A Case for Nebula Scale Mixing Between Non-Carbonaceous and Carbonaceous Chondrite Reservoirs: Testing the Grand Tack Model with Chromium Isotopic Composition of Almahata Sitta Stone 91A

There is an increasing number of Cr-O-Ti isotope studies that show solar system materials are divided into two main populations, one carbonaceous chondrite (CC)-like and the other is non-carbonaceous (NC)-like, with minimal mixing attributed to a gap opened in the protoplanetary disk due to Jupiter's formation. The Grand Tack model suggests there should be large-scale mixing between S- and C-type asteroids, an idea supported by our recent work on chondrule (Delta)17O-54Cr isotope systematics. The Almahata Sitta (AhS) meteorite provides a unique opportunity to test the Grand Tack model. The meteorite fell to Earth in October 2008 and has been linked to the asteroid 2008 TC3 which was discovered just prior to the fall of the AhS stones. The AhS meteorite is composed of up to 700 individual pieces with approx.140 of those pieces having some geochemical and/or petrologic studies. Almahata Sitta is an anomalous polymict ureilite with other meteorite components, including enstatite, ordinary, and carbonaceous chondrites with an approximate abundance of 70% ureilites and 30% chondrites. This observation has lead to the suggestion that TC3 2008 was a loosely aggregated rubble pile-like asteroid with the non-ureilite sample clasts within the rubble-pile. Due to the loosely-aggregated nature of AhS, the object disintegrated during atmospheric entry resulting in the weakly held clasts falling predominantly as individual stones in the AhS collection area. However, recent work has identified one sample of AhS, sample 91A, which may represent two different lithologies coexisting within a single stone. The predominate lithology type in 91A appears to be that of a C2 chondrite based on mineralogy but also contains olivine, pyroxene, and albite that have ureilite-like compositions. Previous Cr isotope investigations into AhS stones are sparse and what data is available show nearly uniform isotopic composition similar to that of typical ureilites with negative 54Cr values

Thermal Adaptation and Diversity in Tropical Ecosystems: Evidence from Cicadas (Hemiptera, Cicadidae)

The latitudinal gradient in species diversity is a central problem in ecology. Expeditions covering approximately 16°54′ of longitude and 21°4′ of latitude and eight Argentine phytogeographic regions provided thermal adaptation data for 64 species of cicadas. We test whether species diversity relates to the diversity of thermal environments within a habitat. There are general patterns of the thermal response values decreasing in cooler floristic provinces and decreasing maximum potential temperature within a habitat except in tropical forest ecosystems. Vertical stratification of the plant communities leads to stratification in species using specific layers of the habitat. There is a decrease in thermal tolerances in species from the understory communities in comparison to middle level or canopy fauna. The understory Herrera umbraphila Sanborn & Heath is the first diurnally active cicada identified as a thermoconforming species. The body temperature for activity in H. umbraphila is less than and significantly different from active body temperatures of all other studied species regardless of habitat affiliation. These data suggest that variability in thermal niches within the heterogeneous plant community of the tropical forest environments permits species diversification as species adapt their physiology to function more efficiently at temperatures different from their potential competitors

Nebula Scale Mixing Between Non-Carbonaceous and Carbonaceous Chondrite Reservoirs: Testing the Grand Tack Model with Almahata Sitta Stones

There is an increasing number of Cr-O-Ti isotope studies that show that solar system materials are divided into two main populations, one carbonaceous chondrite (CC)-like and the other is non-carbonaceous (NCC)-like, with minimal mixing between them attributed to a gap opened in the propoplanetary disk due to Jupiter's formation. The Grand Tack model suggests that there should be a particular time in the disk history when this gap is breached and ensuring a subsequent large-scale mixing between S- and C-type asteroids (inner solar system and outer solar system materials), an idea supported by our recent work on chondrule (Delta)17O-(epsilon)54Cr isotope systematics

Phase 1b Trial of Proteasome Inhibitor Carfilzomib with Irinotecan in Lung Cancer and Other Irinotecan-Sensitive Malignancies That Have Progressed on Prior Therapy (Onyx IST Reference Number: CAR-IST-553)

Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function. Patients with stable asymptomatic brain metastases were eligible. Dose escalation utilized a standard 3 + 3 design. Results Overall, 16 patients were enrolled to three dose levels, with four patients replaced. Three patients experienced dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) was exceeded in Cohort 3. The RP2 dose was carfilzomib 20/36 mg/m2 (given on Days 1, 2, 8, 9, 15, and 16) and irinotecan 125 mg/m2 (Days 1, 8 and 15). Common Grade (Gr) 3 and 4 toxicities included fatigue (19%), thrombocytopenia (19%), and diarrhea (13%). Conclusions Irinotecan and carfilzomib were well tolerated, with common toxicities of fatigue, thrombocytopenia and neutropenic fever. Objective clinical response was 19% (one confirmed partial response (PR) in small cell lung cancer (SCLC) and two unconfirmed); stable disease (SD) was 6% for a disease control rate (DCR) of 25%. The recommended phase II dose was carfilzomib 20/36 mg/m2 and irinotecan125 mg/m2. The phase II evaluation is ongoing in relapsed small cell lung cancer

Bunburra Rockhole: Exploring the geology of a new differentiated basaltic asteroid

Bunburra Rockhole (BR) is the first recovered meteorite of the Desert Fireball Network. It was initially classified as a basaltic eucrite, based on texture, mineralogy, and mineral chemistry but subsequent O isotopic analyses showed that BR's composition lies significantly far away from the HED group of meteorites. This suggested that BR was not a piece of the HED parent body (4 Vesta), but other explanations could also account for the observed oxygen signatures. Possible scenarios include contamination by components from other bodies (chondrites or other achondrites) or that 4 Vesta may not be as equilibrated as hypothesized. After examining multiple pieces with different instruments (CT scans and x-ray maps), no obvious evidence of contamination was found. If BR is not from Vesta, a conundrum exists as no unusual features were found in mineral and bulk trace element chemistry as exist for other anomalous basaltic achondrites such as Ibitira or Asuka 881394. These meteorites have distinct petrological and geochemical characteristics, in addition to their anomalous O isotope compositions, that set them apart from eucrites. Thus, early results provided a somewhat ambiguous picture of BR's petrogenesis and parentage. To clarify the nature of the relationship, if any, between BR and eucrites, we have performed a correlated stable isotope and bulk chemical study of several lithologic fragments

Spin- and energy relaxation of hot electrons at GaAs surfaces

The mechanisms for spin relaxation in semiconductors are reviewed, and the mechanism prevalent in p-doped semiconductors, namely spin relaxation due to the electron-hole exchange interaction, is presented in some depth. It is shown that the solution of Boltzmann-type kinetic equations allows one to obtain quantitative results for spin relaxation in semiconductors that go beyond the original Bir-Aronov-Pikus relaxation-rate approximation. Experimental results using surface sensitive two-photon photoemission techniques show that the spin relaxation-time of electrons in p-doped GaAs at a semiconductor/metal surface is several times longer than the corresponding bulk spin relaxation-times. A theoretical explanation of these results in terms of the reduced density of holes in the band-bending region at the surface is presented.Comment: 33 pages, 12 figures; earlier submission replaced by corrected and expanded version; eps figures now included in the tex

The Minimum-Uncertainty Squeezed States for for Atoms and Photons in a Cavity

We describe a six-parameter family of the minimum-uncertainty squeezed states for the harmonic oscillator in nonrelativistic quantum mechanics. They are derived by the action of corresponding maximal kinematical invariance group on the standard ground state solution. We show that the product of the variances attains the required minimum value 1/4 only at the instances that one variance is a minimum and the other is a maximum, when the squeezing of one of the variances occurs. The generalized coherent states are explicitly constructed and their Wigner function is studied. The overlap coefficients between the squeezed, or generalized harmonic, and the Fock states are explicitly evaluated in terms of hypergeometric functions. The corresponding photons statistics are discussed and some applications to quantum optics, cavity quantum electrodynamics, and superfocusing in channeling scattering are mentioned. Explicit solutions of the Heisenberg equations for radiation field operators with squeezing are found.Comment: 27 pages, no figures, 174 references J. Phys. B: At. Mol. Opt. Phys., Special Issue celebrating the 20th anniversary of quantum state engineering (R. Blatt, A. Lvovsky, and G. Milburn, Guest Editors), May 201

Principles of meiotic chromosome assembly revealed in S. cerevisiae

During meiotic prophase, chromosomes organise into a series of chromatin loops emanating from a proteinaceous axis, but the mechanisms of assembly remain unclear. Here we use Saccharomyces cerevisiae to explore how this elaborate three-dimensional chromosome organisation is linked to genomic sequence. As cells enter meiosis, we observe that strong cohesin-dependent grid-like Hi-C interaction patterns emerge, reminiscent of mammalian interphase organisation, but with distinct regulation. Meiotic patterns agree with simulations of loop extrusion with growth limited by barriers, in which a heterogeneous population of expanding loops develop along the chromosome. Importantly, CTCF, the factor that imposes similar features in mammalian interphase, is absent in S. cerevisiae, suggesting alternative mechanisms of barrier formation. While grid-like interactions emerge independently of meiotic chromosome synapsis, synapsis itself generates additional compaction that matures differentially according to telomere proximity and chromosome size. Collectively, our results elucidate fundamental principles of chromosome assembly and demonstrate the essential role of cohesin within this evolutionarily conserved process

474 Phase 1 study of SEA-TGT, a human, nonfucosylated anti-TIGIT monoclonal antibody with enhanced immune-effector function, in patients with advanced malignancies (SGNTGT-001, trial in progress)

BackgroundT-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory domains (TIGIT), and costimulatory receptor CD226 competitively bind 2 ligands, CD155 and CD112, which are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment.1 2 Dual TIGIT/programmed cell death protein-1 (PD-1) blockade increased tumor antigen-specific CD8+ T-cell expansion and function in vitro and promoted potent antitumor response in vivo.3 4 TIGIT/PD-1 dual blockade using a TIGIT monoclonal antibody (mAb) with intact Fc produced clinical responses in advanced cancer.5 SEA-TGT is an investigational, human, nonfucosylated mAb directed against TIGIT. SEA-TGT binds to TIGIT, blocking inhibitory checkpoint signals directed at T cells. SEA-TGT enhances binding to activating FcγRIIIa and decreases binding to inhibitory FcγRIIb; this depletes immunosuppressive regulatory T cells and amplifies naive and memory T cells, potentially augmenting PD-1 inhibition effects. Preclinically, at suboptimal doses, SEA-TGT plus anti-PD-1 mAbs had superior antitumor activity than either agent alone.6MethodsSafety and antitumor activity of SEA TGT in ~377 adults (≥18 years) will be evaluated in this phase 1, multicenter, open-label, dose-escalation/expansion study. Part A will assess the safety/tolerability of SEA TGT to determine maximum tolerated and recommended doses. Part B will assess the safety and antitumor activity of the recommended dose in disease-specific expansion cohorts. Part C will assess SEA-TGT plus sasanlimab in dose-expansion cohorts after an initial safety run-in. Patients with histologically/cytologically confirmed relapsed/refractory/progressive metastatic solid tumors including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), gastric/gastroesophageal junction carcinoma, cutaneous melanoma, bladder, cervical, ovarian or triple-negative breast cancer, or selected lymphomas will be eligible for Parts A and B. Part C will enroll patients with histologically confirmed advanced NSCLC (high [tumor proportion score (TPS) ≥50%] and low [TPS=1–49%] PD ligand 1 [PD-L1] expression), cutaneous melanoma, and HNSCC without previous anti–PD-1/PD-L1 therapy exposure. SEA TGT will be administered on Day 1 of 21-day cycles.Laboratory abnormalities, adverse events, dose-limiting toxicities, and dose-level safety and activity are primary endpoints. Secondary endpoints are objective response (OR) and complete response (CR) rates, duration of OR/CR, progression-free survival, overall survival, pharmacokinetics (PK), and antidrug antibodies. Exploratory analysis will include pharmacodynamics (PD), PK/PD relationships, biomarkers, and resistance to SEA-TGT. This trial is recruiting in Europe and North America.Trial RegistrationNCT04254107ReferencesBlake SJ, Dougall WC, Miles JJ, et al. Molecular pathways: Targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res 2016;22(21):5183–5188.Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J ImmunoTher Cancer 2020;8:e000957.Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 2014;26(6):923–937.Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015;125(5):2046–2058.Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase 2 study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol 2020;38(15 suppl):9503.Smith A, Zeng W, Lucas S, et al. Poster 1583. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Presented at: American Association for Cancer Research Annual Meeting; April 9–14, 2021; Virtual Meeting.Ethics ApprovalInstitutional review boards or independent ethics committees of participating sites approved the trial, which will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. All patients will provide written informed consent