Recent advances on CAR-T signaling pave the way for prolonged persistence and new modalities in clinic.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies. The importance of the receptor costimulatory domain for long-term CAR-T cell engraftment and therapeutic efficacy was demonstrated with second-generation CAR-T cells. Fifth generation CAR-T cells are currently in preclinical trials. At the same time, the processes that orchestrate the activation and differentiation of CAR-T cells into a specific phenotype that predisposes them to long-term persistence are not fully understood. This review highlights ongoing research aimed at elucidating the role of CAR domains and T-cell signaling molecules involved in these processes.

Is African non-annual killifish Fundulopanchax gardneri (Teleostei; Cyprinodontiformes; Nothobranchiidae) true non-annual?

BACKGROUND: Annual or seasonal killifishes (Cyprinodontiformes: Nothobranchiidae) are unique among fish in their ability to enter into developmental arrests (diapauses: DI, DII, and DIII). They have a short lifespan and their embryos are exceptionally tolerant to a variety of environmental stresses. These traits make them a popular model for studying vertebrate diapause, aging, stress tolerance, genome adaptation, and evolution. In such issues, in a comparative evolutionary framework, Fundulopanchax gardneri, a popular aquarium fish from Africa, is commonly used as a representative non-annual model though its development is not studied in detail and whether it includes diapauses remains uncertain. RESULTS: We described in detail for the first time embryonic development of F. gardneri and revealed it to resemble that in the undoubtedly annual Austrofundulus limnaeus killifish in displaying two developmental depressions. However, if compared with A. limnaeus, these developmental states look like "less intense" versions of DII and DIII rather than true diapauses. CONCLUSIONS: To determine whether developmental depressions in F. gardneri represent "true" diapauses or only their functional equivalents, detailed studies of embryonic development of different killifish both annual and non-annual are needed. Before that, acceptance of F. gardneri as a representative non-annual fish seems premature.

Improved Characterization of Aqueous Single-Walled Carbon Nanotube Dispersions Using Dynamic Light Scattering and Analytical Centrifuge Methods.

Aqueous dispersions of single-walled carbon nanotubes (SWCNTs) with a surfactant were studied by using a combination of differential sedimentation and dynamic light scattering methods. When applied to elongated particles like SWCNTs, the differential sedimentation method makes it possible to measure their diameters in dispersions, while the dynamic light scattering method allows to measure their lengths. Both methods have logarithmic dependence on the ratio between the length and diameter of the particles, and their simultaneous use improves the accuracy of measuring particles' dimensions. It was shown that sonication of dispersions leads not only to unbundling of agglomerates into individual nanotubes but also to a decrease in their lengths and the appearance of new defects detectable in increasing the D/G ratio in the Raman spectra. Unbundling into individual nanotubes occurs after exposure to 1 kWh/L energy density, and the single nanotube diameter with SDBS is ca. 3.3 nm larger than that of the naked nanotubes. Conductivity of thin SWCNT films made out of individual nanotubes demonstrates a power law dependence with the exponent close to the theoretical one for rigid rods.

Allium pallasii and A. caricifolium-Surprisingly Diverse Old Steppe Species, Showing a Clear Geographical Barrier in the Area of Lake Zaysan.

Polymorph Allium pallasii s.l. from monotypic A. sect. Pallasia was studied using a wide spectrum of methods and divided into two clearly morphologically, geographically, cytologically and genetically isolated species: A. pallasii s. str.-North-East Kazakhstan, Western Siberia, and the Altai Mountains; A. caricifolium-Kyrgyzstan, Northwest China, South-East Kazakhstan until Zaysan Lake in the east. Despite serious genetic differences, both species are sisters and are related to species of the A. sect. Codonoprasum (Subg. Allium). Allium caricifolium differs from A. pallasii s. str. by taller stems, dense inflorescence, and with filaments longer than perianth. The possible phylogenetic reasons for the separation of these species are discussed. A nomenclature analysis of synonyms was carried out.

Strategies to Circumvent the Side-Effects of Immunotherapy Using Allogeneic CAR-T Cells and Boost Its Efficacy: Results of Recent Clinical Trials.

Despite the outstanding results of treatment using autologous chimeric antigen receptor T cells (CAR-T cells) in hematological malignancies, this approach is endowed with several constraints. In particular, profound lymphopenia in some patients and the inability to manufacture products with predefined properties or set of cryopreserved batches of cells directed to different antigens in advance. Allogeneic CAR-T cells have the potential to address these issues but they can cause life-threatening graft-versus-host disease or have shorter persistence due to elimination by the host immune system. Novel strategies to create an "off the shelf" allogeneic product that would circumvent these limitations are an extensive area of research. Here we review CAR-T cell products pioneering an allogeneic approach in clinical trials.

Symmetry Effects in Photoinduced Electron Transfer in Chlorin-Quinone Dyads: Adiabatic Suppression in the Marcus Inverted Region.

In donor-acceptor dyads undergoing photoinduced electron transfer (PET), a direction or pathway for electron movement is usually dictated by the redox properties and the separation distance between the donor and acceptor subunits, while the effect of symmetry is less recognized. We have designed and synthesized two isomeric donor-acceptor assemblies in which electronic coupling between donor and acceptor is altered by the orbital symmetry control with the reorganization energy and charge transfer exothermicity being kept unchanged. Analysis of the optical absorption and luminescence spectra, supported by the DFT and TD-DFT calculations, showed that PET in these assemblies corresponds to the Marcus inverted region (MIR) and has larger rate for isomer with weaker electronic coupling. This surprising observation provides the first experimental evidence for theoretically predicted adiabatic suppression of PET in MIR, which unambiguously controlled solely by symmetry.

Skull development in the Iberian newt, Pleurodeles waltl (Salamandridae: Caudata: Amphibia): timing, sequence, variations, and thyroid hormone mediation of bone appearance.

The cranial ossification sequence in Pleurodeles waltl is widely used in phylogenetic analyses of amphibian origin and evolution. However, the patterns published to date are far from completely resolved and contain certain discrepancies. Based on a large sample of P. waltl specimens ranging from early post-hatching larvae to post-metamorphic newts, we determined the most common cranial ossification sequence and revealed its intraspecific variations. Since thyroid hormones (THs) are involved in the mediation of skull development in salamanders, we studied the role of THs in the cranial development of P. waltl. The normal sequence and timing of bone appearance were compared with those in larvae reared under conditions of high (in 1 and 2 ng mL-1 triiodothyronine) and low [in 0.02% thiourea (TU), which inhibits thyroid gland activity] TH levels. Metamorphosis was greatly accelerated in the TH-treated larvae and was arrested in the TU-treated larvae, which retained the larval pattern of the palate and rudimentary external gills even after 2 years of the experiment. Early-appearing bones (the coronoid, vomer, palatine, dentary, squamosal, premaxilla, parasphenoid, pterygoid, prearticular, vomer, frontal, parietal, exoccipital, in this order) arise at the same stages and ages, and follow the same ossification sequence under different TH levels. The timing of the appearance of bones normally arising in the late larval and metamorphic periods (the quadratojugal, orbitosphenoid, prootic, maxilla, nasal, os thyroideum, prefrontal, quadrate, in this order) changes depending on the TH level. The maxilla and nasal display the most pronounced reaction to changes in the TH level: they appear precociously in TH-treated animals, while their appearance is postponed and they remain rudimentary in TU-treated animals. Because of different responses to THs, the order in which late-arising bones appear changes depending on the TH level. Although bones appearing early in larval ontogeny (e.g. the premaxilla, vomer, squamosal, palatine) display no TH-induced reaction when they start to develop, their further differentiation shows dependence on THs, and these bones become TH-inducible closer to metamorphosis. These findings indicate that TH involvement in the mediation of cranial development changes from minimal (if at all) in its early stages to maximal during metamorphosis. It is likely that the appearance of bones early in development is mediated by factors other than THs. Their further development is accompanied by changes in the mechanisms mediating their morphological differentiation. That is, likely non-hormonal mediation becomes replaced or/and complemented by hormonal mediation. The constituent parts of the same bone may exhibit differences in their reactions to changes in TH levels. Although in normal development, the overall cranial ossification sequence is constant, there was variation in the order in which late-appearing bones was recorded. These observations suggest that this variation results from individual variability in the internal TH level. Comparison with other salamanders suggests that (a) the pattern of TH mediation described in P. waltl is common for cranial development of metamorphosing urodeles and (b) the same bone may differ in its TH dependence in different salamanders, e.g. there are interspecific variations in the degree of TH dependence of individual cranial bones.

Ionic Conductance through Graphene: Assessing Its Applicability as a Proton Selective Membrane.

Inspired by recent reports on possible proton conductance through graphene, we have investigated the behavior of pristine graphene and defect engineered graphene membranes for ionic conductance and selectivity with the goal of evaluating a possibility of its application as a proton selective membrane. The averaged conductance for pristine chemical vapor deposited (CVD) graphene at pH1 is ∼4 mS/cm2 but varies strongly due to contributions from the unavoidable defects in our CVD graphene. From the variations in the conductance with electrolyte strength and pH, we can conclude that pristine graphene is fairly selective and the conductance is mainly due to protons. Engineering of the defects with ion beam (He+, Ga+) irradiation and plasma (N2 and H2) treatment showed improved areal conductance with high proton selectivity mostly for He-ion beam and H2 plasma treatments, which agrees with primarily vacancy-free type of defects produced in these cases confirmed by Raman analysis.

Exclusively Proton Conductive Membranes Based on Reduced Graphene Oxide Polymer Composites.

Proton exchange membranes are at the heart of various technologies utilizing electrochemical storage of intermittent energy sources and powering electrical devices. Current state of the art membranes are based on perfluorosulfonic acid, introduced more than a half century ago. Low specificity to protons accompanied by permeance by other species is one of the main impediments for various promising applications in green technologies in an energy sustainable economy. Here we present composite membranes that are exclusively proton selective and do not allow crossover of any ionic or molecular species other than protons. Membranes have high proton conductivity and exceptional mechanical and chemical stability and thus may significantly improve performance of hydrogen-based technologies such as electrolyzers, various kinds of fuel cells, and flow batteries in the future.

Evolutionary selection growth of two-dimensional materials on polycrystalline substrates.

There is a demand for the manufacture of two-dimensional (2D) materials with high-quality single crystals of large size. Usually, epitaxial growth is considered the method of choice 1 in preparing single-crystalline thin films, but it requires single-crystal substrates for deposition. Here we present a different approach and report the synthesis of single-crystal-like monolayer graphene films on polycrystalline substrates. The technological realization of the proposed method resembles the Czochralski process and is based on the evolutionary selection 2 approach, which is now realized in 2D geometry. The method relies on 'self-selection' of the fastest-growing domain orientation, which eventually overwhelms the slower-growing domains and yields a single-crystal continuous 2D film. Here we have used it to synthesize foot-long graphene films at rates up to 2.5 cm h-1 that possess the quality of a single crystal. We anticipate that the proposed approach could be readily adopted for the synthesis of other 2D materials and heterostructures.

Anisotropic Etching of Hexagonal Boron Nitride and Graphene: Question of Edge Terminations.

Chemical vapor deposition (CVD) has been established as the most effective way to grow large area two-dimensional materials. Direct study of the etching process can reveal subtleties of this competing with the growth reaction and thus provide the necessary details of the overall growth mechanism. Here we investigate hydrogen-induced etching of hBN and graphene and compare the results with the classical kinetic Wulff construction model. Formation of the anisotropically etched holes in the center of hBN and graphene single crystals was observed along with the changes in the crystals' circumference. We show that the edges of triangular holes in hBN crystals formed at regular etching conditions are parallel to B-terminated zigzags, opposite to the N-terminated zigzag edges of hBN triangular crystals. The morphology of the etched hBN holes is affected by a disbalance of the B/N ratio upon etching and can be shifted toward the anticipated from the Wulff model N-terminated zigzag by etching in a nitrogen buffer gas instead of a typical argon. For graphene, etched hexagonal holes are terminated by zigzag, while the crystal circumference is gradually changing from a pure zigzag to a slanted angle resulting in dodecagons.

The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-ß2.

Functional activation of the neuronal K(+)-Cl(-) co-transporter KCC2 (also known as SLC12A5) is a prerequisite for shifting GABAA responses from depolarizing to hyperpolarizing during development. Here, we introduce transforming growth factor ß2 (TGF-ß2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-ß2 controls membrane trafficking, surface expression and activity of KCC2 in developing and mature mouse primary hippocampal neurons, as determined by immunoblotting, immunofluorescence, biotinylation of surface proteins and KCC2-mediated Cl(-) extrusion. We also identify the signaling pathway from TGF-ß2 to cAMP-response-element-binding protein (CREB) and Ras-associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-ß2-mediated KCC2 trafficking and functional activation. TGF-ß2 increases colocalization and interaction of KCC2 with Rab11b, as determined by 3D stimulated emission depletion (STED) microscopy and co-immunoprecipitation, respectively, induces CREB phosphorylation, and enhances Rab11b gene expression. Loss of function of either CREB1 or Rab11b suppressed TGF-ß2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-ß2 is a new regulatory factor for KCC2 functional activation and membrane trafficking, and a putative indispensable molecular determinant for the developmental shift of GABAergic transmission.

Simple and Versatile Detection of Viruses Using Anodized Alumina Membranes.

A simple sensor for viral particles based on ionic conductivity through anodized alumina membranes was demonstrated using MS2 bacteriophage as an example. A facile two-point measuring scheme is geared toward realization using a computer's sound card input/output capabilities suitable for a fast and inexpensive point of care testing. The lowest detection concentration down to ~7 pfu/mL and a large dynamic range up to ~2000 pfu/mL were obtained due to physical optimization that included proper length and diameter for the pores, removing the oxide layer at the electrode, as well as the chemical optimization of covalent binding of antibodies to the pore's walls.

Titanium Oxynitride Nanoparticles Anchored on Carbon Nanotubes as Energy Storage Materials.

Sub-8 nm titanium oxynitride (TiON) nanoparticles were uniformly formed on the surface of carbon nanotubes (CNTs) by annealing amorphous TiO2 (a-TiO2) conformally coated CNTs (CNTs/a-TiO2) at 600 °C in ammonia gas. The novel CNTs/TiON nanocomposite was systematically characterized by X-ray diffraction (XRD), high-resolution transmission electron microscopy imaging (HRTEM), scanning transmission electron microscopy-energy dispersive spectroscopy (STEM-EDX), and X-ray photoelectron spectroscopy (XPS). The results show that Ti, O, and N are homogeneously distributed in TiON nanoparticles. The specific capacitance of CNTs/TiON exhibits 187 F g(-1) at a current density of 0.5 A g(-1), which is much higher than that of CNTs (33.4 F g(-1)) and CNTs/TiO2 (83.4 F g(-1)) obtained by annealing CNTs/a-TiO2 at 450 °C in nitrogen gas. CNTs/TiON also exhibits enhanced cycle durability, which enables it to be considered as a promising candidate for supercapacitors.

Frontoparietal Bone in Extinct Palaeobatrachidae (Anura): Its Variation and Taxonomic Value.

Palaeobatrachidae are extinct frogs from Europe closely related to the Gondwanan Pipidae, which includes Xenopus. Their frontoparietal is a distinctive skeletal element which has served as a basis for establishing the genus Albionbatrachus. Because little was known about developmental and individual variation of the frontoparietal, and its usefulness in delimiting genera and species has sometimes been doubted, we investigate its structure in Palaeobatrachus and Albionbatrachus by means of X-ray high resolution computer tomography (micro-CT). To infer the scope of variation present in the fossil specimens, we also examined developmental and interspecific variation in extant Xenopus. In adults of extinct taxa, the internal structure of the frontoparietal bone consists of a superficial and a basal layer of compact bone, with a middle layer of cancellous bone between them, much as in early amphibians. In Albionbatrachus, the layer of cancellous bone, consisting of small and large cavities, was connected with the dorsal, sculptured surface of the bone by a system of narrow canals; in Palaeobatrachus, the layer of cancellous bone and the canals connecting this layer with the dorsal surface of the frontoparietal were reduced. The situation in Palaeobatrachus robustus from the lower Miocene of France is intermediate-while external features support assignment to Palaeobatrachus, the inner structure is similar to that in Albionbatrachus. It may be hypothesized that sculptured frontoparietals with a well-developed layer of cancellous (i.e., vascularized) bone may indicate adaptation to a more terrestrial way of life, whereas a reduced cancellous layer might indicate a permanent water dweller.

Strong and electrically conductive graphene-based composite fibers and laminates.

Graphene is an ideal candidate for lightweight, high-strength composite materials given its superior mechanical properties (specific strength of 130 GPa and stiffness of 1 TPa). To date, easily scalable graphene-like materials in a form of separated flakes (exfoliated graphene, graphene oxide, and reduced graphene oxide) have been investigated as candidates for large-scale applications such as material reinforcement. These graphene-like materials do not fully exhibit all the capabilities of graphene in composite materials. In the current study, we show that macro (2 inch × 2 inch) graphene laminates and fibers can be produced using large continuous sheets of single-layer graphene grown by chemical vapor deposition. The resulting composite structures have potential to outperform the current state-of-the-art composite materials in both mechanical properties and electrical conductivities (>8 S/cm with only 0.13% volumetric graphene loading and 5 × 10(3) S/cm for pure graphene fibers) with estimated graphene contributions of >10 GPa in strength and 1 TPa in stiffness.

Evaluation of the catalytic activity and cytotoxicity of palladium nanocubes: the role of oxygen.

Recently, it has been reported that palladium nanocubes (PdNC) are capable of generating singlet oxygen without photoexcitation simply via chemisorption of molecular oxygen on its surface. Such a trait would make PdNC a highly versatile catalyst suitable in organic synthesis and a Reactive Oxygen Species (ROS) inducing cancer treatment reagent. Here we thoroughly investigated the catalytic activity of PdNC with respect to their ability to produce singlet oxygen and to oxidize 3,3',5,5'-tetramethylbenzidine (TMB), and analyzed the cytotoxic properties of PdNC on HeLa cells. Our findings showed no evidence of singlet oxygen production by PdNC. The nanocubes' activity is not necessarily linked to activation of oxygen. The oxidation of substrate on PdNC can be a first step, followed by PdNC regeneration with oxygen or other oxidant. The catalytic activity of PdNC toward the oxidation of TMB is very high and shows direct two-electron oxidation when the surface of the PdNC is clean and the ratio of TMB/PdNC is not very high. Sequential one electron oxidation is observed when the pristine quality of PdNC surface is compromised by serum or uncontrolled impurities and/or the ratio of TMB/PdNC is high. Clean PdNC in serum-free media efficiently induce apoptosis of HeLa cells. It is the primary route of cell death and is associated with hyperpolarization of mitochondria, contrary to a common mitochondrial depolarization initiated by ROS. Again, the effects are very sensitive to how well the pristine surface of PdNC is preserved, suggesting that PdNC can be used as an apoptosis inducing agent, but only with appropriate drug delivery system.

Water desalination using nanoporous single-layer graphene.

By creating nanoscale pores in a layer of graphene, it could be used as an effective separation membrane due to its chemical and mechanical stability, its flexibility and, most importantly, its one-atom thickness. Theoretical studies have indicated that the performance of such membranes should be superior to state-of-the-art polymer-based filtration membranes, and experimental studies have recently begun to explore their potential. Here, we show that single-layer porous graphene can be used as a desalination membrane. Nanometre-sized pores are created in a graphene monolayer using an oxygen plasma etching process, which allows the size of the pores to be tuned. The resulting membranes exhibit a salt rejection rate of nearly 100% and rapid water transport. In particular, water fluxes of up to 10(6) g m(-2) s(-1) at 40 °C were measured using pressure difference as a driving force, while water fluxes measured using osmotic pressure as a driving force did not exceed 70 g m(-2) s(-1) atm(-1).

Instant gelation synthesis of 3D porous MoS2@C nanocomposites for lithium ion batteries.

Three-dimensional (3D) nanoporous architectures, possessing high surface area, massive pores, and excellent structural stability, are highly desirable for many applications including catalysts and electrode materials in lithium ion batteries. However, the preparation of such materials remains a major challenge. Here, we introduce a novel method, instant gelation, for the synthesis of such materials. The as-prepared porous 3D MoS2@C nanocomposites, with layered MoS2 clusters or strips ingrained in porous and conductive 3D carbon matrix, indeed showed excellent electrochemical performance when applied as anode materials for lithium ion batteries. Its interconnected carbon network ensures good conductivity and fast electron transport; the micro-, and mesoporous nature effectively shortens the lithium ion diffusion path and provides room necessary for volume expansion. The large specific surface area is beneficial for a better contact between electrode materials and electrolyte.