Flight Testing of the TWiLiTE Airborne Molecular Doppler Lidar

In September, 2009 the TWiLiTE (Tropospheric Wind Lidar Technology Experiment) direct detection Doppler lidar was integrated for engineering flight testing on the NASA ER-2 high altitude aircraft. The TWiI,iTE Doppler lidar measures vertical profiles of wind by transmitting a short ultraviolet (355 nm) laser pulse into the atmosphere, collecting the laser light scattered back to the lidar by air molecules and measuring the Doppler shifted frequency of that light. The magnitude of the Doppler shift is proportional to the wind speed of the air in the parcel scattering the laser light. TWiLiTE was developed with funding from the NASA Earth Science Technology Office (ESTO) Instrument Incubator Program (11P). The primary objectives of the TWiLiTE program are twofold: 1) to advance the development of key technologies and subsystems critical for a future space based Global 3-1) Wind Mission, as recommended by the National Research Council in the recent Decadal Survey for Earth Science [1] and 2) to develop, for the first time, a fully autonomous airborne Doppler lidar and to demonstrate tropospheric wind profile measurements from a high altitude downward looking, moving platform to simulate spaceborne measurements. In this paper we will briefly describe the instrument followed by a discussion of the results from the 2009 engineering test flight

Moyal star product approach to the Bohr-Sommerfeld approximation

The Bohr-Sommerfeld approximation to the eigenvalues of a one-dimensional quantum Hamiltonian is derived through order $\hbar^2$ (i.e., including the first correction term beyond the usual result) by means of the Moyal star product. The Hamiltonian need only have a Weyl transform (or symbol) that is a power series in $\hbar$, starting with $\hbar^0$, with a generic fixed point in phase space. The Hamiltonian is not restricted to the kinetic-plus-potential form. The method involves transforming the Hamiltonian to a normal form, in which it becomes a function of the harmonic oscillator Hamiltonian. Diagrammatic and other techniques with potential applications to other normal form problems are presented for manipulating higher order terms in the Moyal series.Comment: 27 pages, no figure

Dissipative Chaos in Semiconductor Superlattices

We consider the motion of ballistic electrons in a miniband of a semiconductor superlattice (SSL) under the influence of an external, time-periodic electric field. We use the semi-classical balance-equation approach which incorporates elastic and inelastic scattering (as dissipation) and the self-consistent field generated by the electron motion. The coupling of electrons in the miniband to the self-consistent field produces a cooperative nonlinear oscillatory mode which, when interacting with the oscillatory external field and the intrinsic Bloch-type oscillatory mode, can lead to complicated dynamics, including dissipative chaos. For a range of values of the dissipation parameters we determine the regions in the amplitude-frequency plane of the external field in which chaos can occur. Our results suggest that for terahertz external fields of the amplitudes achieved by present-day free electron lasers, chaos may be observable in SSLs. We clarify the nature of this novel nonlinear dynamics in the superlattice-external field system by exploring analogies to the Dicke model of an ensemble of two-level atoms coupled with a resonant cavity field and to Josephson junctions.Comment: 33 pages, 8 figure

The use of targeted sequencing and flow cytometry to identify patients with a clinically significant monocytosis

The diagnosis of chronic myelomonocytic leukaemia (CMML) remains centred on morphology, meaning the distinction from a reactive monocytosis is challenging. Mutational analysis and immunophenotyping have been proposed as potential tools for diagnosis however have not been formally assessed in combination. We aimed to investigate the clinical utility of these technologies by performing targeted sequencing, in parallel to current gold standard techniques, on consecutive samples referred for investigation of monocytosis over a 2-year period (n=283). Results were correlated with the morphological diagnosis and objective outcome measures including overall survival (OS) and longitudinal blood counts. Somatic mutations were detected in 79% of patients, being invariably identified in those with a confirmed diagnosis (99%) though also in 57% of patients with non-diagnostic BM features. The OS in non-diagnostic mutated patients was indistinguishable from those with CMML (p=0.118) and significantly worse than unmutated patients (p=0.0002). On multivariate analysis age, ASXL1, CBL, DNMT3A, NRAS & RUNX1 mutations retained significance. Furthermore, the presence of a mutation was associated with a progressive fall in haemoglobin/platelet levels and increasing monocyte counts compared with mutation negative patients. Of note, the immunophenotypic features of non-diagnostic mutated patients were comparable to CMML patients and the presence of aberrant CD56 was highly specific for detecting a mutation. Overall, somatic mutations are detected at high frequency in patients referred with a monocytosis irrespective of diagnosis. In those without a WHO defined diagnosis, the mutation spectrum, immunophenotypic features and OS are indistinguishable from CMML patients and these patients should be managed as such

Excised DNA circles from V(D)J recombination promote relapsed leukaemia

Extrachromosomal DNA amplification is associated with poor cancer prognoses 1 . Large numbers of excised signal circles (ESCs) are produced as by-products of antigen receptor rearrangement during V(D)J recombination 2,3 . However, current dogma states that ESCs are progressively lost through cell division 4 . Here we show that ESCs replicate and persist through many cell generations and share many properties in common with circular extrachromosomal DNAs. Increased ESC copy numbers at diagnosis of B cell precursor acute lymphoblastic leukaemia were highly correlated with subsequent relapse. By taking advantage of the matching recombination footprint that is formed upon the generation of each ESC, we measured ESC persistence and replication and found increased ESC replication in patients who later relapsed. This increased replication is controlled by cell-intrinsic factors and corresponds to increased expression of DNA replication- and repair-associated genes. Consistent with high ESC levels having a role in disease progression, the number of mutations typical of those caused by the V(D)J recombinase–ESC complex was significantly increased at diagnosis in patients who later relapsed. The number of such mutations in genes associated with relapse increased between diagnosis and relapse, and corresponded to clonal expansion of cells with high ESC copy numbers. These data demonstrate that the by-product of V(D)J recombination, when increased in abundance, potently associates with the V(D)J recombinase to cause adverse disease outcomes

Genomic profiling for clinical decision making in myeloid neoplasms and acute leukemia

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation