Crystal structure combined with metabolomics and biochemical studies indicates that FAM3A participates in fatty acid beta-oxidation upon binding of acyl-L-carnitine.

As the first member of the family with sequence similarity 3 (FAM3), FAM3A promotes synthesis of ATP in mitochondria of hepatic cells and cells from other organs. Dysregulations of FAM3A are involved in the development of diabetes and nonalcoholic fatty liver disease (NAFLD). So far, the molecule mechanism under the physiological and pathological functions of FAM3A is largely unexplored. Here, we determined the crystal structure of FAM3A at high resolution of 1.38Å, complexed with an unknown-source compound which was characterized through metabolomics and confirmed as methacholine by thermal shift assay and surface plasmon resonance (SPR). Exploration for natural ligands of FAM3A was conducted through the same molecular interaction assays. The observed binding of acyl-L-carnitine molecules indicated FAM3A participating in fatty acid beta-oxidation. Knockdown and rescue assays coupled with fatty acid oxidation determination confirmed the role of FAM3A in beta-oxidation. This investigation reveals the molecular mechanism for the biological function of FAM3A and would provide basis for identifying drug target for treatment of diabetes and NAFLD.

Carbon Dot-Stabilized Hydrogel Composite: A New Adsorbent for Efficient and Sustainable Pb(II) Removal.

In this paper, a carbon dot hydrogel composite (CDs-Hy) capable of efficiently removing Pb(II) was prepared by hydrogen bonding self-assembly in combination with carbon dots and a hydrogel. CDs-Hy was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS), and the effect of the adsorption conditions on the adsorption efficiency of CDs-Hy was studied. The results of the study showed that the incorporation of carbon dots, on the one hand, significantly increased the adsorption capacity of the material. On the other hand, it can increase the stability of hydrogels in aqueous solution. The possible adsorption mechanisms were further verified as ion exchange and coordination. CDs-Hy is a novel adsorbent material capable of removing Pb2+ efficiently, which can be reused several times with high stability.

Structural basis for the distinct core-antenna assembly of cryptophyte photosystem II.

Photosystem II (PSII) catalyzes the light-driven charge separation and water oxidation reactions of photosynthesis. Eukaryotic PSII core is usually associated with membrane-embedded light-harvesting antennae, which greatly increase the absorbance cross-section of the core. The peripheral antennae in different phototrophs vary considerably in protein composition and arrangement. Photosynthetic cryptophytes possess chlorophyll a/c binding proteins (CACs) that serve as their antennae. How these CACs assemble with the PSII core remains unclear. Here, we report the 2.57-Å resolution structure of cryptophyte PSII-CAC purified from cells at nitrogen-limited stationary growth phase. We show that each monomer of the PSII homodimer contains a core complex, six chlorophyll a/c binding proteins (CACs) and a previously unseen chlorophyll-binding protein (termed CAL-II). Six CACs are arranged as a double-layered arc-shaped non-parallel belt, and two such belts attach to the dimeric core from opposite sides. The CAL-II simultaneously interacts with a number of core subunits and five CACs. The distinct organization of CACs and the presence of CAL-II may play a critical role in stabilizing the dimeric PSII-CAC complex under stress conditions. Our study provides mechanistic insights into the assembly and function of the PSII-CAC complex as well as the possible adaptation of cryptophytes in response to environmental stresses.

Retrospective study of the impact of diabetes on the severity and prognosis of COVID­19.

Patients with diabetes coexisting with viral infection tend to have poor outcomes, but the association between diabetes and coronavirus disease 2019 (COVID-19) prognosis is controversial at present. The present study reviewed and analyzed the data of 1,892 patients with COVID-19 admitted to Shaanxi Provincial People's Hospital (Xi'an, China). Demographic, clinical, laboratory and treatment data as well as clinical outcomes were extracted from the electronic medical records and compared between patients with and without diabetes. Multivariate logistic regression analysis was used to determine the risk factors affecting the prognosis of COVID-19. Compared with patients without diabetes, the levels of glucose, C-reactive protein, procalcitonin, creatinine, total bilirubin and plasma D-dimer were significantly increased in patients with diabetes, while the levels of lymphocytes and albumin were significantly decreased (P<0.05). Multivariate logistic regression analysis revealed that platelet count, albumin, total bilirubin and lymphocytes were significantly correlated with the severity of COVID-19. Diabetes mellitus was an independent prognostic factor that affected the mortality outcome of patients with COVID-19. Additionally, an age of ≥80 years, male sex, cerebral infarction complications and a critical diagnosis of COVID-19 at admission were risk factors for critical illness during hospitalization. The results of the present study suggest that diabetes may be a risk factor for the rapid progression and poor prognosis of COVID-19. Therefore, further attention should be paid to individuals with diabetes in order to prevent rapid deterioration.

Growth phase-dependent reorganization of cryptophyte photosystem I antennae.

Photosynthetic cryptophytes are eukaryotic algae that utilize membrane-embedded chlorophyll a/c binding proteins (CACs) and lumen-localized phycobiliproteins (PBPs) as their light-harvesting antennae. Cryptophytes go through logarithmic and stationary growth phases, and may adjust their light-harvesting capability according to their particular growth state. How cryptophytes change the type/arrangement of the photosynthetic antenna proteins to regulate their light-harvesting remains unknown. Here we solve four structures of cryptophyte photosystem I (PSI) bound with CACs that show the rearrangement of CACs at different growth phases. We identify a cryptophyte-unique protein, PsaQ, which harbors two chlorophyll molecules. PsaQ specifically binds to the lumenal region of PSI during logarithmic growth phase and may assist the association of PBPs with photosystems and energy transfer from PBPs to photosystems.

Structural insights into the catalytic selectivity of glycosyltransferase SgUGT94-289-3 towards mogrosides.

Mogrosides constitute a series of natural sweeteners extracted from Siraitia grosvenorii fruits. These mogrosides are glucosylated to different degrees, with mogroside V (M5) and siamenoside I (SIA) being two mogrosides with high intensities of sweetness. SgUGT94-289-3 constitutes a uridine diphosphate (UDP)-dependent glycosyltransferase (UGT) responsible for the biosynthesis of M5 and SIA, by continuously catalyzing glucosylation on mogroside IIe (M2E) and on the subsequent intermediate mogroside products. However, the mechanism of its promiscuous substrate recognition and multiple catalytic modes remains unclear. Here, we report multiple complex structures and the enzymatic characterization of the glycosyltransferase SgUGT94-289-3. We show that SgUGT94-289-3 adopts a dual-pocket organization in its active site, which allows the two structurally distinct reactive ends of mogrosides to be presented from different pockets to the active site for glucosylation reaction, thus enabling both substrate promiscuity and catalytic regioselectivity. We further identified a structural motif that is essential to catalytic activity and regioselectivity, and generated SgUGT94-289-3 mutants with greatly improved M5/SIA production from M2E in an in vitro one-pot setup.

Exploration of the Healthy Donor Effect Among 0.6 Million Blood Donors in China: Longitudinal Study.

BACKGROUND: The World Health Organization emphasizes the importance of completely voluntary blood donation to maintain safe and sustainable blood supplies. However, the benefits of blood donation for donors, such as reducing the risk of disease, remain a topic of debate due to the existence of the healthy donor effect (HDE). This effect arises because of inherent health differences between blood donors and the general population, and it is also considered a methodological issue. OBJECTIVE: This study aims to generate a more detailed health profile of blood donors from a donor cohort study to mitigate and quantify the HDE and properly interpret the association between blood donation and disease outcomes among blood donors. METHODS: A retrospective cohort study was conducted between January 2012 and December 2018 among donors before their first donation. One-to-one propensity score matching was conducted through a random selection of individuals without any history of blood donation, as reported from their electronic health records. We conducted a Poisson regression between blood donors and non-blood donors before the first donation to estimate the adjusted incidence rate ratio (AIRR) of selected blood donation-related diseases, as defined by 13 categories of International Classification of Diseases, Tenth Revision (ICD-10) codes. RESULTS: Of the 0.6 million blood donors, 15,115 had an inpatient record before their first donation, whereas 17,356 non-blood donors had an inpatient record. For the comparison between blood donors and the matched non-blood donors, the HDE (the disease incidence rate ratio between non-blood donors and blood donors) was an AIRR of 1.152 (95% CI 1.127-1.178; P<.001). Among disease categories not recommended for blood donation in China, the strongest HDE was observed in the ICD-10 D50-D89 codes, which pertain to diseases of the blood and blood-forming organs as well as certain disorders involving the immune mechanism (AIRR 3.225, 95% CI 2.402-4.330; P<.001). After age stratification, we found that people who had their first blood donation between 46-55 years old had the strongest HDE (AIRR 1.816, 95% CI 1.707-1.932; P<.001). Both male and female donors had significant HDE (AIRR 1.082, 95% CI 1.05-1.116; P=.003; and AIRR 1.236, 95% CI 1.196-1.277; P<.001, respectively) compared with matched non-blood donors. CONCLUSIONS: : Our research findings suggest that the HDE is present among blood donors, particularly among female donors and those who first donated blood between the ages of 46 and 55 years. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200055983; https://www.chictr.org.cn/showproj.html?proj=51760.

Multi-omics reveal mechanisms of high enteral starch diet mediated colonic dysbiosis via microbiome-host interactions in young ruminant.

BACKGROUND: Although rumen development is crucial, hindgut undertakes a significant role in young ruminants' physiological development. High-starch diet is usually used to accelerate rumen development for young ruminants, but always leading to the enteral starch overload and hindgut dysbiosis. However, the mechanism behind remains unclear. The combination of colonic transcriptome, colonic luminal metabolome, and metagenome together with histological analysis was conducted using a goat model, with the aim to identify the potential molecular mechanisms behind the disrupted hindgut homeostasis by overload starch in young ruminants. RESULT: Compared with low enteral starch diet (LES), high enteral starch diet (HES)-fed goats had significantly higher colonic pathology scores, and serum diamine oxidase activity, and meanwhile significantly decreased colonic mucosal Mucin-2 (MUC2) protein expression and fecal scores, evidencing the HES-triggered colonic systemic inflammation. The bacterial taxa Prevotella sp. P4-67, Prevotella sp. PINT, and Bacteroides sp. CAG:927, together with fungal taxa Fusarium vanettenii, Neocallimastix californiae, Fusarium sp. AF-8, Hypoxylon sp. EC38, and Fusarium pseudograminearum, and the involved microbial immune pathways including the "T cell receptor signaling pathway" were higher in the colon of HES goats. The integrated metagenome and host transcriptome analysis revealed that these taxa were associated with enhanced pathogenic ability, antigen processing and presentation, and stimulated T helper 2 cell (TH2)-mediated cytokine secretion functions in the colon of HES goats. Further luminal metabolomics analysis showed increased relative content of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), and decreased the relative content of hypoxanthine in colonic digesta of HES goats. These altered metabolites contributed to enhancing the expression of TH2-mediated inflammatory-related cytokine secretion including GATA Binding Protein 3 (GATA3), IL-5, and IL-13. Using the linear mixed effect model, the variation of MUC2 biosynthesis explained by the colonic bacteria, bacterial functions, fungi, fungal functions, and metabolites were 21.92, 20.76, 19.43, 12.08, and 44.22%, respectively. The variation of pathology scores explained by the colonic bacterial functions, fungal functions, and metabolites were 15.35, 17.61, and 57.06%. CONCLUSIONS: Our findings revealed that enteral starch overload can trigger interrupted hindgut host-microbiome homeostasis that led to impaired mucosal, destroyed colonic water absorption, and TH2-mediated inflammatory process. Except for the colonic metabolites mostly contribute to the impaired mucosa, the nonnegligible contribution from fungi deserves more future studies focused on the fungal functions in hindgut dysbiosis of young ruminants. Video Abstract.

Biosynthesis of Epipyrone A Reveals a Highly Specific Membrane-Bound Fungal C-Glycosyltransferase for Pyrone Galactosylation.

Epipyrone A is a unique C-galactosylated 4-hydroxy-2-pyrone derivative with an antifungal potential from the fungus Epicoccum nigrum. We elucidated its biosynthesis via heterologous expression and characterized an unprecedented membrane-bound pyrone C-glycosyltransferase biochemically. Molecular docking and mutagenesis experiments suggested a possible mechanism for the heterocyclic C-glycosylation and the importance of a transmembrane helix for its catalysis. These results expand the repertoire of C-glycosyltransferases and provide new insights into the formation of C-glycosides in fungi.