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We develop a new series of ionic liquids with dual functionality as a dopant for hole transport materials and a passivator for perovskite surfaces, which enables the production of large-area solar modules with efficiencies approaching 20%.

Bacteriophage T7 single-stranded DNA-binding protein (gp2.5) binds to and protects transiently exposed regions of single-stranded DNA (ssDNA) while dynamically interacting with other proteins of the replication complex. We directly visualize fluorescently labelled T7 gp2.5 binding to ssDNA at the single-molecule level. Upon binding, T7 gp2.5 reduces the contour length of ssDNA by stacking nucleotides in a force-dependent manner, suggesting T7 gp2.5 suppresses the formation of secondary structure. Next, we investigate the binding dynamics of T7 gp2.5 and a deletion mutant lacking 21 C-terminal residues (gp2.5-Δ21C) under various template tensions. Our results show that the base sequence of the DNA molecule, ssDNA conformation induced by template tension, and the acidic terminal domain from T7 gp2.5 significantly impact on the DNA binding parameters of T7 gp2.5. Moreover, we uncover a unique template-catalyzed recycling behaviour of T7 gp2.5, resulting in an apparent cooperative binding to ssDNA, facilitating efficient spatial redistribution of T7 gp2.5 during the synthesis of successive Okazaki fragments. Overall, our findings reveal an efficient binding mechanism that prevents the formation of secondary structures by enabling T7 gp2.5 to rapidly rebind to nearby exposed ssDNA regions, during lagging strand DNA synthesis.

Few studies have evaluated the role of autophagy in the development of oxaliplatin (OXT) resistance in colon cancer cells. In this study, we compared the role of autophagy between SNU-C5 colon cancer cells and OXT-resistant SNU-C5 (SNU-C5/OXTR) cells. At the same concentration of OXT, the cytotoxicity of OXT or apoptosis was significantly reduced in SNU-C5/OXTR cells compared with that in SNU-C5 cells. Compared with SNU-C5 cells, SNU-C5/OXTR cells exhibited low levels of autophagy. The expression level of important autophagy proteins, such as autophagy-related protein 5 (Atg5), beclin-1, Atg7, microtubule-associated proteins 1A/1B light chain 3B I (LC3-I), and LC3-II, was significantly lower in SNU-C5/OXTR cells than that in SNU-C5 cells. The expression level of the autophagy-essential protein p62 was also lower in SNU-C5/OXTR cells than in SNU-C5 cells. In SNUC5/ OXTR cells, the production of intracellular reactive oxygen species (ROS) was significantly higher than that in SNU-C5 cells, and treatment with the ROS scavenger N-acetylcysteine restored the reduced autophagy levels. Furthermore, the expression of antioxidant-related nuclear factor erythroid 2-related factor 2 transcription factor, heme oxygenase-1, and Cu/Zn superoxide dismutase were also significantly increased in SNU-C5/OXTR cells. These findings suggest that autophagy is significantly reduced in SNU-C5/OXTR cells compared with SNU-C5 cells, which may be related to the production of ROS in OXT-resistant cells.

Nature biotechnology 41(5), 686 - 697 (2023). doi:10.1038/s41587-022-01611-9, Cytosine base editors (CBEs) enable programmable genomic C·G-to-T·A transition mutations and typically comprise a modified CRISPR–Cas enzyme, a naturally occurring cytidine deaminase, and an inhibitor of uracil repair. Previous studies have shown that CBEs utilizing naturally occurring cytidine deaminases may cause unguided, genome-wide cytosine deamination. While improved CBEs that decrease stochastic genome-wide off-targets have subsequently been reported, these editors can suffer from suboptimal on-target performance. Here, we report the generation and characterization of CBEs that use engineered variants of TadA (CBE-T) that enable high on-target C·G to T·A across a sequence-diverse set of genomic loci, demonstrate robust activity in primary cells and cause no detectable elevation in genome-wide mutation. Additionally, we report cytosine and adenine base editors (CABEs) catalyzing both A-to-I and C-to-U editing (CABE-Ts). Together with ABEs, CBE-Ts and CABE-Ts enable the programmable installation of all transition mutations using laboratory-evolved TadA variants with improved properties relative to previously reported CBEs., Published by Springer Nature, New York, NY

Purpose: There are many studies on sentinel lymph node (SLN) biopsy in thyroid carcinoma but SLN biopsy (SLNB) in papillary thyroid carcinoma (PTC) remains open to debate. Therefore in this retrospective study, the usefulness of SLNB in thyroid carcinoma patients who had micro-PTC without cervical lymphadenopathy was assessed.Methods: SLNB was performed in 114 patients who were diagnosed with micro-PTC in a single lobe without palpable or ultrasound-detected lymph node at the tertiary center between January 2012 and December 2013. After SLNB, all patients underwent total thyroidectomy and central neck dissection or thyroid lobectomy and central neck dissection of the single side.Results: SLNs were identified in 112 of 114 patients with 41 positive SLNs and 71 negative SLNs on intraoperative frozen sections. However, eight negative patients were found to be positive in the final pathology. Sentinel node identification rate and false negative value of SLNB were 98.2% and 11.3%, respectively. In the univariate analysis, higher lymph node metastasis was detected in men than in women. Higher detection number of SLN showed higher probability of lymph node metastasis.Conclusion: SLNB may be helpful in papillary thyroid cancer, especially in male patients. Also, it is useful for the staging of nodal status and clearance of persistent disease.

We analyze the effects of the strain-induced pseudo-magnetic fields (PMFs) originating from nanobubbles (NBs) to examine the possibility for a graphene quantum dot (QD) created by strain engineering. We study the electronic structures and quantum transport properties of graphene subjected to an NB, and report that the presence of PMFs facilitates a strong confinement of Dirac fermions. A circular geometry of the NB locally establishes the characteristic PMFs with $$C_{3}$$ symmetry, resulting in threefold localized states according to the given symmetry. We demonstrate the formation of a graphene QD induced by the NB via the conductance resonances calculated through the NB between opposite quantum Hall edge channels. Analyzing the scattering wavefunctions for the resonances, we confirm the existence of ground and excited states in the graphene QD. In addition, we show a possible valley-polarization in the graphene QD, as a consequence of quantum interference between symmetric and anti-symmetric valley-coupled modes.

Background: Axl, Mer and CSF1 receptor tyrosine kinases play vital roles in promoting the immunosuppressive tumor microenvironment (TME) by affecting myeloid functions (e.g., tumor associated macrophage [TAM], myeloid derived suppression cell [MDSC]) and promoting epithelial-to-mesenchymal transition (EMT). Thus, simultaneous inhibition of Axl, Mer and CSF1R may be an effective strategy for TME modification. Q702 is a novel Axl/Mer/CSF1R kinase inhibitor that affects the immune components (modulating TAM and MDSC populations, inducing CD8+ T cell infiltration and increasing IFN-ɣ in CD8+ T cell) as well as changes in malignant cells such as increasing MHC I on the tumor cells of syngeneic mouse models. These nonclinical results suggest that Q702 monotherapy or Q702 combination with conventional therapies may have considerable potential as a novel treatment strategy for patients with advanced solid tumors. Methods: This is a Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the recommended phase 2 dose (RP2D) in Patients with Advanced Solid Tumors (NCT04648254). Q702 was administered orally for seven days every other week. Peripheral blood samples were obtained on days 1,8,15, and 21. Axl, Mer and CSF1R target engagement is assessed by the quantifications of soluble Axl, Mer and M-CSF in plasma by Luminex xMAP® technology or ELISA. The pharmacodynamic biomarker changes are measured by flow cytometry for immune cell population shifts and IFN-ɣ levels in specific immune cells. Results: PK and PD biomarker samples from 22 patients with various tumor types (e.g. colon, pancreas, esophageal) from the dose escalation phase (4 mg to 240 mg) have been analyzed. Pharmacokinetic studies demonstrated dose proportional increase in Cmax and AUClast of Q702 and its two active metabolites which have activity against Axl and/or CSF1R. Axl and CSF1R target engagement by Q702 treatment is observed in a dose dependent manner. From the 60 mg cohort, target engagement for Axl and CSF1R reached a inhibitory level that was observed in nonclinical models. In the pharmacodynamic biomarker analysis, IFN-ɣ in CD8+ T cells and non-T cell populations is increased. Monocytes and M-MDSC population are decreased in peripheral blood. Conclusion: Up to 240 mg, Q702 has demonstrated the intended pharmacologic activity with acceptable safety profile. In biomarker analysis, immune modulation activity is exerted by Axl/Mer/CSF1R inhibition. Further assessment of pharmacokinetics, pharmacodynamics, safety and antitumor activity will be performed at the expansion phase at the RP2D in patients with selected advanced tumors. Citation Format: Bae Jung Choi, Devalingam Devalingam, Angela Alistar, Anthony El-Khoueiry, Alain Mita, Hwankyu Kang, Jinho Choi, Hyunji Ahn, Jeongjun Kim, Seung-Joo Lee, Yeong-In Yang, Jiye Ahn, Borami Jeon, Jaeseung Kim, Kiyean Nam. Patient pharmacodynamic biomarker and pk evaluation results from an ongoing phase I dose-escalation study of q702, an axl, mer and csf1r kinase inhibitor in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2255.

Background; Q901 is an extremely selective CDK7 inhibitor with potent single agent activity in the multiple in vivo tumor models including small cell lung cancer, cholangiocarcinoma, colon cancer, pancreatic cancer, hormone receptor positive breast cancer, castrate-resistant prostate cancer, and ovarian cancer. Q901 is currently in Phase 1/2 clinical trial for patients with selected advanced solid tumors (ClinicalTrials.gov: NCT05394103). In the preclinical models, Q901 treatment induces DNA damage response (DDR) impairment markers, particularly ones involved in the double-strand break repair mechanisms. This opens up broad range of possibilities for new combination regimen that could benefit from the accumulated DNA damages caused by Q901 treatment. Methods: Various combinations have been tested to evaluate potential clinical regimens in multiple solid tumor models. Two different BRCA wild-type ovarian cancer A2780 and OVCAR3 models, an estrogen receptor positive MCF7 breast cancer model, or a syngeneic RENCA mouse renal cancer model was tested with Q901 in combination with poly ADP-ribose polymerase (PARP) inhibitor, selective estrogen receptor degrader (SERD), an estrogen receptor (ER) PROTAC degrader, or an anti-PD-1 antibody, respectively. Results: In the A2780 model, the PARPi alone group showed 15% TGI (tumor growth inhibition), but significant tumor regression (104% TGI) was observed in the Q901 and PARPi combination. In the OVCAR3 model, the Q901 and PARPi combination group showed 105% TGI, whereas the PARPi alone group showed 38% TGI. In the MCF7 model, SERD alone showed 64% TGI and Q901 combination with SERD showed 94% TGI. Remarkable tumor regression (111% TGI) was observed in the MCF7 model combining ER PROTAC and Q901, whereas ER PROTAC alone group showed 55% TGI. In the RENCA model, the anti-PD-1 antibody alone group showed 13.2% TGI and the combination of Q901 and anti-PD-1 antibody showed 66% TGI. In summary, these preclinical model studies demonstrated significant additive/synergistic effects of the Q901 combination on tumor growth inhibition. Conclusion: The non-clinical data demonstrate that Q901 not only has a potential as a single agent,but can also be used in combination with other therapeutic strategies to develop next-generation cancer therapeutics to potentially address unmet medical needs. Citation Format: Donghoon Yu, Yeejin Jeon, YoonJi Lee, Seung-Joo Lee, Jaeseung Kim, Hyerim Jung, Tae-Kyung Kim, Kiyean Nam. Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5977.

We investigate infinite distance limits in the complex structure moduli space of F-theory compactified on K3 to eight dimensions. While this is among the simplest possible arenas to test ideas about the Swampland Distance Conjecture, it is nevertheless non-trivial enough to improve our understanding of the physics for these limiting geometries, including phenomena of emergence. It also provides a perspective on infinite distance limits from the viewpoint of open strings. The paper has two quite independent themes. In the main part we show that all degenerations of elliptic K3 surfaces at infinite distance as analysed in a companion paper can be interpreted as (partial) decompactification or emergent string limits in F-theory, in agreement with the Emergent String Conjecture. We present a unified geometric picture of the possible towers of states that can become light and illustrate our general claims via the connection between Kulikov models of degenerating K3 surfaces and the dual heterotic string. As an application we classify the possible maximal non-abelian Lie algebras and their Kac-Moody and loop extensions that can arise in the infinite distance limits. In the second part we discuss the infinite distance behaviour of certain exact quartic gauge couplings. We encounter a tension with the hypothesis that effective couplings should be fully generated by integrating out massive states. We show that by appropriately renormalizing the string coupling, at least partial emergence can be achieved., 57 pages, 11 figures

Ammonium toxicity is a significant source of pollution from industrial civilization that is disrupting the balance of natural systems, adversely affecting soil and water quality, and causing several environmental problems that affect aquatic and human life, including the strong promotion of eutrophication and increased dissolved oxygen consumption. Thus, a cheap catalyst is required for power generation and detoxification. Herein, compost soil is employed as a novel electrocatalyst for ammonium degradation and high-power generation. Moreover, its effect on catalytic activity and material performances is systematically optimized and compared by treating it with various reducing agents, including potassium ferricyanide, ferrocyanide, and manganese dioxide. Ammonium fuel was supplied to the compost soil ammonium fuel cell (CS-AFC) at concentrations of 0.1, 0.2, and 0.3 g/mL. The overall results show that ferricyanide affords a maximum power density of 1785.20 mW/m2 at 0.2 g/mL fuel concentration. This study focuses on high-power generation for CS-AFC. CS-AFCs are sustainable for many hours without any catalyst deactivation; however, they need to be refueled at regular intervals (every 12 h). Moreover, CS-AFCs afford the best performance when ferricyanide is used as the electron acceptor at the cathode. This study proposes a cheap electrocatalyst and possible solutions to the more serious energy generation problems. This study will help in recycling ammonium-rich wastewaters as free fuel for running CS-AFC devices to yield high-power generation with reducing agents for ammonium fuel cell power applications.

Bacteriophage T7 encodes its own DNA polymerase, the product of gene 5 (gp5). In isolation, gp5 is a DNA polymerase of low processivity. However, gp5 becomes highly processive upon formation of a complex with Escherichia coli thioredoxin, the product of the trxA gene. Expression of a gp5 variant in which aspartate residues in the metal-binding site of the polymerase domain were replaced by alanine is highly toxic to E. coli cells. This toxicity depends on the presence of a functional E. coli trxA allele and T7 RNA polymerase-driven expression but is independent of the exonuclease activity of gp5. In vitro, the purified gp5 variant is devoid of any detectable polymerase activity and inhibited DNA synthesis by the replisomes of E. coli and T7 in the presence of thioredoxin by forming a stable complex with DNA that prevents replication. On the other hand, the highly homologous Klenow fragment of DNA polymerase I containing an engineered gp5 thioredoxin-binding domain did not exhibit toxicity. We conclude that gp5 alleles encoding inactive polymerases, in combination with thioredoxin, could be useful as a shutoff mechanism in the design of a bacterial cell-growth system.

The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2 with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification, which is maintained when multiplexed across three loci. Delivered as messenger RNA, ABE8s induce no significant levels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.

Purpose To evaluate the effect of the location of the femoral tunnel on 3-dimensional (3D) computed tomography (CT) upon the postoperative tunnel widening after anterior cruciate ligament (ACL) reconstructions. Methods Inclusion criteria were patients who underwent hamstring ACL reconstructions using an adjustable-loop cortical suspension device, underwent 3D CT at the day after surgery, and were followed for a minimum of 2 years after surgery. Exclusion criteria were patients with combined ligament injury and reinjury after reconstruction. Using 3D CT, the center of the femoral tunnel aperture was located on a standardized grid system. The center of the ACL footprint was defined from the literature. The femoral tunnel location was classified as anatomic if it located within 2 standard deviations of the center position. If it was outside the 2 standard deviations, the tunnel was classified as nonanatomic. The patients were divided into either anatomic or nonanatomic groups. Femoral tunnel angles on both sagittal and coronal planes were measured. Both femoral and tibial tunnels measured on anteroposterior and lateral radiographs at immediate postoperative day and at 2 years after surgery. Postoperative knee stability and patient-reported outcomes were evaluated. Results There were 37 patients in anatomical group and 52 patients in nonanatomical group among enrolled 87 patients. There were no differences in demographics between the 2 groups. There were no differences in the femoral tunnel angles and postoperative tunnel widening between the 2 groups. A higher position correlated to the femoral tunnel widening at 2 years postoperatively. Postoperative knee stability and patient-reported outcomes showed no statistically significant differences between the 2 groups. Conclusions There was no significant difference in postoperative tunnel widening or clinical outcomes between anatomic and nonanatomic femoral tunnel location after hamstring ACL reconstructions. A higher position correlated to the femoral tunnel widening at 2 years postoperatively. Level of Evidence Level III, Retrospective comparative study.

Objectives:The purpose of this study is to evaluate the effects of heavy metals (Zn2+, Pb2+, Hg2+, Cd2+) toxicity in a real-time biosensor which is based on measuring the attenuation of light intensity emitted by Vibrio fischeri.Methods:The inhibition test included four heavy metals and the spiked effluent wastewater. The toxicity of the test samples was assessed by freeze-dried bacteria (Vibrio fischeri NRRL-B-11177). The pH of the samples was adjusted to 7±0.2 before conducting the toxicity tests in oder to eliminate potential pH effects. The results obtained from the real-time biosensor that can be measuring the toxicity of the samples as a function of the emitted light. within a short period time (2 min). And then EC20 and EC50 values was estimated from inhibition curves.Results and Discussion:In case of the inhibition test for dilluents of heavy metals, EC20 values were estimated as < 0.2 mg/L for Zn(II), 0.45 mg/L for Hg(II), 0.58 mg/L for Cd(II) and 1.95 mg/L for Pb(II) and EC50 values were estimated as 0.25 mg/L for Zn(II), 0.5~1.0 mg/L for Hg(II), 1.38 mg/L for Cd(II) and 3.76 mg/L for Pb(II). The sensitivity ranking of heavy metals was in order as Zn(II) > Hg(II), > Cd(II) > Pb(II). In case of the inhibition test for the spiked effluent wastewater, EC20 values were estimated as 0.38 mg/L for Hg(II), 0.58 mg/L for Zn(II), 1.45 mg/L for Pb(II) and 1.95 mg/L for Cd(II) and EC50 values were estimated as 0.53 mg/L for Hg(II), 1.13 mg/L for Zn(II), 6.44 mg/L for Pb(II) and 7.82 mg/L for Cd(II). The sensitivity ranking of the spiked effluent wastewater was in order as Hg(II) > Zn(II) > Pb(II) > Cd(II). Compared to the Emssion Limit Value (ELV) in Korea, the EC20 value of Zn(II) was found to be lower than ELV so that it was suitable for screening of Zn(II) as to meet the criteria of effluent wastewater. However, the other EC20 value of heavy metals can be used to control the unit processes and avoid accidental discharge.Conclusions:The assessment of the toxicity of four heavy metals and spiked samples with them was performed in this study, by real-time biosensor using bioluminescent bacteria. The EC20 value of the spiked sample with Zn(II) has been found to be 0.58 mg/L lower than its ELV so that it was considered as a suitable screening for determining whether or not to exceed the permissible limit value. The use of real-time biosensor is required in combination with physicochemical analyses for an integrated screening of the industrial effluent properties.

The volatile compounds and sensory profiles of 18 different types of distilled

This report lays the foundation stone for the real time detector to control and monitor antibiotic resistant bacteria’s. To start with, firstly, the green synthesis of silver nanoparticles were done by the bio-reduction of silver nitrate using different concentrations of medicinal plant extract taken from the leaves of Azadirachta indica (neem). The well-known standard surface plasmon resonance (SPR) wavelength of 430 nm and the characteristic brown color of the solution confirms the formation of eco-friendly silver nanoparticles. The silver nanoparticle size in the range of 10–20 nm was observed from TEM measurements for the sample showing best SPR which was further selected for conjugation with QDs. Secondly glutathione capped ZnS:Mn QDs were synthesized and conjugated with silver nanoparticles (0.09–0.1 mg/mL) and then their zone of inhibition studies were done using antibiotic resistant gram positive as well as gram negative bacteria’s i.e. Staphylococcus aureus and Escherichia coli respectively. Lastly, time resolved photoluminescence studies of the conjugated system were done to correlate zone of inhibition (antibiotic sensitivity) with silver nanoparticle concentration in both the cases of a gram positive bacteria and gram negative bacteria. Luminescence intensity of glutathione capped QDs conjugated silver nanoparticles decreases with increasing concentration of silver nanoparticles in tune with the increasing zone of inhibition (antibiotic sensitivity). This is very important for making a fluorescence based detector to monitor antibiotic resistant bacteria’s.

K-Ras exists in two distinct structural conformations specific to binding of GDP and GTP nucleotides. The cycling between an inactive, GDP-bound state and an active, GTP-bound state is regulated by guanine nucleotide exchange factors and GTPase activating proteins, respectively. The activated form of K-Ras regulates cell proliferation, differentiation and survival by controlling several downstream signaling pathways. Oncogenic mutations that attenuate the GTPase activity of K-Ras result in accumulation of this key signaling protein in its hyperactivated state, leading to uncontrolled cellular proliferation and tumorogenesis. Mutations at position 12 are the most prevalent in K-Ras associated cancers, hence K-RasG12C has become a recent focus of research for therapeutic intervention. Here we report 1HN, 15N, and 13C backbone and 1H, 13C side-chain resonance assignments for the 19.3 kDa (aa 1–169) human K-Ras protein harboring an oncogenic G12C mutation in the active GppNHp-bound form (K-RasG12C-GppNHp), using heteronuclear, multidimensional NMR spectroscopy at 298K. Triple-resonance data assisted the assignments of the backbone 1H, 15N, and 13C resonances of 126 out of 165 non-proline residues. The vast majority of unassigned residues are exchange-broadened beyond detection on the NMR time scale and belong to the P-loop and two flexible Switch regions.

Thermal energy storage is an essential technology for using renewable energy to reduce building energy consumption. Among the various energy technologies, much attention has been paid to latent thermal energy storage system using phase change materials because of its large capacity of thermal energy. However, due to the low thermal conductivity of the phase change materials, the system has disadvantages at low charging and discharging rates. To address this issue, a new latent heat thermal energy storage system using a flexible and thin pouch is proposed. The effectively designed pouch arrangement and thin pouch shape provide better heat transfer performance. The real product is tested at various flow rates of heat transfer fluids and the thermal and fluid characteristics of the system are analyzed by the computational fluid dynamics model. As a result, the proposed system has 1.4 times larger amount of discharged energy than that of the water storage system. Moreover, the system can reduce charging, discharging, and total process times by 1.7, 2.5, and 2.2 times, respectively, compared with the conventional sphere capsule piling system.

Neural network-based algorithms provide a promising approach to jet classification problems, such as boosted top jet tagging. To date, NN-based top taggers demonstrated excellent performance in Monte Carlo studies. In this paper, we construct a top-jet tagger based on a Convolutional Neural Network (CNN), and apply it to parton-level boosted top samples, with and without an additional gluon in the final state. We show that the jet observable defined by the CNN obeys the canonical definition of infrared safety: it is unaffected by the presence of the extra gluon, as long as it is soft or collinear with one of the quarks. Our results indicate that the CNN tagger is robust with respect to possible mis-modeling of soft and collinear final-state radiation by Monte Carlo generators., Comment: 7 pages, 8 figures, final version to be published in JHEP

The magnetic properties of a ZnMnO diluted magnetic semiconductor isovalently doped with Mg and S have been successfully studied. ZnMnO alloys were prepared with different concentrations of magnesium and sulfur by using ultrasonic spray pyrolysis technique; additionally, the films were doped for free charge carriers by using nitrogen. For ZnMnO doped with 5% of Mg, the Curie temperature reached 104 K, and second-phase magnetic precipitates were observed with increasing Mg concentration. On the other hand, the sulfur doped ZnMnO showed an increased Curie temperature higher than room temperature due to increased number of holes which mediated the magnetic exchange interaction between magnetic ions.

We investigate the interplay between the enumerative geometry of Calabi-Yau fourfolds with fluxes and the modularity of elliptic genera in four-dimensional string theories. We argue that certain contributions to the elliptic genus are given by derivatives of modular or quasi-modular forms, which encode BPS invariants of Calabi-Yau or non-Calabi-Yau threefolds that are embedded in the given fourfold. As a result, the elliptic genus is only a quasi-Jacobi form, rather than a modular or quasi-modular one in the usual sense. This manifests itself as a holomorphic anomaly of the spectral flow symmetry, and in an elliptic holomorphic anomaly equation that maps between different flux sectors. We support our general considerations by a detailed study of examples, including non-critical strings in four dimensions. For the critical heterotic string, we explain how anomaly cancellation is restored due to the properties of the derivative sector. Essentially, while the modular sector of the elliptic genus takes care of anomaly cancellation involving the universal B-field, the quasi-Jacobi one accounts for additional B-fields that can be present. Thus once again, diverse mathematical ingredients, namely here the algebraic geometry of fourfolds, relative Gromow-Witten theory pertaining to flux backgrounds, and the modular properties of (quasi-)Jacobi forms, conspire in an intriguing manner precisely as required by stringy consistency., 90 pages, 4 figures; v2: minor comments added to match published version

We study quantum corrections in four-dimensional theories with $N=1$ supersymmetry in the context of Quantum Gravity Conjectures. According to the Emergent String Conjecture, infinite distance limits in quantum gravity either lead to decompactification of the theory or result in a weakly coupled string theory. We verify this conjecture in the framework of $N=1$ supersymmetric F-theory compactifications to four dimensions including perturbative $\alpha'$ as well as non-perturbative corrections. After proving uniqueness of the emergent critical string at the classical level, we show that quantum corrections obstruct precisely those limits in which the scale of the emergent critical string would lie parametrically below the Kaluza-Klein scale. Limits in which the tension of the asymptotically tensionless string sits at the Kaluza-Klein scale, by contrast, are not obstructed. In the second part of the paper we study the effect of quantum corrections for the Weak Gravity Conjecture away from the strict weak coupling limit. We propose that gauge threshold corrections and mass renormalisation effects modify the super-extremality bound in four dimensions. For the infinite distance limits in F-theory the classical super-extremality bound is generically satisfied by a sublattice of states in the tower of excitations of an emergent heterotic string. By matching the F-theory $\alpha'$ corrections to gauge threshold corrections of the dual heterotic theory we predict how the masses of this tower must be renormalised in order for the Weak Gravity Conjecture to hold at the quantum level., Comment: 75 pages, 7 figures; v2: references added, typos corrected, minor clarifications; v3: references added, version accepted for publication in JHEP

As a key regulator of its dual role in transcription and cell cycle progression, CDK7 has been determined to be an attractive therapeutic target in a variety of tumor types driven by cell cycle dysregulation and aberrant control of the transcriptional processes. Q901 is an irreversible small molecule inhibitor with extreme selectivity and potent inhibition activity for CDK7, which forms a covalent bond with C312 of the CDK7 C-terminal domain. Q901 demonstrated selective cytotoxic activities in a broad spectrum of solid tumor lineages. TP53 mutation could be a potential predictive marker for the Q901 response as TP53 wild-type cancer cells demonstrates a significantly increased cytotoxic response compared to TP53 mutant cells in the bioinformatic analysis. In addition, gene expression profiling analysis showed a dose-response increase of POLR2A expression upon Q901 treatment and a correlation with tumor growth inhibition rate, indicating that POLR2A might be a potential PD marker for the Q901-induced response. Taken together, these data support the clinical development of Q901 for solid tumor indications. Q901 is progressing to IND-enabling studies to support the start of Phase 1 oncology clinical trials in early 2022. Citation Format: Donghoon Yu, Yeejin Jeon, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam. Q901; a highly selective covalent cdk7 inhibitor inducing substantial anti-tumor effect in a broad spectrum of solid tumor lineages [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 2574.

The existing proteasome inhibitors, such as bortezomib and ixazomib, are effective in multiple myeloma, but have little activity against solid tumors. These are covalent boronic acid-based compounds and are associated with undesired side effects, mainly hematologic toxicity and peripheral neuropathy. A variety of improved covalent proteasome inhibitors have been developed, but lack of oral availability and low distribution in tumors make them ineffective in solid tumors. In addition, they still have a narrow therapeutic window due to unexpected adverse effects such as cardiac and pulmonary toxicity. We report a non-covalent and rapidly reversible proteasome inhibitor as a potential anti-cancer agent against solid tumors as well as multiple myeloma. These novel inhibitors, called QL compounds, are non-covalent chymotrypsin-like selective proteasome inhibitors that can be taken orally. They effectively inhibited tumor growth in multiple myeloma xenograft model without hematologic toxicity through improved PK properties, especially partition of compound between plasma and RBC. Moreover, this improved PK properties of the QL compounds allowed for sufficient distribution outside the blood compartment and induced tumor growth inhibition in some types of solid cancer xenograft models that were sensitive to proteasome inhibition. These results indicate that non-covalent and rapidly reversible proteasome inhibitors are an ideal strategy for multiple myeloma and potential agents for solid tumors. Citation Format: Won-Gyun Ahn, Yeejin Jeon, Yeong-In Yang, Jaeseung Kim, Seung-Joo Lee, Uwe Koch, Gunther Zischinsky, Axel Choidas, Ayesha Pasha, Bert Klebl, Robert Huber, Michael Hamacher, Kiyean Nam. A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers [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 416.

The T7 primase-helicase plays a pivotal role in the replication of T7 DNA. Using affinity isolation of peptide-nucleic acid crosslinks and mass spectrometry, we identify protein regions in the primase-helicase and T7 DNA polymerase that form contacts with the RNA primer and DNA template. The contacts between nucleic acids and the primase domain of the primase-helicase are centered in the RNA polymerase subdomain of the primase domain, in a cleft between the N-terminal subdomain and the topoisomerase-primase fold. We demonstrate that residues along a beta sheet in the N-terminal subdomain that contacts the RNA primer are essential for phage growth and primase activity in vitro. Surprisingly, we found mutations in the primase domain that had a dramatic effect on the helicase. Substitution of a residue conserved in other DnaG-like enzymes, R84A, abrogates both primase and helicase enzymatic activities of the T7 primase-helicase. Alterations in this residue also decrease binding of the primase-helicase to ssDNA. However, mass photometry measurements show that these mutations do not interfere with the ability of the protein to form the active hexamer.

The volatile compounds and sensory profiles of 18 different types of distilled soju, chosen with regard to various raw materials and distillation methods (atmospheric vs. vacuum), were explored using headspace solid-phase microextraction (HS-SPME) with gas chromatography-mass spectrometry (GC-MS) and descriptive analysis. General chemical properties such as pH, total acidity (TA), total soluble solids (°Brix), and lactic acid concentration were also determined. A total of 56 volatile compounds, comprising 31 esters, 11 alcohols, 1 acid, 4 aldehydes, 3 ketones, and 6 miscellaneous compounds, were identified. From the principal component analysis (PCA) of the volatile data, samples made using atmospheric distillation such as MSO and PJU showed a clear difference from decompressed distillation samples. Based on the PCA of the sensory data, there was also a clear distinction between samples by their distillation method. To explore relationships among chemical, volatile, and sensory data sets, multiple factor analysis (MFA) was applied. Yeasty and earthy flavors showed a close relationship with 1-nonanol, octatonic acid, and longer-chain esters such as ethyl phenylacetate and ethyl tetradecanoate, and with chemical parameters such as TA, °Brix, and lactic acid.

The Helicobacter pylori type IV secretion system (T4SS) encoded on the cag pathogenicity island (cagPAI) secretes the CagA oncoprotein and other effectors into the gastric epithelium. During murine infection, T4SS function is lost in an immune-dependent manner, typically as a result of in-frame recombination in the middle repeat region of cagY, though single nucleotide polymorphisms (SNPs) in cagY or in other essential genes may also occur. Loss of T4SS function also occurs in gerbils, nonhuman primates, and humans, suggesting that it is biologically relevant and not simply an artifact of the murine model. Here, we sought to identify physiologically relevant conditions under which T4SS function is maintained in the murine model. We found that loss of H. pylori T4SS function in mice was blunted by systemic Salmonella coinfection and completely eliminated by dietary iron restriction. Both have epidemiologic parallels in humans, since H. pylori strains from individuals in developing countries, where iron deficiency and systemic infections are common, are also more often cagPAI+ than strains from developed countries. These results have implications for our fundamental understanding of the cagPAI and also provide experimental tools that permit the study of T4SS function in the murine model. IMPORTANCE The type IV secretion system (T4SS) is the major Helicobacter pylori virulence factor, though its function is lost during murine infection. Loss of function also occurs in gerbils and in humans, suggesting that it is biologically relevant, but the conditions under which T4SS regulation occurs are unknown. Here, we found that systemic coinfection with Salmonella and iron deprivation each promote retention of T4SS function. These results improve our understanding of the cag pathogenicity island (cagPAI) and provide experimental tools that permit the study of T4SS function in the murine model.

We investigate holomorphic anomalies of partition functions underlying string compactifications on Calabi-Yau fourfolds with background fluxes. For elliptic fourfolds the partition functions have an alternative interpretation as elliptic genera of N=1 supersymmetric string theories in four dimensions, or as generating functions for relative Gromov-Witten invariants of fourfolds with fluxes. We derive the holomorphic anomaly equations by starting from the BCOV formalism of topological strings, and translating them into geometrical terms. The result can be recast into modular and elliptic anomaly equations. As a new feature, as compared to threefolds, we find an extra contribution which is given by a gravitational descendant invariant. This leads to linear terms in the anomaly equations, which support an algebra of derivatives mapping between partition functions of the various flux sectors. These geometric features are mirrored by certain properties of quasi-Jacobi forms. We also offer an interpretation of the physics from the viewpoint of the worldsheet theory., 67 pages, 4 figures; v2: Appendix E added, references added, typos corrected, matches published version

Volatile compositions and sensory characteristics of 11 commercially distilled soju samples were investigated using headspace solid-phase microextraction (HS-SPME) with gas chromatography-mass spectrometry (GC-MS) and sensory descriptive analysis. A total of 59 major volatile compounds, consisting of 32 esters, 10 alcohols, 2 acids, 5 aldehydes, 3 ketones, 1 hydrocarbon, 1 furan, 2 phenols, and 3 miscellaneous compounds, were identified. From the principal component analysis (PCA) of volatile data, MSJ made by atmospheric distillation showed a clear distinction in volatile compositions compared to that of other samples made by vacuum distillation. Based on PCA of the sensory data determined by a panel of ten judges, MSJ was associated with a large amount of longer chain esters that showed high intensities in bitter taste and yeast/nuruk-related flavor attributes. HYJ, LPJ, and HAJ made with rice as a raw material were associated with lower intensities of the alcohol aroma, while JRJ and OKJ aged in oak barrels were associated with fruit flavor, sweet flavor, and brandy aroma. In the partial least squares regression (PLSR) analysis to see any relationship between volatile and sensory data, longer chain esters like ethyl tetradecanoate, and ethyl hexadecanoate were highly associated with bleach aroma. In contrast, positive correlations were seen with barley aroma and yeast flavor with hexanal, nonanal, benzaldehyde, and 2-methoxy-phenol.

Volatile compositions and sensory characteristics of 11 commercially distilled soju samples were investigated using headspace solid-phase microextraction (HS-SPME) with gas chromatography-mass spectrometry (GC-MS) and sensory descriptive analysis. A total of 59 major volatile compounds, consisting of 32 esters, 10 alcohols, 2 acids, 5 aldehydes, 3 ketones, 1 hydrocarbon, 1 furan, 2 phenols, and 3 miscellaneous compounds, were identified. From the principal component analysis (PCA) of volatile data, MSJ made by atmospheric distillation showed a clear distinction in volatile compositions compared to that of other samples made by vacuum distillation. Based on PCA of the sensory data determined by a panel of ten judges, MSJ was associated with a large amount of longer chain esters that showed high intensities in bitter taste and yeast/nuruk-related flavor attributes. HYJ, LPJ, and HAJ made with rice as a raw material were associated with lower intensities of the alcohol aroma, while JRJ and OKJ aged in oak barrels were associated with fruit flavor, sweet flavor, and brandy aroma. In the partial least squares regression (PLSR) analysis to see any relationship between volatile and sensory data, longer chain esters like ethyl tetradecanoate, and ethyl hexadecanoate were highly associated with bleach aroma. In contrast, positive correlations were seen with barley aroma and yeast flavor with hexanal, nonanal, benzaldehyde, and 2-methoxy-phenol.

Significance This manuscript reports on a member of the FK506/rapamycin family, WDB002, and the realization that FKBP-mediated recognition is a genetically programmable modality that enables engagement of topologically flat targets. FKBP-mediated recognition is thus nature’s strategy for drugging the “undruggable.” The surface of FKBP engages three completely unrelated targets—calcineurin, MTOR, and CEP250—with high-target affinity and specificity, using different constellations of amino acid residues. Target specificity is determined solely by the “variable domain” of the bound small molecule alone, suggesting the modality might be generalizable to other undruggable targets through variable domain engineering. Finally, since WDB002 targets CEP250, it may be a promising starting point for developing a treatment for COVID-19., The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein–WDB002 and protein–protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise “undruggable” targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

Cytosine base editors (CBEs) enable efficient, programmable reversion of T•A to C•G point mutations in the human genome. Recently, cytosine base editors with rAPOBEC1 were reported to induce unguided cytosine deamination in genomic DNA and cellular RNA. Here we report eight next-generation CBEs (BE4 with either RrA3F [wt, F130L], AmAPOBEC1, SsAPOBEC3B [wt, R54Q], or PpAPOBEC1 [wt, H122A, R33A]) that display comparable DNA on-target editing frequencies, whilst eliciting a 12- to 69-fold reduction in C-to-U edits in the transcriptome, and up to a 45-fold overall reduction in unguided off-target DNA deamination relative to BE4 containing rAPOBEC1. Further, no enrichment of genome-wide C•G to T•A edits are observed in mammalian cells following transfection of mRNA encoding five of these next-generation editors. Taken together, these next-generation CBEs represent a collection of base editing tools for applications in which minimized off-target and high on-target activity are required., Cytosine base editors have been reported to induce off-target mutations in DNA and RNA. Here the authors identify next-generation CBEs with reduced guide-independent off-target editing profiles and retain high on-target editing activity.

/introductory paragraphCytosine base editors (CBEs) are molecular machines which enable efficient and programmable reversion of T•A to C•G point mutations in the human genome without induction of DNA double strand breaks1, 2. Recently, the foundational cytosine base editor (CBE) ‘BE3’, containing rAPOBEC1, was reported to induce unguided, genomic DNA3, 4 and cellular RNA5 cytosine deamination when expressed in living cells. To mitigate spurious off-target events, we developed a sensitive, high-throughput cellular assay to select next-generation CBEs that display reduced spurious deamination profiles relative to rAPOBEC1-based CBEs, whilst maintaining equivalent or superior on-target editing frequencies. We screened 153 CBEs containing cytidine deaminase enzymes with diverse sequences and identified four novel CBEs with the most promising on/off target ratios. These spurious-deamination-minimized CBEs (BE4 with either RrA3F, AmAPOBEC1, SsAPOBEC3B, or PpAPOBEC1) were further optimized for superior on- and off-target DNA editing profiles through structure-guided mutagenesis of the deaminase domain. These next-generation CBEs display comparable overall DNA on-target editing frequencies, whilst eliciting a 10- to 49-fold reduction in C-to-U edits in the transcriptome of treated cells, and up to a 33-fold overall reduction in unguided off-target DNA deamination relative to BE4 containing rAPOBEC1. Taken together, these next-generation CBEs represent a new collection of base editing tools for applications in which minimization of spurious deamination is desirable and high on-target activity is required.

We re-examine current and future constraints on a heavy dilaton coupled to a simple dark sector consisting of a Majorana fermion or a St\"uckelberg vector field. We include three different treatments of dilaton-Higgs mixing, paying particular attention to a gauge-invariant formulation of the model. Moreover, we also invite readers to re-examine effective field theories of vector dark matter, which we show are missing important terms. Along with the latest Higgs coupling data, heavy scalar search results, and dark matter density/direct detection constraints, we study the LHC bounds on the model and estimate the prospects of dark matter production at the future HL-LHC and 100 TeV FCC colliders. We additionally compute novel perturbative unitarity constraints involving vector dark matter, dilaton and gluon scattering., Comment: 18 pages, 10 figures

Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair., DNA glycosylases are lesion-specific enzymes that recognize specific nucleobase damages and catalyze their excision through cleavage of the glycosidic bond. Here, the authors present the crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase bound to undamaged DNA and to DNA containing an intrahelical oxoG lesion and further analyse these structures with molecular dynamics simulations, which allows them to characterise the base-extrusion pathways.