Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through ...defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
We compute the instantaneous contributions to the spherical harmonic modes of gravitational waveforms from compact binary systems in general orbits up to the third post-Newtonian (PN) order. We ...further extend these results for compact binaries in quasielliptical orbits using the 3PN quasi-Keplerian representation of the conserved dynamics of compact binaries in eccentric orbits. Using the multipolar post-Minkowskian formalism, starting from the different mass and current-type multipole moments, we compute the spin-weighted spherical harmonic decomposition of the instantaneous part of the gravitational waveform. These are terms which are functions of the retarded time and do not depend on the history of the binary evolution. Together with the hereditary part, which depends on the binary's dynamical history, these waveforms form the basis for construction of accurate templates for the detection of gravitational wave signals from binaries moving in quasielliptical orbits.
ABSTRACT
Many scientific investigations of photometric galaxy surveys require redshift estimates, whose uncertainty properties are best encapsulated by photometric redshift (photo-z) posterior ...probability density functions (PDFs). A plethora of photo-z PDF estimation methodologies abound, producing discrepant results with no consensus on a preferred approach. We present the results of a comprehensive experiment comparing 12 photo-z algorithms applied to mock data produced for The Rubin Observatory Legacy Survey of Space and Time Dark Energy Science Collaboration. By supplying perfect prior information, in the form of the complete template library and a representative training set as inputs to each code, we demonstrate the impact of the assumptions underlying each technique on the output photo-z PDFs. In the absence of a notion of true, unbiased photo-z PDFs, we evaluate and interpret multiple metrics of the ensemble properties of the derived photo-z PDFs as well as traditional reductions to photo-z point estimates. We report systematic biases and overall over/underbreadth of the photo-z PDFs of many popular codes, which may indicate avenues for improvement in the algorithms or implementations. Furthermore, we raise attention to the limitations of established metrics for assessing photo-z PDF accuracy; though we identify the conditional density estimate loss as a promising metric of photo-z PDF performance in the case where true redshifts are available but true photo-z PDFs are not, we emphasize the need for science-specific performance metrics.
We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing ...efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like” properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.
Context. The James Webb Space Telescope’s (JWST’s) unprecedented combination of sensitivity, spatial resolution, and infrared coverage has enabled a new era of galaxy morphology exploration across ...most of cosmic history. Aims. We analyze the near-infrared (NIR ∼ 0.8 − 1 μm) rest-frame morphologies of galaxies with log M * / M ⊙ > 9 in the redshift range of 0 < z < 6, compare with previous HST-based results and release the first JWST-based morphological catalog of ∼20 000 galaxies in the CEERS survey. Methods. We classified the galaxies in our sample into four main broad classes: spheroid, disk+spheroid, disk, and disturbed, based on imaging with four filters: F 150 W , F 200 W , F 356 W , and F 444 W . We used convolutional neural networks (CNNs) trained on HST/WFC3 labeled images and domain-adapted to JWST/NIRCam. Results. We find that ∼90% and ∼75% of galaxies at z < 3 have the same early and late and regular and irregular classification, respectively, in JWST and HST imaging when considering similar wavelengths. For small (large) and faint objects, JWST-based classifications tend to systematically present less bulge-dominated systems (peculiar galaxies) than HST-based ones, but the impact on the reported evolution of morphological fractions is less than ∼10%. Using JWST-based morphologies at the same rest-frame wavelength (∼0.8 − 1 μm), we confirm an increase in peculiar galaxies and a decrease in bulge-dominated galaxies with redshift, as reported in previous HST-based works, suggesting that the stellar mass distribution, in addition to light distribution, is more disturbed in the early Universe. However, we find that undisturbed disk-like systems already dominate the high-mass end of the late-type galaxy population (log M * / M ⊙ > 10.5) at z ∼ 5, and bulge-dominated galaxies also exist at these early epochs, confirming a rich and evolved morphological diversity of galaxies ∼1 Gyr after the Big Bang. Finally, we find that the morphology-quenching relation is already in place for massive galaxies at z > 3, with massive quiescent galaxies (log M * / M ⊙ > 10.5) being predominantly bulge-dominated.
A domino approach of Heck coupling was used to synthesize β-trifluoromethylstyrene derivatives from iodoarenes and 1-iodo-3,3,3-trifluoropropane in moderate to good yields. This method avoids the use ...of low-boiling, gaseous reagents such as 3,3,3-trifluoropropene, and additives and phosphines in the catalytic system.
ABSTRACT A neonate born of third-degree consanguineous marriage presented on day 12 of life with congestive cardiac failure. A male sibling died at 3 months of age, cause of which was not known. He ...was treated with decongestive measures and multiple inotropes. 2D Echocardiogram revealed severe Left ventricular dysfunction with prominent trabeculations and deep recesses in the left ventricle suggestive of Left ventricular non-compaction. He was also found to have horse-shoe kidney. Considering the presence of cardiac left ventricular non compaction, horse-shoe kidney and family history of neonatal death and pregnancy loss clinical exome sequencing was done. It detected a homozygous missense variant in exon 6 of the AGK gene suggestive of Senger’s syndrome. Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions. At 8 months of age, cardiac transplantation was successfully done and baby has been doing well post-transplantation. LVNC in children is rare with an estimated incidence of 0.11 per 100,000, the highest incidence being during infancy. Senger’s syndrome is autosomal recessive in inheritance. Senger’s syndrome associated with Left ventricular non compaction has been reported only once in literature so far. Renal manifestations in the form of horse shoe kidney like in our index baby has not been reported previously with Senger’s syndrome.
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