Federated Learning Backdoor Attack Based on Frequency Domain Injection.

Federated learning (FL) is a distributed machine learning framework that enables scattered participants to collaboratively train machine learning models without revealing information to other participants. Due to its distributed nature, FL is susceptible to being manipulated by malicious clients. These malicious clients can launch backdoor attacks by contaminating local data or tampering with local model gradients, thereby damaging the global model. However, existing backdoor attacks in distributed scenarios have several vulnerabilities. For example, (1) the triggers in distributed backdoor attacks are mostly visible and easily perceivable by humans; (2) these triggers are mostly applied in the spatial domain, inevitably corrupting the semantic information of the contaminated pixels. To address these issues, this paper introduces a frequency-domain injection-based backdoor attack in FL. Specifically, by performing a Fourier transform, the trigger and the clean image are linearly mixed in the frequency domain, injecting the low-frequency information of the trigger into the clean image while preserving its semantic information. Experiments on multiple image classification datasets demonstrate that the attack method proposed in this paper is stealthier and more effective in FL scenarios compared to existing attack methods.

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma.

Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma-associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.

Genome-Wide Identification and Expression Profile Analysis of the SnRK2 Gene Family in Nicotiana tabacum.

SnRK2 protein kinase family plays an important role in plant response to abiotic stress and has been identified in various plants. This study aimed to identify SnRK2 genes in tobacco and systematically analyze their expression under abscisic acid treatment and abiotic stress. We identified 22 NtSnRK2 members, which were divided into three groups and located on 13 chromosomes, mainly at both ends of the chromosomes; additionally, 11 duplicated NtSnRK2 gene pairs were observed. Phylogenetic analysis showed that these SnRK2 members were divided into three groups in tobacco. The motifs of NtSnRK2 proteins in the same group were highly similar. Subcellular localization indicated that NtSnRK2s in Group3 were present in the nucleus, cytomembrane, and cytoplasm. Gene expression pattern analysis revealed that NtSnRK2 genes played a role in the responses to several abiotic stresses (salt, drought, and low-temperature stress), indicating that they are widely involved in the adaptation of tobacco to adverse environmental conditions.

Novel Small Molecule Fibroblast Growth Factor 23 Inhibitors Increase Serum Phosphate and Improve Skeletal Abnormalities in Hyp Mice.

Excess fibroblast growth factor (FGF) 23 causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the fibroblast growth factor receptor/α-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design, we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23. Additional structure-activity studies developed a series of ZINC13407541 analogs with enhanced drug-like properties. In this study, we tested in a preclinical Hyp mouse homolog of XLH a direct connect analog [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] (8n), which exhibited the greatest stability in microsomal assays, and [(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] (13a), which exhibited increased in vitro potency. Using cryo-electron microscopy structure and computational docking, we identified a key binding residue (Q156) of the FGF23 antagonists, ZINC13407541, and its analogs (8n and 13a) in the N-terminal domain of FGF23 protein. Site-directed mutagenesis and bimolecular fluorescence complementation-fluorescence resonance energy transfer assay confirmed the binding site of these three antagonists. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and increased serum phosphate and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations in Hyp mice. Long-term parenteral treatment with 8n or 13a also enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate in Hyp mice. The more potent 13a compound had greater therapeutic effects in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat excess FGF23-mediated disorders. SIGNIFICANCE STATEMENT: This study used structure-based drug design and medicinal chemistry approaches to identify and optimize small molecules with different stability and potency, which antagonize excessive actions of fibroblast growth factor 23 (FGF23) in hereditary hypophosphatemic rickets. The findings confirmed that these antagonists bind to the N-terminus of FGF23 to inhibit its binding to and activation of the fibroblast growth factor receptors/α-Klotho signaling complex. Administration of these lead compounds improved phosphate homeostasis and abnormal skeletal phenotypes in a preclinical Hyp mouse model.

Enzymatic dimerization in the biosynthetic pathway of microbial natural products.

Covering: up to August 2020The dramatic increase in the identification of dimeric natural products generated by microorganisms and plants has played a significant role in drug discovery. The biosynthetic pathways of these products feature inherent dimerization reactions, which are valuable for biosynthetic applications and chemical transformations. The extraordinary mechanisms of the dimerization of secondary metabolites should advance our understanding of the uncommon chemical rules for natural product biosynthesis, which will, in turn, accelerate the discovery of dimeric reactions and molecules in nature and provide promising strategies for the total synthesis of natural products through dimerization. This review focuses on the enzymes involved in the dimerization in the biosynthetic pathway of microbial natural products, with an emphasis on cytochrome P450s, laccases, and intermolecular [4 + 2] cyclases, along with other atypical enzymes. The identification, characterization, and catalytic landscapes of these enzymes are also introduced.

Associations of prenatal metabolomics profiles with early childhood growth trajectories and obesity risk in African Americans: the CANDLE study.

OBJECTIVE: Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring. METHODS: This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers' plasma samples collected during the second trimester. The children's BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes. RESULTS: The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95-4.54) and 2.03 (1.54-2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03-0.18) and 0.07 (0.02-0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively. CONCLUSIONS: Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.

A dual-targeting ruthenium nanodrug that inhibits primary tumor growth and lung metastasis via the PARP/ATM pathway.

BACKGROUND: Many studies have found that ruthenium complexes possess unique biochemical characteristics and inhibit tumor growth or metastasis. RESULTS: Here, we report the novel dual-targeting ruthenium candidate 2b, which has both antitumor and antimetastatic properties and targets tumor sites through the enhanced permeability and retention (EPR) effect and transferrin/transferrin receptor (TF/TFR) interaction. The candidate 2b is composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b triggered DNA cleavage and thus blocked cell cycle progression and induced apoptosis via the PARP/ATM pathway. In vivo, 2b inhibited not only Lewis lung cancer (LLC) tumor growth but also lung metastasis. We detected apoptosis and decreased CD31 expression in tumor tissues, and ruthenium accumulated in the primary tumor tissue of C57BL/6 mice implanted with LLC cells. CONCLUSIONS: Thus, we conclude that 2b targets tumors, inhibits tumor growth and prevents lung metastasis.

Pd/Cu-Catalyzed Defluorinative Carbonylative Coupling of Aryl Iodides and gem-Difluoroalkenes: Efficient Synthesis of α-Fluorochalcones.

An unprecedented and challenging defluorinative carbonylation was achieved. Enabled by a Pd/Cu cooperative catalyst system, the first example of defluorinative carbonylative coupling has been established. With gem-difluoroalkenes and aryl iodides as the substrates, this methodology offers flexible and facile access to privileged α-fluorochalcones under mild reaction conditions in moderate-to-excellent yields. Mechanistic studies indicated transmetalation between palladium and copper intermediates as a crucial step of the catalytic cycle.

A General and Highly Selective Palladium-Catalyzed Hydroamidation of 1,3-Diynes.

A chemo-, regio-, and stereoselective mono-hydroamidation of (un)symmetrical 1,3-diynes is described. Key for the success of this novel transformation is the utilization of an advanced palladium catalyst system with the specific ligand Neolephos. The synthetic value of this general approach to synthetically useful α-alkynyl-α, ß-unsaturated amides is showcased by diversification of several structurally complex molecules and marketed drugs. Control experiments and density-functional theory (M06L-SMD) computations also suggest the crucial role of the substrate in controlling the regioselectivity of unsymmetrical 1,3-diynes.

Efficient Palladium-Catalyzed Carbonylation of 1,3-Dienes: Selective Synthesis of Adipates and Other Aliphatic Diesters.

The dicarbonylation of 1,3-butadiene to adipic acid derivatives offers the potential for a more cost-efficient and environmentally benign industrial process. However, the complex reaction network of regioisomeric carbonylation and isomerization pathways, make a selective and direct transformation particularly difficult. Here, we report surprising solvent effects on this palladium-catalysed process in the presence of 1,2-bis-di-tert-butylphosphin-oxylene (dtbpx) ligands, which allow adipate diester formation from 1,3-butadiene, carbon monoxide, and methanol with 97 % selectivity and 100 % atom-economy under scalable conditions. Under optimal conditions a variety of di- and triesters from 1,2- and 1,3-dienes can be obtained in good to excellent yields.

GLL398, an oral selective estrogen receptor degrader (SERD), blocks tumor growth in xenograft breast cancer models.

PURPOSE: Selective estrogen receptor degrader (SERD) has proven clinically effective in treating advanced or metastatic breast cancer since the approval of fulvestrant by FDA in 2002. Recent expansion of indications as a first line monotherapy and as combination therapy with CDK4/6 inhibitors further extends its clinical utility as an efficacious breast cancer endocrine regimen. However, the poor pharmacokinetic properties of fulvestrant and its injection-only administration route has driven continued efforts to develop orally bioavailability SERD that could potentially improve clinical response to SERD treatment. GLL398, a boron-modified GW5638 analog, showed superior oral bioavailability, while retaining both antiestrogenic activity and ER degrading efficacy at a potency level comparable to the more active metabolite of GW5638, GW7604. METHODS: Here we used molecular modeling, ER (Y537S) binding assay, MCF-7 Xenograft tumor, and patient-derived xenograft (PDX) tumor model to conduct further studies on the pharmacology and metabolism of GLL398. RESULTS: Consistent with GLL398's robust activities in breast cancer cells that either are tamoxifen resistant or express constitutively active, mutant ESR1 (Y537S), it was found to bind the mutant ERY537S with high affinity. Molecular modeling of the binding mode of GLL398 to ER also found its molecular interactions consistent with the experimentally determined high binding affinity towards WT ER and ERY537S. To test the in vivo efficacy of GLL398, mice bearing MCF-7-derived xenograft breast tumors and patient-derived xenograft tumors harboring ERY537S were treated with GLL398 which potently inhibited tumor growth in mice. CONCLUSIONS: This study demonstrates GLL398 is an oral SERD that has therapeutic efficacy in clinically relevant breast tumor models.

Rv1075c of Mycobacterium tuberculosis is a GDSL-Like Esterase and Is Important for Intracellular Survival.

Mycobacterium tuberculosis lipid metabolism pathways facilitate access to carbon and energy sources during infection. M. tuberculosis gene Rv1075c was annotated as a conserved hypothetical protein. We identified that Rv1075c amino acid sequence shares similarities with other bacterial lipase/esterases and we demonstrated that it has esterase activity, with preference for short-chain fatty acids, particularly acetate, with highest activity at 45°C, pH 9. Site-direct mutagenesis revealed its activity triad as Ser80, Asp244, and His247. We further determined that rRv1075c hydrolyzed triacetin and tributyrin, and it was mainly distributed in cell wall and membrane. Its expression was induced at pH 4.5, mimicking the acidic phagosome of macrophages. Mutation of Rv1075c led to reduced bacterial growth in THP-1 cells and human peripheral blood mononuclear cell-derived macrophages, and attenuated M. tuberculosis infection in mice. Our data suggest that Rv1075c is involved in ester and fatty acid metabolism inside host cells.

Tailored Palladium Catalysts for Selective Synthesis of Conjugated Enynes by Monocarbonylation of 1,3-Diynes.

For the first time, the monoalkoxycarbonylation of easily available 1,3-diynes to give synthetically useful conjugated enynes has been realized. Key to success was the design and utilization of the new ligand 2,2'-bis(tert-butyl(pyridin-2-yl)phosphanyl)-1,1'-binaphthalene (Neolephos), which permits the palladium-catalyzed selective carbonylation under mild conditions, providing a general preparation of functionalized 1,3-enynes in good-to-high yields with excellent chemoselectivities. Synthetic applications that showcase the possibilities of this novel methodology include an efficient one-pot synthesis of 4-aryl-4H-pyrans as well as the rapid construction of various heterocyclic, bicyclic, and polycyclic compounds.

Direct and Selective Synthesis of Adipic and Other Dicarboxylic Acids by Palladium-Catalyzed Carbonylation of Allylic Alcohols.

A general and direct synthesis of dicarboxylic acids including industrially important adipic acid by palladium-catalyzed dicarbonylation of allylic alcohol is reported. Specifically, the combination of PdCl2 and a bisphosphine ligand (HeMaRaphos) promotes two different carbonylation reactions with high activity and excellent selectivity.

Ligand-Controlled Palladium-Catalyzed Carbonylation of Alkynols: Highly Selective Synthesis of α-Methylene-ß-Lactones.

The first general and regioselective Pd-catalyzed cyclocarbonylation to give α-methylene-ß-lactones is reported. Key to the success for this process is the use of a specific sterically demanding phosphine ligand based on N-arylated imidazole (L11) in the presence of Pd(MeCN)2 Cl2 as pre-catalyst. A variety of easily available alkynols provide under additive-free conditions the corresponding α-methylene-ß-lactones in moderate to good yields with excellent regio- and diastereoselectivity. The applicability of this novel methodology is showcased by the direct carbonylation of biologically active molecules including natural products.

Enzymatic Intermolecular Hetero-Diels-Alder Reaction in the Biosynthesis of Tropolonic Sesquiterpenes.

Diels-Alder reactions are among the most powerful synthetic transformations to construct complex natural products. Despite that increasing of enzymatic intramolecular Diels-Alder reactions have been discovered, natural intermolecular Diels-Alderases are rarely described. Here, we report an intermolecular hetero-Diels-Alder reaction in the biosynthesis of tropolonic sesquiterpenes and functionally characterize EupfF as the first fungal intermolecular hetero-Diels-Alderase. We demonstrate that EupfF catalyzed the dehydration of a hydroxymethyl-containing tropolone (5) to generate a reactive tropolone o-quinone methide (6) and might further stereoselectively control the subsequent intermolecular hetero-Diels-Alder reaction with (1E,4E,8Z)-humulenol (8) to produce enantiomerically pure neosetophomone B (1). Our results reveal the biosynthetic pathway of 1 and expand the repertoire of activities of Diels-Alder cyclases.

Coumarins and P450s, Studies Reported to-Date.

Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions into more polar and easier to excrete species. In addition to their role in detoxification, they play important roles in the biosynthesis of endogenous compounds and the bioactivation of xenobiotics. Coumarins, phytochemicals abundant in food and commonly used in fragrances and cosmetics, have been shown to interact with P450 enzymes as substrates and/or inhibitors. In this review, these interactions and their significance in pharmacology and toxicology are discussed in detail.

Anti-Mycobacterium tuberculosis Terpenoids from Resina Commiphora.

Four new compounds including two new sesquiterpenoid dimers, commiphoroids E (1) and F (2), a new triterpenoid (3), and a new sesquiterpenoid (4), along with three known terpenoids (5-7) were isolated from Resina Commiphora, whose structures were identified by NMR spectra, HRESIMS, and X-ray diffraction analysis. Compounds 1 and 2 both bear an O-bridge ring and feature a plausible [4 + 2] Diels-Alder cycloaddition reaction. Antimycobacterial activities show that all the tested compounds (200 µM) could inhibit the growth of both sensitive and clinically multi-drug resistant (MDR) isolated strains. In addition, cellular toxicity of the isolates against human cancer cells and THP-1 monocyte cells was examined.

Stereoselective Synthesis of Highly Substituted Conjugated Dienes via Pd-Catalyzed Carbonylation of 1,3-Diynes.

The stereoselective synthesis of conjugated dienes was realized for the first time via Pd-catalyzed alkoxycarbonylation of easily available 1,3-diynes. Key to success is the utilization of the specific ligand 1,1'-ferrocenediyl-bis(tert-butyl(pyridin-2-yl)phosphine) (L1), which allows this novel transformation to proceed at room temperature. A range of 1,2,3,4-tetrasubstituted conjugated dienes are obtained in this straightforward access in high yields and selectivities. The synthetic utility of the protocol is showcased in the concise synthesis of several important intermediates for construction of natural products rac-cagayanin, rac-galbulin, rac-agastinol, and cannabisin G.

Pd-Catalyzed Selective Carbonylation of gem-Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters.

The first catalyst for the alkoxycarbonylation of gem-difluoroalkenes is described. This novel catalytic transformation proceeds in the presence of Pd(acac)2 /1,2-bis((di-tert-butylphosphan-yl)methyl)benzene (btbpx) (L4) and allows for an efficient and straightforward access to a range of difluoromethylated esters in high yields and regioselectivities. The synthetic utility of the protocol is showcased in the practical synthesis of a Cyclandelate analogue using this methodology as the key step.