Thermodynamics, Adhesion, and Wetting at Li/Cu(-Oxide) Interfaces: Relevance for Anode-Free Lithium-Metal Batteries.

A rechargeable battery that employs a Li metal anode requires that Li be plated in a uniform fashion during charging. In "anode-free" configurations, this plating will occur on the surface of the Cu current collector (CC) during the initial cycle and in any subsequent cycle where the capacity of the cell is fully accessed. Experimental measurements have shown that the plating of Li on Cu can be inhomogeneous, which can lower the efficiency of plating and foster the formation of Li dendrites. The present study employs a combination of first-principles calculations and sessile drop experiments to characterize the thermodynamics and adhesive (i.e., wetting) properties of interfaces involving Li and other phases present on or near the CC. Interfaces between Li and Cu, Cu2O, and Li2O are considered. The calculations predict that both Cu and Cu2O surfaces are lithiophilic. However, sessile drop measurements reveal that Li wetting occurs readily only on pristine Cu. This apparent discrepancy is explained by the occurrence of a spontaneous conversion reaction, 2 Li + Cu2O → Li2O + 2 Cu, that generates Li2O as one of its products. Calculations and sessile drop measurements show that Li does not wet (newly formed) Li2O. Hence, Li that is deposited on a Cu CC where surface oxide species are present will encounter a compositionally heterogeneous substrate comprising lithiophillic (Cu) and lithiophobic (Li2O) regions. These initial heterogeneities have the potential to influence the longer-term behavior of the anode under cycling. In sum, the present study provides insights into the early stage processes associated with Li plating in anode-free batteries and describes mechanisms that contribute to inefficiencies in their operation.

Adsorption of Natural Gas in Metal-Organic Frameworks: Selectivity, Cyclability, and Comparison to Methane Adsorption.

Evaluation of metal-organic frameworks (MOFs) for adsorbed natural gas (ANG) technology employs pure methane as a surrogate for natural gas (NG). This approximation is problematic, as it ignores the impact of other heavier hydrocarbons present in NG, such as ethane and propane, which generally have more favorable adsorption interactions with MOFs compared to methane. Herein, using quantitative Raman spectroscopic analysis and Monte Carlo calculations, we demonstrate the adsorption selectivity of high-performing MOFs, such as MOF-5, MOF-177, and SNU-70, for a methane and ethane mixture (95:5) that mimics the composition of NG. The impact of selectivity on the storage and deliverable capacities of these adsorbents during successive cycles of adsorption and desorption, simulating the filling and emptying of an ANG tank, is also demonstrated. The study reveals a gradual reduction in the storage performance of MOFs, particularly with smaller pore volumes, due to ethane accumulation over long-term cycling, until a steady state is reached with substantially degraded storage performance.

Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .

Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors.

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-TRM) formation is activation in the presence of the pleotropic cytokine, transforming growth factor ß (TGF-ß), which enforces a core program of both "stemness" and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of "stem-like" CAR-TRM cells resistant to tumor-associated dysfunction, possessing an enhanced ability to accumulate in situ and rapidly eliminate cancer cells for more effective immunotherapy.

Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell-Intrinsic Dysfunction.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon-mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-ß exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon-associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biological system. SIGNIFICANCE: To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell-intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway-induced dysfunction and improves memory differentiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies. This article is highlighted in the In This Issue feature, p. 1501.

BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion.

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.

Microscale Determination of Binary Gas Adsorption Isotherms in MOFs.

The experimental determination of mixed gas isotherms is challenging and thus rarely performed. Nevertheless, characterizing the performance of adsorbents toward mixtures of gases is critical in most adsorptive separations. Here, the utility of Raman spectroscopy in determining binary gas adsorption isotherms on the microscale with metal-organic framework (MOF) single crystals is demonstrated for quantifying C2H6/CH4 selectivity. The influence of pore size on sorption selectivity is determined experimentally. The technique also allows determination of kinetics of methane adsorption in MOFs, which is critical for refueling times in adsorbed natural gas storage.

Discovery of Salt Hydrates for Thermal Energy Storage.

Thermal energy storage (TES) has the potential to improve the efficiency of many applications but has not been widely deployed. The viability of a TES system depends upon the performance of its underlying storage material; improving the energy density of TES materials is an important step in accelerating the adoption of TES systems. For applications in thermochemical energy storage, salt hydrates are a promising class of materials due to their relatively high energy densities and their reversibility. Despite their promise, relatively few salt hydrates have been characterized, presenting the possibility that new hydrate compositions with superior properties may exist. Here, the energy densities, turning temperatures, and thermodynamic stabilities of 5292 hypothetical salt hydrates are predicted using high-throughput density functional theory calculations. The hydrates of several metal fluorides, including CaF2, VF2, and CoF3, are identified as stable TES materials with class-leading energy densities and operating temperatures suitable for use in domestic heating and intermediate-temperature applications. The promising performance of these materials is demonstrated at the system level by parameterizing an operating model of a solar thermal TES system with data from the new hydrates. Finally, machine learning models for salt hydrate thermodynamics are developed and used to identify design guidelines for maximizing the energy density. In total, the new materials and design rules reported here are expected to nurture the implementation of TES systems.

Proteins, possibly human, found in World War II concentration camp artifact.

Museums displaying artifacts of the human struggle against oppression are often caught in their own internal struggle between presenting factual and unbiased descriptions of their collections, or relying on testament of survivors. Often this quandary is resolved in favor of what can be verified, not what is remembered. However, with improving instrumentation, methods and informatic approaches, science can help uncover evidence able to reconcile memory and facts. Following World War II, thousands of small, cement-like disks with numbers impressed on one side were found at concentration camps throughout Europe. Survivors claimed these disks were made of human cremains; museums erred on the side of caution-without documentation of the claims, was it justifiable to present them as fact? The ability to detect species relevant biological material in these disks could help resolve this question. Proteomic mass spectrometry of five disks revealed all contained proteins, including collagens and hemoglobins, suggesting they were made, at least in part, of animal remains. A new protein/informatics approach to species identification showed that while human was not always identified as the top contributor, human was the most likely explanation for one disk. To our knowledge, this is the first demonstration of protein recovery from cremains. Data are available via ProteomeXchange with identifier PXD035267.

Computational Identification and Experimental Demonstration of High-Performance Methane Sorbents.

Remarkable methane uptake is demonstrated experimentally in three metal-organic frameworks (MOFs) identified by computational screening: UTSA-76, UMCM-152 and DUT-23-Cu. These MOFs outperform the benchmark sorbent, HKUST-1, both volumetrically and gravimetrically, under a pressure swing of 80 to 5 bar at 298 K. Although high uptake at elevated pressure is critical for achieving this performance, a low density of high-affinity sites (coordinatively unsaturated metal centers) also contributes to a more complete release of stored gas at low pressure. The identification of these MOFs facilitates the efficient storage of natural gas via adsorption and provides further evidence of the utility of computational screening in identifying overlooked sorbents.

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

PSMA-targeting TGFß-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-ß. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-ß receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-ß-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

The role of justice perceptions in formal and informal university technology transfer.

We extend organizational justice theory by investigating the justice perceptions of academic entrepreneurs regarding interactions with their universities. We assess how these justice perceptions influence the propensity of academic entrepreneurs to engage in different forms of commercialization, as well as the moderating role of entrepreneurial identity and prosocial motivation. We test our predictions using data from 1,329 academic entrepreneurs at 25 major U.S. research universities. Our results indicate that organizational justice is positively associated with intentions to engage in formal (i.e., sanctioned) technology transfer, and negatively associated with intentions to engage in informal (unsanctioned and noncompliant) technology transfer, which we characterize as a form of organizational deviance. Our findings also show that entrepreneurial identity and prosocial motivation (i.e., a focus on oneself vs. others) amplify and attenuate, respectively, the relationship between justice perceptions and technology transfer intentions. Finally, although intentions to engage in formal technology transfer predict subsequent behavior, intentions to engage in informal technology transfer do not. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Dynamics of Hydroxyl Anions Promotes Lithium Ion Conduction in Antiperovskite Li2OHCl.

Li2OHCl is an exemplar of the antiperovskite family of ionic conductors, for which high ionic conductivities have been reported, but in which the atomic-level mechanism of ion migration is unclear. The stable phase is both crystallographically defective and disordered, having ∼1/3 of the Li sites vacant, while the presence of the OH- anion introduces the possibility of rotational disorder that may be coupled to cation migration. Here, complementary experimental and computational methods are applied to understand the relationship between the crystal chemistry and ionic conductivity in Li2OHCl, which undergoes an orthorhombic to cubic phase transition near 311 K (≈38 °C) and coincides with the more than a factor of 10 change in ionic conductivity (from 1.2 × 10-5mS/cm at 37 °C to 1.4 × 10-3 mS/cm at 39 °C). X-ray and neutron experiments conducted over the temperature range 20-200 °C, including diffraction, quasi-elastic neutron scattering (QENS), the maximum entropy method (MEM) analysis, and ab initio molecular dynamics (AIMD) simulations, together show conclusively that the high lithium ion conductivity of cubic Li2OHCl is correlated to "paddlewheel" rotation of the dynamic OH- anion. The present results suggest that in antiperovskites and derivative structures a high cation vacancy concentration combined with the presence of disordered molecular anions can lead to high cation mobility.

A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia.

BackgroundAntibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.MethodsWe performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies.ResultsEighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5-30] vs. 7 [2.75-12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.ConclusionTwo units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial RegistrationClinicalTrials.gov NCT04397757.FundingUniversity of Pennsylvania.

Predicting hydrogen storage in MOFs via machine learning.

The H2 capacities of a diverse set of 918,734 metal-organic frameworks (MOFs) sourced from 19 databases is predicted via machine learning (ML). Using only 7 structural features as input, ML identifies 8,282 MOFs with the potential to exceed the capacities of state-of-the-art materials. The identified MOFs are predominantly hypothetical compounds having low densities (<0.31 g cm-3) in combination with high surface areas (>5,300 m2 g-1), void fractions (∼0.90), and pore volumes (>3.3 cm3 g-1). The relative importance of the input features are characterized, and dependencies on the ML algorithm and training set size are quantified. The most important features for predicting H2 uptake are pore volume (for gravimetric capacity) and void fraction (for volumetric capacity). The ML models are available on the web, allowing for rapid and accurate predictions of the hydrogen capacities of MOFs from limited structural data; the simplest models require only a single crystallographic feature.

Optimizing Hydrogen Storage in MOFs through Engineering of Crystal Morphology and Control of Crystal Size.

Metal-organic frameworks (MOFs) are promising materials for hydrogen storage that fail to achieve expected theoretical values of volumetric storage density due to poor powder packing. A strategy that improves packing efficiency and volumetric hydrogen gas storage density dramatically through engineered morphologies and controlled-crystal size distributions is presented that holds promise for maximizing storage capacity for a given MOF. The packing density improvement, demonstrated for the benchmark sorbent MOF-5, leads to a significant enhancement of volumetric hydrogen storage performance relative to commercial MOF-5. System model projections demonstrate that engineering of crystal morphology/size or use of a bimodal distribution of cubic crystal sizes in tandem with system optimization can surpass the 25 g/L volumetric capacity of a typical 700 bar compressed storage system and exceed the DOE targets 2020 volumetric capacity (30 g/L). Finally, a critical link between improved powder packing density and reduced damage upon compaction is revealed leading to sorbents with both high surface area and high density.