Thousands of conductance levels in memristors integrated on CMOS.

Neural networks based on memristive devices1-3 have the ability to improve throughput and energy efficiency for machine learning4,5 and artificial intelligence6, especially in edge applications7-21. Because training a neural network model from scratch is costly in terms of hardware resources, time and energy, it is impractical to do it individually on billions of memristive neural networks distributed at the edge. A practical approach would be to download the synaptic weights obtained from the cloud training and program them directly into memristors for the commercialization of edge applications. Some post-tuning in memristor conductance could be done afterwards or during applications to adapt to specific situations. Therefore, in neural network applications, memristors require high-precision programmability to guarantee uniform and accurate performance across a large number of memristive networks22-28. This requires many distinguishable conductance levels on each memristive device, not only laboratory-made devices but also devices fabricated in factories. Analog memristors with many conductance states also benefit other applications, such as neural network training, scientific computing and even 'mortal computing'25,29,30. Here we report 2,048 conductance levels achieved with memristors in fully integrated chips with 256 × 256 memristor arrays monolithically integrated on complementary metal-oxide-semiconductor (CMOS) circuits in a commercial foundry. We have identified the underlying physics that previously limited the number of conductance levels that could be achieved in memristors and developed electrical operation protocols to avoid such limitations. These results provide insights into the fundamental understanding of the microscopic picture of memristive switching as well as approaches to enable high-precision memristors for various applications. Fig. 1 HIGH-PRECISION MEMRISTOR FOR NEUROMORPHIC COMPUTING.: a, Proposed scheme of the large-scale application of memristive neural networks for edge computing. Neural network training is performed in the cloud. The obtained weights are downloaded and accurately programmed into a massive number of memristor arrays distributed at the edge, which imposes high-precision requirements on memristive devices. b, An eight-inch wafer with memristors fabricated by a commercial semiconductor manufacturer. c, High-resolution transmission electron microscopy image of the cross-section view of a memristor. Pt and Ta serve as the bottom electrode (BE) and top electrode (TE), respectively. Scale bars, 1 µm and 100 nm (inset). d, Magnification of the memristor material stack. Scale bar, 5 nm. e, As-programmed (blue) and after-denoising (red) currents of a memristor are read by a constant voltage (0.2 V). The denoising process eliminated the large-amplitude RTN observed in the as-programmed state (see Methods). f, Magnification of three nearest-neighbour states after denoising. The current of each state was read by a constant voltage (0.2 V). No large-amplitude RTN was observed, and all of the states can be clearly distinguished. g, An individual memristor on the chip was tuned into 2,048 resistance levels by high-resolution off-chip driving circuitry, and each resistance level was read by a d.c. voltage sweeping from 0 to 0.2 V. The target resistance was set from 50 µS to 4,144 µS with a 2-µS interval between neighbouring levels. All readings at 0.2 V are less than 1 µS from the target conductance. Bottom inset, magnification of the resistance levels. Top inset, experimental results of an entire 256 × 256 array programmed by its 6-bit on-chip circuitry into 64 32 × 32 blocks, and each block is programmed into one of the 64 conductance levels. Each of the 256 × 256 memristors has been previously switched over one million cycles, demonstrating the high endurance and robustness of the devices.

Revitalizing interface in protonic ceramic cells by acid etch.

Protonic ceramic electrochemical cells hold promise for operation below 600 °C (refs. 1,2). Although the high proton conductivity of the bulk electrolyte has been demonstrated, it cannot be fully used in electrochemical full cells because of unknown causes3. Here we show that these problems arise from poor contacts between the low-temperature processed oxygen electrode-electrolyte interface. We demonstrate that a simple acid treatment can effectively rejuvenate the high-temperature annealed electrolyte surface, resulting in reactive bonding between the oxygen electrode and the electrolyte and improved electrochemical performance and stability. This enables exceptional protonic ceramic fuel-cell performance down to 350 °C, with peak power densities of 1.6 W cm-2 at 600 °C, 650 mW cm-2 at 450 °C and 300 mW cm-2 at 350 °C, as well as stable electrolysis operations with current densities above 3.9 A cm-2 at 1.4 V and 600 °C. Our work highlights the critical role of interfacial engineering in ceramic electrochemical devices and offers new understanding and practices for sustainable energy infrastructures.

Ultralow contact resistance between semimetal and monolayer semiconductors.

Advanced beyond-silicon electronic technology requires both channel materials and also ultralow-resistance contacts to be discovered1,2. Atomically thin two-dimensional semiconductors have great potential for realizing high-performance electronic devices1,3. However, owing to metal-induced gap states (MIGS)4-7, energy barriers at the metal-semiconductor interface-which fundamentally lead to high contact resistance and poor current-delivery capability-have constrained the improvement of two-dimensional semiconductor transistors so far2,8,9. Here we report ohmic contact between semimetallic bismuth and semiconducting monolayer transition metal dichalcogenides (TMDs) where the MIGS are sufficiently suppressed and degenerate states in the TMD are spontaneously formed in contact with bismuth. Through this approach, we achieve zero Schottky barrier height, a contact resistance of 123 ohm micrometres and an on-state current density of 1,135 microamps per micrometre on monolayer MoS2; these two values are, to the best of our knowledge, the lowest and highest yet recorded, respectively. We also demonstrate that excellent ohmic contacts can be formed on various monolayer semiconductors, including MoS2, WS2 and WSe2. Our reported contact resistances are a substantial improvement for two-dimensional semiconductors, and approach the quantum limit. This technology unveils the potential of high-performance monolayer transistors that are on par with state-of-the-art three-dimensional semiconductors, enabling further device downscaling and extending Moore's law.

Phonon stability boundary and deep elastic strain engineering of lattice thermal conductivity.

Recent studies have reported the experimental discovery that nanoscale specimens of even a natural material, such as diamond, can be deformed elastically to as much as 10% tensile elastic strain at room temperature without the onset of permanent damage or fracture. Computational work combining ab initio calculations and machine learning (ML) algorithms has further demonstrated that the bandgap of diamond can be altered significantly purely by reversible elastic straining. These findings open up unprecedented possibilities for designing materials and devices with extreme physical properties and performance characteristics for a variety of technological applications. However, a general scientific framework to guide the design of engineering materials through such elastic strain engineering (ESE) has not yet been developed. By combining first-principles calculations with ML, we present here a general approach to map out the entire phonon stability boundary in six-dimensional strain space, which can guide the ESE of a material without phase transitions. We focus on ESE of vibrational properties, including harmonic phonon dispersions, nonlinear phonon scattering, and thermal conductivity. While the framework presented here can be applied to any material, we show as an example demonstration that the room-temperature lattice thermal conductivity of diamond can be increased by more than 100% or reduced by more than 95% purely by ESE, without triggering phonon instabilities. Such a framework opens the door for tailoring of thermal-barrier, thermoelectric, and electro-optical properties of materials and devices through the purposeful design of homogeneous or inhomogeneous strains.

Li metal deposition and stripping in a solid-state battery via Coble creep.

Solid-state lithium metal batteries require accommodation of electrochemically generated mechanical stress inside the lithium: this stress can be1,2 up to 1 gigapascal for an overpotential of 135 millivolts. Maintaining the mechanical and electrochemical stability of the solid structure despite physical contact with moving corrosive lithium metal is a demanding requirement. Using in situ transmission electron microscopy, we investigated the deposition and stripping of metallic lithium or sodium held within a large number of parallel hollow tubules made of a mixed ionic-electronic conductor (MIEC). Here we show that these alkali metals-as single crystals-can grow out of and retract inside the tubules via mainly diffusional Coble creep along the MIEC/metal phase boundary. Unlike solid electrolytes, many MIECs are electrochemically stable in contact with lithium (that is, there is a direct tie-line to metallic lithium on the equilibrium phase diagram), so this Coble creep mechanism can effectively relieve stress, maintain electronic and ionic contacts, eliminate solid-electrolyte interphase debris, and allow the reversible deposition/stripping of lithium across a distance of 10 micrometres for 100 cycles. A centimetre-wide full cell-consisting of approximately 1010 MIEC cylinders/solid electrolyte/LiFePO4-shows a high capacity of about 164 milliampere hours per gram of LiFePO4, and almost no degradation for over 50 cycles, starting with a 1× excess of Li. Modelling shows that the design is insensitive to MIEC material choice with channels about 100 nanometres wide and 10-100 micrometres deep. The behaviour of lithium metal within the MIEC channels suggests that the chemical and mechanical stability issues with the metal-electrolyte interface in solid-state lithium metal batteries can be overcome using this architecture.

Caught in the crossfire: Fears of Chinese-American scientists.

The US global leadership in science and technology has greatly benefitted from immigrants from other countries, most notably from China in the recent decades. However, feeling the pressure of potential federal investigations since the 2018 launch of the China Initiative, scientists of Chinese descent in the United States now face higher incentives to leave the United States and lower incentives to apply for federal grants. Analyzing data pertaining to institutional affiliations of more than 200 million scientific papers, we find a steady increase in the return migration of scientists of Chinese descent from the United States to China. We also conducted a survey of scientists of Chinese descent employed by US universities in tenured or tenure-track positions (n = 1,304), with results revealing general feelings of fear and anxiety that lead them to consider leaving the United States and/or stop applying for federal grants. If the situation is not corrected, American science will likely suffer the loss of scientific talent to China and other countries.

Mechanochemical upcycling of spent LiCoO2 to new LiNi0.80Co0.15Al0.05O2 battery: An atom economy strategy.

The use of strong acids and low atom efficiency in conventional hydrometallurgical recycling of spent lithium-ion batteries (LIBs) results in significant secondary wastes and CO2 emissions. Herein, we utilize the waste metal current collectors in spent LIBs to promote atom economy and reduce chemicals consumption in a conversion process of spent Li1-xCoO2 (LCO) → new LiNi0.80Co0.15Al0.05O2 (NCA) cathode. Mechanochemical activation is employed to achieve moderate valence reduction of transition metal oxides (Co3+→Co2+,3+) and efficient oxidation of current collector fragments (Al0→Al3+, Cu0→Cu1+,2+), and then due to stored internal energy from ball-milling, the leaching rates of Li, Co, Al, and Cu in the ≤4 mm crushed products uniformly approach 100% with just weak acetic acid. Instead of corrosive precipitation reagents, larger Al fragments (≥4 mm) are used to control the oxidation/reduction potential (ORP) in the aqueous leachate and induce the targeted removal of impurity ions (Cu, Fe). After the upcycling of NCA precursor solution to NCA cathode powders, we demonstrate excellent electrochemical performance of the regenerated NCA cathode and improved environmental impact. Through life cycle assessments, the profit margin of this green upcycling path reaches about 18%, while reducing greenhouse gas emissions by 45%.

Manipulating solid-state spin concentration through charge transport.

Solid-state defects are attractive platforms for quantum sensing and simulation, e.g., in exploring many-body physics and quantum hydrodynamics. However, many interesting properties can be revealed only upon changes in the density of defects, which instead is usually fixed in material systems. Increasing the interaction strength by creating denser defect ensembles also brings more decoherence. Ideally one would like to control the spin concentration at will while keeping fixed decoherence effects. Here, we show that by exploiting charge transport, we can take some steps in this direction, while at the same time characterizing charge transport and its capture by defects. By exploiting the cycling process of ionization and recombination of NV centers in diamond, we pump electrons from the valence band to the conduction band. These charges are then transported to modulate the spin concentration by changing the charge state of material defects. By developing a wide-field imaging setup integrated with a fast single photon detector array, we achieve a direct and efficient characterization of the charge redistribution process by measuring the complete spectrum of the spin bath with micrometer-scale spatial resolution. We demonstrate a two-fold concentration increase of the dominant spin defects while keeping the T2 of the NV center relatively unchanged, which also provides a potential experimental demonstration of the suppression of spin flip-flops via hyperfine interactions. Our work paves the way to studying many-body dynamics with temporally and spatially tunable interaction strengths in hybrid charge-spin systems.

Excitatory Spinal Lhx9-Derived Interneurons Modulate Locomotor Frequency in Mice.

Locomotion allows us to move and interact with our surroundings. Spinal networks that control locomotion produce rhythm and left-right and flexor-extensor coordination. Several glutamatergic populations, Shox2 non-V2a, Hb9-derived interneurons, and, recently, spinocerebellar neurons have been proposed to be involved in the mouse rhythm generating networks. These cells make up only a smaller fraction of the excitatory cells in the ventral spinal cord. Here, we set out to identify additional populations of excitatory spinal neurons that may be involved in rhythm generation or other functions in the locomotor network. We use RNA sequencing from glutamatergic, non-glutamatergic, and Shox2 cells in the neonatal mice from both sexes followed by differential gene expression analyses. These analyses identified transcription factors that are highly expressed by glutamatergic spinal neurons and differentially expressed between Shox2 neurons and glutamatergic neurons. From this latter category, we identified the Lhx9-derived neurons as having a restricted spinal expression pattern with no Shox2 neuron overlap. They are purely glutamatergic and ipsilaterally projecting. Ablation of the glutamatergic transmission or acute inactivation of the neuronal activity of Lhx9-derived neurons leads to a decrease in the frequency of locomotor-like activity without change in coordination pattern. Optogenetic activation of Lhx9-derived neurons promotes locomotor-like activity and modulates the frequency of the locomotor activity. Calcium activities of Lhx9-derived neurons show strong left-right out-of-phase rhythmicity during locomotor-like activity. Our study identifies a distinct population of spinal excitatory neurons that regulates the frequency of locomotor output with a suggested role in rhythm-generation in the mouse alongside other spinal populations.

Defective branched-chain amino acid catabolism in dorsal root ganglia contributes to mechanical pain.

Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here, we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observed the downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation.

Oxide Cathodes: Functions, Instabilities, Self Healing, and Degradation Mitigations.

Recent progress in high-energy-density oxide cathodes for lithium-ion batteries has pushed the limits of lithium usage and accessible redox couples. It often invokes hybrid anion- and cation-redox (HACR), with exotic valence states such as oxidized oxygen ions under high voltages. Electrochemical cycling under such extreme conditions over an extended period can trigger various forms of chemical, electrochemical, mechanical, and microstructural degradations, which shorten the battery life and cause safety issues. Mitigation strategies require an in-depth understanding of the underlying mechanisms. Here we offer a systematic overview of the functions, instabilities, and peculiar materials behaviors of the oxide cathodes. We note unusual anion and cation mobilities caused by high-voltage charging and exotic valences. It explains the extensive lattice reconstructions at room temperature in both good (plasticity and self-healing) and bad (phase change, corrosion, and damage) senses, with intriguing electrochemomechanical coupling. The insights are critical to the understanding of the unusual self-healing phenomena in ceramics (e.g., grain boundary sliding and lattice microcrack healing) and to novel cathode designs and degradation mitigations (e.g., suppressing stress-corrosion cracking and constructing reactively wetted cathode coating). Such mixed ionic-electronic conducting, electrochemically active oxides can be thought of as almost "metalized" if at voltages far from the open-circuit voltage, thus differing significantly from the highly insulating ionic materials in electronic transport and mechanical behaviors. These characteristics should be better understood and exploited for high-performance energy storage, electrocatalysis, and other emerging applications.

Novel quantitative immunohistochemistry method using histone H3, family 3B as the internal reference standard for measuring human epidermal growth factor receptor 2 expression in breast cancer.

BACKGROUND: Immunohistochemistry (IHC) is an essential technique in surgical and clinical pathology for detecting diagnostic, prognostic, and predictive biomarkers for personalized cancer therapy. However, the lack of standardization and reference controls results in poor reproducibility, and a reliable tool for IHC quantification is urgently required. The objective of this study was to describe a novel approach in which H3F3B (histone H3, family 3B) can be used as an internal reference standard to quantify protein expression levels using IHC. METHODS: The authors enrolled 89 patients who had human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). They used a novel IHC-based assay to measure protein expression using H3F3B as the internal reference standard. H3F3B was uniformly expressed at the protein level in all tumor regions in cancer tissues. HER2 expression levels were measured with the H-score using HALO software. RESULTS: Kaplan-Meier analysis indicated that, among patients who had HER2-positive BC in The Cancer Genome Atlas data set and the authors' data set, the subgroup with low HER2 expression had a significantly better prognosis than the subgroup with high HER2 expression. Furthermore, the authors observed that HER2 expression levels were precisely evaluated using the proposed method, which can classify patients who are at higher risk of HER2-positive BC to receive trastuzumab-based adjuvant therapy. Dual-color IHC with H3F3B is an excellent tool for internal and external quality control of HER2 expression assays. CONCLUSIONS: The proposed IHC-based quantification method accurately assesses HER2 expression levels and provides insights for predicting clinical prognosis in patients with HER2-positive BC who receive trastuzumab-based adjuvant therapy.

Highly Selective and Reversible Detection of Simulated Breath Hydrogen Sulfide Using Fe-Doped CuO Hollow Spheres: Enhanced Surface Redox Reaction by Multi-Valent Catalysts.

The precise and reversible detection of hydrogen sulfide (H2S) at high humidity condition, a malodorous and harmful volatile sulfur compound, is essential for the self-assessment of oral diseases, halitosis, and asthma. However, the selective and reversible detection of trace concentrations of H2S (≈0.1 ppm) in high humidity conditions (exhaled breath) is challenging because of irreversible H2S adsorption/desorption at the surface of chemiresistors. The study reports the synthesis of Fe-doped CuO hollow spheres as H2S gas-sensing materials via spray pyrolysis. 4 at.% of Fe-doped CuO hollow spheres exhibit high selectivity (response ratio ≥ 34.4) over interference gas (ethanol, 1 ppm) and reversible sensing characteristics (100% recovery) to 0.1 ppm of H2S under high humidity (relative humidity 80%) at 175 °C. The effect of multi-valent transition metal ion doping into CuO on sensor reversibility is confirmed through the enhancement of recovery kinetics by doping 4 at.% of Ti- or Nb ions into CuO sensors. Mechanistic details of these excellent H2S sensing characteristics are also investigated by analyzing the redox reactions and the catalytic activity change of the Fe-doped CuO sensing materials. The selective and reversible detection of H2S using the Fe-doped CuO sensor suggested in this work opens a new possibility for halitosis self-monitoring.

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.

Inflammation-Mediated Aberrant Glucose Metabolism in Subchondral Bone Induces Osteoarthritis.

Osteoarthritis (OA) is an entire joint disease with pathological alteration in both articular cartilage and subchondral bone. It has been recognized recently the association between metabolic syndrome and OA, particularly glucose metabolism in regulation of articular cartilage homeostasis and joint integrity. Whereas the role of glucose metabolism in subchondral bone sclerosis remains largely unknown during pathogenesis of OA. Consistent with common OA features, we observed subchondral bone sclerosis and abnormal bone remodeling in human OA joints and murine OA joints as reflected by hyperactive bone resorption and overall bone formation which was measured via dynamic histomorphometry. Osx-CreER;tdTomato mice also displayed the similar overall bone formation under injury-induced OA condition. Immunohistochemistry further revealed increased IL-1ß expression in human and murine OA subchondral bone. Given the inflammatory environment in joints under OA condition, we treated MC3T3-E1 cell, a pre-osteoblast cell line, with IL-1ß in this study and demonstrated that IL-1ß treatment could stimulate the cell osteogenic differentiation and meanwhile upregulate glycolysis and oxidative phosphorylation in cell cultures. More importantly, intraperitoneal injection of 2-deoxy-D-glucose (2-DG) and oligomycin (OGM), respectively, suppressed the subchondral bone glycolysis and oxidative phosphorylation in mice. Consequently, 2-DG and OGM treatment attenuated abnormal osteoblast differentiation and protected against aberrant bone formation in subchondral bone and articular cartilage degradation in wildtype mice following with joint injury. Collectively, these data strongly suggest glycolysis and oxidative may serve as important therapeutic targets for OA treatment.

Plasma-derived from human umbilical cord blood restores ovarian function and improves serum reproductive hormones levels in mice with premature ovarian insufficiency (POI) through cytokines and growth factors.

Premature ovarian insufficiency (POI) patients experience a decline in ovarian function and a reduction in serum reproductive hormones, leading to a significant impact on the outcomes of assisted reproductive technology. Despite the absence of an effective clinical treatment to restore fertility in POI patients, recent research has indicated that cord blood plasma (CBP) derived from human umbilical cord blood (hUCB) may offer therapeutic benefits for various degenerative diseases. The primary aim of this study is to explore approaches for enhancing ovarian function and serum reproductive hormones through the administration of CBP in a murine model. Initially, hUCB was utilized to obtain CBP (CBP), which was subsequently analyzed for cytokine and growth factor profiles in comparison to adult blood plasma (ABP) by use of flow cytometry. Subsequently, POI mouse models were established through the induction of 4-vinylcyclohexene diepoxide, followed by the injection of CBP into the tail. At 7, 14, and 21 days posttreatment, mouse ovaries and blood were collected, and their estrus cycle, body weight, and ovarian weights were evaluated using precise electronic balance. Finally, ovarian morphology and follicle number were assessed through HE staining, while serum levels of anti-Müllerian hormone (AMH), estradiol (E2) and follicle-stimulating hormone (FSH) were determined by ELISA. Our study revealed that individuals with CBP exhibited significantly lower concentrations of proinflammatory cytokines, including IL-ß (p < 0.01) and IL-2 (p < 0.05), while displaying elevated levels of anti-inflammatory cytokines and chemokines, such as IL-2, IL-4, IL-6, IL-8, IL-12P70, IL-17A, IP-10, interferon-γ, and tumor necrosis factor-α (p < 0.01). Furthermore, CBP demonstrated remarkably higher levels of growth factors, including transforming growth factor-ß1, vascular endothelial growth factor, and insulin-like growth factor-1 (p < 0.01) than ABP. Notably, our investigation also revealed that CBP restored the content of serum reproductive hormones, such as AMH, E2, and FSH (p < 0.05), and increased the number of primordial and primary follicles (p < 0.01) and decreased the number of luteal and atretic follicles (p < 0.01) in vivo. Our findings suggested that CBP-secreted cytokines and growth factors could be restored POI ovarian function, enhanced serum reproductive hormones and rescued follicular development in vivo. These findings further support the potential of CBP as a promising strategy in clinical applications for POI related infertility.

Exponentially Enhanced Non-Hermitian Cooling.

Certain non-Hermitian systems exhibit the skin effect, whereby the wave functions become exponentially localized at one edge of the system. Such exponential amplification of wavefunction has received significant attention due to its potential applications in, e.g., classical and quantum sensing. However, the opposite edge of the system, featured by exponentially suppressed wave functions, remains largely unexplored. Leveraging this phenomenon, we introduce a non-Hermitian cooling mechanism, which is fundamentally distinct from traditional refrigeration or laser cooling techniques. Notably, non-Hermiticity will not amplify thermal excitations, but rather redistribute them. Hence, thermal excitations can be cooled down at one edge of the system, and the cooling effect can be exponentially enhanced by the number of auxiliary modes, albeit with a lower bound that depends on the dissipative interaction with the environment. Non-Hermitian cooling does not rely on intricate properties such as exceptional points or nontrivial topology, and it can apply to a wide range of excitations.

Obtaining the best igRNAs for bystander-less correction of all ABE-reversible pathogenic SNVs using high-throughput screening.

Imperfect -gRNA (igRNA) provides a simple strategy for single-base editing of a base editor. However, a significant number of igRNAs need to be generated and tested for each target locus to achieve efficient single-base reversion of pathogenic single nucleotide variations (SNVs), which hinders the direct application of this technology. To provide ready-to-use igRNAs for single-base and bystander-less correction of all the adenine base editor (ABE)-reversible pathogenic SNVs, we employed a high-throughput method to edit all 5,253 known ABE-reversible pathogenic SNVs, each with multiple systematically designed igRNAs, and two libraries of 96,000 igRNAs were tested. A total of 1,988 SNV loci could be single-base reversed by igRNA with a >30% efficiency. Among these 1,988 loci, 378 SNV loci exhibited an efficiency of more than 90%. At the same time, the bystander editing efficiency of 76.62% of the SNV loci was reduced to 0%, while remaining below 1% for another 18.93% of the loci. These ready-to-use igRNAs provided the best solutions for a substantial portion of the 4,657 pathogenic/likely pathogenic SNVs. In this work, we overcame one of the most significant obstacles of base editors and provide a ready-to-use platform for the genetic treatment of diseases caused by ABE-reversible SNVs.

Imperfect guide-RNA (igRNA) enables CRISPR single-base editing with ABE and CBE.

CRISPR base editing techniques tend to edit multiple bases in the targeted region, which is a limitation for precisely reverting disease-associated single-nucleotide polymorphisms (SNPs). We designed an imperfect gRNA (igRNA) editing methodology, which utilized a gRNA with one or more bases that were not complementary to the target locus to direct base editing toward the generation of a single-base edited product. Base editing experiments illustrated that igRNA editing with CBEs greatly increased the single-base editing fraction relative to normal gRNA editing with increased editing efficiencies. Similar results were obtained with an adenine base editor (ABE). At loci such as DNMT3B, NSD1, PSMB2, VIATA hs267 and ANO5, near-perfect single-base editing was achieved. Normally an igRNA with good single-base editing efficiency could be selected from a set of a few igRNAs, with a simple protocol. As a proof-of-concept, igRNAs were used in the research to construct cell lines of disease-associated SNP causing primary hyperoxaluria construction research. This work provides a simple strategy to achieve single-base base editing with both ABEs and CBEs and overcomes a key obstacle that limits the use of base editors in treating SNP-associated diseases or creating disease-associated SNP-harboring cell lines and animal models.

Sliding ferroelectricity in 2D van der Waals materials: Related physics and future opportunities.

Near the 100th anniversary of the discovery of ferroelectricity, so-called sliding ferroelectricity has been proposed and confirmed recently in a series of experiments that have stimulated remarkable interest. Such ferroelectricity exists widely and exists only in two-dimensional (2D) van der Waals stacked layers, where the vertical electric polarization is switched by in-plane interlayer sliding. Reciprocally, interlayer sliding and the "ripplocation" domain wall can be driven by an external vertical electric field. The unique combination of intralayer stiffness and interlayer slipperiness of 2D van der Waals layers greatly facilitates such switching while still maintaining environmental and mechanical robustness at ambient conditions. In this perspective, we discuss the progress and future opportunities in this behavior. The origin of such ferroelectricity as well as a general rule for judging its existence are summarized, where the vertical stacking sequence is crucial for its formation. This discovery broadens 2D ferroelectrics from very few material candidates to most of the known 2D materials. Their low switching barriers enable high-speed data writing with low energy cost. Related physics like Moiré ferroelectricity, the ferroelectric nonlinear anomalous Hall effect, and multiferroic coupling are discussed. For 2D valleytronics, nontrivial band topology and superconductivity, their possible couplings with sliding ferroelectricity via certain stacking or Moiré ferroelectricity also deserve interest. We provide critical reviews on the current challenges in this emerging area.