Highlights d Lipophilic statins and lipophilic bisphosphonates are potent vaccine adjuvants d Modulation of post-translational protein prenylation confers adjuvanticity d Decreased protein prenylation augments antigen preservation and presentation d Statin-or bisphosphonate-mediated vaccination synergizes with anti-PD1 against cancer

NKCC and KCC transporters mediate coupled transport of Na++K++Cl− and K++Cl− across the plasma membrane, thus regulating cell Cl− concentration and cell volume and playing critical roles in transepithelial salt and water transport and in neuronal excitability. The function of these transporters has been intensively studied, but a mechanistic understanding has awaited structural studies of the transporters. Here, we present the cryo-electron microscopy (cryo-EM) structures of the two neuronal cation-chloride cotransporters human NKCC1 (SLC12A2) and mouse KCC2 (SLC12A5), along with computational analysis and functional characterization. These structures highlight essential residues in ion transport and allow us to propose mechanisms by which phosphorylation regulates transport activity.

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Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections. In a mouse sepsis model, the capsules enabled human pathogens Streptococcus pneumoniae and Escherichia coli to circumvent the recognition of liver-resident macrophage Kupffer cells (KCs) in a capsular serotype-dependent manner. In contrast to effective capture of acapsular bacteria by KCs, the encapsulated bacteria are partially (low-virulence types) or completely (high-virulence types) “untouchable” for KCs. We finally identified the asialoglycoprotein receptor (ASGR) as the first known capsule receptor on KCs to recognize the low-virulence serotype-7F and -14 pneumococcal capsules. Our data identify the molecular interplay between the capsules and KCs as a master controller of the fate and virulence of encapsulated bacteria, and suggest that the interplay is targetable for therapeutic control of septic infections.

Vitis amurensis is a wild Vitis plant that can withstand extreme cold temperatures. However, the accumulation of metabolites during cold acclimation (CA) in V. amurensis remains largely unknown. In this study, plantlets of V. amurensis and V. vinifera cv. Muscat of Hamburg were treated at 4 °C for 24 and 72 h, and changes of metabolites in leaves were detected by gas chromatography coupled with time-of-flight mass spectrometry. Most of the identified metabolites, including carbohydrates, amino acids, and organic acids, accumulated in the two types of grape after CA. Galactinol, raffinose, fructose, mannose, glycine, and ascorbate were continuously induced by cold in V. amurensis, but not in Muscat of Hamburg. Twelve metabolites, including isoleucine, valine, proline, 2-oxoglutarate, and putrescine, increased in V. amurensis during CA. More galactinol, ascorbate, 2-oxoglutarate, and putrescine, accumulated in V. amurensis, but not in Muscat of Hamburg, during CA, which may be responsible for the excellent cold tolerance in V. amurensis. The expression levels of the genes encoding β-amylase (BAMY), galactinol synthase (GolS), and raffinose synthase (RafS) were evaluated by quantitative reverse transcription-PCR. The expression BAMY (VIT_02s0012 g00170) and RafS (VIT_05s0077 g00840) were primarily responsible for the accumulation of maltose and raffinose, respectively. The accumulation of galactinol was attributed to different members of GolS in the two grapes. In conclusion, these results show the inherent differences in metabolites between V. amurensis and V. vinifera under CA.