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The onset of the Late Paleolithic period in Korea, represented by the appearance of stemmed points and blades, was a key event in the dispersal of modern humans in Northeast Asia. Previous studies have mainly focused on possible origin locations of these new technologies. The specific cultural processes of the appearance of stemmed points and blades have rarely been considered. We explore these cultural processes by applying a cultural transmission framework to investigate the social contexts of the emergence of these new technologies. Our main question is: what was the dominant mode of cultural transmission during this time of technological innovation in the Korean Late Paleolithic? Following Bettinger and Eerkens (1999), we evaluated models of guided variation and indirect bias using data from Korean assemblages containing stemmed points. To evaluate these models and understand the transmission processes, we computed correlation coefficients and coefficients of variation (CV). We found that information about the new technology was likely transmitted via guided variation with small contribution from indirect bias. Some attributes, including length and width, were transmitted with less variation while other attributes have more variation. Our results suggest that the dominant mode of cultural transmission for the earliest stemmed points was guided variation. A slight shift in the social context of transmission towards indirect bias was observed in the later chronological phase. We assume that individuals or groups developed stemmed points by experimenting with existing blade technologies and then copied crucial parts of a successful model to ensure the quality to optimize tool usage. As a result, the shape of stemmed points became more standardized among their social groups.

How often, and in what contexts, have archaeologists discussed racism over the last four decades? Do societal events lead to sustained discussions of racism among the academic community? Here, the authors seek to answer these questions by applying computational text analysis methods to 68176 abstracts from 41 meetings of the Society for American Archaeology. Discussions of racism are found to be rare—usually a passing mention in the context of broader social issues. Historical archaeologists have addressed racism more frequently than other archaeologists. The results form a baseline against which the discipline's engagement with racism as a research theme and with anti-racist strategies might be tracked.

Kethoxal-assisted ssDNA sequencing (KAS-seq) is gaining popularity as a robust and effective approach to study the dynamics of transcriptionally engaged RNA polymerases through profiling of genome-wide single-stranded DNA (ssDNA). Its latest variant, spKAS-seq, a strand-specific version of KAS-seq, has been developed to map genome-wide R-loop structures by detecting imbalances of ssDNA on two strands. However, user-friendly, open-source analysis pipelines for KAS-seq data are still lacking. Here we present KAS-pipe2 as a flexible and integrated toolkit to facilitate the analysis and interpretation of KAS-seq data. KAS-pipe2 can perform standard analyses such as quality control, read alignment, and differential RNA polymerase activity analysis. In addition, KAS-pipe2 introduces many novel features, including, but not limited to: calculation of transcriptional indexes, identification of single-stranded transcribing enhancers, and high-resolution mapping of R-loops. We use benchmark datasets to demonstrate that KAS-pipe2 provides a powerful framework to study transient transcriptional regulatory programs. KAS-pipe2 is available at https://github.com/Ruitulyu/KAS-pipe2.

Excessive, high doses of ultraviolet B (UVB) UVB irradiation are known to cause skin cancer, aging and immunosuppression. On the contrary, moderate low doses of UVB irradiation are shown to be essential and beneficial to human health, including a tumor-suppressive effect. However, the mechanism by which low levels of UVB suppress tumorigenesis remains unclear. Here, using tumor-bearing mouse models, we show that moderate low repetitive UVB irradiation increases the percentage of activated CD4

Intrasynovial flexor tendon lacerations of the hand are clinically problematic, typically requiring operative repair and extensive rehabilitation. The small-molecule connective tissue growth factor (CTGF) mimics, oxotremorine M (Oxo-M) and 4-PPBP maleate (4-PPBP), have been shown to improve tendon healing in small animal models by stimulating the expansion and differentiation of perivascular CD146+ cells. To enhance intrasynovial flexor tendon healing, small-molecule CTGF mimics were delivered to repaired canine flexor tendons via porous sutures. In vitro studies demonstrated that Oxo-M and 4-PPBP retained their bioactivity and could be released from porous sutures in a sustained manner. However, in vivo delivery of the CTGF mimics did not improve intrasynovial tendon healing. Histologic analyses and expression of tenogenic, extracellular matrix, inflammation, and remodeling genes showed similar outcomes in treated and untreated repairs across two time points. Although in vitro experiments revealed that CTGF mimics stimulated robust responses in extrasynovial tendon cells, there was no response in intrasynovial tendon cells, explaining the lack of in vivo effects. The results of the current study indicate that therapeutic strategies for tendon repair must carefully consider the environment and cellular makeup of the particular tendon for improving the healing response.

Global genome repair (GGR), a subpathway of nucleotide excision repair, corrects bulky helix-distorting DNA lesions across the whole genome and is essential for preventing mutagenesis and skin cancer. Here, we show that METTL14 (methyltransferase-like 14), a critical component of the N(6)-methyladenosine (m(6)A) RNA methyltransferase complex, promotes GGR through regulating m(6)A mRNA methylation–mediated DDB2 translation and suppresses ultraviolet B (UVB) radiation-induced skin tumorigenesis. UVB irradiation down-regulates METTL14 protein through NBR1-dependent selective autophagy. METTL14 knockdown decreases GGR and DDB2 abundance. Conversely, overexpression of wild-type METTL14 but not its enzymatically inactive mutant increases GGR and DDB2 abundance. METTL14 knockdown decreases m(6)A methylation and translation of the DDB2 transcripts. Adding DDB2 reverses the GGR repair defect in METTL14 knockdown cells, indicating that METTL14 facilitates GGR through regulating DDB2 m(6)A methylation and translation. Similarly, knockdown of YTHDF1, an m(6)A reader promoting translation of m(6)A-modified transcripts, decreases DDB2 protein levels. Both METTL14 and YTHDF1 bind to the DDB2 transcript. In mice, skin-specific heterozygous METTL14 deletion increases UVB-induced skin tumorigenesis. Furthermore, METTL14 as well as DDB2 is down-regulated in human and mouse skin tumors and by chronic UVB irradiation in mouse skin, and METTL14 level is associated with the DDB2 level, suggesting a tumor-suppressive role of METTL14 in UVB-associated skin tumorigenesis in association with DDB2 regulation. Taken together, these findings demonstrate that METTL14 is a target for selective autophagy and acts as a critical epitranscriptomic mechanism to regulate GGR and suppress UVB-induced skin tumorigenesis.

Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans worldwide. Although hepatitis E is self-limiting without chronic infection development, HEV infection often leads to severe liver diseases causing high mortality in pregnant women in addition to chronic hepatitis and cirrhosis in immunosuppressed patients. In this study, we investigated the effect of a Liriope platyphylla ethanol extract (LPE) on HEV replication. Interestingly, LPE suppressed replication of the genotype 3 HEV replicon. Sequential solvent fractionation revealed that the ethyl acetate (EA) fraction of LPE exerts the most potent inhibitory effects. With the aid of activity-guided fractionation and multi-step column chromatography, spicatoside A was subsequently isolated in the EA fraction of LPE and specifically shown to exert inhibitory effects on replication of the genotype 3 HEV replicon. In addition, spicatoside A interfered with replication of the HEV genotype 3 strain 47832c and expression of HEV ORF2 capsid proteins. Our findings clearly support the potential utility of spicatoside A as an effective anti-HEV agent.

Skin cancer is the most common form of cancer, with over 5 million cases reported in 2021. UVB exposure derived from sunlight is the major carcinogenic driver of skin cancer and poses a major public health risk. In response to UVB exposure, keratinocytes must activate DNA repair pathways to avoid mutagenesis. In addition to DNA repair pathways, cells initiate well-coordinated DNA damage response pathways to facilitate the repair process, including arresting global transcription. Here we report the use of kethoxal-assisted single-strand DNA-Sequencing (KAS-Seq) technology to profile the transcriptional dynamics that underlie the DNA damage response upon UVB exposure. Mechanistically, KAS-Seq involves the addition of an azide-tagged kethoxal group (N3-kethoxal) to DNA samples, which then reacts with guanines on single-stranded DNA (ssDNA). A “KAS signal” is therefore only obtained when DNA is unwound, allowing the N3-kethoxal reaction with accessible guanines to occur. Accordingly, in response to DNA damage, DNA can form ssDNA bubbles in order to facilitate DNA damage recognition and repair processes. KAS-Seq is therefore a suitable method to profile the transcriptional dynamics that occur in response to UVB-induced DNA damage. Here we show that UVB exposure in normal human keratinocytes (NHEK) cells induces a temporal and dynamic reprogramming in transcription using KAS-Seq. In terms of global transcription, our data show that the greatest loss of KAS signal occurs rapidly between 30mins and 3hrs post-UVB exposure, signifying transcriptional arrest. Interestingly, KAS signal is regained between 6-24hrs post-UVB, which is representative of a transition towards transcriptional recovery and induction of DNA damage processes. Furthermore, a more discrete and targeted analysis shows that the gain and loss of KAS signals primarily occur within the gene body, followed by promoter and intergenic regions. Overall, our data shows that transcriptional control in response to UVB-induced DNA damage is both dynamic and temporal. Further analysis is required to identify which transcriptional phenotype (transcriptional arrest or transcriptional recovery) is the most deleterious to the cell and DNA damage repair processes when disrupted. Additionally, we aim to further elucidate the molecular mechanisms that underlie these global changes in transcription, which will provide expanded insights into the wide-ranging oncogenic mechanisms that underlie UVB exposure. Citation Format: Emma A. Wilkinson, Tong Wu, Gayoung Park, Yan-Hong Cui, Chuan He, Yu-Ying He. Kethoxal-assisted single-stranded DNA sequencing (KAS-seq) reveals dynamic and temporal changes in transcription in response to UVB exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 227.

The development of a vaccine to prevent Zika virus (ZIKV) infection has been one of the priorities in infectious disease research in recent years. There have been numerous attempts to develop an effective vaccine against ZIKV. It is imperative to choose the safest and the most effective ZIKV vaccine from all candidate vaccines to control this infection globally. We have employed a dual serotype of prime-boost recombinant vesicular stomatitis virus (VSV) vaccine strategy, to develop a ZIKV vaccine candidate, using a type 1 IFN-receptor knock-out (Ifnar −/−) mouse model for challenge studies. Prime vaccination with an attenuated recombinant VSV Indiana serotype (rVSVInd) carrying a genetically modified ZIKV envelope (E) protein gene followed by boost vaccination with attenuated recombinant VSV New Jersey serotype (rVSVNJ) carrying the same E gene induced robust adaptive immune responses. In particular, rVSV carrying the ZIKV E gene with the honeybee melittin signal peptide (msp) at the N terminus and VSV G protein transmembrane domain and cytoplasmic tail (Gtc) at the C terminus of the E gene induced strong protective immune responses. This vaccine regimen induced highly potent neutralizing antibodies and T cell responses in the absence of an adjuvant and protected Ifnar -/- mice from a lethal dose of the ZIKV challenge.

Thymosin beta-4 (Tβ4) is an actin-sequestering peptide that plays important roles in regeneration and remodeling of injured tissues. However, its function in a naturally occurring pathogenic bacterial infection model has remained elusive. We adopted Tβ4-overexpressing transgenic (Tg) mice to investigate the role of Tβ4 in acute pulmonary infection and systemic sepsis caused by Legionella pneumophila. Upon infection, Tβ4-Tg mice demonstrated significantly lower bacterial loads in the lung, less hyaline membranes and necrotic abscess, with lower interstitial infiltration of neutrophils, CD4+, and CD8+ T cells. Bronchoalveolar lavage fluid of Tβ4-Tg mice possessed higher bactericidal activity against exogenously added L. pneumophila, suggesting that constitutive expression of Tβ4 could efficiently control L. pneumophila. Furthermore, qPCR analysis of lung homogenates demonstrated significant reduction of interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), which primarily originate from lung macrophages, in Tβ4-Tg mice after pulmonary infection. Upon L. pneumophila challenge of bone marrow-derived macrophages (BMDM) in vitro, secretion of IL-1β and TNF-α proteins was also reduced in Tβ4-Tg macrophages, without affecting their survival. The anti-inflammatory effects of BMDM in Tβ4-Tg mice on each cytokine were affected when triggering with tlr2, tlr4, tlr5, or tlr9 ligands, suggesting that anti-inflammatory effects of Tβ4 are likely mediated by the reduced activation of Toll-like receptors (TLR). Finally, Tβ4-Tg mice in a systemic sepsis model were protected from L. pneumophila-induced lethality compared to wild-type controls. Therefore, Tβ4 confers effective resistance against L. pneumophila via two pathways, a bactericidal and an anti-inflammatory pathway, which can be harnessed to treat acute pneumonia and septic conditions caused by L. pneumophila in humans.

The present study is aimed at the development of compositional simulation models of the co-injection of CO2 and CH4 during the water-alternating-gas (WAG) process in order to assess the efficiency of carbon capture and storage in combination with enhanced oil recovery (CCS-EOR). The co-injection of CO2 and CH4 occupies more reservoir pore volume and causes higher reservoir pressure than CO2 WAG, thus leading to an enhanced early EOR performance. However, the overall EOR performance of the co-injection method becomes lower than that of CO2 WAG due to the reduced miscibility and sweep efficiency upon further CH4 addition. The decrease in gas displacement and sweep efficiency weaken the hysteresis effects upon the residual trapping mechanism. However, the solubility trapping mechanism takes effect because the co-injection generates higher average reservoir pressure than does the CO2 WAG. The index of global warming potential (GWP) in a mole unit is employed to quantify the carbon storage effects of CO2 and co-injection WAG cases. According to the index, 1 mole of CH4 sequestration has the same effects as that of 10 moles of CO2 for global warming mitigation. In conclusion, the carbon storage effects are enhanced as CH4 concentration in the WAG increases.

This study proposes a hydraulic fracture propagation model with a mixed mode comprising opening and sliding modes to describe a complex fracture network in a naturally fractured shale gas formation. We combine the fracture propagation model with the mixed mode and the uniaxial strain model with tectonic impacts to calculate the stress distribution using geomechanical properties. A discrete fracture network is employed to realize the fracture network composed of natural and hydraulic fractures. We compare the fracture propagation behaviours of three cases representing the Barnett, Marcellus, and Eagle Ford shale gas formations. Sensitivity analysis is performed to investigate the effects of the geomechanical properties of the reservoir on the sliding mode’s contribution to the mixed mode. The numerical results highlight the significance of the mixed mode for the accurate assessment of fracture propagation behaviours in shale gas formations with high brittleness.

Transient electronics represents an emerging technology whose defining feature is an ability to dissolve, disintegrate or otherwise physically disappear in a controlled manner. Envisioned applications include resorbable/degradable biomedical implants, hardware-secure memory devices, and zero-impact environmental sensors. 2D materials may have essential roles in these systems due to their unique mechanical, thermal, electrical, and optical properties. Here, we study the bioabsorption of CVD-grown monolayer MoS2, including long-term cytotoxicity and immunological biocompatibility evaluations in biofluids and tissues of live animal models. The results show that MoS2 undergoes hydrolysis slowly in aqueous solutions without adverse biological effects. We also present a class of MoS2-based bioabsorbable and multi-functional sensor for intracranial monitoring of pressure, temperature, strain, and motion in animal models. Such technology offers specific, clinically relevant roles in diagnostic/therapeutic functions during recovery from traumatic brain injury. Our findings support the broader use of 2D materials in transient electronics and qualitatively expand the design options in other areas.

Biologically and environmentally resorbable electronic devices support application possibilities that cannot be addressed with conventional technologies. This paper presents highly conductive, water-soluble composites that can be printed to form contacts, interconnects, antennas, and other important features that are essential to nearly all systems of this type. An optimized material formulation involves in situ polymerization to yield a polyanhydride containing a dispersion of molybdenum microparticles at appropriate concentrations. Comparisons of essential physical and electrical properties of these materials to those of composites formed with other polymers and other metal microparticles reveal the relevant considerations. Various functional demonstrations of screen-printed test structures and devices illustrate the suitability of these conductive inks for use in water-soluble electronic devices. A key advantage of the material introduced here compared to alternatives is its ability to maintain conductance over significant periods of time while immersed in relevant aqueous solutions. Studies involving live animal models establish the biocompatibility.

This study develops an integrative simulation model of a water alternating gas (WAG) process that co-injects carbon dioxide (CO2) and methane (CH4)–CO2–CH4 WAG—for formation damage caused by asphaltene deposition in an oil reservoir. The influences of CH4 addition into the injection gas stream are analyzed in terms of enhanced oil recovery (EOR) and carbon capture and storage (CCS). Asphaltene precipitation and deposition mechanisms are examined by fluid modeling and compositional simulation, respectively. Fluid modeling is performed using Burke Oil 1 experimental data. Compositional simulation is conducted for a 13-year CO2–CH4 WAG case. Compared with 100% CO2 WAG, addition of CH4 decreases oil displacement efficiency due to reduced miscibility while mitigating asphaltene deposition. This relief of formation damage compensates for oil recovery. The CCS performance of CO2–CH4 WAG is investigated by residual and solubility trapping processes. The overall carbon storage effect of CO2–CH4 WAG is quantified using global warming potential. These results highlight the significance of CO2–CH4 co-injection to improve the performance of CCS-EOR and of integrative modeling with asphaltene for an accurate performance evaluation of CO2–CH4 WAG.

This study integrates a convolutional neural network (CNN) within the framework of robust optimization for determining the placement of an oil production well at a petroleum reservoir under geological uncertainty. The proposed algorithm identifies the well location that maximizes the expectation of cumulative oil production of equiprobable realizations. CNN, which inputs near-wellbore permeability and outputs cumulative oil production at a feasible well location, is trained to correlate between petrophysical spatial data and hydrocarbon productivity with several realizations. The trained CNN estimates the productivity at every feasible well location for all given realizations. The approach is tested with application to a set of realizations describing a channelized oil reservoir with an aquifer. The validity of the approach is evaluated by comparing the similarity between the full-physics reservoir simulation (RS) and CNN results for qualified well locations. The most productive well location based on the simulation results is selected as the optimal well placement. The performance of the CNN is also compared with that of an artificial neural network (ANN) for cases with varied numbers of realizations that provide training data with the neural networks. CNN outperforms ANN because of its feature extraction of multi-dimensional data from convolution. A sensitivity analysis is conducted to analyze the effects of the volume of training data on the predictability of the neural networks with k-fold cross-validation. The findings highlight that the integrated approach can be used as an efficient decision-making tool for solving well placement optimization problems with accuracy at an affordable computational cost.

The time of arrival of people in Australia is an unresolved question. It is relevant to debates about when modern humans first dispersed out of Africa and when their descendants incorporated genetic material from Neanderthals, Denisovans and possibly other hominins. Humans have also been implicated in the extinction of Australia’s megafauna. Here we report the results of new excavations conducted at Madjedbebe, a rock shelter in northern Australia. Artefacts in primary depositional context are concentrated in three dense bands, with the stratigraphic integrity of the deposit demonstrated by artefact refits and by optical dating and other analyses of the sediments. Human occupation began around 65,000 years ago, with a distinctive stone tool assemblage including grinding stones, ground ochres, reflective additives and ground-edge hatchet heads. This evidence sets a new minimum age for the arrival of humans in Australia, the dispersal of modern humans out of Africa, and the subsequent interactions of modern humans with Neanderthals and Denisovans. Optical dating of sediments containing stone artefacts newly excavated at Madjedbebe, Australia, indicate that human occupation began around 65,000 years ago, thereby setting a new minimum age for the arrival of people in Australia. When did humans first colonize Australia? The date of the initial landing on the continent that is now associated with cold lager and 'Waltzing Matilda' has been highly controversial. Dates from a site called Madjedbebe in northern Australia had put the presence of modern humans in Australia at between 60,000 and 50,000 years ago, but these results have since been hotly contested. Here, the results from a comprehensive program of dating of new excavations at the site confirm that people first arrived there around 65,000 years ago. The results show that humans reached Australia well before the extinction of the Australian megafauna and the disappearance of Homo floresiensis in neighbouring Indonesia.

Legionella pneumophila is an etiological agent of the severe pneumonia known as Legionnaires' disease (LD). This gram-negative bacterium is thought to replicate naturally in various freshwater amoebae, but also replicates in human alveolar macrophages. Inside host cells, legionella induce the production of non-endosomal replicative phagosomes by injecting effector proteins into the cytosol. Innate immune responses are first line defenses against legionella during early phases of infection, and distinguish between legionella and host cells using germline-encoded pattern recognition receptors such as Toll-like receptors , NOD-like receptors, and RIG-I-like receptors, which sense pathogen-associated molecular patterns that are absent in host cells. During pulmonary legionella infections, various inflammatory cells such as macrophages, neutrophils, natural killer (NK) cells, large mononuclear cells, B cells, and CD4+ and CD8+ T cells are recruited into infected lungs, and predominantly occupy interstitial areas to control legionella. During pulmonary legionella infections, the interplay between distinct cytokines and chemokines also modulates innate host responses to clear legionella from the lungs. Recognition by NK cell receptors triggers effector functions including secretion of cytokines and chemokines, and leads to lysis of target cells. Crosstalk between NK cells and dendritic cells, monocytes, and macrophages provides a major first-line defense against legionella infection, whereas activation of T and B cells resolves the infection and mounts legionella-specific memory in the host.

With the rapid growth of the wireless communication industry, humans are extensively exposed to electromagnetic fields (EMF) comprised of radiofrequency (RF). The skin is considered the primary target of EMFs given its outermost location. Recent evidence suggests that extremely low frequency (ELF)-EMF can improve the efficacy of DNA repair in human cell-lines. However, the effects of EMF-RF on DNA damage remain unknown. Here, we investigated the impact of EMF-long term evolution (LTE, 1.762 GHz, 8 W/kg) irradiation on DNA double-strand break (DSB) using the murine melanoma cell line B16 and the human keratinocyte cell line HaCaT. EMF-LTE exposure alone did not affect cell viability or induce apoptosis or necrosis. In addition, DNA DSB damage, as determined by the neutral comet assay, was not induced by EMF-LTE irradiation. Of note, EMF-LTE exposure can attenuate the DNA DSB damage induced by physical and chemical DNA damaging agents (such as ionizing radiation (IR, 10 Gy) in HaCaT and B16 cells and bleomycin (BLM, 3 μM) in HaCaT cells and a human melanoma cell line MNT-1), suggesting that EMF-LTE promotes the repair of DNA DSB damage. The protective effect of EMF-LTE against DNA damage was further confirmed by attenuation of the DNA damage marker γ-H2AX after exposure to EMF-LTE in HaCaT and B16 cells. Most importantly, irradiation of EMF-LTE (1.76 GHz, 6 W/kg, 8 h/day) on mice in vivo for 4 weeks reduced the γ-H2AX level in the skin tissue, further supporting the protective effects of EMF-LTE against DNA DSB damage. Furthermore, p53, the master tumor-suppressor gene, was commonly upregulated by EMF-LTE irradiation in B16 and HaCaT cells. This finding suggests that p53 plays a role in the protective effect of EMF-LTE against DNA DSBs. Collectively, these results demonstrated that EMF-LTE might have a protective effect against DNA DSB damage in the skin, although further studies are necessary to understand its impact on human health.

Dependency between human failure events (HFEs) is often analyzed as a part of the conventional human reliability analysis (HRA) process for nuclear power plants (NPPs). None of the existing methods have considered an application to multi-unit (MU) scenarios. In this study, we introduce a novel approach to evaluate the dependencies between HFEs in cases of MU event scenarios. We focus on developing a set of MU HFE dependency evaluation elements and their evaluation criteria based on the framework of the single-unit evaluation elements that have been utilized in the HRA practice for NPPs. The unique MU HFE dependency evaluation elements are defined, and we present a new dependency evaluation tree for qualitative analysis. In addition, important cases are provided to demonstrate the application of the proposed method, including four MU initiating events: MU loss of offsite power, MU loss of condenser vacuum, MU general transient, and MU loss of ultimate heat sink. Quantitative analysis with several illustrative HFEs in MU probabilistic safety assessment (PSA) cutsets are also presented. This method fills the gap of a HFE dependency analysis method in the case of MU PSA.

Impaired signaling, downstream of 2B4, is associated with colitis in human patients with XLP ; however, the precise mechanism by which 2B4 maintains gut integrity remains unknown. In dextran sodium sulfate (DSS)-fed reciprocal chimera mice, massive tissue destruction was observed due to lack of 2B4 in hematopoietic compartments, in particular Ly6ChighCD11b+ monocyte subsets within the lamina propria leukocytes. Not only did the number of Ly6ChighCD11b+ monocytes get significantly reduced, their intrinsic capacity to produce IL-1β during DSS stimulation was also drastically impaired in 2B4−/− mice. These defects led to an impaired IL-22 secretion in ILCs and IL-18 production in gut epithelial cells in the 2B4−/− mice. Furthermore, severe inflammatory phenotypes seen in 2B4−/− mice could only be rescued by adoptive transfer of Ly6ChighCD11b+ monocytes, but not with BMDC or NK cells. Therefore, 2B4 functions as an important receptor in inflammatory monocytes in response to commensal microbiota during acute colonic inflammation.

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma., FTO is an m6A demethylase. Here, the authors show that FTO promotes melanoma tumorigenicity and contributes to resistance to anti-PD1 blockade, while FTO inhibition sensitizes melanoma to anti-PD1 blockade.

A soft chemical route to amino acid layered double hydroxide (LDH) nanohybrids was demonstrated on the basis of an intercalative ion-exchange reaction. Two different amino acids, phenylalanine and glutamic acid, were intercalated and stabilized in the interlayer space of a 2-dimensional double hydroxide lattice by electrostatic interaction. An attempt was also made to understand the effect of the intracrystalline structure of the amino acid in the LDH on the specific surface area, porosity, and gas sorption properties of the hybrid. According to the X-ray diffraction analysis, the basal spacings of LDH intercalated with phenylalanine and LDH intercalated with glutamic acid were expanded to 1.80 and 1.22 nm, respectively, relative to that of the pristine Mg2Al-NO3-LDH (0.88 nm), which indicates that amino acid molecules were successfully intercalated into the LDH. Fourier transform infrared spectra for both samples confirmed that the carboxylic acid group in the amino acid is anionic carboxylate under basic conditions and it eventually interacts with the positively charged LDH surface. From N2 adsorption/desorption analysis, the BET specific surface area of the LDH intercalated with phenylalanine was found to be twice as large as that for the LDH intercalated with glutamic acid. However, the CO2 adsorption capacity of the former was determined to be three times more enhanced than that of the latter, due to an enhanced specific surface area and effective amine sites to form carbamates. The CO2 uptake capacity in the present study is influenced not only by the specific surface area but also by the number of reactive amine sites in the pore, as the amine groups of amino acids interact with adsorbed CO2 molecules to form carbamates by a zwitterionic mechanism even at low temperature. Refereed/Peer-reviewed