Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia

Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors

End-to-end numerical modeling of the Roman Space Telescope coronagraph

The Roman Space Telescope will have the first advanced coronagraph in space, with deformable mirrors for wavefront control, low-order wavefront sensing and maintenance, and a photon-counting detector. It is expected to be able to detect and characterize mature, giant exoplanets in reflected visible light. Over the past decade the performance of the coronagraph in its flight environment has been simulated with increasingly detailed diffraction and structural/thermal finite element modeling. With the instrument now being integrated in preparation for launch within the next few years, the present state of the end-to-end modeling is described, including the measured flight components such as deformable mirrors. The coronagraphic modes are thoroughly described, including characteristics most readily derived from modeling. The methods for diffraction propagation, wavefront control, and structural and thermal finite-element modeling are detailed. The techniques and procedures developed for the instrument will serve as a foundation for future coronagraphic missions such as the Habitable Worlds Observatory.Comment: 113 pages, 85 figures, to be published in SPIE Journal of Astronomical Telescopes, Instruments, and System

Communications Biophysics

Contains research objectives and reports on six research projects split into three sections.National Institutes of Health (Grant 5 P01 NS13126-07)National Institutes of Health (Training Grant 5 T32 NS07047-05)National Institutes of Health (Training Grant 2 T32 NS07047-06)National Science Foundation (Grant BNS 77-16861)National Institutes of Health (Grant 5 R01 NS1284606)National Institutes of Health (Grant 5 T32 NS07099)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 5 R01 NS14092-04)Gallaudet College SubcontractKarmazin Foundation through the Council for the Arts at M.I.T.National Institutes of Health (Grant 1 R01 NS1691701A1)National Institutes of Health (Grant 5 R01 NS11080-06)National Institutes of Health (Grant GM-21189

Nancy Grace Roman Space Telescope Coronagraph Instrument Observation Calibration Plan

NASA's next flagship mission, the Nancy Grace Roman Space Telescope, is a 2.4-meter observatory set to launch no later than May 2027. Roman features two instruments: the Wide Field Imager and the Coronagraph Instrument. Roman's Coronagraph is a Technology Demonstration that will push the current capabilities of direct imaging to smaller contrast ratios ($\sim$10$^{-9}$) and inner-working angles (3~$\lambda$/D). In order to achieve this high precision, Roman Coronagraph data must be calibrated to remove as many potential sources of error as possible. Here we present a detailed overview of the Nancy Grace Roman Space Telescope Coronagraph Instrument Observation Calibration Plan including identifying potential sources of error and how they will be mitigated via on-sky calibrations.Comment: Posting for public information on the current status of the Roman Coronagraph Observation Calibration Plan; latest updates as of July 29, 202

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A systematic approach to mapping recessive disease genes in individuals from outbred populations

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

The Lamb shift in muonic hydrogen and the proton radius

By means of pulsed laser spectroscopy applied to muonic hydrogen (μ− p) we have measured the 2S F = 1 1/2 − 2PF = 2 3/2 transition frequency to be 49881.88(76) GHz. By comparing this measurement with its theoretical prediction based on bound-state QED we have determined a proton radius value of rp = 0.84184 (67) fm. This new value is an order of magnitude preciser than previous results but disagrees by 5 standard deviations from the CODATA and the electronproton scattering values. An overview of the present effort attempting to solve the observed discrepancy is given. Using the measured isotope shift of the 1S-2S transition in regular hydrogen and deuterium also the rms charge radius of the deuteron rd = 2.12809 (31) fm has been determined. Moreover we present here the motivations for the measurements of the μ 4He + and μ 3He + 2S-2P splittings. The alpha and triton charge radii are extracted from these measurements with relative accuracies of few 10 − 4. Measurements could help to solve the observed discrepancy, lead to the best test of hydrogen-like energy levels and provide crucial tests for few-nucleon ab-initio theories and potentials

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.</p

Polarization calibration of the BICEP3 CMB polarimeter at the South Pole

The BICEP3 CMB Polarimeter is a small-aperture refracting telescope located at the South Pole and is specifically designed to search for the possible signature of inflationary gravitational waves in the Cosmic Microwave Background (CMB). The experiment measures polarization on the sky by differencing the signal of co-located, orthogonally polarized antennas coupled to Transition Edge Sensor (TES) detectors. We present precise measurements of the absolute polarization response angles and polarization efficiencies for nearly all of BICEP3's ~800 functioning polarization-sensitive detector pairs from calibration data taken in January 2018. Using a Rotating Polarized Source (RPS), we mapped polarization response for each detector over a full 360 degrees of source rotation and at multiple telescope boresight rotations from which per-pair polarization properties were estimated. In future work, these results will be used to constrain signals predicted by exotic physical models such as Cosmic Birefringence