Condensed Layer Deposition of Nanoscopic TiO2 Overlayers on High-Surface-Area Electrocatalysts.

Encapsulating an electrocatalytic material with a semipermeable, nanoscopic oxide overlayer offers a promising approach to enhancing its stability, activity, and/or selectivity compared to an unencapsulated electrocatalyst. However, applying nanoscopic oxide encapsulation layers to high-surface-area electrodes such as nanoparticle-supported porous electrodes is a challenging task. This study demonstrates that the recently developed condensed layer deposition (CLD) method can be used for depositing nanoscopic (sub-10 nm thick) titanium dioxide (TiO2) overlayers onto high-surface-area platinized carbon foam electrodes. Characterization of the overlayers by transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS) showed that the films are amorphous, while X-ray photoelectron spectroscopy confirmed that they exhibit TiO2 stoichiometry. Electrodes were also characterized by hydrogen underpotential deposition (Hupd) and carbon monoxide (CO) stripping, demonstrating that the Pt electrocatalysts remain electrochemically active after encapsulation. Additionally, copper underpotential deposition (Cuupd) measurements revealed that TiO2 overlayers are effective at blocking Cu2+ from reaching the TiO2/Pt buried interface and were used to estimate that between 43 and 98% of Pt surface sites were encapsulated. Overall, this study shows that CLD is a promising approach for depositing nanoscopic protective overlayers on high-surface-area electrodes.

General Route to Colloidally Stable, Low-Dispersity Manganese-Based Ternary Spinel Oxide Nanocrystals.

While certain ternary spinel oxides have been well-explored with colloidal nanochemistry, notably the ferrite spinel family, ternary manganese (Mn)-based spinel oxides have not been tamed. A key composition is cobalt (Co)-Mn oxide (CMO) spinel, CoxMn3-xO4, that, despite exemplary performance in multiple electrochemical applications, has few reports in the colloidal literature. Of these reports, most show aggregated and polydisperse products. Here, we describe a synthetic method for small, colloidally stable CMO spinel nanocrystals with tunable composition and low dispersity. By reacting 2+ metal-acetylacetonate (M(acac)2) precursors in an amine solvent under an oxidizing environment, we developed a pathway that avoids the highly reducing conditions of typical colloidal synthesis reactions; these reducing conditions typically push the system toward a monoxide impurity phase. Through surface chemistry studies, we identify organic byproducts and their formation mechanism, enabling us to engineer the surface and obtain colloidally stable nanocrystals with low organic loading. We report a CMO/carbon composite with low organic contents that performs the oxygen reduction reaction (ORR) with a half-wave potential (E1/2) of 0.87 V vs RHE in 1.0 M potassium hydroxide at 1600 rpm, rivaling previous reports for the highest activity of this material in ORR electrocatalysis. We extend the general applicability of this procedure to other Mn-based spinel nanocrystals such as Zn-Mn-O, Fe-Mn-O, Ni-Mn-O, and Cu-Mn-O. Finally, we show the scalability of this method by producing inorganic nanocrystals at the gram scale.

Understanding the Structural Evolution of IrFeCoNiCu High-Entropy Alloy Nanoparticles under the Acidic Oxygen Evolution Reaction.

High-entropy alloy (HEA) nanoparticles are promising catalyst candidates for the acidic oxygen evolution reaction (OER). Herein, we report the synthesis of IrFeCoNiCu-HEA nanoparticles on a carbon paper substrate via a microwave-assisted shock synthesis method. Under OER conditions in 0.1 M HClO4, the HEA nanoparticles exhibit excellent activity with an overpotential of ∼302 mV measured at 10 mA cm-2 and improved stability over 12 h of operation compared to the monometallic Ir counterpart. Importantly, an active Ir-rich shell layer with nanodomain features was observed to form on the surface of IrFeCoNiCu-HEA nanoparticles immediately after undergoing electrochemical activation, mainly due to the dissolution of the constituent 3d metals. The core of the particles was able to preserve the characteristic homogeneous single-phase HEA structure without significant phase separation or elemental segregation. This work illustrates that under acidic operating conditions, the near-surface structure of HEA nanoparticles is susceptible to a certain degree of structural dynamics.

Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy.

INTRODUCTION: Adoptive cellular therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated promising clinical benefits in several solid tumors, but the efficacy of this therapy might be compromised by the "prone-to-exhaustion" phenotype of TIL and poor persistence in vivo. This calls for a robust expansion process to produce a large number of cells for clinical usage while at the same time maintaining favorable anti-tumor function and memory phenotype. Previous studies showed that the PI3K-AKT signaling pathway plays a key role in the regulation of T cell activation, differentiation and memory formation. METHOD: We modulated the PI3K-AKT pathway in TIL isolated from cervical and ovarian cancer by application of AKT or PI3K inhibitors or CRISPR knockout of AKT1 and/or AKT2, and characterized their effects on TIL phenotype and effector function. Mechanistic study was further performed with RNA-seq analysis of AKT1/2 KO TIL in comparison to control TIL. RESULT: The inhibition of either PI3K or AKT led to an increase in the population of effector CD8+ T cells with upregulation of activation markers, elevated CD39- CD69- memory T cells, and significantly enhanced cytotoxicity when cocultured with tumor cell lines and patient-derived tumor samples. Moreover, dual knockout of AKT1 and AKT2 largely phenocopies the functional impact of AKT or PI3K inhibition on TIL. This result was further validated by RNA-seq analysis indicating that AKT1/2 ablation primarily regulates T cell differentiation and function-related programs. CONCLUSION: Modulation of PI3K-AKT signaling represents a promising strategy to enhance TIL stemness and cytotoxicity and improve the clinical outcome of current TIL-based therapy to treat solid tumors.

Kinetic Trapping of Photoluminescent Frameworks During High-Concentration Synthesis of Non-Emissive Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) are porous, crystalline materials constructed from organic linkers and inorganic nodes with potential utility in gas separations, drug delivery, sensing, and catalysis. Small variations in MOF synthesis conditions can lead to a range of accessible frameworks with divergent chemical or photophysical properties. New methods to controllably access phases with tailored properties would broaden the scope of MOFs that can be reliably prepared for specific applications. Herein, we demonstrate that simply increasing the reaction concentration during the solvothermal synthesis of M2(dobdc) (M = Mg, Mn, Ni; dobdc4- = 2,5-dioxido-1,4-benzenedicarboxylate) MOFs unexpectedly leads to trapping of a new framework termed CORN-MOF-1 (CORN = Cornell University) instead. In-depth spectroscopic, crystallographic, and computational studies support that CORN-MOF-1 has a similar structure to M2(dobdc) but with partially protonated linkers and charge-balancing or coordinated formate groups in the pores. The resultant variation in linker spacings causes CORN-MOF-1 (Mg) to be strongly photoluminescent in the solid state, whereas H4dobdc and Mg2(dobdc) are weakly emissive due to excimer formation. In-depth photophysical studies suggest that CORN-MOF-1 (Mg) is the first MOF based on the H2dobdc2- linker that likely does not emit via an excited state intramolecular proton transfer (ESIPT) pathway. In addition, CORN-MOF-1 variants can be converted into high-quality samples of the thermodynamic M2(dobdc) phases by heating in N,N-dimethylformamide (DMF). Overall, our findings support that high-concentration synthesis provides a straightforward method to identify new MOFs with properties distinct from known materials and to produce highly porous samples of MOFs, paving the way for the discovery and gram-scale synthesis of framework materials.

Experimental Research on Vibration-Damping Effect of Combined Shear Hinge Prefabricated Steel Spring Floating Slab Track.

OBJECTIVE: The cast-in-place steel spring floating slab track (SSFST) is difficult to maintain and repair, while the mechanical strength of the end of the traditional prefabricated SSFST is poor. In order to overcome the above shortcomings, a shear-hinge-combined prefabricated SSFST was developed, and an indoor test was carried out to analyze its vibration-damping effect. METHODS: A combined shear hinge SSFST connection model with two length sizes was established. The dynamic response amplitude and frequency response characteristics of the foundation (ground) under different isolator installations and fatigue loads were studied, and the vibration-damping performance of two sizes of combined shear hinge SSFST was evaluated. RESULTS: The vibration-damping effect of the steel spring vibration isolator mainly acts in the middle and low-frequency bands of 16-400 Hz, and the vibration near 10 Hz will be aggravated after the vibration isolator is installed. The vibration index and variation law of the two sizes of SSFST are similar, and the vibration response of 4.8 m SSFST is slightly less than 3.6 m SSFST. There is almost no change in each index when the load is 5 million times, and there is a certain range of change when the load is 10 million times, but the overall change is small. CONCLUSIONS: The combined shear hinge prefabricated SSFST can have an excellent isolation effect on vibration and can still maintain good vibration-damping ability within 10 million fatigue loads (about 5 years); 4.8 m SSFST should be laid in straight sections with higher train speeds, while 3.6 m SSFST should be applied in curved sections to ensure smooth lines.

Peripheral eosinophil counts predict efficacy of anti-CD19 CAR-T cell therapy against B-lineage non-Hodgkin lymphoma.

Rationale: The onset of cytokine release syndrome (CRS) and in vivo persistence of anti-CD19 chimeric antigen receptor T (CAR-T) cells after infusion correlate with clinical responsiveness. However, there are no known baseline biomarkers that can predict the prognosis of patients with B-lineage non-Hodgkin lymphoma (B-NHL). The aim of this study was to identify blood cell populations associated with beneficial outcomes in B-NHL patients administered CAR-T cell immunotherapies. Methods: We enumerated peripheral blood and CAR-T cells by retrospectively analyzing three CAR-T cell trials involving 65 B-NHL patients. We used a preclinical model to elucidate the eosinophil mechanism in CAR-T cell therapy. Results: During an observation period up to 30 mo, B-NHL patients with higher baseline eosinophil counts had higher objective response rates than those with low eosinophil counts. Higher baseline eosinophil counts were also significantly associated with durable progression-free survival (PFS). The predictive significance of baseline eosinophil counts was validated in two independent cohorts. A preclinical model showed that eosinophil depletion impairs the intratumoral infiltration of transferred CAR-T cells and reduces CAR-T cell antitumor efficacy. Conclusion: The results of this study suggest that peripheral eosinophils could serve as stratification biomarkers and a recruitment machinery to facilitate anti-CD19 CAR-T cell therapy in B-NHL patients.

The Building Data Genome Project 2, energy meter data from the ASHRAE Great Energy Predictor III competition.

This paper describes an open data set of 3,053 energy meters from 1,636 non-residential buildings with a range of two full years (2016 and 2017) at an hourly frequency (17,544 measurements per meter resulting in approximately 53.6 million measurements). These meters were collected from 19 sites across North America and Europe, with one or more meters per building measuring whole building electrical, heating and cooling water, steam, and solar energy as well as water and irrigation meters. Part of these data was used in the Great Energy Predictor III (GEPIII) competition hosted by the American Society of Heating, Refrigeration, and Air-Conditioning Engineers (ASHRAE) in October-December 2019. GEPIII was a machine learning competition for long-term prediction with an application to measurement and verification. This paper describes the process of data collection, cleaning, and convergence of time-series meter data, the meta-data about the buildings, and complementary weather data. This data set can be used for further prediction benchmarking and prototyping as well as anomaly detection, energy analysis, and building type classification.

Boosting Lattice Oxygen Oxidation of Perovskite to Efficiently Catalyze Oxygen Evolution Reaction by FeOOH Decoration.

In the process of oxygen evolution reaction (OER) on perovskite, it is of great significance to accelerate the hindered lattice oxygen oxidation process to promote the slow kinetics of water oxidation. In this paper, a facile surface modification strategy of nanometer-scale iron oxyhydroxide (FeOOH) clusters depositing on the surface of LaNiO3 (LNO) perovskite is reported, and it can obviously promote hydroxyl adsorption and weaken Ni-O bond of LNO. The above relevant evidences are well demonstrated by the experimental results and DFT calculations. The excellent hydroxyl adsorption ability of FeOOH-LaNiO3 (Fe-LNO) can obviously optimize OH- filling barriers to promote lattice oxygen-participated OER (LOER), and the weakened Ni-O bond of LNO perovskite can obviously reduce the reaction barrier of the lattice oxygen participation mechanism (LOM). Based on the above synergistic catalysis effect, the Fe-LNO catalyst exhibits a maximum factor of 5 catalytic activity increases for OER relative to the pristine perovskite and demonstrates the fast reaction kinetics (low Tafel slope of 42 mV dec-1) and superior intrinsic activity (TOFs of ~40 O2 S-1 at 1.60 V vs. RHE).

Boosting the electrocatalytic performance of NiFe layered double hydroxides for the oxygen evolution reaction by exposing the highly active edge plane (012).

The intrinsic activity of NiFe layer double hydroxides (LDHs) for the oxygen evolution reaction (OER) suffers from its predominantly exposed (003) basal plane, which is thought to have poor activity. Herein, we construct a hierarchal structure of NiFe LDH nanosheet-arrays-on-microplates (NiFe NSAs-MPs) to elevate the electrocatalytic activity of NiFe LDHs for the OER by exposing a high-activity plane, such as the (012) edge plane. It is surprising that the NiFe NSAs-MPs show activity of 100 mA cm-2 at an overpotential (η) of 250 mV, which is five times higher than that of (003) plane-dominated NiFe LDH microsheet arrays (NiFe MSAs) at the same η, representing the excellent electrocatalytic activity for the OER in alkaline media. Besides, we analyzed the OER activities of the (003) basal plane and the (012) and (110) edge planes of NiFe LDHs by density functional theory with on-site Coulomb interactions (DFT+U), and the calculation results indicated that the (012) edge plane exhibits the best catalytic performance among the various crystal planes because of the oxygen coordination of the Fe site, which is responsible for the high catalytic activity of NiFe NSAs-MPs.

Porous Microrod Arrays Constructed by Carbon-Confined NiCo@NiCoO2 Core@Shell Nanoparticles as Efficient Electrocatalysts for Oxygen Evolution.

The study of cost-efficient and high-performance electrocatalysts for oxygen evolution reaction (OER) has attracted much attention. Here, porous microrod arrays constructed by carbon-confined NiCo@NiCoO2 core@shell nanoparticles (NiCo@NiCoO2 /C PMRAs) are fabricated by the reductive carbonization of bimetallic (Ni, Co) metal-organic framework microrod arrays (denoted as NiCo-MOF MRAs) and subsequent controlled oxidative calcination. They successfully combine the desired merits including large specific surface areas, high conductivity, and multiple electrocatalytic active sites for OER. In addition, the oxygen vacancies in NiCo@NiCoO2 /C PMRAs significantly improve the conductivity of NiCoO2 and accelerate the kinetics of OER. The above advantages obviously enhance the electrocatalytic performance of NiCo@NiCoO2 /C PMRAs. The experimental results demonstrate that the NiCo@NiCoO2 /C PMRAs as electrocatalysts exhibit high catalytic activity, low overpotential, and high stability for OER in alkaline media. The strategy reported will open up a new route for the fabrication of porous bimetallic composite electrocatalysts derived from MOFs with controllable morphology for electrochemical energy conversion devices.

In Vivo Expansion and Antitumor Activity of Coinfused CD28- and 4-1BB-Engineered CAR-T Cells in Patients with B Cell Leukemia.

Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3ζ T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo. Patients with B cell leukemia were infused with a mixture of two types of CD19-specific CAR-T cells, individually bearing CD28 (28ζ) and 4-1BB (BBζ) costimulatory signaling domains. We found that such a clinical procedure was feasible and safe. Complete remission (CR) was observed in five of seven enrolled patients, with two patients exhibiting durable CR lasting more than 15 months. The in vivo expansion pattern of 28ζ and BBζ CAR-T cells varied significantly among individual patients. These results confirm a feasible method of comparing different CAR designs within individual patients, potentially offering objective insights that may facilitate the development of optimal CAR-T cell-based immunotherapies.

Activating CoOOH Porous Nanosheet Arrays by Partial Iron Substitution for Efficient Oxygen Evolution Reaction.

Iron-substituted CoOOH porous nanosheet arrays grown on carbon fiber cloth (denoted as Fex Co1-x OOH PNSAs/CFC, 0≤x≤0.33) with 3D hierarchical structures are synthesized by in situ anodic oxidation of α-Co(OH)2 NSAs/CFC in solution of 0.01 m (NH4 )2 Fe(SO4 )2 . X-ray absorption fine spectra (XAFS) demonstrate that CoO6 octahedral structure in CoOOH can be partially substituted by FeO6 octahedrons during the transformation from α-Co(OH)2 to Fex Co1-x OOH, and this is confirmed for the first time in this study. The content of Fe in Fex Co1-x OOH, no more than 1/3 of Co, can be controlled by adjusting the in situ anodic oxidation time. Fe0.33 Co0.67 OOH PNSAs/CFC shows superior OER electrocatalytic performance, with a low overpotential of 266 mV at 10 mA cm-2 , small Tafel slope of 30 mV dec-1 , and high durability.

The zinc finger E-box-binding homeobox 1 (Zeb1) promotes the conversion of mouse fibroblasts into functional neurons.

The zinc finger E-box-binding transcription factor Zeb1 plays a pivotal role in the epithelial-mesenchymal transition. Numerous studies have focused on the molecular mechanisms by which Zeb1 contributes to this process. However, the functions of Zeb1 beyond the epithelial-mesenchymal transition remain largely elusive. Using a transdifferentiation system to convert mouse embryonic fibroblasts (MEFs) into functional neurons via the neuronal transcription factors achaete-scute family bHLH (basic helix-loop-helix) transcription factor1 (Ascl1), POU class 3 homeobox 2 (POU3F2/Brn2), and neurogenin 2 (Neurog2, Ngn2) (ABN), we found that Zeb1 was up-regulated during the early stages of transdifferentiation. Knocking down Zeb1 dramatically attenuated the transdifferentiation efficiency, whereas Zeb1 overexpression obviously increased the efficiency of transdifferentiation from MEFs to neurons. Interestingly, Zeb1 improved the transdifferentiation efficiency induced by even a single transcription factor (e.g. Asc1 or Ngn2). Zeb1 also rapidly promoted the maturation of induced neuron cells to functional neurons and improved the formation of neuronal patterns and electrophysiological characteristics. Induced neuron cells could form functional synapse in vivo after transplantation. Genome-wide RNA arrays showed that Zeb1 overexpression up-regulated the expression of neuron-specific genes and down-regulated the expression of epithelial-specific genes during conversion. Taken together, our results reveal a new role for Zeb1 in the transdifferentiation of MEFs into neurons.

Tet3-Mediated DNA Demethylation Contributes to the Direct Conversion of Fibroblast to Functional Neuron.

The direct conversion of somatic cells to neurons by bypassing the multipotent cell state may be a powerful approach for personalized medicine. In addition to neuronal transcription factors and multiple small molecules, we find that epigenetic modification also contributes to the direct conversion of fibroblasts to neurons. Here, we show that Tet3, a DNA dioxygenase, can rapidly and efficiently convert fibroblasts directly into functional neurons. The induced neurons (iNs) express pan and mature neuronal markers such as Tuj1, Synapsin, and neuronal nuclei (NeuN). Gene expression profiles demonstrate distinct neuron-specific gene clusters in iNs compared with primary neurons. Induced neurons display maturing firing patterns and form functional synapses. Additionally, we observe that the level of 5hmC in iNs gradually increases during the time course of transdifferentiation. These findings suggest that DNA demethylation may regulate direct lineage commitment, representing an avenue for investigating the process of transdifferentiation.

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin.

Abnormalities in parvalbumin (PV)-expressing interneurons cause neurodevelopmental disorders such as epilepsy, autism, and schizophrenia. Unlike other types of neurons that can be efficiently differentiated from pluripotent stem cells, PV neurons were minimally generated using a conventional differentiation strategy. In this study we developed an adenovirus-based transdifferentiation strategy that incorporates an additional chemical compound for the efficient generation of induced PV (iPV) neurons. The chemical compound forskolin combined with Ascl1 induced ∼80% of mouse fibroblasts to iPV neurons. The iPV neurons generated by this procedure matured 5-7 days post infection and were characterized by electrophysiological properties and known neuronal markers, such as PV and GABA. Our studies, therefore, identified an efficient approach for generating PV neurons.

Autophagy-related gene Atg5 is essential for astrocyte differentiation in the developing mouse cortex.

Astrocyte differentiation is essential for late embryonic brain development, and autophagy is active during this process. However, it is unknown whether and how autophagy regulates astrocyte differentiation. Here, we show that Atg5, which is necessary for autophagosome formation, regulates astrocyte differentiation. Atg5 deficiency represses the generation of astrocytes in vitro and in vivo. Conversely, Atg5 overexpression increases the number of astrocytes substantially. We show that Atg5 activates the JAK2-STAT3 pathway by degrading the inhibitory protein SOCS2. The astrocyte differentiation defect caused by Atg5 loss can be rescued by human Atg5 overexpression, STAT3 overexpression, and SOCS2 knockdown. Together, these data demonstrate that Atg5 regulates astrocyte differentiation, with potential implications for brain disorders with autophagy deficiency.

Retinoic acid receptor γ (Rarg) and nuclear receptor subfamily 5, group A, member 2 (Nr5a2) promote conversion of fibroblasts to functional neurons.

Somatic cells can be reprogrammed to neurons and various other cell types with retrovirus or lentivirus. The limitation of this technology is that these genome-integration viruses may increase the risk of gene mutation and cause insertional mutagenesis. We recently found that non-integration adenovirus carrying neuronal transcription factors can induce fibroblasts to neurons. However, the conversion efficiency by the adenovirus is lower than that of the retrovirus or lentivirus. Therefore, it is crucial to identify other factors or chemical compounds to obtain neurons with high efficiency. In this study we show that the combination of Rarg (retinoic acid receptor γ) and Nr5a2 (nuclear receptor subfamily 5, group A, member 2; also known as Lrh-1 (liver receptor homologue 1)) rapidly promote the iN cell maturation within 1 week and greatly facilitate the conversion with neuronal purities of ∼50% and yields of >130%. They also improve neuronal pattern formation, electrophysiological characteristics, and functional integration in vivo. Moreover, the chemical compound agonists to Rarg and Nr5a2 function effectively as well. This approach may be used for the generation and application of iN cells in regenerative medicine.

N-cadherin is a novel ERα anchor that protects against 6-OHDA damage to dopaminergic cells.

Parkinson's disease is a neurodegenerative disorder caused by the selective loss of dopaminergic (DA) neurons. In this study, we investigated the protective roles of glial cell line-derived neurotrophic factor (GDNF) and 17ß-estradiol (E2) in the neuron cell line MN9D following treatment with 6-hydroxydopamine. This result showed that phosphorylation of protein kinase B (Akt) was significantly increased in treated MN9D cells following co-application of GDNF and E2 compared with only GDNF or E2. Moreover, GDNF enhanced the E2-induced translocation of estrogen receptor α (ERα) from the cytosol to the membrane. Immunoprecipitation experiments showed that the translocated ERα interacted with neural cadherin (N-cadherin) in the membrane. Site-directed mutagenesis of Tyr860 (Y860) in N-cadherin inhibited its interaction with ERα. Combined with the fact that GDNF can stimulate N-cadherin Y860 phosphorylation, we hypothesize that N-cadherin is a novel anchor for ERα, and phosphorylation at Y860 further increases ER's capacity to activate the neuroprotective phosphatidyl inositol-3 kinase/Akt pathway. This study provides evidence that co-application of GDNF and E2 exert important protective effects on DA neurons by increasing the interaction between ERα and N-cadherin.