Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Impact of a Turbulent Ocean Surface on Laser Beam Propagation.

The roughness of the ocean surface significantly impacts air-to-sea imaging, oceanographic monitoring, and optical communication. Most current and previous methods for addressing this roughness and its impact on optical propagation are either entirely statistical or theoretical, or are 'mixed methods' based on a combination of statistical models and parametric-based physical models. In this paper, we performed experiments in a 50-foot-wave tank on wind-generated waves, in which we varied the wind speed to measure how the surface waves affect the laser beam propagation and develop a geometrical optical model to measure and analyze the refraction angle and slope angle of the laser beam under various environmental conditions. The study results show that the laser beam deviations/distortions and laser beam footprint size are strongly related to wind speed and laser beam incidence angle.

Unraveling the Gentamicin Drug Product Complexity Reveals Variation in Microbiological Activities and Nephrotoxicity.

The gentamicin drug product is a complex mixture of numerous components, many of which have not individually undergone safety and efficacy assessments. This is in contrast to the majority of medicines that require rigorous characterizations of trace impurities and are dosed as single components. In gentamicin, four components, known as gentamicin congeners C1, C1a, C2, and C2a, comprise the majority of the mixture. A liquid chromatography-mass spectroscopy analysis revealed that the relative abundances of each gentamicin congener in commercial formulations can vary up to 1.9-fold depending on the commercial source of the gentamicin. To determine if the gentamicin used for antibiotic susceptibility testing (AST) would be predictive of the microbiological activity of the product used to dose patients, the relative abundances of the four congeners contained on commercial AST disks were measured. It was found that the congener abundances on the commercial AST disks varied up to 4.1-fold. After purification of the four gentamicin congeners, similar potencies against bacterial strains lacking aminoglycoside-modifying enzymes (AMEs) were observed. However, the potency of the congeners against strains harboring a common AME differed up to 128-fold. Nephrotoxicity of the individual gentamicin congeners also differed significantly in cell-based and repeat-dose rat nephrotoxicity studies. Variations in the composition of commercial gentamicin products combined with toxicity differences between gentamicin congeners suggest that some gentamicin formulations may be more nephrotoxic. Our results also raise the concern that gentamicin susceptibility test results may not be predictive of patient outcomes and could lead to unexpected clinical treatment failures.

Earthquakes drive large-scale submarine canyon development and sediment supply to deep-ocean basins.

Although the global flux of sediment and carbon from land to the coastal ocean is well known, the volume of material that reaches the deep ocean-the ultimate sink-and the mechanisms by which it is transferred are poorly documented. Using a globally unique data set of repeat seafloor measurements and samples, we show that the moment magnitude (Mw) 7.8 November 2016 Kaikoura earthquake (New Zealand) triggered widespread landslides in a submarine canyon, causing a powerful "canyon flushing" event and turbidity current that traveled >680 km along one of the world's longest deep-sea channels. These observations provide the first quantification of seafloor landscape change and large-scale sediment transport associated with an earthquake-triggered full canyon flushing event. The calculated interevent time of ~140 years indicates a canyon incision rate of 40 mm year-1, substantially higher than that of most terrestrial rivers, while synchronously transferring large volumes of sediment [850 metric megatons (Mt)] and organic carbon (7 Mt) to the deep ocean. These observations demonstrate that earthquake-triggered canyon flushing is a primary driver of submarine canyon development and material transfer from active continental margins to the deep ocean.

Propagation of partially coherent beams with convex-shaped spatial coherence modulation in vertical turbulent links.

The convex partially coherent beam (CPCB) is a special type of nonuniformly correlated beam with a convex-shaped complex degree of coherence (DoC) distributions. Previously our research has illustrated the potential of CPCBs with super-Gaussian DoCs in free-space optical communications (FSOC), mainly manifested as self-focusing which can be transferred into extra scintillation reduction and SNR gain. In this study, the effects of the DoC transition slopes are analyzed and more details about the turbulence propagation of CPCBs with super-Gaussian shaped DoC are revealed. By means of wave optics simulation, the longitudinal intensity evolution of the CPCB is explored, showing that the DoC slope has a profound influence on the self-focusing features such as the focusing plane and the peak intensity. Aperture scintillation and mean SNR at the receiver end of some short-range vertical turbulent links are numerically computed. The obtained results show that, with CPCBs, an ~2 dB SNR gain can be achieved as compared to conventional Gaussian Schell-modal (GSM) beams. However, CPCBs are preferred only in shorter links, which is found to be relevant to the power-in-the-bucket of the receiving aperture. Furthermore, the impacts of the ratio of the source coherence time to the detector integration time are investigated, implying that the CPCB is less susceptible than the GSM. We have also examined the off-axis scintillation of the CPCB. Due to its convex-shaped DoC, the CPCB has significantly reduced off-axis scintillation, which can be beneficial in the presence of pointing errors.

Radiological outcome of innocent infant hip clicks.

Radiographic follow-up is questioned for infants with hip clicks who have normal results from ultrasound scan examination of the hips. Infants whose sole risk factor for developmental dysplasia of the hip was a soft tissue hip click who had a normal ultrasound scan on initial assessment were identified. A follow-up 6-month pelvis radiograph was assessed. The acetabular index, position of femoral ossific nucleus and Shenton's line were measured. Rotated radiographs were excluded. One hundred and seventy-one infants (193 clicking hips) met the criteria for inclusion. All parameters measured were within normal ranges. In this study infants with hip clicks and a normal hip ultrasound scan on initial assessment had a normal radiograph at 6 months.