A synergistic therapy against influenza virus A/H1N1/PR8 by a HA1 specific neutralizing single-domain VL and an RNA hydrolyzing scFv.

The emergence of anti-influenza drug-resistant strains poses a challenge for influenza therapy due to mutations in the virus's surface protein. Recently, there has been increasing interest in combination therapy consisting of two or more drugs as a potential alternative approach, aiming to enhance therapeutic efficacy. In this study, we investigated a novel synergistic therapy with a vertical effect using a single-domain VL-HA1-specific antibody against H1N1/PR8 and a horizontal effect using an RNA catalytic antibody with broad-spectrum influenza antiviral drug. We isolated a single-domain VL-HA1-specific (NVLH8) antibody binding to the virus particles showing a neutralizing activity against influenza virus A, specifically H1N1/PR8, as determined by the reduction in plaque number and lower viral HA protein expression in vitro. The neutralizing antibody likely prevented the viral entry, specifically at the viral genome-releasing step. Additionally, the 3D8 scFv hydrolyzed viral RNAs in the cytoplasm, including mRNA, vRNA, and cRNA in MDCK cells. The combined treatment of neutralizing antibodies for a vertical effect and 3D8 scFv for a horizontal effect produced a synergistic effect providing a novel approach against viral diseases when compared with a single treatment. Our results indicated that combining treatment, in particular two proteins exhibiting different mechanisms of action increased the antiviral activity against the influenza virus.

An RNA-hydrolyzing recombinant minibody prevents both influenza A virus and coronavirus in co-infection models.

With the lifting of COVID-19 non-pharmaceutical interventions, the resurgence of common viral respiratory infections was recorded in several countries worldwide. It facilitates viral co-infection, further burdens the already over-stretched healthcare systems. Racing to find co-infection-associated efficacy therapeutic agents need to be rapidly established. However, it has encountered numerous challenges that necessitate careful investigation. Here, we introduce a potential recombinant minibody-associated treatment, 3D8 single chain variable fragment (scFv), which has been developed as a broad-spectrum antiviral drug that acts via its nucleic acid catalytic and cell penetration abilities. In this research, we demonstrated that 3D8 scFv exerted antiviral activity simultaneously against both influenza A viruses (IAVs) and coronaviruses in three established co-infection models comprising two types of coronaviruses [beta coronavirus-human coronavirus OC43 (hCoV-OC43) and alpha coronavirus-porcine epidemic diarrhea virus (PEDV)] in Vero E6 cells, two IAVs [A/Puerto Rico/8/1934 H1N1 (H1N1/PR8) and A/X-31 (H3N2/X-31)] in MDCK cells, and a combination of coronavirus and IAV (hCoV-OC43 and adapted-H1N1) in Vero E6 cells by a statistically significant reduction in viral gene expression, proteins level, and approximately around 85%, 65%, and 80% of the progeny of 'hCoV-OC43-PEDV', 'H1N1/PR8-H3N2/X-31', and 'hCoV-OC43-adapted-H1N1', respectively, were decimated in the presence of 3D8 scFv. Taken together, we propose that 3D8 scFv is a promising broad-spectrum drug for treatment against RNA viruses in co-infection.

Comparing the Biomechanical Stability of Cerclage Cable with Plate Insert Versus Locking Screw in Periprosthetic Humeral Fracture.

BACKGROUND: In the setting of periprosthetic humeral fractures, the humeral stem of the implant represents a substantial challenge to the optimal method of proximal fixation. This study aimed to compare the initial biomechanical stability provided by cerclage cables with a locking plate insert versus bicortical locking screws (i.e., the gold standard for fixation) in fresh cadaveric humeri. METHODS: After calculating the sample size, we utilized 10 sets of cadaveric specimens and created a 5-mm osteotomy gap 120 mm distal to the tip of the greater tuberosity, simulating a Wright and Cofield type-B periprosthetic humeral fracture on each specimen. Using 3 locking screws for distal fragment fixation, identical in all specimens, the specimens were assigned to Group A (3 cerclage cables with a plate insert) or Group B (3 locking bicortical screws) for proximal fragment fixation. Biomechanical tests included stiffness in varus and valgus bending, torsion, and axial compression, and a single load to failure. RESULTS: No significant differences were observed in the biomechanical metrics between the 2 groups. CONCLUSIONS: Our study revealed that fixation with use of cerclage cables with a plate insert demonstrated biomechanical stability comparable with that of bicortical locking screw fixation when addressing the proximal fragment in Wright and Cofield type-B periprosthetic humeral fractures. CLINICAL RELEVANCE: For proximal fragment fixation of periprosthetic humeral fractures, cerclage cables with a plate insert can be utilized as an effective fixation method that offers initial fixation strength that is comparable to the use of 3 locking bicortical screws.

Synergetic Enhancement of Quantum Yield and Exciton Lifetime of Monolayer WS2 by Proximal Metal Plate and Negative Electric Bias.

The efficiency of light emission is a critical performance factor for monolayer transition metal dichalcogenides (1L-TMDs) for photonic applications. While various methods have been studied to compensate for lattice defects to improve the quantum yield (QY) of 1L-TMDs, exciton-exciton annihilation (EEA) is still a major nonradiative decay channel for excitons at high exciton densities. Here, we demonstrate that the combined use of a proximal Au plate and a negative electric gate bias (NEGB) for 1L-WS2 provides a dramatic enhancement of the exciton lifetime at high exciton densities with the corresponding QY enhanced by 30 times and the EEA rate constant decreased by 80 times. The suppression of EEA by NEGB is attributed to the reduction of the defect-assisted EEA process, which we also explain with our theoretical model. Our results provide a synergetic solution to cope with EEA to realize high-intensity 2D light emitters using TMDs.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Emulation Evaluation of Interior Beam-Column Connections in PC and RC Moment-Resisting Frames.

Precast concrete (PC) structures have many advantages, but their use in the construction of middle- to high-rise buildings is limited. The construction of PC structures requires skills in various operations such as transportation, assembly, lifting, and structural soundness. In particular, regarding the seismic design of PC structures, it is necessary to clearly evaluate whether they have the same structural performance and usability as integral RC (cast-in-place) structures. In this paper, an experimental study was conducted to investigate whether PC members can achieve a seismic performance equivalent to that of RC members in beam-column joints, which are representative moment-resisting frames. The main variables are the two types of structural systems (intermediate and special moment-resisting frames) and the design flexural strength ratio of the columns and beams. The experimental and analytical results showed that the seismic performance of the PC specimens was equivalent to that of the RC specimens in terms of strength, stiffness, energy dissipation, and strain distribution, except for the specimen with splice sleeve bond failure of the column reinforcement (poor filling of the internal mortar). In addition, the I series satisfied the present emulation evaluation criteria for special moment-resisting frames of PC structures, confirming the possibility of applying intermediate moment-resisting frames.

Development of rapid and effective oil-spill response system integrated with oil collection, recovery and storage devices for small oil spills at initial stage: From lab-scale study to field-scale test.

In the present study, through the laboratory-to-field scale experiments and trials, we report the development and evaluation of an integrated oil-spill response system capable of oil collection, recovery (separation), and storage, for a timely and effective response to the initial stage of oil-spill accidents. With the laboratory-scale experiments, first, we evaluate that the water-surface waves tend to abate the oil recovery rate below 80% (it is above 95% for the optimized configuration without the waves), which is overcome by installing the hydrophilic (and oleophobic) porous structures at the inlet and/or near the water outlet of the separator. In the follow-up meso-scale towing tank tests with a scaled-up prototype, (i) we optimize the maneuverability of the assembled system depending on the speed and existence of waves, and (ii) evaluate the oil recovery performance (more than 80% recovery for the olive oil and Bunker A fuel oil). Although more thorough investigations and improvements are needed, a recovery rate of over 50% can be achieved for the newly enforced marine fuel oil (low sulfur fuel oil, LSFO) that was not targeted at the time of development. Finally, we perform a series of field tests with a full-scale system, to evaluate the rapid deployment and operational stability in the real marine environment. The overall floating balance and coordination of each functional part are sustained to be stable during the straight and rotary maneuvers up to the speed of 5 knots. Also, the collection of the floating debris (mimicking the spilled oil) is demonstrated in the field test. The present system is now being tested by the Korea Coast Guard and we believe that it will be very powerful to prevent the environmental damage due to the oil spills.

Meningioma Originating From Choroid Plexus of Foramen of Luschka: A Rare Case Report and Tip of Differential Diagnosis.

Meningiomas are the most common benign brain tumors, and most of them originate from the dura mater. However, in some cases, they can originate from the choroid plexus, and they are rarely found in the posterior cranial fossa. A 63-year-old female patient presented with dizziness and swallowing difficulty and was found to have a homogeneously enhancing mass in the right posterior cranial fossa. Mass removal was performed through retrosigmoid suboccipital craniotomy, and the mass was confirmed to originate from the choroid plexus. The pathological diagnosis was meningothelial meningioma. The patient had temporary swallowing difficulty but recovered without any neurological sequelae. We report a rare case of a lower cerebellopontine angle meningioma without dural attachment originating from the choroid plexus of the foramen of Luschka.

Bamboo Shoot and Artemisia capillaris Extract Mixture Ameliorates Dextran Sodium Sulfate-Induced Colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract and is characterized by recurrent chronic inflammation and mucosal damage of the gastrointestinal tract. Recent studies have demonstrated that bamboo shoot (BS) and Artemisia capillaris (AC) extracts enhance anti-inflammatory effects in various disease models. However, it is uncertain whether there is a synergistic protective effect of BS and AC in dextran sodium sulfate (DSS)-induced colitis. In the current study, we tested the combined effects of BS and AC extracts (BA) on colitis using in vivo and in vitro models. Compared with control mice, oral administration of DSS exacerbated colon length and increased the disease activity index (DAI) and histological damage. In DSS-induced colitis, treatment with BA significantly alleviated DSS-induced symptoms such as colon shortening, DAI, histological damage, and colonic pro-inflammatory marker expression compared to single extracts (BS or AC) treatment. Furthermore, we found BA treatment attenuated the ROS generation, F-actin formation, and RhoA activity compared with the single extract (BS or AC) treatment in DSS-treated cell lines. Collectively, these findings suggest that BA treatment has a positive synergistic protective effect on colonic inflammation compared with single extracts, it may be a highly effective complementary natural extract mixture for the prevention or treatment of IBD.

Enhancing neutralizing activity against influenza H1N1/PR8 by engineering a single-domain VL-M2 specific into a bivalent form.

Flu disease, with high mortality and morbidity, is caused by the influenza virus. Influenza infections are most effectively prevented through vaccination, but it requires annual reformulation due to the antigenic shift or drift of hemagglutinin and neuraminidase proteins. Increasing resistance to available anti-influenza drugs was also recently reported. The M2 surface protein of the influenza virus is an attractive target for universal vaccine development as it is highly conserved and multifunctional throughout the viral life cycle. This study aimed to discover a single-chain variable fragment (scFv) targeting the M2 protein of influenza A H1N1/PR8, showing neutralizing activity through plaque inhibition in virus replication. Several candidates were isolated using bio-panning, including scFv and single-domain VL target M2 protein, which was displayed on the yeast surface. The scFv/VL proteins were obtained with high yield and high purity through soluble expression in E. coli BL21 (DE3) pLysE strains. A single-domain VL-M2-specific antibody, NVLM10, exhibited the highest binding affinity to influenza virions and was engineered into a bivalent format (NVL2M10) to improve antigen binding. Both antibodies inhibited virus replication in a dose-dependent manner, determined using plaque reduction- and immunocytochemistry assays. Furthermore, bivalent anti-M2 single-domain VL antibodies significantly reduced the plaque number and viral HA protein intensity as well as viral genome (HA and NP) compared to the monovalent single-domain VL antibodies. This suggests that mono- or bivalent single-domain VL antibodies can exhibit neutralizing activity against influenza virus A, as determined through binding to virus particle activity.

A Novel Approach of Antiviral Drugs Targeting Viral Genomes.

Outbreaks of viral diseases, which cause morbidity and mortality in animals and humans, are increasing annually worldwide. Vaccines, antiviral drugs, and antibody therapeutics are the most effective tools for combating viral infection. The ongoing coronavirus disease 2019 pandemic, in particular, raises an urgent need for the development of rapid and broad-spectrum therapeutics. Current antiviral drugs and antiviral antibodies, which are mostly specific at protein levels, have encountered difficulties because the rapid evolution of mutant viral strains resulted in drug resistance. Therefore, degrading viral genomes is considered a novel approach for developing antiviral drugs. The current article highlights all potent candidates that exhibit antiviral activity by digesting viral genomes such as RNases, RNA interference, interferon-stimulated genes 20, and CRISPR/Cas systems. Besides that, we introduce a potential single-chain variable fragment (scFv) that presents antiviral activity against various DNA and RNA viruses due to its unique nucleic acid hydrolyzing characteristic, promoting it as a promising candidate for broad-spectrum antiviral therapeutics.

A Therapeutically Active Minibody Exhibits an Antiviral Activity in Oseltamivir-Resistant Influenza-Infected Mice via Direct Hydrolysis of Viral RNAs.

Emerging Oseltamivir-resistant influenza strains pose a critical public health threat due to antigenic shifts and drifts. We report an innovative strategy for controlling influenza A infections by use of a novel minibody of the 3D8 single chain variable fragment (scFv) showing intrinsic viral RNA hydrolyzing activity, cell penetration activity, and epidermal cell penetration ability. In this study, we examined 3D8 scFv's antiviral activity in vitro on three different H1N1 influenza strains, one Oseltamivir-resistant (A/Korea/2785/2009pdm) strain, and two Oseltamivir-sensitive (A/PuertoRico/8/1934 and A/X-31) strains. Interestingly, the 3D8 scFv directly digested viral RNAs in the ribonucleoprotein complex. scFv's reduction of influenza viral RNA including viral genomic RNA, complementary RNA, and messenger RNA during influenza A infection cycles indicated that this minibody targets all types of viral RNAs during the early, intermediate, and late stages of the virus's life cycle. Moreover, we further addressed the antiviral effects of 3D8 scFv to investigate in vivo clinical outcomes of influenza-infected mice. Using both prophylactic and therapeutic treatments of intranasal administered 3D8 scFv, we found that Oseltamivir-resistant H1N1-infected mice showed 90% (prophylactic effects) and 40% (therapeutic effects) increased survival rates, respectively, compared to the control group. The pathological signs of influenza A in the lung tissues, and quantitative analyses of the virus proliferations supported the antiviral activity of the 3D8 single chain variable fragment. Taken together, these results demonstrate that 3D8 scFv has antiviral therapeutic potentials against a wide range of influenza A viruses via the direct viral RNA hydrolyzing activity.

Effect of Ground Granulated Blast Furnace Slag Replacement Ratio on Structural Performance of Precast Concrete Beams.

This study was conducted to investigate the effect of ground granulated blast furnace slag on the structural performance of precast concrete beams, evaluating the flexural, shear and bonding performance by using the replacement ratio of the ground granulated blast furnace slag as a variable. The design strength of the concrete was set at 45 MPa in consideration of the characteristics of precast concrete products, and the replacement ratio of the ground granulated blast furnace slag to replace cement was 30 to 70%. The experimental results showed that all specimens had similar behavioral characteristics regardless of the replacement ratio of the ground granulated blast furnace slag. Comparison of the prediction results obtained by ACI 318-19 and EC 2 showed that the mean flexural strength and shear strength were higher than 1.19 and 1.43, respectively, and the mean bond strength was 1.57, satisfying the required performance. Therefore, the experimental results showed that in using the ground granulated blast furnace slag as an admixture for precast concrete, the cement replacement ratio may be increased up to 70% without causing any problems in securing the structural performance. Summarizing the results of the present study, a ground granulated blast furnace slag replacement ratio of 50% or lower may be reasonably applied.

Boosting quantum yields in two-dimensional semiconductors via proximal metal plates.

Monolayer transition metal dichalcogenides (1L-TMDs) have tremendous potential as atomically thin, direct bandgap semiconductors that can be used as convenient building blocks for quantum photonic devices. However, the short exciton lifetime due to the defect traps and the strong exciton-exciton interaction in TMDs has significantly limited the efficiency of exciton emission from this class of materials. Here, we show that exciton-exciton interaction in 1L-WS2 can be effectively screened using an ultra-flat Au film substrate separated by multilayers of hexagonal boron nitride. Under this geometry, induced dipolar exciton-exciton interaction becomes quadrupole-quadrupole interaction because of effective image dipoles formed within the metal. The suppressed exciton-exciton interaction leads to a significantly improved quantum yield by an order of magnitude, which is also accompanied by a reduction in the exciton-exciton annihilation (EEA) rate, as confirmed by time-resolved optical measurements. A theoretical model accounting for the screening of the dipole-dipole interaction is in a good agreement with the dependence of EEA on exciton densities. Our results suggest that fundamental EEA processes in the TMD can be engineered through proximal metallic screening, which represents a practical approach towards high-efficiency 2D light emitters.

Ameliorative Effects of Pueraria lobata Extract on Postmenopausal Symptoms through Promoting Estrogenic Activity and Bone Markers in Ovariectomized Rats.

Pueraria lobata (Willd.) Ohwi, known as kudzu, is one of the most popular traditional medicines in Asian countries. It has been widely used as a natural alternative to hormone replacement therapy for treating postmenopausal symptoms. This study aimed to investigate the estrogenic effect of P. lobata extract (PE) against postmenopausal osteoporosis in ovariectomized (OVX) rats. OVX rats were treated with PE (25-1600 mg/kg) for 8 weeks. Biochemical parameters, estradiol, and bone turnover markers (e.g., osteocalcin, C-terminal telopeptide fragment of type I collagen, deoxypyridinoline, and pyridinoline) were measured in plasma samples. In addition, estrogen receptor-alpha (ER-α) protein expression and morphology of uterine were evaluated. Long-term treatment with PE did not cause liver damage in OVX rats. PE supplementation reduced body weight gain in obese rats with high lipid accumulation induced by ovariectomy. Furthermore, PE exhibited a protective effect against insulin resistance, hyperlipidemia, and hepatic lipid peroxidation. PE treatment increased uterine weight and thickness of the uterine layers in cases of uterus atrophy due to removal of ovaries. The levels of bone turnover markers, which were significantly increased in OVX rats, were decreased by PE treatment. Western blotting analysis showed that ER-α protein expression was upregulated in PE-treated rats compared with OVX rats. These results suggest that PE could be a promising alternative functional food for improving menopausal symptoms.

Effect of Surface Roughness Characteristics on Structural Performance of Hollow Core Slabs.

This study was conducted to evaluate the flexural performance of hollow core slabs (HCS) incorporating the effect of surface roughness. The HCSs are suitable for long span structures due to reduced self-weight. The specimens were HCS with topping concrete and the variables were cross sectional height and surface roughness. The tests were conducted on simply supported beams under four-point loads. The results showed that specimens with interface roughness applied in the lengthwise direction of members exhibited ductile flexural behavior up to peak load than those with interface roughness applied in the member width direction. Their flexural strength was also higher by 1-7% on average, indicating that they are advantageous in improving structural performance.

2D Materials for Skin-Mountable Electronic Devices.

Skin-mountable devices that can directly measure various biosignals and external stimuli and communicate the information to the users have been actively studied owing to increasing demand for wearable electronics and newer healthcare systems. Research on skin-mountable devices is mainly focused on those materials and mechanical design aspects that satisfy the device fabrication requirements on unusual substrates like skin and also for achieving good sensing capabilities and stable device operation in high-strain conditions. 2D materials that are atomically thin and possess unique electrical and optical properties offer several important features that can address the challenging needs in wearable, skin-mountable electronic devices. Herein, recent research progress on skin-mountable devices based on 2D materials that exhibit a variety of device functions including information input and output and in vitro and in vivo healthcare and diagnosis is reviewed. The challenges, potential solutions, and perspectives on trends for future work are also discussed.

Broad-Spectrum Antiviral Activity of 3D8, a Nucleic Acid-Hydrolyzing Single-Chain Variable Fragment (scFv), Targeting SARS-CoV-2 and Multiple Coronaviruses In Vitro.

The virus behind the current pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the etiology of novel coronavirus disease (COVID-19) and poses a critical public health threat worldwide. Effective therapeutics and vaccines against multiple coronaviruses remain unavailable. Single-chain variable fragment (scFv), a recombinant antibody, exhibits broad-spectrum antiviral activity against DNA and RNA viruses owing to its nucleic acid-hydrolyzing property. The antiviral activity of 3D8 scFv against SARS-CoV-2 and other coronaviruses was evaluated in Vero E6 cell cultures. Viral growth was quantified with quantitative RT-qPCR and plaque assay. The nucleic acid-hydrolyzing activity of 3D8 was assessed through abzyme assays of in vitro viral transcripts and cell viability was determined by MTT assay. We found that 3D8 inhibited the replication of SARS-CoV-2, human coronavirus OC43 (HCoV-OC43), and porcine epidemic diarrhea virus (PEDV). Our results revealed the prophylactic and therapeutic effects of 3D8 scFv against SARS-CoV-2 in Vero E6 cells. Immunoblot and plaque assays showed the reduction of coronavirus nucleoproteins and infectious particles, respectively, in 3D8 scFv-treated cells. These data demonstrate the broad-spectrum antiviral activity of 3D8 against SARS-CoV-2 and other coronaviruses. Thus, it could be considered a potential antiviral countermeasure against SARS-CoV-2 and zoonotic coronaviruses.

Alcohol stimulates the proliferation of mouse small intestinal epithelial cells via Wnt signaling.

The intestinal epithelium is one of the fastest renewing tissues in mammals and is a barrier against toxic substances such as alcohol. Excessive alcohol can induce intestinal damage leading to intestinal bowel diseases. Thus, the control of small intestinal epithelial cell (IEC) regeneration is thought to be important for homeostasis in response to epithelium damage. However, reports on how epithelial cells respond to small intestinal damage are scarce. We investigated the effects of alcohol consumption on small intestinal epithelial cells of mice. To verify that alcohol altered the small intestinal epithelium, we used 8-10 weeks old male C57BL/6J mice for models of chronic and binge alcohol consumption (the NIAAA model) in addition to an organoid model. Alcohol promoted the proliferative activity of IECs and intestinal stem cells (ISCs) in intestinal crypts. Alcohol consumption increased expression of the proliferation marker cyclin D1 and activated the p44/42 MAPK (Erk1/2) signaling pathway in small intestinal epithelial cells. The Wnt target genes were markedly increased in IECs from alcohol-treated mice. In the small intestinal organoid model exposed to alcohol, the organoid area and numbers of buds increased with alcohol concentrations up to 0.5% similar to in vivo observations. These results suggest that alcohol consumption stimulates the proliferation of small intestinal epithelial cells via Wnt signaling.

Static Rashba Effect by Surface Reconstruction and Photon Recycling in the Dynamic Indirect Gap of APbBr3 (A = Cs, CH3NH3) Single Crystals.

Recently, halide perovskites have gained significant attention from the perspective of efficient spintronics owing to the Rashba effect. This effect occurs as a consequence of strong spin-orbit coupling under a noncentrosymmetric environment, which can be dynamic and/or static. However, there exist intense debates on the origin of broken inversion symmetry since the halide perovskites typically crystallize into a centrosymmetric structure. In order to clarify the issue, we examine both dynamic and static effects in the all-inorganic CsPbBr3 and organic-inorganic CH3NH3PbBr3 (MAPbBr3) perovskite single crystals by employing temperature- and polarization-dependent photoluminescence excitation spectroscopy. The perovskite single crystals manifest the dynamic effect by photon recycling in the indirect Rashba gap, causing dual peaks in the photoluminescence. However, the effect vanishes in CsPbBr3 at low temperatures (<50 K) accompanied by a striking color change of the crystal, arising presumably from lower degrees of freedom for inversion symmetry breaking associated with the thermal motion of the spherical Cs cation compared with the polar MA cation in MAPbBr3. We also show that the static Rashba effect occurs only in MAPbBr3 below 90 K, presumably due to surface reconstruction via MA-cation ordering, which likely extends across a few layers from the crystal surface to the interior. We further demonstrate that this static Rashba effect can be completely suppressed upon surface treatment with polymethyl methacrylate (PMMA) coating. We believe that our results provide a rationale for the Rashba effects in halide perovskites.