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The histone variant macroH2A is generally linked to transcriptionally inactive chromatin, but how macroH2A regulates chromatin structure and functions in the transcriptional process remains elusive. This study reveals that while the integration of human macroH2A1.2 into nucleosomes does not affect their stability or folding dynamics, it notably hinders the maintenance of facilitates chromatin transcription's (FACT's) function. We show that FACT effectively diminishes the stability of macroH2A1.2-nucleosomes and expedites their depletion subsequent to the initial unfolding process. Furthermore, we identify the residue S139 in macroH2A1.2 as a critical switch to modulate FACT's function in nucleosome maintenance. Genome-wide analyses demonstrate that FACT-mediated depletion of macroH2A-nucleosomes allows the correct localization of macroH2A, while the S139 mutation reshapes macroH2A distribution and influences stimulation-induced transcription and cellular response in macrophages. Our findings provide mechanistic insights into the intricate interplay between macroH2A and FACT at the nucleosome level and elucidate their collective role in transcriptional regulation and immune response of macrophages.
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Histonas , Nucleosomas , Transcripción Genética , Factores de Elongación Transcripcional , Humanos , Nucleosomas/metabolismo , Nucleosomas/genética , Histonas/metabolismo , Histonas/genética , Factores de Elongación Transcripcional/genética , Factores de Elongación Transcripcional/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Animales , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Macrófagos/metabolismo , Mutación , Ensamble y Desensamble de Cromatina , Ratones , Cromatina/metabolismo , Cromatina/genética , Regulación de la Expresión Génica , Células RAW 264.7 , Unión Proteica , Células HEK293RESUMEN
The high volatility of the price of cobalt and the geopolitical limitations of cobalt mining have made the elimination of Co a pressing need for the automotive industry1. Owing to their high energy density and low-cost advantages, high-Ni and low-Co or Co-free (zero-Co) layered cathodes have become the most promising cathodes for next-generation lithium-ion batteries2,3. However, current high-Ni cathode materials, without exception, suffer severely from their intrinsic thermal and chemo-mechanical instabilities and insufficient cycle life. Here, by using a new compositionally complex (high-entropy) doping strategy, we successfully fabricate a high-Ni, zero-Co layered cathode that has extremely high thermal and cycling stability. Combining X-ray diffraction, transmission electron microscopy and nanotomography, we find that the cathode exhibits nearly zero volumetric change over a wide electrochemical window, resulting in greatly reduced lattice defects and local strain-induced cracks. In-situ heating experiments reveal that the thermal stability of the new cathode is significantly improved, reaching the level of the ultra-stable NMC-532. Owing to the considerably increased thermal stability and the zero volumetric change, it exhibits greatly improved capacity retention. This work, by resolving the long-standing safety and stability concerns for high-Ni, zero-Co cathode materials, offers a commercially viable cathode for safe, long-life lithium-ion batteries and a universal strategy for suppressing strain and phase transformation in intercalation electrodes.
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Rechargeable lithium-ion batteries with high energy density that can be safely charged and discharged at high rates are desirable for electrified transportation and other applications1-3. However, the sub-optimal intercalation potentials of current anodes result in a trade-off between energy density, power and safety. Here we report that disordered rock salt4,5 Li3+xV2O5 can be used as a fast-charging anode that can reversibly cycle two lithium ions at an average voltage of about 0.6 volts versus a Li/Li+ reference electrode. The increased potential compared to graphite6,7 reduces the likelihood of lithium metal plating if proper charging controls are used, alleviating a major safety concern (short-circuiting related to Li dendrite growth). In addition, a lithium-ion battery with a disordered rock salt Li3V2O5 anode yields a cell voltage much higher than does a battery using a commercial fast-charging lithium titanate anode or other intercalation anode candidates (Li3VO4 and LiV0.5Ti0.5S2)8,9. Further, disordered rock salt Li3V2O5 can perform over 1,000 charge-discharge cycles with negligible capacity decay and exhibits exceptional rate capability, delivering over 40 per cent of its capacity in 20 seconds. We attribute the low voltage and high rate capability of disordered rock salt Li3V2O5 to a redistributive lithium intercalation mechanism with low energy barriers revealed via ab initio calculations. This low-potential, high-rate intercalation reaction can be used to identify other metal oxide anodes for fast-charging, long-life lithium-ion batteries.
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Hereditary hearing loss has a genetic and phenotypic heterogeneity. However, it is still difficult to explain this heterogeneity perfectly with known deafness genes. Here, we report a novel causative gene EPHA10 as well as its non-coding variant in 5' untranslated region identified in a family with post-lingual autosomal dominant non-syndromic hearing loss from southern China. One affected member of this family had an ideal hearing restoration after cochlear implantation. We speculated that there were probable deafness-causing abnormalities in the cochlea according to clinical imaging and auditory evaluations. A heterozygous variant c.-81_-73delinsAGC was found co-segregating with hearing loss. Epha10 was expressed in mouse cochlea at both transcription and translation levels. The variant caused upregulation of EPHA10 which may result from promoter activity enhancement after sequence change. Overexpression of Eph (the homolog of human EPHA10) exerted effects on the structure and function of chordotonal organ in fly model. In summary, our study linked pseudo-kinase EPHA10 to hearing loss in humans for the first time.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Animales , Ratones , Humanos , Regulación hacia Arriba , Regiones no Traducidas 5' , Mutación , Sordera/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Linaje , Receptores de la Familia Eph/genéticaRESUMEN
Unconventional 1T'-phase transition metal dichalcogenides (TMDs) have aroused tremendous research interest due to their unique phase-dependent physicochemical properties and applications. However, due to the metastable nature of 1T'-TMDs, the controlled synthesis of 1T'-TMD monolayers (MLs) with high phase purity and stability still remains a challenge. Here we report that 4H-Au nanowires (NWs), when used as templates, can induce the quasi-epitaxial growth of high-phase-purity and stable 1T'-TMD MLs, including WS2, WSe2, MoS2 and MoSe2, via a facile and rapid wet-chemical method. The as-synthesized 4H-Au@1T'-TMD core-shell NWs can be used for ultrasensitive surface-enhanced Raman scattering (SERS) detection. For instance, the 4H-Au@1T'-WS2 NWs have achieved attomole-level SERS detections of Rhodamine 6G and a variety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins. This work provides insights into the preparation of high-phase-purity and stable 1T'-TMD MLs on metal substrates or templates, showing great potential in various promising applications.
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Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.
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Fibrosis Pulmonar Idiopática , Macrófagos , Humanos , Ratones , Animales , Modelos Animales de Enfermedad , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/genética , Fibrosis , ADN , BleomicinaRESUMEN
Layered lithiated oxides are promising materials for next generation Li-ion battery cathode materials; however, instability during cycling results in poor performance over time compared to the high capacities theoretically possible with these materials. Here we report the characterizations of a Li1.47Mn0.57Al0.13Fe0.095Co0.105Ni0.095O2.49 high-entropy layered oxide (HELO) with the Li2MO3 structure where M = Mn, Al, Fe, Co, and Ni. Using electron microscopy and X-ray spectroscopy, we identify a homogeneous Li2MO3 structure stabilized by the entropic contribution of oxygen vacancies. This defect-driven entropy would not be attainable in the LiMO2 structure sometimes observed in similar materials as a secondary phase owing to the presence of fewer O sites and a 3+ oxidation state for the metal site; instead, a Li2-γMO3-δ is produced. Beyond Li2MO3, this defect-driven entropy approach to stabilizing novel compositions and phases can be applied to a wide array of future cathode materials including spinel and rock salt structures.
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Fusion of transmitter-containing vesicles with plasma membranes at the synaptic and neuromuscular junctions mediates neurotransmission and muscle contractions, respectively, thereby underlying all thoughts and actions. The fusion process is driven by the coupled folding and assembly of three synaptic SNARE proteins--syntaxin-1 and SNAP-25 on the target plasma membrane (t-SNAREs) and VAMP2 on the vesicular membrane (v-SNARE) into a four-helix bundle. Their assembly is chaperoned by Munc18-1 and many other proteins to achieve the speed and accuracy required for neurotransmission. However, the physiological pathway of SNARE assembly and its coupling to membrane fusion remains unclear. Here, we review recent progress in understanding SNARE assembly and membrane fusion, with a focus on results obtained by single-molecule manipulation approaches and electric recordings of single fusion pores. We describe two pathways of synaptic SNARE assembly, their associated intermediates, energetics, and kinetics. Assembly of the three SNAREs in vitro begins with the formation of a t-SNARE binary complex, on which VAMP2 folds in a stepwise zipper-like fashion. Munc18-1 significantly alters the SNARE assembly pathway: syntaxin-1 and VAMP2 first bind on the surface of Munc18-1 to form a template complex, with which SNAP-25 associates to conclude SNARE assembly and displace Munc18-1. During membrane fusion, multiple trans-SNARE complexes cooperate to open a dynamic fusion pore in a manner dependent upon their copy number and zippering states. Together, these results demonstrate that stepwise and cooperative SNARE assembly drive stagewise membrane fusion.
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Fusión de Membrana , Proteínas SNARE , Cinética , Fusión de Membrana/fisiología , Proteínas Munc18/química , Proteínas Munc18/genética , Proteínas Munc18/metabolismo , Proteínas Qa-SNARE , Proteínas SNARE/química , Proteínas SNARE/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/genética , Proteína 2 de Membrana Asociada a Vesículas/metabolismoRESUMEN
Pollen development is critical to plant reproduction, but the underlying regulatory molecular mechanisms have not been fully elucidated. The Arabidopsis (Arabidopsis thaliana) EFR3 OF PLANT 3 (EFOP3) and EFR3 OF PLANT 4 (EFOP4) genes encode members of the Armadillo (ARM) repeat superfamily that play key roles in pollen development. Herein, we demonstrate that EFOP3 and EFOP4 are co-expressed in pollen at anther stages 10-12, but loss-of-function of both EFOP3 and EFOP4 leads to male gametophyte sterility, irregular intine, and shriveled pollen grains at anther stage 12. We further established that full-length EFOP3 and EFOP4 specifically localize to the plasma membrane, and the integrity of these proteins is essential for pollen development. We observed uneven intine, less organized cellulose and reduced pectin content in mutant pollen compared with the wild-type. These, together with the misexpression of several genes related to cell wall metabolism in efop3-/- efop4+/- mutants, suggest that EFOP3 and EFOP4 may indirectly regulate the expression of these genes to affect intine formation, thus controlling Arabidopsis pollen fertility in a functionally redundant manner. Moreover, transcriptome analysis showed that the absence of EFOP3 and EFOP4 function affects multiple pollen development pathways. These results enhance our understanding of EFOPs proteins and their role in pollen development.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Polen , Fertilidad , Reproducción/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
BACKGROUND: Iron status has been associated with functional outcomes after ischemic stroke (IS). Nonetheless, this association may be affected by confounders. We perform Mendelian randomization to clarify the causal association between iron status and functional outcome after IS. METHODS: We obtained summary-level statistics related to iron status biomarkers from a meta-analysis of a gene-wide association study conducted by the Genetics of Iron Status Consortium, which included 11 discovery cohorts and 8 replication cohorts. We also took genetic variants related to 4 biomarkers of iron status from combining gene-wide association study results of Iceland, the United Kingdom, and Denmark to perform a replicate Mendelian randomization analysis. This data set included 4 iron status biomarkers, namely, ferritin, total iron binding capacity, iron, and transferrin saturation (TSAT). The confounders in these data sets have been adjusted to mitigate the collider bias. We acquired summary statistics data sets for functional outcomes following IS from the gene-wide association study meta-analysis conducted by the Genetics of Ischemic Stroke Functional Outcome Consortium. The genetic estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Scale score, including 3741 cases with good functional outcomes (modified Rankin Scale score, 0-2) and 2280 subjects with poor functional outcomes poststroke (modified Rankin Scale score, 3-6). Inverse variance weighting was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Reported with odds ratios (ORs) of stroke outcome with per SD unit increase in genetically determined iron status biomarker, TSAT and iron were associated with poor functional outcome after IS (TSAT: OR, 1.36 [95% CI, 1.23-1.50]; P=2.27×10-9; iron: OR, 1.44 [95% CI, 1.13-1.85]; P=0.0033). In replicate Mendelian randomization analysis, the detrimental effects of iron on poor functional outcome after IS remained stable (OR, 1.60 [95% CI, 1.24-2.08]; P=0.0003). In the meta-analysis, iron and TSAT were associated with poor functional outcomes after IS (TSAT: ORmeta, 1.35 [95% CI, 1.23-1.48]; iron: ORmeta, 1.51 [95% CI, 1.27-1.81]). Through sensitivity analyses and reverse Mendelian randomization analyses, we confirmed the robustness of the results. CONCLUSIONS: Our study provides evidence suggesting a potential causal relationship between iron status and poor functional outcomes after IS. Future studies are required to illuminate the underlying mechanism.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Hierro , Ferritinas , Causalidad , Accidente Cerebrovascular/genética , Biomarcadores , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The development of Pt-based catalysts for use in fuel cells that meet performance targets of high activity, maximized stability, and low cost remains a huge challenge. Herein, we report a nitrogen (N)-doped high-entropy alloy (HEA) electrocatalyst that consists of a Pt-rich shell and a N-doped PtCoFeNiCu core on a carbon support (denoted as N-Pt/HEA/C). The N-Pt/HEA/C catalyst showed a high mass activity of 1.34 A mgPt-1 at 0.9 V for the oxygen reduction reaction (ORR) in rotating disk electrode (RDE) testing, which substantially outperformed commercial Pt/C and most of the other binary/ternary Pt-based catalysts. The N-Pt/HEA/C catalyst also demonstrated excellent stability in both RDE and membrane electrode assembly (MEA) testing. Using operando X-ray absorption spectroscopy (XAS) measurements and theoretical calculations, we revealed that the enhanced ORR activity of N-Pt/HEA/C originated from the optimized adsorption energy of intermediates, resulting in the tailored electronic structure formed upon N-doping. Furthermore, we showed that the multiple metal-nitrogen bonds formed synergistically improved the corrosion resistance of the 3d transition metals and enhanced the ORR durability.
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Alkali metal-based metal-organic frameworks (MOFs) with permanent porosity are scarce because of their high tendency to coordinate with solvents such as water. However, these MOFs are lightweight and bear gravimetric benefits for gas adsorption related applications. In this study, we present the successful construction of a microporous MOF, designated as HIAM-111, built solely on sodium ions by using an octacarboxylate linker. The structure of HIAM-111 is based on 8-connected Na4 clusters and exhibits a novel topology with an underlying 32,42,8-c net. Remarkably, HAM-111 possesses a robust and highly porous framework with a BET surface area of 1561 m2/g, significantly surpassing that of the previously reported Na-MOFs. Further investigations demonstrate that HIAM-111 is capable of separating C2H2/CO2 and purifying C2H4 directly from C2H4/C2H2/C2H6 with high adsorption capacities. The current work may shed light on the rational design of robust and porous MOFs based on alkali metals.
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Electrochemical synthesis of ammonia via the nitrate reduction reaction (NO3RR) has been intensively researched as an alternative to the traditional Haber-Bosch process. Most research focuses on the low concentration range representative of the nitrate level in wastewater, leaving the high concentration range, which exists in nuclear and fertilizer wastes, unexplored. The use of a concentrated electrolyte (≥1 M) for higher rate production is hampered by poor hydrogen transfer kinetics. Herein, we demonstrate that a cocatalytic system of Ru/Cu2O catalyst enables NO3RR at 10.0 A in 1 M nitrate electrolyte in a 16 cm2 flow electrolyzer, with 100% faradaic efficiency toward ammonia. Detailed mechanistic studies by deuterium labeling and operando Fourier transform infrared (FTIR) spectroscopy allow us to probe the hydrogen transfer rate and intermediate species on Ru/Cu2O. Ab initio molecular dynamics (AIMD) simulations reveal that adsorbed hydroxide on Ru nanoparticles increases the density of the hydrogen-bonded water network near the Cu2O surface, which promotes the hydrogen transfer rate. Our work highlights the importance of engineering synergistic interactions in cocatalysts for addressing the kinetic bottleneck in electrosynthesis.
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BACKGROUND: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. METHODS: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. FINDINGS: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). INTERPRETATION: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. FUNDING: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.
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Hipotensión , Paquetes de Atención al Paciente , Humanos , Adolescente , Adulto , Presión Sanguínea , Resultado del Tratamiento , Hemorragia Cerebral/tratamiento farmacológico , Cuidados Críticos , Anticoagulantes/uso terapéuticoRESUMEN
Amino acid homeostasis is interconnected with the immune network of plants. During plant-pathogen interaction, amino acid transporters (AATs) have been shown to be involved in plant immune responses. However, the molecular mechanism by which how AATs function in this process remains elusive. In this study, we identify OsMP1 that acts as a quantitative trait locus against blast fungus from a joint analysis of GWAS and QTL mapping in rice. Heterogeneous expression of OsMP1 in yeast supports its function in transporting a wide range of amino acids, including Thr, Ser, Phe, His and Glu. OsMP1 could also mediate 15N-Glu efflux and influx in Xenopus oocyte cells. The expression of OsMP1 is dramatically induced by Magnaporthe oryzae in the resistant landrace Heikezijing, while remaining unresponsive in the susceptible landrace Suyunuo. Overexpressing OsMP1 in Suyunuo enhances disease resistance to blast fungus and leaf-blight bacterium without yield penalty. Furthermore, the overexpression of OsMP1 leads to increased accumulation of Thr, Ser, Phe and His in the leaves. And the heightened levels of these amino acids contribute to reduced disease susceptibility, which is associated with upregulated jasmonic acid pathway. Thus, our results elucidate the pivotal role of OsMP1 in disease resistance and provide a potential target for breeding more resistant rice cultivars without compromising yield.
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Fast and high-fidelity qubit initialization is crucial for low-frequency qubits such as fluxonium, and in applications of many quantum algorithms and quantum error correction codes. In a circuit quantum electrodynamics system, the initialization is typically achieved by transferring the state between the qubit and a short-lived cavity through microwave driving, also known as the sideband cooling process in atomic system. Constrained by the selection rules from the parity symmetry of the wave functions, the sideband transitions are only enabled by multiphoton processes which require multitone or strong driving. Leveraging the flux tunability of fluxonium, we circumvent this limitation by breaking flux symmetry to enable an interaction between a noncomputational qubit transition and the cavity excitation. With single-tone sideband driving, we realize qubit initialization with a fidelity exceeding 99% within a duration of 300 ns, robust against the variation of control parameters. Furthermore, we show that our initialization scheme has a built-in benefit in simultaneously removing the second-excited state population of the qubit, and can be easily incorporated into a large-scale fluxonium processor.
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The fluxonium qubits have emerged as a promising platform for gate-based quantum information processing. However, their extraordinary protection against charge fluctuations comes at a cost: when coupled capacitively, the qubit-qubit interactions are restricted to XX interactions. Consequently, effective ZZ or XZ interactions are only constructed either by temporarily populating higher-energy states, or by exploiting perturbative effects under microwave driving. Instead, we propose and demonstrate an inductive coupling scheme, which offers a wide selection of native qubit-qubit interactions for fluxonium. In particular, we leverage a built-in, flux-controlled ZZ interaction to perform qubit entanglement. To combat the increased flux-noise-induced dephasing away from the flux-insensitive position, we use a continuous version of the dynamical decoupling scheme to perform noise filtering. Combining these, we demonstrate a 20 ns controlled-z gate with a mean fidelity of 99.53%. More than confirming the efficacy of our gate scheme, this high-fidelity result also reveals a promising but rarely explored parameter space uniquely suitable for gate operations between fluxonium qubits.
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Extended synaptotagmins (E-Syts) mediate lipid exchange between the endoplasmic reticulum (ER) and the plasma membrane (PM). Anchored on the ER, E-Syts bind the PM via an array of C2 domains in a Ca2+- and lipid-dependent manner, drawing the two membranes close to facilitate lipid exchange. How these C2 domains bind the PM and regulate the ER-PM distance is not well understood. Here, we applied optical tweezers to dissect PM binding by E-Syt1 and E-Syt2. We detected Ca2+- and lipid-dependent membrane-binding kinetics of both E-Syts and determined the binding energies and rates of individual C2 domains or pairs. We incorporated these parameters in a theoretical model to recapitulate salient features of E-Syt-mediated membrane contacts observed in vivo, including their equilibrium distances and probabilities. Our methods can be applied to study other proteins containing multiple membrane-binding domains linked by disordered polypeptides.
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Calcio , Pinzas Ópticas , Calcio/metabolismo , Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Lípidos/análisisRESUMEN
BACKGROUND: The morphology of tumor thrombus varies from person to person and it may affect surgical methods and tumor prognosis. However, studies on the morphology of tumor thrombus are limited. The purpose of our study was to evaluate the impact of tumor thrombus morphology on surgical complexity. METHODS: We retrospectively reviewed the clinical data of 229 patients with renal cell carcinoma combined with inferior vena cava (IVC) tumor thrombus who underwent surgical treatment at Peking University Third Hospital between January 2014 and December 2021. The patients were divided into floating morphology (107 patients) and filled morphology (122 patients) tumor thrombi groups. Chi-square and Mann-Whitney U tests were used for categorical and continuous variables, respectively. Postoperative complications were evaluated using the Clavien-Dindo surgical complication classification method. RESULTS: Patients with filled morphology tumor thrombus required more surgical techniques than those with floating morphology tumor thrombus, which was reflected in more open surgeries (P < 0.001), more IVC interruptions (Pâ<0.001), lesser use of the delayed occlusion of the proximal inferior vena cava (DOPI) technique (P < 0.001), and a greater need for cut-off of the short hepatic vein (P < 0.001) and liver dissociation (P = 0.001). Filled morphology significantly increased the difficulty of surgery in patients with renal cell carcinoma with tumor thrombus, reflected in longer operation time (P < 0.001), more surgical blood loss (Pâ<0.001), more intra-operative blood transfusion (P < 0.001), and longer postoperative hospital stay (P < 0.001). Filled morphology tumor thrombus also led to more postoperative complications (53% vs. 20%; P < 0.001). CONCLUSION: Compared with floating morphology thrombus, filled morphology thrombus significantly increased the difficulty of surgery in patients with renal cell carcinoma with IVC tumor thrombus.
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Carcinoma de Células Renales , Neoplasias Renales , Células Neoplásicas Circulantes , Vena Cava Inferior , Trombosis de la Vena , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Vena Cava Inferior/patología , Vena Cava Inferior/cirugía , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , China/epidemiología , Células Neoplásicas Circulantes/patología , Trombosis de la Vena/patología , Trombosis de la Vena/cirugía , Anciano , Nefrectomía/métodos , Complicaciones Posoperatorias/epidemiología , AdultoRESUMEN
OBJECTIVES: To build self-supervised foundation models for multicontrast MRI of the whole brain and evaluate their efficacy in assisting diagnosis of brain tumors. METHODS: In this retrospective study, foundation models were developed using 57,621 enhanced head MRI scans through self-supervised learning with a pretext task of cross-contrast context restoration with two different content dropout schemes. Downstream classifiers were constructed based on the pretrained foundation models and fine-tuned for brain tumor detection, discrimination, and molecular status prediction. Metrics including accuracy, sensitivity, specificity, and area under the ROC curve (AUC) were used to evaluate the performance. Convolutional neural networks trained exclusively on downstream task data were employed for comparative analysis. RESULTS: The pretrained foundation models demonstrated their ability to extract effective representations from multicontrast whole-brain volumes. The best classifiers, endowed with pretrained weights, showed remarkable performance with accuracies of 94.9, 92.3, and 80.4%, and corresponding AUC values of 0.981, 0.972, and 0.852 on independent test datasets in brain tumor detection, discrimination, and molecular status prediction, respectively. The classifiers with pretrained weights outperformed the convolutional classifiers trained from scratch by approximately 10% in terms of accuracy and AUC across all tasks. The saliency regions in the correctly predicted cases are mainly clustered around the tumors. Classifiers derived from the two dropout schemes differed significantly only in the detection of brain tumors. CONCLUSIONS: Foundation models obtained from self-supervised learning have demonstrated encouraging potential for scalability and interpretability in downstream brain tumor-related tasks and hold promise for extension to neurological diseases with diffusely distributed lesions. CLINICAL RELEVANCE STATEMENT: The application of our proposed method to the prediction of key molecular status in gliomas is expected to improve treatment planning and patient outcomes. Additionally, the foundation model we developed could serve as a cornerstone for advancing AI applications in the diagnosis of brain-related diseases.