Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells.

Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell-mediated tumor regression and postulated that antifibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1-induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with blunted TGF-ß receptor signaling, reduced collagen deposition, and depletion of immunosuppressive fibroblasts.

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation.

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.

Leukopenia is an independent risk factor for early postoperative complications following incision and drainage of anorectal abscess.

AIM: Few data are available regarding the management of anorectal abscess in patients with leukopenia. The aim of this study was to investigate the impact of leukopenia among patients undergoing incision and drainage for anorectal abscess. METHOD: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database identified patients from 2015 to 2020. Perianal fistulas and supralevator abscesses were excluded. Patients were grouped based on white blood cell (WBC) count: WBC < 4.5 cells/µl, WBC = 4.5-11.0 cells/µl and WBC > 11.0 cells/µl. The 30-day overall complications and outcomes were compared using regression models, accounting for demographics and comorbidities. RESULTS: Ten thousand two hundred and forty (70.3% male) patients were identified. Univariate analysis showed that, compared with patients with leukocytosis (WBC > 11.0 cells/µl) and normal WBC count (WBC = 4.5-11.0 cells/µl), patients with leukopenia (WBC <4.5 cells/µl) had higher rates of overall (p < 0.001), pulmonary (p < 0.001) and haematological complications (p < 0.001). They also had higher rates of readmission (p < 0.001), reoperation (p = 0.005), discharge to a care facility (p = 0.003), increased length of hospital stay (p = 0.004) and death (p < 0.001). Multivariable analysis identified leukopenia as an independent risk factor for overall complications [odds ratio (OR) 2.31, 95% CI 1.65-3.24; p < 0.001], pulmonary complications (OR 5.65, 95% CI 1.88-16.97; p = 0.002), haematological complications (OR 4.30, 95% CI 2.94-6.28; p < 0.001), unplanned readmission (OR 2.20, 95% CI 1.43-3.40; p < 0.001), reoperation (OR 1.80, 95% CI 1.10-2.93; p = 0.019) and death (OR 2.77, 95% CI 1.02-7.52; p = 0.046). Discharge to a care facility and length of stay were not significant on multivariable analysis. CONCLUSION: Leukopenia is associated with increased risk for pulmonary and haematological complications, readmissions, reoperations, discharge to a care facility and death after incision and drainage for anorectal abscess.

Size-Dependent Brittle-to-Ductile Transition in Silica Glass Nanofibers.

Silica (SiO2) glass, an essential material in human civilization, possesses excellent formability near its glass-transition temperature (Tg > 1100 °C). However, bulk SiO2 glass is very brittle at room temperature. Here we show a surprising brittle-to-ductile transition of SiO2 glass nanofibers at room temperature as its diameter reduces below 18 nm, accompanied by ultrahigh fracture strength. Large tensile plastic elongation up to 18% can be achieved at low strain rate. The unexpected ductility is due to a free surface affected zone in the nanofibers, with enhanced ionic mobility compared to the bulk that improves ductility by producing more bond-switching events per irreversible bond loss under tensile stress. Our discovery is fundamentally important for understanding the damage tolerance of small-scale amorphous structures.

Nucleation and atomic layer reaction in nickel silicide for defect-engineered Si nanochannels.

At the nanoscale, defects can significantly impact phase transformation processes and change materials properties. The material nickel silicide has been the industry standard electrical contact of silicon microelectronics for decades and is a rich platform for scientific innovation at the conjunction of materials and electronics. Its formation in nanoscale silicon devices that employ high levels of strain, intentional, and unintentional twins or grain boundaries can be dramatically different from the commonly conceived bulk processes. Here, using in situ high-resolution transmission electron microscopy (HRTEM), we capture single events during heterogeneous nucleation and atomic layer reaction of nickel silicide at various crystalline boundaries in Si nanochannels for the first time. We show through systematic experiments and analytical modeling that unlike other typical face-centered cubic materials such as copper or silicon the twin defects in NiSi2 have high interfacial energies. We observe that these twin defects dramatically change the behavior of new phase nucleation and can have direct implications for ultrascaled devices that are prone to defects or may utilize them to improve device performance.

Dynamic process of phase transition from wurtzite to zinc blende structure in InAs nanowires.

In situ high-resolution transmission electron microscopy revealed the precipitation of the zinc-blende (ZB) structure InAs at the liquid/solid interface or liquid/solid/amorphous carbon triple point at high temperature. Subsequent to its precipitation, detailed analysis demonstrates unique solid to solid wurtzite (WZ) to ZB phase transition through gliding of sharp steps with Shockley partial dislocations. The most intriguing phenomenon was that each step is 6 {111} atomic layers high and the step migrated without any mechanical stress applied. We believe that this is the first direct in situ observation of WZ-ZB transition in semiconductor nanowires. A model was proposed in which three Shockley partial dislocations collectively glide on every two {0001} planes (corresponds to six atomic planes in an unit). The collective glide mechanism does not need any applied shear stress.

Gold catalyzed nickel disilicide formation: a new solid-liquid-solid phase growth mechanism.

The vapor-liquid-solid (VLS) mechanism is the predominate growth mechanism for semiconductor nanowires (NWs). We report here a new solid-liquid-solid (SLS) growth mechanism of a silicide phase in Si NWs using in situ transmission electron microcopy (TEM). The new SLS mechanism is analogous to the VLS one in relying on a liquid-mediating growth seed, but it is fundamentally different in terms of nucleation and mass transport. In SLS growth of Ni disilicide, the Ni atoms are supplied from remote Ni particles by interstitial diffusion through a Si NW to the pre-existing Au-Si liquid alloy drop at the tip of the NW. Upon supersaturation of both Ni and Si in Au, an octahedral nucleus of Ni disilicide (NiSi2) forms at the center of the Au liquid alloy, which thereafter sweeps through the Si NW and transforms Si into NiSi2. The dissolution of Si by the Au alloy liquid mediating layer proceeds with contact angle oscillation at the triple point where Si, oxide of Si, and the Au alloy meet, whereas NiSi2 is grown from the liquid mediating layer in an atomic stepwise manner. By using in situ quenching experiments, we are able to measure the solubility of Ni and Si in the Au-Ni-Si ternary alloy. The Au-catalyzed mechanism can lower the formation temperature of NiSi2 by 100 °C compared with an all solid state reaction.

In situ transmission electron microscopy observations of electrochemical oxidation of Li2O2.

In this Letter, we report the first in situ transmission electron microscopy observation of electrochemical oxidation of Li2O2, providing insights into the rate limiting processes that govern charge in Li-O2 cells. In these studies, oxidation of electrochemically formed Li2O2 particles, supported on multiwall carbon nanotutubes (MWCNTs), was found to occur preferentially at the MWCNT/Li2O2 interface, suggesting that electron transport in Li2O2 ultimately limits the oxidation kinetics at high rates or overpotentials.

Nanovoid formation and annihilation in gallium nanodroplets under lithiation-delithiation cycling.

The irreversible chemomechanical degradation is a critical issue in the development of high-capacity electrode materials for the next-generation lithium (Li)-ion batteries. Here we report the self-healing behavior of gallium nanodroplets (GaNDs) under electrochemical cycling at room temperature, observed with in situ transmission electron microscopy (TEM). During lithiation, the GaNDs underwent a liquid-to-solid phase transition, forming a crystalline phase (LixGa) with ~160% volume expansion. Owing to the uneven Li flow during lithiation, the fully lithiated GaNDs exhibited highly distorted morphologies. Upon delithiation, the reverse phase transition occurred, accompanied with the nucleation and growth of a nanosized void. After the GaNDs were fully delithiated, the nanovoid gradually annihilated. Our analysis, along with phase field modeling and experimental measurements of the void growth and annihilation, provides mechanistic insights into the void formation and annihilation mechanism. The GaNDs may function as an effective healing agent in durable composite electrodes for high-performance Li-ion batteries, wherein active components, such as Si, are susceptible to fracture.

Tailoring lithiation behavior by interface and bandgap engineering at the nanoscale.

Controlling the transport of lithium (Li) ions and their reaction with electrodes is central in the design of Li-ion batteries for achieving high capacity, high rate, and long lifetime. The flexibility in composition and structure enabled by tailoring electrodes at the nanoscale could drastically change the ionic transport and help meet new levels of Li-ion battery performance. Here, we demonstrate that radial heterostructuring can completely suppress the commonly observed surface insertion of Li ions in all reported nanoscale systems to date and to exclusively induce axial lithiation along the [111] direction in a layer-by-layer fashion. The new lithiation behavior is achieved through the deposition of a conformal, epitaxial, and ultrathin silicon (Si) shell on germanium (Ge) nanowires, which creates an effective chemical potential barrier for Li ion diffusion through and reaction at the nanowire surface, allowing only axial lithiation and volume expansion. These results demonstrate for the first time that interface and bandgap engineering of electrochemical reactions can be utilized to control the nanoscale ionic transport/insertion paths and thus may be a new tool to define the electrochemical reactions in Li-ion batteries.

Two-phase electrochemical lithiation in amorphous silicon.

Lithium-ion batteries have revolutionized portable electronics and will be a key to electrifying transport vehicles and delivering renewable electricity. Amorphous silicon (a-Si) is being intensively studied as a high-capacity anode material for next-generation lithium-ion batteries. Its lithiation has been widely thought to occur through a single-phase mechanism with gentle Li profiles, thus offering a significant potential for mitigating pulverization and capacity fade. Here, we discover a surprising two-phase process of electrochemical lithiation in a-Si by using in situ transmission electron microscopy. The lithiation occurs by the movement of a sharp phase boundary between the a-Si reactant and an amorphous Li(x)Si (a-Li(x)Si, x ~ 2.5) product. Such a striking amorphous-amorphous interface exists until the remaining a-Si is consumed. Then a second step of lithiation sets in without a visible interface, resulting in the final product of a-Li(x)Si (x ~ 3.75). We show that the two-phase lithiation can be the fundamental mechanism underpinning the anomalous morphological change of microfabricated a-Si electrodes, i.e., from a disk shape to a dome shape. Our results represent a significant step toward the understanding of the electrochemically driven reaction and degradation in amorphous materials, which is critical to the development of microstructurally stable electrodes for high-performance lithium-ion batteries.

Direct measurement of coherency limits for strain relaxation in heteroepitaxial core/shell nanowires.

The growth of heteroepitaxially strained semiconductors at the nanoscale enables tailoring of material properties for enhanced device performance. For core/shell nanowires (NWs), theoretical predictions of the coherency limits and the implications they carry remain uncertain without proper identification of the mechanisms by which strains relax. We present here for the Ge/Si core/shell NW system the first experimental measurement of critical shell thickness for strain relaxation in a semiconductor NW heterostructure and the identification of the relaxation mechanisms. Axial and tangential strain relief is initiated by the formation of periodic a/2 <110> perfect dislocations via nucleation and glide on {111} slip-planes. Glide of dislocation segments is directly confirmed by real-time in situ transmission electron microscope observations and by dislocation dynamics simulations. Further shell growth leads to roughening and grain formation which provides additional strain relief. As a consequence of core/shell strain sharing in NWs, a 16 nm radius Ge NW with a 3 nm Si shell is shown to accommodate 3% coherent strain at equilibrium, a factor of 3 increase over the 1 nm equilibrium critical thickness for planar Si/Ge heteroepitaxial growth.

Microstructural evolution of tin nanoparticles during in situ sodium insertion and extraction.

The microstructural changes and phase transformations of tin nanoparticles during electrochemical sodiation were studied with a nanosized sodium ion battery using in situ transmission electron microscopy. It was found that the first sodiation process occurred in two steps; that is, the crystalline Sn nanoparticles were initially sodiated via a two-phase mechanism with a migrating phase boundary to form a Na-poor, amorphous Na(x)Sn alloy (x ~ 0.5), which was further sodiated to several Na-rich amorphous phases and finally to the crystallized Na(15)Sn(4) (x = 3.75) via a single-phase mechanism. The volumetric expansion was about 60% in the first step and 420% after the second step. However, despite the huge expansion, cracking or fracture was not observed, which is attributed to the second step of the single-phase sodiation that accommodates large portion of the sodiation-induced stress over the entire particle. Excellent cyclability was also observed during the reversible sodiation/desodiation cycles, showing great potential of Sn nanoparticles as a robust electrode material for rechargeable batteries.

Ultrashort channel silicon nanowire transistors with nickel silicide source/drain contacts.

We demonstrate the shortest transistor channel length (17 nm) fabricated on a vapor-liquid-solid (VLS) grown silicon nanowire (NW) by a controlled reaction with Ni leads on an in situ transmission electron microscope (TEM) heating stage at a moderate temperature of 400 °C. NiSi(2) is the leading phase, and the silicide-silicon interface is an atomically sharp type-A interface. At such channel lengths, high maximum on-currents of 890 (µA/µm) and a maximum transconductance of 430 (µS/µm) were obtained, which pushes forward the performance of bottom-up Si NW Schottky barrier field-effect transistors (SB-FETs). Through accurate control over the silicidation reaction, we provide a systematic study of channel length dependent carrier transport in a large number of SB-FETs with channel lengths in the range of 17 nm to 3.6 µm. Our device results corroborate with our transport simulations and reveal a characteristic type of short channel effects in SB-FETs, both in on- and off-state, which is different from that in conventional MOSFETs, and that limits transport parameter extraction from SB-FETs using conventional field-effect transconductance measurements.

Orientation-dependent interfacial mobility governs the anisotropic swelling in lithiated silicon nanowires.

Recent independent experiments demonstrated that the lithiation-induced volume expansion in silicon nanowires, nanopillars, and microslabs is highly anisotropic, with predominant expansion along the <110> direction but negligibly small expansion along the <111> direction. The origin of such anisotropic behavior remains elusive. Here, we develop a chemomechanical model to study the phase evolution and morphological changes in lithiated silicon nanowires. The model couples the diffusive reaction of lithium with the lithiation-induced elasto-plastic deformation. We show that the apparent anisotropic swelling is critically controlled by the orientation-dependent mobility of the core-shell interface, i.e., the lithiation reaction rate at the atomically sharp phase boundary between the crystalline core and the amorphous shell. Our results also underscore the importance of structural relaxation by plastic flow behind the moving phase boundary, which is essential to quantitative prediction of the experimentally observed morphologies of lithiated silicon nanowires. The study sheds light on the lithiation-mediated failure in nanowire-based electrodes, and the modeling framework provides a basis for simulating the morphological evolution, stress generation, and fracture in high-capacity electrodes for the next-generation lithium-ion batteries.

Influence of Basalt/Polypropylene Fiber on Permeability and Uniaxial Compressive Properties of Waste Tire Rubberized Concrete.

The rubber particles obtained from the grinding of waste tires can replace a portion of the fine aggregates in concrete, thus effectively reducing the level of environmental damage and saving resources. However, when concrete is mixed with rubber, it greatly reduces its strength. In this study, by introducing basalt fiber (BF) and polypropylene fiber (PF) as modified materials in rubberized concrete, the influence of the fiber type/volume ratio on the slump, water absorption, static uniaxial compression, and permeability of the rubberized concrete was tested. The axial compression stress-strain relationship was analyzed, the effect of the fiber type/volume ratio on the energy dissipation of the rubberized concrete during uniaxial compression was expounded, and a stress-strain constitutive model under uniaxial compression was established. The test results showed that the fiber reduces the fluidity and water absorption of the rubberized concrete. Compared with the polypropylene fiber, the basalt fiber increased the strength of the rubberized concrete, while the polypropylene fiber mainly inhibited the expansion and penetration of the macroscopic crack of the rubberized concrete. The mixing of the basalt fiber and polypropylene fiber significantly decreased the release rate of the elastic strain energy of the rubberized concrete, increased the dissipation energy, and thus improved its ductility and toughness. During a loading process under confining pressure, the permeability of the tested specimen decayed exponentially, and the fiber greatly enhanced the anti-permeability of the rubber concrete.

In situ visualization of birth and annihilation of grain boundaries in an Au nanocrystal.

The formation and vanishing processes of a low angle grain boundary (GB) in nanosized Au during tension and release of stress, respectively, were obsvered by in situ high resolution transmission electron microscopy. The nucleation of perfect dislocations led to the formation of a 15° low angle GB inside an Au nanocrystal upon off-axial tensile loading (coupled uniaxial tensile and bending stress). Strikingly, the dislocations were completely annihilated accompanied with the disappearance of the GB after the removal of external stress, indicating that plastic bending is recoverable in the nanocrystal. The back force and surface stress played important roles in such a pseudoelastic behavior. This transient GB dynamics cannot be captured in ex situ experimental investigations. Such pseudoelastic bending deformation in nanosized crystals will have an important impact on the designing of nanomechanical devices with ultrahigh bending capability.

In situ observation of graphene sublimation and multi-layer edge reconstructions.

We induced sublimation of suspended few-layer graphene by in situ Joule-heating inside a transmission electron microscope. The graphene sublimation fronts consisted of mostly {1100} zigzag edges. Under appropriate conditions, a fractal-like "coastline" morphology was observed. Extensive multiple-layer reconstructions at the graphene edges led to the formation of unique carbon nanostructures, such as sp(2)-bonded bilayer edges (BLEs) and nanotubes connected to BLEs. Flat fullerenes/nanopods and nanotubes tunneling multiple layers of graphene sheets were also observed. Remarkably, >99% of the graphene edges observed during sublimation are BLEs rather than monolayer edges (MLEs), indicating that BLEs are the stable edges in graphene at high temperatures. We reproduced the "coastline" sublimation morphologies by kinetic Monte Carlo (kMC) simulations. The simulation revealed geometrical and topological features unique to quasi-2-dimensional (2D) graphene sublimation and reconstructions. These reconstructions were enabled by bending, which cannot occur in first-order phase transformations of 3D bulk materials. These results indicate that substrate of multiple-layer graphene can offer unique opportunities for tailoring carbon-based nanostructures and engineering novel nano-devices with complex topologies.

Direct observations of confined layer slip in Cu/Nb multilayers.

In situ nanoindentation of a 30 nm Cu/20 nm Nb multilayer film in a transmission electron microscope revealed confined layer slip as the dominant deformation mechanism. Dislocations were observed to nucleate from the Cu-Nb interfaces in both layers. Dislocation glide was confined by interfaces to occur within each layer, without transmission across interfaces. Cu and Nb layers co-deformed to large plastic strains without cracking. These microscopy observations provide insights in the unit mechanisms of deformation, work hardening, and recovery in nanoscale metallic multilayers.

In situ nanomechanics of GaN nanowires.

The deformation, fracture mechanisms, and the fracture strength of individual GaN nanowires were measured in real time using a transmission electron microscope-scanning probe microscope (TEM-SPM) platform. Surface mediated plasticity, such as dislocation nucleation from a free surface and plastic deformation between the SPM probe (the punch) and the nanowire contact surface were observed in situ. Although local plasticity was observed frequently, global plasticity was not observed, indicating the overall brittle nature of this material. Dislocation nucleation and propagation is a precursor before the fracture event, but the fracture surface shows brittle characteristic. The fracture surface is not straight but kinked at (10-10) or (10-11) planes. Dislocations are generated at a stress near the fracture strength of the nanowire, which ranges from 0.21 to 1.76 GPa. The results assess the mechanical properties of GaN nanowires and may provide important insight into the design of GaN nanowire devices for electronic and optoelectronic applications.