Table_1_A more than four-fold sex-specific difference of autism spectrum disorders and the possible contribution of pesticide usage in China 1990–2030.DOCX

Autism spectrum disorders (ASDs) are prevalent in children and adolescents and disproportionately affect males, and the main contributing factors underlying male vulnerability remain widely unknown. Pesticide use is widely reported to be associated with ASD risk, and the cases of pesticide poisoning incidence in rural areas are remarkably higher than those in the urban areas while the prevalence of ASDs in rural areas was higher than that in urban areas and the rate of male pesticide poisoning was significantly higher than female. Thus, pesticide usage may be an important contributing factor for causing sex-specific differences of ASD incidence. ASD burden was analyzed by using the data of ASD number, ASD rate (ASD cases per 100,000 persons) and disability-adjusted life years (DALYs) from 1990 to 2019. The changes from 1990 to 2030 were predicted using autoregressive integrated moving average (ARIMA) in time series forecasting based on the small values of Akaike information criterion and Bayesian information criterion. Finally, the relationship between ASD rate and pesticide usage risk index (PURI) was analyzed via Pearson's correlation coefficient. ASD number, ASD rate and DALYs will be reduced by 45.5% ± 8.2% (t = 9.100 and p = 0.0119), 56.6% ± 10.2% (t = 9.111 and p = 0.0118), and 44.9% ± 7.0% (t = 20.90 and p = 0.0023) from 1990 to 2030 in China. PURI has a strong relationship with ASD rate (rho = 0.953 to 0.988 and p < 0.0001). Pesticide poisoning incidence in males is up to 2-fold higher than that in females. ASD number and DALYs in males are 4-fold higher than those in females. Furthermore, there is growing evidence supporting that males are more susceptible than females to pesticides with sex differences in neurotoxicogenetics. Therefore, pesticide poisoning may be a contributing factor for causing the sex differences of ASD. Much work still needs to be done to confirm that.</p

Chemoenzymatic Approaches to Izidine Alkaloids: An Efficient Total Synthesis of (+)-Absouline and Laburnamine

Izidines are widespread structural motifs among alkaloid natural products and are also important building blocks commonly found in pharmaceuticals. Here, we report a concise and scalable chemoenzymatic synthetic route for the highly efficient asymmetric synthesis of 1-aminopyrrolizidine alkaloids, including (+)-absouline and laburnamine. The key stereoselective transformation is based on a biocatalytic cascade involving two biosynthetic enzymes from the loline biosynthetic pathway, a Mannich cyclase LolT and a decarboxylase LolD. We also demonstrate the generality of this chemoenzymatic approach for rapid access of diverse enantiopure amino-izidine motifs. Our work demonstrated the synthetic prowess of LolT and LolD, and it has paved the way for future study on the structure–activity relationship of amino-izidine analogues

Chemoenzymatic Approaches to Izidine Alkaloids: An Efficient Total Synthesis of (+)-Absouline and Laburnamine

Izidines are widespread structural motifs among alkaloid natural products and are also important building blocks commonly found in pharmaceuticals. Here, we report a concise and scalable chemoenzymatic synthetic route for the highly efficient asymmetric synthesis of 1-aminopyrrolizidine alkaloids, including (+)-absouline and laburnamine. The key stereoselective transformation is based on a biocatalytic cascade involving two biosynthetic enzymes from the loline biosynthetic pathway, a Mannich cyclase LolT and a decarboxylase LolD. We also demonstrate the generality of this chemoenzymatic approach for rapid access of diverse enantiopure amino-izidine motifs. Our work demonstrated the synthetic prowess of LolT and LolD, and it has paved the way for future study on the structure–activity relationship of amino-izidine analogues

Biosynthesis of Long-Chain <i>N</i>‑Acyl Amide by a Truncated Polyketide Synthase–Nonribosomal Peptide Synthetase Hybrid Megasynthase in Fungi

Truncated iterative polyketide synthase–nonribosomal peptide synthetase (PKS-NRPS) megasynthases in which only the C domain is present are widespread in fungi, yet nearly all members have unknown functions. Bioinformatics analysis showed that the C domains of such PKS-C enzymes are noncanonical due to substitution at the second histidine in the active site H<b>H</b>xxxDG motif. Here, we used genome mining strategy to characterize a cryptic PKS-C hybrid from Talaromyces wortmanii and discovered the products are reduced long-chain polyketides amidated with a specific ω-amino acid 5-aminopentanoic acid (5PA). The wortmanamides resemble long-chain <i>N</i>-acyl-amide signaling lipids that target diverse receptors including GPCRs. The noncanonical C domain of this PKS-C hybrid was also demonstrated to be a bona fide condensation domain that specifically selects 5PA and catalyzes amidation to release polyketide chain

Supplemental Material - Does Long-Term Shift Work Increase the Risk of Dementia? A Systematic Review and Meta-Analysis

Supplemental Material for Does Long-Term Shift Work Increase the Risk of Dementia? A Systematic Review and Meta-Analysis by Yang Hai, Ying Xue, and Yu-hong Wang in American Journal of Alzheimer's Disease & Other Dementias®</p

Crystal Structure of an Arginase-like Protein from <i>Trypanosoma brucei</i> That Evolved without a Binuclear Manganese Cluster

The X-ray crystal structure of an arginase-like protein from the parasitic protozoan <i>Trypanosoma brucei</i>, designated TbARG, is reported at 1.80 and 2.38 Å resolution in its reduced and oxidized forms, respectively. The oxidized form of TbARG is a disulfide-linked hexamer that retains the overall architecture of a dimer of trimers in the reduced form. Intriguingly, TbARG does not contain metal ions in its putative active site, and amino acid sequence comparisons indicate that all but one of the residues required for coordination to the catalytically obligatory binuclear manganese cluster in other arginases are substituted here with residues incapable of metal ion coordination. Therefore, the structure of TbARG is the first of a member of the arginase/deacetylase superfamily that is not a metalloprotein. Although we show that metal binding activity is easily reconstituted in TbARG by site-directed mutagenesis and confirmed in X-ray crystal structures, it is curious that this protein and its parasitic orthologues evolved away from metal binding function. Knockout of the TbARG gene from the genome demonstrated that its function is not essential to cultured bloodstream-form <i>T. brucei</i>, and metabolomics analysis confirmed that the enzyme has no role in the conversion of l-arginine to l-ornithine in these cells. While the molecular function of TbARG remains enigmatic, the fact that the <i>T. brucei</i> genome encodes only this protein and not a functional arginase indicates that the parasite must import l-ornithine from its host to provide a source of substrate for ornithine decarboxylase in the polyamine biosynthetic pathway, an active target for the development of antiparasitic drugs

Structural Basis for Aza-Glycine Stabilization of Collagen

Previously, we have demonstrated that replacement of the strictly conserved glycine in collagen with aza-glycine provides a general solution for stabilizing triple helical collagen peptides (Chenoweth, D. M.; et al. <i>J. Am. Chem. Soc.</i> <b>2016</b>, <i>138</i>, 9751; <b>2015</b>, <i>137</i>, 12422). The additional hydrogen bond and conformational constraints provided by aza-glycine increases the thermal stability and rate of folding in collagen peptides composed of Pro-Hyp-Gly triplet repeats, allowing for truncation to the smallest self-assembling peptide systems observed to date. Here we show that aza-glycine substitution enhances the stability of an arginine-containing collagen peptide and provide a structural basis for this stabilization with an atomic resolution crystal structure. These results demonstrate that a single nitrogen atom substitution for a glycine alpha-carbon increases the peptide’s triple helix melting temperature by 8.6 °C. Furthermore, we provide the first structural basis for stabilization of triple helical collagen peptides containing aza-glycine and we demonstrate that minimal alteration to the peptide backbone conformation occurs with aza-glycine incorporation

Crystal Structure of <i>Schistosoma mansoni</i> Arginase, a Potential Drug Target for the Treatment of Schistosomiasis

The X-ray crystal structure of arginase from <i>Schistosoma mansoni</i> (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although the amino acid sequence of SmARG is only 42% identical with that of human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2­(<i>S</i>)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide a proof of concept for this approach in the enhancement of enzyme–inhibitor affinity

Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation

Hydroalkoxylation is a powerful and efficient method of forming C–O bonds and cyclic ethers in synthetic chemistry. In studying the biosynthesis of the fungal natural product herque­inone, we identified an enzyme that can perform an intra­molecular enantio­selective hydro­alkoxyl­ation reaction. PhnH catalyzes the addition of a phenol to the terminal olefin of a reverse prenyl group to give a dihydro­benzo­furan product. The enzyme accelerates the reaction by 3 × 10⁵-fold compared to the uncatalyzed reaction. PhnH belongs to a super­family of proteins with a domain of unknown function (DUF3237), of which no member has a previously verified function. The discovery of PhnH demonstrates that enzymes can be used to promote the enantio­selective hydro­alkoxyl­ation reaction and form cyclic ethers

Table_3_Multi-omics approaches to understand pathogenicity during potato early blight disease caused by Alternaria solani.XLSX

Potato early blight (PEB), a foliar disease of potato during the growing period, caused by Alternaria sp., is common in major potato-producing areas worldwide. Effective agents to control this disease or completely resistant potato varieties are absent. Large-scale use of fungicides is limited due to possibility of increase in pathogen resistance and the requirements of ecological agriculture. In this study, we focused on the composition and infection characteristics of early blight pathogens in Yunnan Province and screened candidate pathogenesis-related pathways and genes. We isolated 85 strains of Alternaria sp. fungi from typical early blight spots in three potato-growing regions in Yunnan Province from 2018 to 2022, and identified 35 strains of Alternaria solani and 50 strains of Alternaria alternata by morphological characterization and ITS sequence comparison, which were identified as the main and conditional pathogens causing early blight in potato, respectively. Scanning electron microscope analysis confirmed only A. solani producing appressorium at 4 h after inoculation successfully infected the leaf cells. Via genome assembly and annotation, combine transcriptome and proteomic analysis, the following pathogenicity-related unit, transcription factors and metabolic pathway were identified: (1) cell wall-degrading enzymes, such as pectinase, keratinase, and cellulase; (2) genes and pathways related to conidia germination and pathogenicity, such as ubiquitination and peroxisomes; and (3) transcription factors, such as Zn-clus, C2H2, bZIP, and bHLH. These elements were responsible for PEB epidemic in Yunnan.</p