A Porphyrin Iron(III) π-Dication Species and its Relevance in Catalyst Design for the Umpolung of Nucleophiles

Isoporphyrins have recently been identified as remarkable species capable of turning the nucleophile attached to the porphyrin ring into an electrophile, thereby providing umpolung of reactivity (Inorg. Chem. 2022, 61, 8105–8111). They are generated by nucleophilic attack on an iron(III) π-dication, a class of species that has received scant attention. Here, we explore the effect of the porphyrin meso-substituent and report a iron(III) π-dication bearing the meso-tetraphenylporphyrin (TPP) ligand. We provide an extensive study of the species by UV/Vis absorption, 2H NMR, EPR, applied field Mössbauer, and resonance Raman spectroscopy. We further explore the system's highly dynamic and tunable properties and address the nature of the axial ligands as well as the conformation of the porphyrin ring. The insights presented are essential for the rational design of catalysts for the umpolung of nucleophiles. Such catalytic avenues could for example provide a novel method for electrophilic chlorinations. We further examine the importance of electronic tuning of the porphyrin by nature of the meso-substituent as a factor in catalyst design.</p

RobustMQ: Benchmarking Robustness of Quantized Models

Quantization has emerged as an essential technique for deploying deep neural networks (DNNs) on devices with limited resources. However, quantized models exhibit vulnerabilities when exposed to various noises in real-world applications. Despite the importance of evaluating the impact of quantization on robustness, existing research on this topic is limited and often disregards established principles of robustness evaluation, resulting in incomplete and inconclusive findings. To address this gap, we thoroughly evaluated the robustness of quantized models against various noises (adversarial attacks, natural corruptions, and systematic noises) on ImageNet. The comprehensive evaluation results empirically provide valuable insights into the robustness of quantized models in various scenarios, for example: (1) quantized models exhibit higher adversarial robustness than their floating-point counterparts, but are more vulnerable to natural corruptions and systematic noises; (2) in general, increasing the quantization bit-width results in a decrease in adversarial robustness, an increase in natural robustness, and an increase in systematic robustness; (3) among corruption methods, \textit{impulse noise} and \textit{glass blur} are the most harmful to quantized models, while \textit{brightness} has the least impact; (4) among systematic noises, the \textit{nearest neighbor interpolation} has the highest impact, while bilinear interpolation, cubic interpolation, and area interpolation are the three least harmful. Our research contributes to advancing the robust quantization of models and their deployment in real-world scenarios.Comment: 15 pages, 7 figure

Mechanistic elucidation of two catalytically versatile iron(II)- and α-ketoglutarate-dependent enzymes: cases beyond hydroxylation

Iron(II)- and α-ketoglutarate-dependent (Fe/αKG) enzymes catalyze a large array of reactions. Although hydroxylation reaction catalyzed by these enzymes has been investigated in great details, involving the ferryl (FeIV=O) as a key reactive intermediate. The mechanisms of reactions other than hydroxylation are still largely unknown. By using a combined biochemical, bio-organic, and spectroscopic approach, we have studied the mechanisms of two newly discovered Fe/αKG enzymes, FtmOx1 (endoperoxidase) and AsqJ (desaturase/epoxidase), revealing their strategies in controlling reactivity, namely the effect of redox/polar residues near the iron center, the electronic properties of the substrate, and the intrinsic reactivity of the ferryl intermediate.Accepted manuscrip

Isolation and Induction: Training Robust Deep Neural Networks against Model Stealing Attacks

Despite the broad application of Machine Learning models as a Service (MLaaS), they are vulnerable to model stealing attacks. These attacks can replicate the model functionality by using the black-box query process without any prior knowledge of the target victim model. Existing stealing defenses add deceptive perturbations to the victim's posterior probabilities to mislead the attackers. However, these defenses are now suffering problems of high inference computational overheads and unfavorable trade-offs between benign accuracy and stealing robustness, which challenges the feasibility of deployed models in practice. To address the problems, this paper proposes Isolation and Induction (InI), a novel and effective training framework for model stealing defenses. Instead of deploying auxiliary defense modules that introduce redundant inference time, InI directly trains a defensive model by isolating the adversary's training gradient from the expected gradient, which can effectively reduce the inference computational cost. In contrast to adding perturbations over model predictions that harm the benign accuracy, we train models to produce uninformative outputs against stealing queries, which can induce the adversary to extract little useful knowledge from victim models with minimal impact on the benign performance. Extensive experiments on several visual classification datasets (e.g., MNIST and CIFAR10) demonstrate the superior robustness (up to 48% reduction on stealing accuracy) and speed (up to 25.4x faster) of our InI over other state-of-the-art methods. Our codes can be found in https://github.com/DIG-Beihang/InI-Model-Stealing-Defense.Comment: Accepted by ACM Multimedia 202

DCAF1 controls T-cell function via p53-dependent and -independent mechanisms

On activation, naive T cells grow in size and enter cell cycle to mount immune response. How the fundamental processes of T-cell growth and cell cycle entry are regulated is poorly understood. Here we report that DCAF1 (Ddb1–cullin4-associated-factor 1) is essential for these processes. The deletion of DCAF1 in T cells impairs their peripheral homeostasis. DCAF1 is upregulated on T-cell receptor activation and critical for activation-induced T-cell growth, cell cycle entry and proliferation. In addition, DCAF1 is required for T-cell expansion and function during anti-viral and autoimmune responses in vivo. DCAF1 deletion leads to a drastic stabilization of p53 protein, which can be attributed to a requirement of DCAF1 for MDM2-mediated p53 poly-ubiquitination. Importantly, p53 deletion rescues the cell cycle entry defect but not the growth defect of DCAF1-deficient cells. Therefore, DCAF1 is vital for T-cell function through p53-dependent and -independent mechanisms

Control of Intestinal Inflammation, Colitis-Associated Tumorigenesis, and Macrophage Polarization by Fibrinogen-Like Protein 2

Fibrinogen-like protein 2 (Fgl2) is critical for immune regulation in the inflammatory state. Elevated Fgl2 levels are observed in patients with inflammatory bowel disease (IBD), but little is known about its functional significance. In this study, we sought to investigate the role of Fgl2 in the development of intestinal inflammation and colitis-associated colorectal cancer (CAC). Here, we report that Fgl2 deficiency increased susceptibility to dextran sodium sulfate-induced colitis and CAC in a mouse model. During colitis development, the expression of the membrane-bound and secreted forms of Fgl2 (mFgl2 and sFgl2, respectively) in the colon were increased and predominantly expressed by colonic macrophages. In addition, using bone marrow chimeric mice, we determined that Fgl2 function in colitis is strictly related to its expression in the hematopoietic cells. Loss of Fgl2 induced the polarization of M1, but suppressed that of M2 both in vivo and in vitro, independent of intestinal inflammation. Thus, Fgl2 suppresses intestinal inflammation and CAC development through its role in macrophage polarization and may serve as a therapeutic target in inflammatory diseases, including IBD

Dihydroartemisinin ameliorates inflammatory disease by its reciprocal effects on Th and Treg cell function via modulating mTOR pathway

Dihydroartemisinin (DHA) is an important derivative of an herb medicine Artemisia annua L., used in ancient China. DHA is currently used world-wide to treat malaria by killing malaria-causing parasites. In addition to this prominent effect, DHA is suggested to regulate cellular functions, such as angiogenesis, tumor cell growth and immunity. Nonetheless, how DHA affects T cell function remains poorly understood. We found that DHA potently suppressed Th cell differentiation in vitro. Unexpectedly however, DHA greatly promoted Treg cell generation, in a manner dependent on TGF-βR:Smad signal. In addition, DHA treatment effectively reduced EAE onset and ameliorated ongoing EAE in mice. Administration of DHA significantly decreased Th but increased Treg cells in EAE-inflicted mice without apparent global immune suppression. Moreover, DHA modulated mTOR pathway, because mTOR signal was attenuated in T cells upon DHA treatment. Importantly, enhanced Akt activity neutralized DHA-mediated effects on T cells in an mTOR dependent fashion. This study therefore reveals a novel immune regulatory function of DHA to reciprocally regulate Th and Treg cell generation through modulating mTOR pathway. It addresses how DHA regulates immune function and suggests a new type of drug for treating diseases where mTOR activity to be tempered

Spectroscopic Description of the E1 State of Mo Nitrogenase Based on Mo and Fe X‑ray Absorption and Mössbauer Studies

Mo nitrogenase (N2ase) utilizes a two-component protein system, the catalytic MoFe and its electron-transfer partner FeP, to reduce atmospheric dinitrogen (N2) to ammonia (NH3). The FeMo cofactor contained in the MoFe protein serves as the catalytic center for this reaction and has long inspired model chemistry oriented toward activating N2. This field of chemistry has relied heavily on the detailed characterization of how Mo N2ase accomplishes this feat. Understanding the reaction mechanism of Mo N2ase itself has presented one of the most challenging problems in bioinorganic chemistry because of the ephemeral nature of its catalytic intermediates, which are difficult, if not impossible, to singly isolate. This is further exacerbated by the near necessity of FeP to reduce native MoFe, rendering most traditional means of selective reduction inept. We have now investigated the first fundamental intermediate of the MoFe catalytic cycle, E1, as prepared both by low-flux turnover and radiolytic cryoreduction, using a combination of Mo Kα highenergy-resolution fluorescence detection and Fe K-edge partial-fluorescence-yield X-ray absorption spectroscopy techniques. The results demonstrate that the formation of this state is the result of an Fe-centered reduction and that Mo remains redoxinnocent. Furthermore, using Fe X-ray absorption and 57Fe Mössbauer spectroscopies, we correlate a previously reported unique species formed under cryoreducing conditions to the natively formed E1 state through annealing, demonstrating the viability of cryoreduction in studying the catalytic intermediates of MoFe

OvoAMtht from Methyloversatilis thermotolerans ovothiol biosynthesis is a bifunction enzyme: thiol oxygenase and sulfoxide synthase activities

Mononuclear non-heme iron enzymes are a large class of enzymes catalyzing a wide-range of reactions. In this work, we report that a non-heme iron enzyme in Methyloversatilis thermotolerans, OvoAMtht, has two different activities, as a thiol oxygenase and a sulfoxide synthase. When cysteine is presented as the only substrate, OvoAMtht is a thiol oxygenase. In the presence of both histidine and cysteine as substrates, OvoAMtht catalyzes the oxidative coupling between histidine and cysteine (a sulfoxide synthase). Additionally, we demonstrate that both substrates and the active site iron's secondary coordination shell residues exert exquisite control over the dual activities of OvoAMtht (sulfoxide synthase vs. thiol oxygenase activities). OvoAMtht is an excellent system for future detailed mechanistic investigation on how metal ligands and secondary coordination shell residues fine-tune the iron-center electronic properties to achieve different reactivities.R35 GM136294 - NIGMS NIH HHSPublished versio

Retraction note: endoperoxide formation by an α-ketoglutarate-dependent mononuclear non-haem iron enzyme

Accepted manuscrip