Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides.

Emerging data have shown that previously defined noncoding genomes might encode peptides that bind human leukocyte antigen (HLA) as cryptic antigens to stimulate adaptive immunity1,2. However, the significance and mechanisms of action of cryptic antigens in anti-tumour immunity remain unclear. Here mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I-binding cryptic antigenic peptides that were noncanonically translated by a tumour-specific circular RNA (circRNA): circFAM53B. The cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen-specific cytotoxic T cells, which led to effective tumour control. Overall, our findings reveal that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.

Strong yet ductile nanolamellar high-entropy alloys by additive manufacturing.

Additive manufacturing produces net-shaped components layer by layer for engineering applications1-7. The additive manufacture of metal alloys by laser powder bed fusion (L-PBF) involves large temperature gradients and rapid cooling2,6, which enables microstructural refinement at the nanoscale to achieve high strength. However, high-strength nanostructured alloys produced by laser additive manufacturing often have limited ductility3. Here we use L-PBF to print dual-phase nanolamellar high-entropy alloys (HEAs) of AlCoCrFeNi2.1 that exhibit a combination of a high yield strength of about 1.3 gigapascals and a large uniform elongation of about 14 per cent, which surpasses those of other state-of-the-art additively manufactured metal alloys. The high yield strength stems from the strong strengthening effects of the dual-phase structures that consist of alternating face-centred cubic and body-centred cubic nanolamellae; the body-centred cubic nanolamellae exhibit higher strengths and higher hardening rates than the face-centred cubic nanolamellae. The large tensile ductility arises owing to the high work-hardening capability of the as-printed hierarchical microstructures in the form of dual-phase nanolamellae embedded in microscale eutectic colonies, which have nearly random orientations to promote isotropic mechanical properties. The mechanistic insights into the deformation behaviour of additively manufactured HEAs have broad implications for the development of hierarchical, dual- and multi-phase, nanostructured alloys with exceptional mechanical properties.

Low glycaemic diets alter lipid metabolism to influence tumour growth.

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.

KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas.

Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.

Tuning element distribution, structure and properties by composition in high-entropy alloys.

High-entropy alloys are a class of materials that contain five or more elements in near-equiatomic proportions1,2. Their unconventional compositions and chemical structures hold promise for achieving unprecedented combinations of mechanical properties3-8. Rational design of such alloys hinges on an understanding of the composition-structure-property relationships in a near-infinite compositional space9,10. Here we use atomic-resolution chemical mapping to reveal the element distribution of the widely studied face-centred cubic CrMnFeCoNi Cantor alloy2 and of a new face-centred cubic alloy, CrFeCoNiPd. In the Cantor alloy, the distribution of the five constituent elements is relatively random and uniform. By contrast, in the CrFeCoNiPd alloy, in which the palladium atoms have a markedly different atomic size and electronegativity from the other elements, the homogeneity decreases considerably; all five elements tend to show greater aggregation, with a wavelength of incipient concentration waves11,12 as small as 1 to 3 nanometres. The resulting nanoscale alternating tensile and compressive strain fields lead to considerable resistance to dislocation glide. In situ transmission electron microscopy during straining experiments reveals massive dislocation cross-slip from the early stage of plastic deformation, resulting in strong dislocation interactions between multiple slip systems. These deformation mechanisms in the CrFeCoNiPd alloy, which differ markedly from those in the Cantor alloy and other face-centred cubic high-entropy alloys, are promoted by pronounced fluctuations in composition and an increase in stacking-fault energy, leading to higher yield strength without compromising strain hardening and tensile ductility. Mapping atomic-scale element distributions opens opportunities for understanding chemical structures and thus providing a basis for tuning composition and atomic configurations to obtain outstanding mechanical properties.

CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to prevent DNA hypermethylation and ensure normal transcription in growing oocytes.

The DNA methylation is gradually acquired during oogenesis, a process sustained by successful follicle development. However, the functional roles of methyl-CpG-binding protein 2 (MeCP2), an epigenetic regulator displaying specifical binding with methylated DNA, remains unknown in oogenesis. In this study, we found MeCP2 protein was highly expressed in primordial and primary follicle, but was almost undetectable in secondary follicles. However, in aged ovary, MeCP2 protein is significantly increased in both oocyte and granulosa cells. Overexpression of MeCP2 in growing oocyte caused transcription dysregulation, DNA hypermethylation, and genome instability, ultimately leading to follicle growth arrest and apoptosis. MeCP2 is targeted by DCAF13, a substrate recognition adaptor of the Cullin 4-RING (CRL4) E3 ligase, and polyubiquitinated for degradation in both cells and oocytes. Dcaf13-null oocyte exhibited an accumulation of MeCP2 protein, and the partial rescue of follicle growth arrest induced by Dcaf13 deletion was observed following MeCP2 knockdown. The RNA-seq results revealed that large amounts of genes were regulated by the DCAF13-MeCP2 axis in growing oocytes. Our study demonstrated that CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to ensure normal DNA methylome and transcription in growing oocytes. Moreover, in aged ovarian follicles, deceased DCAF13 and DDB1 protein were observed, indicating a potential novel mechanism that regulates ovary aging.

RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications.

RNA modification is a dynamic and reversible process regulated by a series of writers, erasers and readers (WERs). Abnormal changes of WERs will disrupt the RNA modification homeostasis of their target genes, leading to the dysregulation of RNA metabolisms such as RNA stability and translation, and consequently to diseases such as cancer. A public repository hosting the regulatory relationships between WERs and their target genes will help in understanding the roles of RNA modifications in various physiological and pathological conditions. Previously, we developed a database named 'm6A2Target' to host targets of WERs in m6A, one of the most prevalent RNA modifications in eukaryotic cells. To host all RNA modification (RM)-related WER-target associations, we hereby present an updated database, named 'RM2Target' (http://rm2target.canceromics.org/). In this update, RM2Target encompasses 1 619 653 WER-target associations for nine RNA modifications in human and mouse, including m6A, m6Am, m5C, m5U, m1A, m7G, pseudouridine, 2'-O-Me and A-to-I. Extensive annotations of target genes are available in RM2Target, including but not limited to basic gene information, RNA modifications, RNA-RNA/RNA-protein interactions and related diseases. Altogether, we expect that RM2Target will facilitate further downstream functional and mechanistic studies in the field of RNA modification research.

Unraveling the origin of extra strengthening in gradient nanotwinned metals.

Materials containing heterogeneous nanostructures hold great promise for achieving superior mechanical properties. However, the strengthening effect due to plastically inhomogeneous deformation in heterogeneous nanostructures has not been clearly understood. Here, we investigate a prototypical heterogeneous nanostructured material of gradient nanotwinned (GNT) Cu to unravel the origin of its extra strength arising from gradient nanotwin structures relative to uniform nanotwin counterparts. We measure the back and effective stresses of GNT Cu with different nanotwin thickness gradients and compare them with those of homogeneous nanotwinned Cu with different uniform nanotwin thicknesses. We find that the extra strength of GNT Cu is caused predominantly by the extra back stress resulting from nanotwin thickness gradient, while the effective stress is almost independent of the gradient structures. The combined experiment and strain gradient plasticity modeling show that an increasing structural gradient in GNT Cu produces an increasing plastic strain gradient, thereby raising the extra back stress. The plastic strain gradient is accommodated by the accumulation of geometrically necessary dislocations inside an unusual type of heterogeneous dislocation structure in the form of bundles of concentrated dislocations. Such a heterogeneous dislocation structure produces microscale internal stresses leading to the extra back stress in GNT Cu. Altogether, this work establishes a fundamental connection between the gradient structure and extra strength in GNT Cu through the mechanistic linkages of plastic strain gradient, heterogeneous dislocation structure, microscale internal stress, and extra back stress. Broadly, this work exemplifies a general approach to unraveling the strengthening mechanisms in heterogeneous nanostructured materials.

Synergistic Biofilter Tube for Promoting Scarless Tendon Regeneration.

Inspired by the imbalance between extrinsic and intrinsic tendon healing, this study fabricated a new biofilter scaffold with a hierarchical structure based on a melt electrowriting technique. The outer multilayered fibrous structure with connected porous characteristics provides a novel passageway for vascularization and isolates the penetration of scar fibers, which can be referred to as a biofilter process. In vitro experiments found that the porous architecture in the outer layer can effectively prevent cell infiltration, whereas the aligned fibers in the inner layer can promote cell recruitment and growth, as well as the expression of tendon-associated proteins in a simulated friction condition. It was shown in vivo that the biofilter process could promote tendon healing and reduce scar invasion. Herein, this novel strategy indicates great potential to design new biomaterials for balancing extrinsic and intrinsic healing and realizing scarless tendon healing.

Enhanced NMDA receptor pathway and glutamate transmission in the hippocampal dentate gyrus mediate the spatial learning and memory impairment of obese rats.

Obesity has been linked with the impairment of spatial memory and synaptic plasticity but the molecular mechanisms remained unidentified. Since glutamatergic transmission and NMDA receptor neural pathways in hippocampal dentate gyrus (DG) are essential in the learning and memory, we aimed to investigate glutamate (Glu) and NMDA receptor signaling of DG in spatial learning and memory in diet-induced obesity (DIO) rats. Spatial learning and memory were assessed via Morris water maze (MWM) test on control (Ctr) and DIO rats. Extracellular concentration of Glu in the DG was determined using in vivo microdialysis and HPLC. The protein expressions of NMDA receptor subunit 2B (NR2B), brain-derived neurotrophic factor (BDNF), the activation of calcium/calmodulin-dependent kinase II (CaMKII) and cAMP-response-element-binding protein (CREB) in the DG were observed by western blot. Spatial learning and memory were impaired in DIO rats compared to those of Ctr. NR2B expression was increased, while BDNF expression and CaMKII and CREB activation were decreased in DG of DIO rats. Extracellular concentration of Glu was increased in Ctr on the 3rd and 4th days of the MWM test, but significant further increment was observed in DIO rats. Microinjection of an NMDA antagonist (MK-801) into the DG reversed spatial learning and memory impairment. Such effects were accompanied by greater BDNF expression and CaMKII/CREB activation in the DG of DIO rats. In conclusion, the enhancement of Glu-NMDA receptor transmission in the hippocampal DG contributes to the impairment of spatial learning and memory in DIO rats, maybe via the modulation of CaMKII-CREB-BDNF signaling pathway.

Metal-Free Heterogeneous Asymmetric Hydrogenation of Olefins Promoted by Chiral Frustrated Lewis Pair Framework.

The development of metal-free and recyclable catalysts for significant yet challenging transformations of naturally abundant feedstocks has long been sought after. In this work, we contribute a general strategy of combining the rationally designed crystalline covalent organic framework (COF) with a newly developed chiral frustrated Lewis pair (CFLP) to afford chiral frustrated Lewis pair framework (CFLPF), which can efficiently promote the asymmetric olefin hydrogenation in a heterogeneous manner, outperforming the homogeneous CFLP counterpart. Notably, the metal-free CFLPF exhibits superior activity/enantioselectivity in addition to excellent stability/recyclability. A series of in situ spectroscopic studies, kinetic isotope effect measurements, and density-functional theory computational calculations were also performed to gain an insightful understanding of the superior asymmetric hydrogenation catalysis performances of CFLPF. Our work not only increases the versatility of catalysts for asymmetric catalysis but also broadens the reactivity of porous organic materials with the addition of frustrated Lewis pair (FLP) chemistry, thereby suggesting a new approach for practical and substantial transformations through the advancement of novel catalysts from both concept and design perspectives.

Residual Immunity from Smallpox Vaccination and Possible Protection from Mpox, China.

Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China.

The transcriptional regulatory module CsHB5-CsbZIP44 positively regulates abscisic acid-mediated carotenoid biosynthesis in citrus (Citrus spp.).

Carotenoids contribute to fruit coloration and are valuable sources of provitamin A in the human diet. Abscisic acid (ABA) plays an essential role in fruit coloration during citrus fruit ripening, but little is known about the underlying mechanisms. Here, we identified a novel bZIP transcription activator called CsbZIP44, which serves as a central regulator of ABA-mediated citrus carotenoid biosynthesis. CsbZIP44 directly binds to the promoters of four carotenoid metabolism-related genes (CsDXR, CsGGPPs, CsBCH1 and CsNCED2) and activates their expression. Furthermore, our research indicates that CsHB5, a positive regulator of ABA and carotenoid-driven processes, activates the expression of CsbZIP44 by binding to its promoter. Additionally, CsHB5 interacts with CsbZIP44 to form a transcriptional regulatory module CsHB5-CsbZIP44, which is responsive to ABA induction and promotes carotenoid accumulation in citrus. Interestingly, we also discover a positive feedback regulation loop between the ABA signal and carotenoid biosynthesis mediated by the CsHB5-CsbZIP44 transcriptional regulatory module. Our findings show that CsHB5-CsbZIP44 precisely modulates ABA signal-mediated carotenoid metabolism, providing an effective strategy for quality improvement of citrus fruit and other crops.

Myelin oligodendrocyte glycoprotein antibody and N-methyl-d-aspartate receptor antibody overlapping syndrome: insights from the recent case reports.

The overlapping of two or more types of neural autoantibodies in one patient has increasingly been documented in recent years. The coexistence of myelin oligodendrocyte glycoprotein (MOG) and N-methyl-d-aspartate receptor (NMDAR) antibodies is most common, which leads to a unique condition known as the MOG antibody and NMDAR antibody overlapping syndrome (MNOS). Here, we have reviewed the pathogenesis, clinical manifestations, paraclinical features, and treatment of MNOS. Forty-nine patients with MNOS were included in this study. They were young males with a median onset age of 23 years. No tumors were observed in the patients, and 24 of them reported prodromal symptoms. The most common clinical presentations were psychiatric symptoms (35/49) and seizures (25/49). Abnormalities on magnetic resonance imaging involved the brainstem (11/49), cerebellum (9/49), and parietal lobe (9/49). Most patients mostly responded to immunotherapy and had a good long-term prognosis. However, the overall recurrence rate of MNOS was higher than that of mono antibody-positive diseases. The existence of concurrent NMDAR antibodies should be suspected in patients with MOG antibody-associated disease having psychiatric symptoms, seizures, movement disorders, or autonomic dysfunction. Similarly, serum MOG antibody testing should be performed when patients with anti-NMDAR encephalitis present with atypical clinical manifestations, such as visual impairment and limb weakness, and neuroradiological findings, such as optic nerve, spinal cord, or infratentorial involvement or meningeal enhancement. Early detection of the syndrome and prompt treatment can be beneficial for these patients, and maintenance immunosuppressive therapy is recommended due to the high overall recurrence rate of the syndrome.

Quantitative tests revealing hydrogen-enhanced dislocation motion in α-iron.

Hydrogen embrittlement jeopardizes the use of high-strength steels in critical load-bearing applications. However, uncertainty regarding how hydrogen affects dislocation motion, owing to the lack of quantitative experimental evidence, hinders our understanding of hydrogen embrittlement. Here, by studying the well-controlled, cyclic, bow-out motions of individual screw dislocations in α-iron, we find that the critical stress for initiating dislocation motion in a 2 Pa electron-beam-excited H2 atmosphere is 27-43% lower than that in a vacuum environment, proving that hydrogen enhances screw dislocation motion. Moreover, we find that aside from vacuum degassing, cyclic loading and unloading facilitates the de-trapping of hydrogen, allowing the dislocation to regain its hydrogen-free behaviour. These findings at the individual dislocation level can inform hydrogen embrittlement modelling and guide the design of hydrogen-resistant steels.

Effects of the stress hyperglycemia ratio on long-term mortality in patients with triple-vessel disease and acute coronary syndrome.

AIMS: Risk assessment for triple-vessel disease (TVD) remain challenging. Stress hyperglycemia represents the regulation of glucose metabolism in response to stress, and stress hyperglycemia ratio (SHR) is recently found to reflect true acute hyperglycemic status. This study aimed to evaluate the prognostic value of SHR and its role in risk stratification in TVD patients with acute coronary syndrome (ACS). METHODS: A total of 3812 TVD patients with ACS with available baseline SHR measurement were enrolled from two independent centers. The endpoint was cardiovascular mortality. Cox regression was used to evaluate the association between SHR and cardiovascular mortality. The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) II (SSII) was used as the reference model in the model improvement analysis. RESULTS: During a median follow-up of 5.1 years, 219 (5.8%) TVD patients with ACS suffered cardiovascular mortality. TVD patients with ACS with high SHR had an increased risk of cardiovascular mortality after robust adjustment for confounding (high vs. median SHR: adjusted hazard ratio 1.809, 95% confidence interval 1.160-2.822, P = 0.009), which was fitted as a J-shaped pattern. The prognostic value of the SHR was found exclusively among patients with diabetes instead of those without diabetes. Moreover, addition of SHR improved the reclassification abilities of the SSII model for predicting cardiovascular mortality in TVD patients with ACS. CONCLUSIONS: The high level of SHR is associated with the long-term risk of cardiovascular mortality in TVD patients with ACS, and is confirmed to have incremental prediction value beyond standard SSII. Assessment of SHR may help to improve the risk stratification strategy in TVD patients who are under acute stress.

Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance.

PURPOSE: Consensus on the choice of the most accurate imaging strategy in diabetic foot infective and non-infective complications is still lacking. This document provides evidence-based recommendations, aiming at defining which imaging modality should be preferred in different clinical settings. METHODS: This working group includes 8 nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), 3 radiologists and 3 clinicians (one diabetologist, one podiatrist and one infectious diseases specialist) selected for their expertise in diabetic foot. The latter members formulated some clinical questions that are not completely covered by current guidelines. These questions were converted into statements and addressed through a systematic analysis of available literature by using the PICO (Population/Problem-Intervention/Indicator-Comparator-Outcome) strategy. Each consensus statement was scored for level of evidence and for recommendation grade, according to the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. RESULTS: Nine clinical questions were formulated by clinicians and used to provide 7 evidence-based recommendations: (1) A patient with a positive probe-to-bone test, positive plain X-rays and elevated ESR should be treated for presumptive osteomyelitis (OM). (2) Advanced imaging with MRI and WBC scintigraphy, or [18F]FDG PET/CT, should be considered when it is needed to better evaluate the location, extent or severity of the infection, in order to plan more tailored treatment. (3) In a patient with suspected OM, positive PTB test but negative plain X-rays, advanced imaging with MRI or WBC scintigraphy + SPECT/CT, or with [18F]FDG PET/CT, is needed to accurately assess the extent of the infection. (4) There are no evidence-based data to definitively prefer one imaging modality over the others for detecting OM or STI in fore- mid- and hind-foot. MRI is generally the first advanced imaging modality to be performed. In case of equivocal results, radiolabelled WBC imaging or [18F]FDG PET/CT should be used to detect OM or STI. (5) MRI is the method of choice for diagnosing or excluding Charcot neuro-osteoarthropathy; [18F]FDG PET/CT can be used as an alternative. (6) If assessing whether a patient with a Charcot foot has a superimposed infection, however, WBC scintigraphy may be more accurate than [18F]FDG PET/CT in differentiating OM from Charcot arthropathy. (7) Whenever possible, microbiological or histological assessment should be performed to confirm the diagnosis. (8) Consider appealing to an additional imaging modality in a patient with persisting clinical suspicion of infection, but negative imaging. CONCLUSION: These practical recommendations highlight, and should assist clinicians in understanding, the role of imaging in the diagnostic workup of diabetic foot complications.

Protein Deceleration and Sequencing Using Si3N4-CNT Hybrid Nanopores.

Protein sequencing is crucial for understanding the complex mechanisms driving biological functions and is of utmost importance in molecular diagnostics and medication development. Nanopores have become an effective tool for single molecule sensing, however, the weak charge and non-uniform charge distribution of protein make capturing and sensing very challenging, which poses a significant obstacle to the development of nanopore-based protein sequencing. In this study, to facilitate capturing of the unfolded protein, highly charged peptide was employed in our simulations, we found that the velocity of unfolded peptide translocating through a hybrid nanopore composed of silicon nitride membrane and carbon nanotube is much slower compared to bare silicon nitride nanopore, it is due to the significant interaction between amino acids and the surface of carbon nanotube. Moreover, by introducing variations in the charge states at the boundaries of carbon nanotube nanopores, the competition and combination of the electrophoretic and electroosmotic flows through the nanopores could be controlled, we then successfully regulated the translocation velocity of unfolded proteins through the hybrid nanopores. The proposed hybrid nanopore effectively retards the translocation velocity of protein through it, facilitates the acquisition of ample information for accurate amino acid identification.

N-Indole-Substituted Imidazolylidene Pd-PEPPSI Precatalysts: Enhanced Performance with a 3,5-Diisopropyl-4-indolyl Moiety.

Pd-PEPPSI complexes of N-(4-indolyl)-N'-phenylimidazol-2-ylidene (IIn) ligands with a 5-isopropyl-4-indolyl moiety are synthesized and evaluated in heteroarene C-H arylation, Suzuki-Miyaura cross-coupling, and Buchwald-Hartwig amination reactions. The IIn-Pd complex bearing a 3,5-diisopropyl-4-indolyl substituent (C5) exhibits the best catalytic activity in this series and substantially outperforms commercial precatalyst PEPPSI-Pd-IPr. The results also suggest that the alkyl group at position 3 of the 4-indolyl moiety shows stronger impacts than that at position 5.

Unfolding of protein using MoS2/SnS2heterostructure for nanopore-based sequencing.

Protein sequencing is crucial for understanding the complex mechanisms driving biological functions. However, proteins are usually folded in their native state and the mechanism of fast protein conformation transitions still remains unclear, which make protein sequencing challenging. Molecular dynamics simulations with accurate force field are now able to observe the entire folding/unfolding process, providing valuable insights into protein folding mechanisms. Given that proteins can be unfolded, nanopore technology shows great potential for protein sequencing. In this study, we proposed to use MoS2/SnS2heterostructures to firstly unfold proteins and then detect them by a nanopore in the heterostructural membrane. All-atom molecular dynamics simulations performed in this work provided rich atomic-level information for a comprehensive understanding of protein unfolding process and mechanism on the MoS2/SnS2heterostructure, it was found that the strong binding of protein to SnS2nanostripe and hydrogen bond breaking were the main reasons for unfolding the protein on the heterostructure. After the protein was fully unfolded, it was restrained on the nanostripe because of the affinity of protein to the SnS2nanostripe. Thus by integrating the proposed unfolding technique with nanopore technology, detection of linear unfolded peptide was realized in this work, allowing for the identification of protein components, which is essential for sequencing proteins in the near future.