the reacting molecules and conditions, which serve as features for building supervised ML models.In this Account, we present a review and perspective on three studies conducted by our group where ML models have been employed to predict reaction yield. First, we focus on a small reaction data set where 16 phosphine ligands were evaluated in a single Ni-catalyzed Suzuki-Miyaura cross-coupling reaction, and the reaction yield was modeled with linear regression. In this setting, where the regression complexity is strongly limited by the amount of available data, we emphasize the importance of identifying single features that are directly relevant to reactivity. Next, we focus on models trained on two larger data sets obtained with high-throughput experimentation (HTE). With hundreds to thousands of reactions available, more complex models can be explored, for example, models that algorithmically perform feature selection from a broad set of candidate features. We examine how a variety of ML algorithms model these data sets and how well these models generalize to out-of-sample substrates. Specifically, we compare the ML models that use DFT-based featurization to a baseline model that is obtained with features that carry no physical information, that is, random features, and to a naive non-ML model that averages yields of reactions that share the same conditions and substrate combinations. We find that for only one of the two data sets, DFT-based featurization leads to a significant, although moderate, out-of-sample prediction improvement. The source of this improvement was further isolated to specific features which allowed us to formulate a testable mechanistic hypothesis that was validated experimentally. Finally, we offer remarks on supervised ML model building on HTE data sets focusing on algorithmic improvements in model training.Statistical methods in chemistry have a rich history, but only recently has ML gained widespread attention in reaction development. As the untapped potential of ML is explored, novel tools are likely to arise from future research. Our studies suggest that supervised ML can lead to improved predictions of reaction yield over simpler modeling methods and facilitate mechanistic understanding of reaction dynamics. However, further research and development is required to establish ML as an indispensable tool in reactivity modeling.

Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates 1 . Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems 2 . Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models 3 . Bayesian optimization has also been recently applied in chemistry 4-9 ; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimization outperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML., (© 2020 by The American Society of Hematology.)

A cross-electrophile coupling reaction of epoxides and (hetero)aryl iodides that operates via the merger of three catalytic cycles involving a Ni-, Ti-, and organic photoredox catalyst has been developed. Three distinct classes of epoxides, styrene oxides, cyclic epoxides, and terminal aliphatic epoxides, all undergo coupling in moderate to good yield and high regioselectivity with the use of three different nitrogen-based ligands for Ni under otherwise identical reaction conditions. The mild reaction conditions accommodate a broad scope of abundant and complex coupling partners. Mechanistic studies suggest that when styrene oxides are employed radical intermediates are involved via Ti-radical ring-opening of the epoxide. Conversely, for terminal aliphatic epoxides, involvement of an iodohydrin intermediate enables the formation of the unexpected linear product., Competing Interests: The authors declare no competing financial interest.

Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via β-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.

Synthetic organic chemistry has seen major advances due to the merger of nickel and photoredox catalysis. A growing number of Ni-photoredox reactions are proposed to involve generation of excited nickel species, sometimes even in the absence of a photoredox catalyst. To gain insights about these excited states, two of our groups previously studied the photophysics of Ni( t -Bu bpy)( o -Tol)Cl, which is representative of proposed intermediates in many Ni-photoredox reactions. This complex was found to have a long-lived excited state (τ = 4 ns), which was computationally assigned as a metal-to-ligand charge transfer (MLCT) state with an energy of 1.6 eV (38 kcal/mol). This work evaluates the computational assignment experimentally using a series of related complexes. Ultrafast UV-Vis and mid-IR transient absorption data suggest that a MLCT state is generated initially upon excitation but decays to a long-lived state that is 3 d-d rather than 3 MLCT in character. Dynamic cis , trans -isomerization of the square planar complexes was observed in the dark using 1 H NMR techniques, supporting that this 3 d-d state is tetrahedral and accessible at ambient temperature. Through a combination of transient absorption and NMR studies, the 3 d-d state was determined to lie ∼0.5 eV (12 kcal/mol) above the ground state. Because the 3 d-d state features a weak Ni-aryl bond, the excited Ni(II) complexes can undergo Ni homolysis to generate aryl radicals and Ni(I), both of which are supported experimentally. Thus, photoinduced Ni-aryl homolysis offers a novel mechanism of initiating catalysis by Ni(I).

T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. While it has been shown that TAL1/LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2/Lyl1; however, NHD13 can also promote T-ALL via an alternative pathway.

Antiferromagnets have recently emerged as attractive platforms for spintronics applications, offering fundamentally new functionalities compared with their ferromagnetic counterparts. Whereas nanoscale thin-film materials are key to the development of future antiferromagnetic spintronic technologies, existing experimental tools tend to suffer from low resolution or expensive and complex equipment requirements. We offer a simple, high-resolution alternative by addressing the ubiquitous surface magnetization of magnetoelectric antiferromagnets in a granular thin-film sample on the nanoscale using single-spin magnetometry in combination with spin-sensitive transport experiments. Specifically, we quantitatively image the evolution of individual nanoscale antiferromagnetic domains in 200 nm thin films of Cr 2 O 3 in real space and across the paramagnet-to-antiferromagnet phase transition, finding an average domain size of 230 nm, several times larger than the average grain size in the film. These experiments allow us to discern key properties of the Cr 2 O 3 thin film, including the boundary magnetic moment density, the variation of critical temperature throughout the film, the mechanism of domain formation, and the strength of exchange coupling between individual grains comprising the film. Our work offers novel insights into the magnetic ordering mechanism of Cr 2 O 3 and firmly establishes single-spin magnetometry as a versatile and widely applicable tool for addressing antiferromagnetic thin films on the nanoscale.

Quantum emitters in solids are being developed for a range of quantum technologies, including quantum networks, computing, and sensing. However, a remaining challenge is the poor photon collection due to the high refractive index of most host materials. Here we overcome this limitation by introducing monolithic parabolic reflectors as an efficient geometry for broadband photon extraction from quantum emitter and experimentally demonstrate this device for the nitrogen-vacancy (NV) center in diamond. Simulations indicate a photon collection efficiency exceeding 75% across the visible spectrum and experimental devices, fabricated using a high-throughput gray scale lithography process, demonstrating a photon extraction efficiency of (41 ± 5)%. This device enables a raw experimental detection efficiency of (12 ± 1)% with fluorescence detection rates as high as (4.114 ± 0.003) × 10 6 counts per second (cps) from a single NV center. Enabled by our deterministic emitter localization and fabrication process, we find a high number of exceptional devices with an average count rate of (3.1 ± 0.9) × 10 6 cps.

Here we investigate the photophysics and photochemistry of Ni(II) aryl halide complexes common to cross-coupling and Ni/photoredox reactions. Computational and ultrafast spectroscopic studies reveal that these complexes feature long-lived 3 MLCT excited states, implicating Ni as an underexplored alternative to precious metal photocatalysts. Moreover, we show that 3 MLCT Ni(II) engages in bimolecular electron transfer with ground-state Ni(II), which enables access to Ni(III) in the absence of external oxidants or photoredox catalysts. As such, it is possible to facilitate Ni-catalyzed C-O bond formation solely by visible light irradiation, thus representing an alternative strategy for catalyst activation in Ni cross-coupling reactions.

The hematopoietically expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16 Ink4a and p19 Arf However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of interleukin-3 (IL-3)-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA-binding and N-terminal-repressive domains of Hhex for promyelocytic transformation. This included the N-terminal promyelocytic leukemia protein (Pml) interaction domain, although deletion of Pml failed to prevent Hhex -induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16 Ink4a or p19 Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test the potential for Hhex overexpression to contribute to leukemic transformation, Hhex -transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus, Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus., (© 2018 by The American Society of Hematology.)

Chromatin Immunoprecipitation (ChIP) using antibodies specific for histone modifications is a powerful technique for assessing the epigenetic states of cell populations by either quantitative PCR (ChIP-PCR) or next generation sequencing analysis (ChIP-Seq). Here we describe the procedure for ChIP of histone marks in myeloid leukaemia cell lines and the subsequent purification of genomic DNA associated with repressive and activating histone modifications for further analysis. This procedure can be widely applied to a variety of histone marks to assess both activating and repressive modifications in the context of myeloid leukaemia.

The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin - Sca + Kit + cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16 Ink 4 a and p19 Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957., (© 2017 AlphaMed Press.)

We report a redox-neutral formylation of aryl chlorides that proceeds through selective 2-functionalization of 1,3-dioxolane through nickel and photoredox catalysis. This scalable benchtop approach provides a distinct advantage over traditional reductive carbonylation in that no carbon monoxide, pressurized gas, or stoichiometric reductant is employed. The mild conditions give unprecedented scope from abundant and complex aryl chloride starting materials., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We study the depolarization dynamics of a dense ensemble of dipolar interacting spins, associated with nitrogen-vacancy centers in diamond. We observe anomalously fast, density-dependent, and nonexponential spin relaxation. To explain these observations, we propose a microscopic model where an interplay of long-range interactions, disorder, and dissipation leads to predictions that are in quantitative agreement with both current and prior experimental results. Our results pave the way for controlled many-body experiments with long-lived and strongly interacting ensembles of solid-state spins.

Here we report the development of a C(sp 3 )-H cross-coupling platform enabled by the catalytic generation of chlorine radicals by nickel and photoredox catalysis. Aryl chlorides serve as both cross-coupling partners and the chlorine radical source for the α-oxy C(sp 3 )-H arylation of cyclic and acyclic ethers. Mechanistic studies suggest that photolysis of a Ni(III) aryl chloride intermediate, generated by photoredox-mediated single-electron oxidation, leads to elimination of a chlorine radical in what amounts to the sequential capture of two photons. Arylations of a benzylic C(sp 3 )-H bond of toluene and a completely unactivated C(sp 3 )-H bond of cyclohexane demonstrate the broad implications of this manifold for accomplishing numerous C(sp 3 )-H bond functionalizations under exceptionally mild conditions., Competing Interests: Notes The authors declare no competing financial interest.

Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16(INK4a) and p19(ARF), which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal., (© 2016 Shields et al.; Published by Cold Spring Harbor Laboratory Press.)

Efficient readout of individual electronic spins associated with atomlike impurities in the solid state is essential for applications in quantum information processing and quantum metrology. We demonstrate a new method for efficient spin readout of nitrogen-vacancy (NV) centers in diamond. The method is based on conversion of the electronic spin state of the NV to a charge-state distribution, followed by single-shot readout of the charge state. Conversion is achieved through a spin-dependent photoionization process in diamond at room temperature. Using NVs in nanofabricated diamond beams, we demonstrate that the resulting spin readout noise is within a factor of 3 of the spin projection noise level. Applications of this technique for nanoscale magnetic sensing are discussed.

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute leukemias, in particular poor prognosis early T-cell precursor-like (ETP-) acute lymphoblastic leukemia (ALL). The primary effect of Lmo2 is to cause self-renewal of developing CD4(-)CD8(-) (double negative, DN) T cells in the thymus, leading to serially transplantable thymocytes that eventually give rise to leukemia. These self-renewing thymocytes are intrinsically radioresistant implying that they may be a source of leukemia relapse after therapy. The homeobox transcription factor, Hhex, is highly upregulated in Lmo2-transgenic thymocytes and can phenocopy Lmo2 in inducing thymocyte self-renewal, implying that Hhex may be a key component of the Lmo2-induced self-renewal program. To test this, we conditionally deleted Hhex in the thymi of Lmo2-transgenic mice. Surprisingly, this did not prevent accumulation of DN thymocytes, nor alter the rate of overt leukemia development. However, deletion of Hhex abolished the transplantation capacity of Lmo2-transgenic thymocytes and overcame their radioresistance. We found that Hhex regulates Kit expression in Lmo2-transgenic thymocytes and that abrogation of Kit signaling phenocopied loss of Hhex in abolishing the transplantation capacity and radioresistance of these cells. Thus, targeting the Kit signaling pathway may facilitate the eradication of leukemia-initiating cells in immature T-cell leukemias in which it is expressed.

We report the observation of stable optical transitions in nitrogen-vacancy (NV) centers created by ion implantation. Using a combination of high temperature annealing and subsequent surface treatment, we reproducibly create NV centers with zero-phonon lines (ZPL) exhibiting spectral diffusion that is close to the lifetime-limited optical line width. The residual spectral diffusion is further reduced by using resonant optical pumping to maintain the NV(-) charge state. This approach allows for placement of NV centers with excellent optical coherence in a well-defined device layer, which is a crucial step in the development of diamond-based devices for quantum optics, nanophotonics, and quantum information science.

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases.

Tyrosine phosphorylation-dependent signaling, as mediated by members of the epidermal growth factor receptor (EGFR) family (ErbB1 to -4) of protein tyrosine kinases (PTKs), Src family PTKs (SFKs), and cytokines such as interleukin-6 (IL-6) that signal via signal transducer and activator of transcription 3 (STAT3), is critical to the development and progression of many human breast cancers. EGFR, SFKs, and STAT3 can serve as substrates for the protein tyrosine phosphatase TCPTP (PTPN2). Here we report that TCPTP protein levels are decreased in a subset of breast cancer cell lines in vitro and that TCPTP protein is absent in a large proportion of "triple-negative" primary human breast cancers. Homozygous TCPTP deficiency in murine mammary fat pads in vivo is associated with elevated SFK and STAT3 signaling, whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signaling. On the other hand, TCPTP reconstitution in human breast cancer cell lines severely impaired cell proliferation and suppressed anchorage-independent growth in vitro and xenograft growth in vivo. These studies establish TCPTP's potential to serve as a tumor suppressor in human breast cancer.

The realization of efficient optical interfaces for solid-state atom-like systems is an important problem in quantum science with potential applications in quantum communications and quantum information processing. We describe and demonstrate a technique for coupling single nitrogen vacancy (NV) centers to suspended diamond photonic crystal cavities with quality factors up to 6000. Specifically, we present an enhancement of the NV center's zero-phonon line fluorescence by a factor of ~ 7 in low-temperature measurements.

A variety of nanoscale photonic, mechanical, electronic, and optoelectronic devices require scalable thin film fabrication. Typically, the device layer is defined by thin film deposition on a substrate of a different material, and optical or electrical isolation is provided by the material properties of the substrate or by removal of the substrate. For a number of materials this planar approach is not feasible, and new fabrication techniques are required to realize complex nanoscale devices. Here, we report a three-dimensional fabrication technique based on anisotropic plasma etching at an oblique angle to the sample surface. As a proof of concept, this angled-etching methodology is used to fabricate free-standing nanoscale components in bulk single-crystal diamond, including nanobeam mechanical resonators, optical waveguides, and photonic crystal and microdisk cavities. Potential applications of the fabricated prototypes range from classical and quantum photonic devices to nanomechanical-based sensors and actuators.

We propose and demonstrate a new approach for achieving enhanced light-matter interactions with quantum emitters. Our approach makes use of a plasmon resonator composed of defect-free, highly crystalline silver nanowires surrounded by patterned dielectric distributed Bragg reflectors. These resonators have an effective mode volume (V(eff)) 2 orders of magnitude below the diffraction limit and a quality factor (Q) approaching 100, enabling enhancement of spontaneous emission rates by a factor exceeding 75 at the cavity resonance. We also show that these resonators can be used to convert a broadband quantum emitter to a narrow-band single-photon source with color-selective emission enhancement.