Generation of 583 fs optical pulses at 10†GHz from a regeneratively mode-locked fiber laser combining nonlinear polarization evolution.

A regeneratively mode-locked erbium fiber laser was numerically investigated and experimentally demonstrated, which was able to generate a 583 fs pulse train at 10 GHz via intracavity pulse compression with nonlinear polarization evolution (NPE). To excite the NPE at such a high repetition rate, a dispersion map was intentionally introduced to obtain short pulses accompanied by high peaks through soliton-like pulse shaping. Numerical simulations indicated that steady-state oscillation with pulses below 1 ps can be successfully established using this laser configuration. Experimentally, we obtained a pulse duration of 583 fs and a 3 dB spectral width of 4.5 nm at an average output power of 15.6 mW. Simultaneously, supermode suppression of more than 80 dB was also obtained from the appropriate biased NPE.

A Catalytic Method to Activate Nitromethane by the Cooperation of Homo- and Heterogeneous Catalysis.

The achievement of directly activating and utilizing bulk small molecules has remained a longstanding objective in the field of chemical synthesis. The present work reports a catalytic activation method for bulk chemical nitromethane (MeNO2 ). This method combines homogeneous Lewis acid with recyclable heterogeneous Brønsted acid catalysis, featuring practicality, sustainability, and low cost, thus solving the inherent drawbacks of previous Nef processes where stoichiometric reductants or activators were required. By combining the advantages of both homo- and heterogeneous catalysts, this chemistry may not only offer new opportunities for the further development of MeNO2 as a nitrogen source for organic synthesis, but also promote the catalysis design in synthetic chemistry.

Manganese Transfer Hydrogenases Based on the Biotin-Streptavidin Technology.

Artificial (transfer) hydrogenases have been developed for organic synthesis, but they rely on precious metals. Native hydrogenases use Earth-abundant metals, but these cannot be applied for organic synthesis due, in part, to their substrate specificity. Herein, we report the design and development of manganese transfer hydrogenases based on the biotin-streptavidin technology. By incorporating bio-mimetic Mn(I) complexes into the binding cavity of streptavidin, and through chemo-genetic optimization, we have obtained artificial enzymes that hydrogenate ketones with nearly quantitative yield and up to 98 % enantiomeric excess (ee). These enzymes exhibit broad substrate scope and high functional-group tolerance. According to QM/MM calculations and X-ray crystallography, the S112Y mutation, combined with the appropriate chemical structure of the Mn cofactor plays a critical role in the reactivity and enantioselectivity of the artificial metalloenzyme (ArMs). Our work highlights the potential of ArMs incorporating base-meal cofactors for enantioselective organic synthesis.

Catalytic Electrophilic Halogenation of Arenes with Electron-Withdrawing Substituents.

The electrophilic halogenation of arenes is perhaps the simplest method to prepare aryl halides, which are important structural motifs in agrochemicals, materials, and pharmaceuticals. However, the nucleophilicity of arenes is weakened by the electron-withdrawing substituents, whose electrophilic halogenation reactions usually require harsh conditions and lead to limited substrate scopes and applications. Therefore, the halogenation of arenes containing electron-withdrawing groups (EWGs) and complex bioactive compounds under mild conditions has been a long-standing challenge. Herein, we describe Brønsted acid-catalyzed halogenation of arenes with electron-withdrawing substituents under mild conditions, providing an efficient protocol for aryl halides. The hydrogen bonding of Brønsted acid with the protic solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) enables this transformation and thus solves this long-standing problem.

Biofertilizers can enhance nitrogen use efficiency of sugarcane.

Fertilizers are costly inputs into crop systems. To compensate for inefficiencies and losses from soil, farmers apply on average double the amount of nitrogen (N) fertilizer acquired by crops. We explored if N efficiency improves with biofertilizers formulated with organic waste, mineral N or plant growth-promoting rhizobacteria (PGPR). We compared treatments receiving mineral N fertilizer or biofertilizers at industry-recommended (100%) or lower (60%) N rates at two commercial sugarcane farms. Biofertilizer at the 60% N-rate generated promising results at one farm with significantly higher biomass and sugar yield than the no-N control, which matched the 100% mineral N treatment. This yield difference was accompanied by a shift in microbial diversity and composition. Correlation analysis confirmed that shifts in microbial communities were strongly linked to soil mineral N levels, as well as crop productivity and yield. Microbial co-occurrence networks further revealed that biofertilizer, including treatments with an added PGPR, can enhance bacterial associations, especially in the context of complex fungal networks. Collectively, the results confirm that biofertilizers have quantifiable effects on soil microbial communities in a crop system setting, which underscores the opportunities for biofertilizers to promote N use efficiency and the circular N economy.

Practical Enzymatic Production of Carbocycles.

The Pd-catalyzed carbon-carbon bond formation pioneered by Heck in 1969 has dominated medicinal chemistry development for the ensuing fifty years. As the demand for more complex three-dimensional active pharmaceuticals continues to increase, preparative enzyme-mediated assembly, by virtue of its exquisite selectivity and sustainable nature, is poised to provide a practical and affordable alternative for accessing such compounds. In this minireview, we summarize recent state-of-the-art developments in practical enzyme-mediated assembly of carbocycles. When appropriate, background information on the enzymatic transformation is provided and challenges and/or limitations are also highlighted.

Responses of microbial function, biomass and heterotrophic respiration, and organic carbon in fir plantation soil to successive nitrogen and phosphorus fertilization.

Carbon dioxide (CO2) emissions from forest ecosystems originate largely from soil respiration, and microbial heterotrophic respiration plays a critical role in determining organic carbon (C) stock. This study investigated the impacts of successive nitrogen (N) and phosphorus (P) fertilization after 9 years on soil organic C stock; CO2 emission; and microbial biomass, community, and function in a Chinese fir plantation. The annual fertilization rates were (1) CK, control without N or P fertilization; (2) N50, 50 kg N ha-1; (3) N100, 100 kg N ha-1; (4) P50, 50 kg P ha-1; (5) N50P50, 50 kg N ha-1 + 50 kg P ha-1; and (6) N100P50, 100 kg N ha-1 + 50 kg P ha-1. The N100P50 treatment had the highest cumulative soil CO2 emissions, but the CK treatment had the lowest cumulative soil CO2 emissions among all treatments. The declines of soil organic C (SOC) after successive 9-year fertilization were in the order of 100 kg N ha-1 year-1 > 50 kg N ha-1 year-1 > CK. Compared to the CK treatment, successive N fertilization significantly changed soil microbial communities at different application rates and increased the relative gene abundances of glycoside hydrolases, glycosyl transferases, carbohydrate-binding modules, and polysaccharide lyases at 100 kg N ha-1 year-1. Relative to P fertilization alone (50 kg P ha-1 year-1), combined N and P fertilization significantly altered the soil microbial community structure and favored more active soil microbial metabolism. Microbial community and metabolism changes caused by N fertilization could have enhanced CO2 emission from heterotrophic respiration and eventually led to the decrease in organic C stock in the forest plantation soil. KEY POINTS: • N fertilization, alone or with P, favored more active microbial metabolism genes. • 100 kg N ha-1 fertilization significantly changed microbial community and function. • N fertilization led to a "domino effect" on the decrease of soil C stock.

Terrestrial N2 O emissions and related functional genes under climate change: A global meta-analysis.

Nitrous oxide (N2 O) emissions from soil contribute to global warming and are in turn substantially affected by climate change. However, climate change impacts on N2 O production across terrestrial ecosystems remain poorly understood. Here, we synthesized 46 published studies of N2 O fluxes and relevant soil functional genes (SFGs, that is, archaeal amoA, bacterial amoA, nosZ, narG, nirK and nirS) to assess their responses to increased temperature, increased or decreased precipitation amounts, and prolonged drought (no change in total precipitation but increase in precipitation intervals) in terrestrial ecosystem (i.e. grasslands, forests, shrublands, tundra and croplands). Across the data set, temperature increased N2 O emissions by 33%. However, the effects were highly variable across biomes, with strongest temperature responses in shrublands, variable responses in forests and negative responses in tundra. The warming methods employed also influenced the effects of temperature on N2 O emissions (most effectively induced by open-top chambers). Whole-day or whole-year warming treatment significantly enhanced N2 O emissions, but daytime, nighttime or short-season warming did not have significant effects. Regardless of biome, treatment method and season, increased precipitation promoted N2 O emission by an average of 55%, while decreased precipitation suppressed N2 O emission by 31%, predominantly driven by changes in soil moisture. The effect size of precipitation changes on nirS and nosZ showed a U-shape relationship with soil moisture; further insight into biotic mechanisms underlying N2 O emission response to climate change remain limited by data availability, underlying a need for studies that report SFG. Our findings indicate that climate change substantially affects N2 O emission and highlights the urgent need to incorporate this strong feedback into most climate models for convincing projection of future climate change.

Plant growth promoting rhizobacteria increase the efficiency of fertilisers while reducing nitrogen loss.

More than half of the applied conventional fertiliser nitrogen (N) in cropping systems can be lost to the environment, resulting in water and air pollution. Farming systems that ensure efficient fertiliser use are crucial to sustain crop productivity without harming the environment. One avenue to achieve this is the use of bio-fertilisers with recognised benefits for plant nutrition and soil heath. Within this area, plant growth promoting rhizobacteria (PGPR) are increasingly applied to enhance plant nutrient acquisition and assimilation. Here, we investigated if PGPR can improve fertiliser performance. We show that the addition of PGPR to soils amended with 50% organic and 50% conventional N fertilisers increased the growth of kikuyu grass (Pennisetum clandestinum), producing yields similar to those obtained using 100% conventional N fertiliser. Encouragingly, this combination also reduced mineral N leaching by 95% relative to the all conventional fertiliser treatment. These findings suggest that using organic and synthetic fertilisers together in the presence of PGPR is a promising approach for sustaining plant growth while reducing potential pollution from inefficient use of conventional N fertilisers.

Vertical Distribution of Soil Denitrifying Communities in a Wet Sclerophyll Forest under Long-Term Repeated Burning.

Soil biogeochemical cycles are largely mediated by microorganisms, while fire significantly modifies biogeochemical cycles mainly via altering microbial community and substrate availability. Majority of studies on fire effects have focused on the surface soil; therefore, our understanding of the vertical distribution of microbial communities and the impacts of fire on nitrogen (N) dynamics in the soil profile is limited. Here, we examined the changes of soil denitrification capacity (DNC) and denitrifying communities with depth under different burning regimes, and their interaction with environmental gradients along the soil profile. Results showed that soil depth had a more pronounced impact than the burning treatment on the bacterial community size. The abundance of 16S rRNA and denitrification genes (narG, nirK, and nirS) declined exponentially with soil depth. Surprisingly, the nosZ-harboring denitrifiers were enriched in the deeper soil layers, which was likely to indicate that the nosZ-harboring denitrifiers could better adapt to the stress conditions (i.e., oxygen deficiency, nutrient limitation, etc.) than other denitrifiers. Soil nutrients, including dissolved organic carbon (DOC), total soluble N (TSN), ammonium (NH(4)(+)), and nitrate (NO(3)(-)), declined significantly with soil depth, which probably contributed to the vertical distribution of denitrifying communities. Soil DNC decreased significantly with soil depth, which was negligible in the depths below 20 cm. These findings have provided new insights into niche separation of the N-cycling functional guilds along the soil profile, under a varied fire disturbance regime.

A Terahertz Metasurface Sensor Based on Quasi-BIC for Detection of Additives in Infant Formula.

Prohibited additives in infant formula severely affect the health of infants. Terahertz (THz) spectroscopy has enormous application potential in analyte detection due to its rich fingerprint information content. However, there is limited research on the mixtures of multiple analytes. In this study, we propose a split ring metasurface that supports magnetic dipole bound states in the continuum (BIC). By breaking the symmetry, quasi-BIC with a high quality (Q) factor can be generated. Utilizing an angle-scanning strategy, the frequency of the resonance dip can be shifted, resulting in the plotting of an envelope curve which can reflect the molecular fingerprint of the analytes. Two prohibited additives found in infant formula, melamine and vanillin, can be identified in different proportions. Furthermore, a metric similar to the resolution in chromatographic analysis is introduced and calculated to be 0.61, indicating that these two additives can be detected simultaneously. Our research provides a new solution for detecting additives in infant formula.

Enhancing Multi-Spectral Fingerprint Sensing for Trace Explosive Molecules with All-Silicon Metasurfaces.

Spectroscopy is a powerful tool to identify the specific fingerprints of analytes in a label-free way. However, conventional sensing methods face unavoidable barriers in analyzing trace-amount target molecules due to the difficulties of enhancing the broadband molecular absorption. Here, we propose a sensing scheme to achieve strong fingerprint absorption based on the angular-scanning strategy on an all-silicon metasurface. By integrating the mid-infrared and terahertz sensing units into a single metasurface, the sensor can efficiently identify 2,4-DNT with high sensitivity. The results reveal that the fingerprint peak in the enhanced fingerprint spectrum is formed by the linked envelope. It exhibits a significant enhancement factor exceeding 64-fold in the terahertz region and more than 55-fold in the mid-infrared region. Particularly, the corresponding identification limit of 2,4-DNT is 1.32 µg cm-2, respectively. Our study will provide a novel research idea in identifying trace-amount explosives and advance practical applications of absorption spectroscopy enhancement identification in civil and military security industries.

Self-assembled nanoparticles based on cationic mono-/AIE tetra-nuclear Ir(III) complexes: long wavelength absorption/near-infrared emission photosensitizers for photodynamic therapy.

Cyclometalated Ir(III) complexes as photosensitizers (PSs) have attracted widespread attention because of their good photostability and efficient 1O2 production ability. However, their strong absorption in the UV-vis region severely limits their applications in photodynamic therapy (PDT) because the short wavelength illuminating light can be easily absorbed by the skin and subcutaneous adipose tissue causing damage to the patient's normal tissue. Herein, mono- and tetra-nuclear Ir(III) complex-porphyrin conjugates are rationally designed and synthesized, especially [TPP-4Ir]4+ exhibits obvious aggregation-induced emission (AIE) characteristics. PSs comprising Ir(III) complex-porphyrin conjugates self-assembled as nanoparticles (NPs) are successfully achieved. The obtained [TPP-Ir]+ NPs and [TPP-4Ir]4+ NPs exhibit long wavelength absorption (500-700 nm) and near-infrared emission (635-750 nm), successfully overcoming the inherent defects of short wavelength absorption of traditional Ir(III) complexes. Moreover, [TPP-4Ir]4+ NPs exhibit good biocompatibility, high 1O2 generation ability, low half-maximal inhibitory concentration (IC50) (0.47 × 10-6 M), potent cytotoxicity toward cancer cells and superior cellular uptake under white light irradiation. This work extends the scope for transition metal complex PSs with promising clinical applications.

Non-target impacts of pesticides on soil N transformations, abundances of nitrifying and denitrifying genes, and nitrous oxide emissions.

Agriculture is the leading contributor to global nitrous oxide (N2O) emissions, mostly from soils. We examined the non-target impacts of four pesticides on N transformations, N cycling genes and N2O emissions from sugarcane-cropped soil. The pesticides, including a herbicide glyphosate (GLY), an insecticide imidacloprid (IMI), a fungicide methoxy ethyl mercuric chloride (MEMC) and a fumigant methyl isothiocyanate (MITC), were added to the soil and incubated in laboratory at 25 °C. The soil microcosms were maintained at two water contents, 55 % and 90 % water holding capacity (WHC), to simulate aerobic and partly anaerobic conditions, respectively. Half of the soil samples received an initial application of KNO3 and were then maintained at 90 % WHC for 38 d, whilst the other half received (NH4)2SO4 and were maintained at 55 % WHC for 28 d followed by 10 d at 90 % WHC to favour denitrification. Responses of individual functional genes involved in nitrification and denitrification to the pesticides and their relationships to N2O emissions varied with time and soil water. Overall, MITC had pronounced repressive effects on AOA and AOB amoA gene abundances and gross nitrification. Under 55 % WHC during the initial 28 d, N2O emissions were low for all treatments (≤62 µg N kg-1 soil). However, under 90 % WHC (either during the first 28 d or the increase in water content from 55 to 90 % WHC after 28 d) the cumulative N2O emissions increased markedly. Overall, under 90 % WHC the cumulative N2O emissions were 19 (control) to 79-fold (MITC) higher than under 55% WHC; with the highest emissions observed in the MITC treatment (3140 µg N kg-1 soil). This was associated with increases in gross nitrate consumption rates and abundances of denitrifying genes (nirK, nirS and qnorB). Therefore, to minimise N2O emissions, MITC should not be applied to field under wet conditions favouring denitrification.

AIE-active Ir(III) complexes functionalised with a cationic Schiff base ligand: synthesis, photophysical properties and applications in photodynamic therapy.

Photodynamic therapy (PDT) is a promising cancer treatment method. Traditional small-molecule photosensitizers (PSs) suffer from low intersystem crossing (ISC) ability and aggregation-caused quenching (ACQ), which adversely affects the luminous efficiency and singlet oxygen (1O2) yield of PSs in the aggregated state. Ir(III) complexes are promising PSs with long excited-state lifetime, good photophysical and photochemical properties and large Stokes shifts. Aggregation-induced emission (AIE) characteristics could reduce the nonradiative recombination and improve the ISC ability of excited states through the restriction of the intramolecular motions in aggregated states. Accordingly, two AIE-active Ir(III) complexes Ir-1-N+ and Ir-2-N+ were successfully designed and obtained based on Schiff base ligands. Experimental results showed that Ir-1-N+ and Ir-2-N+ have good photophysical properties and the corresponding nanoparticles (NPs) have good water solubility and 1O2 generation ability. Notably, Ir-2-N+ NPs can be efficiently taken up by mouse breast cancer cells (4T1 cells) with good biocompatibility, low dark toxicity and excellent phototoxicity. This work demonstrates a versatile strategy for exploiting efficient transition metal PSs with a cationic ligand in PDT.

AIE-active iridium(III) complex integrated with upconversion nanoparticles for NIR-irradiated photodynamic therapy.

The integration of an aggregation induced emission (AIE)-active Ir(III) complex and upconversion nanoparticles (UCNPs) has achieved a NIR-irradiated photosensitizer (PS), UCNPs@Ir-2-N. This PS has satisfactory biocompatibility, excellent phototoxicity, good accumulation in cells and high 1O2 generation ability, thereby effectively killing 4T1 mouse cancer cells in vitro. This work has potential for future photodynamic therapy (PDT) applications.

Alzheimer-like tau accumulation in dentate gyrus mossy cells induces spatial cognitive deficits by disrupting multiple memory-related signaling and inhibiting local neural circuit.

Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD-like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg-AD mice. Further investigation demonstrated that the ventral DG (vDG) mossy cell-specific overexpressing hTau for 3 months induced spatial cognitive deficits, while expressing hTau N368 for only 1 month caused remarkable spatial cognitive impairment with more prominent tau pathologies. By in vivo electrophysiological and optic fiber recording, we observed that the vDG mossy cell-specific overexpression of hTau N368 disrupted theta oscillations with local neural network inactivation in the dorsal DG subset, suggesting impairment of the ventral to dorsal neural circuit. The mossy cell-specific transcriptomic data revealed that multiple AD-associated signaling pathways were disrupted by hTau N368, including reduction of synapse-associated proteins, inhibition of AKT and activation of glycogen synthase kinase-3ß. Importantly, chemogenetic activating mossy cells efficiently attenuated the hTau N368-induced spatial cognitive deficits. Together, our findings indicate that the mossy cell pathological tau accumulation could induce the AD-like spatial memory deficit by inhibiting the local neural network activity, which not only reveals new pathogenesis underlying the mossy cell-related spatial memory loss but also provides a mouse model of Mossy cell-specific hTau accumulation for drug development in AD and the related tauopathies.

Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.

BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One-way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One-way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.

Oxoammonium salts are catalysing efficient and selective halogenation of olefins, alkynes and aromatics.

Electrophilic halogenation reactions have been a reliable approach to accessing organohalides. During the past decades, various catalytic systems have been developed for the activation of haleniums. However, there is still a short of effective catalysts, which could cover various halogenation reactions and broad scope of unsaturated compounds. Herein, TEMPO (2,2,6,6-tetramethylpiperidine nitroxide) and its derivatives are disclosed as active catalysts for electrophilic halogenation of olefins, alkynes, and aromatics. These catalysts are stable, readily available, and reactive enough to activate haleniums including Br+, I+ and even Cl+ reagents. This catalytic system is applicable to various halogenations including haloarylation of olefins or dibromination of alkynes, which were rarely realized in previous Lewis base catalysis or Lewis acid catalysis. The high catalytic ability is attributed to a synergistic activation model of electrophilic halogenating reagents, where the carbonyl group and the halogen atom are both activated by present TEMPO catalysis.

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models.

Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells. Methods: A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity. Results: C004019 induced a robust tau clearance via promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance in vivo. Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions. Conclusions: The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both in vitro and in vivo, which provides a promising drug candidate for AD and the related tauopathies.