Genetic information is translated into proteins by the ribosome. Structural studies of the ribosome and of its complexes with factors and inhibitors have provided invaluable information on the mechanism of protein synthesis. Ribosome inhibitors are among the most successful antimicrobial drugs and constitute more than half of all medicines used to treat infections. However, bacterial infections are becoming increasingly difficult to treat because the microbes have developed resistance to the most effective antibiotics, creating a major public health care threat. This has spurred a renewed interest in structure-function studies of protein synthesis inhibitors, and in few cases, compounds have been developed into potent therapeutic agents against drug-resistant pathogens. In this review, we describe the modes of action of many ribosome-targeting antibiotics, highlight the major resistance mechanisms developed by pathogenic bacteria, and discuss recent advances in structure-assisted design of new molecules.
Commercial or clinical
tissue adhesives are currently limited due
to their weak bonding strength on wet biological tissue surface, low
biological compatibility, and slow adhesion formation. Although catechol-modified
hyaluronic acid (HA) adhesives are developed, they suffer from limitations:
insufficient adhesiveness and overfast degradation, attributed to
low substitution of catechol groups. In this study, we demonstrate
a simple and efficient strategy to prepare mussel-inspired HA hydrogel
adhesives with improved degree of substitution of catechol groups.
Because of the significantly increased grafting ratio of catechol
groups, dopamine-conjugated dialdehyde–HA (DAHA) hydrogels
exhibit excellent tissue adhesion performance (i.e., adhesive strength
of 90.0 ± 6.7 kPa), which are significantly higher than those
found in dopamine-conjugated HA hydrogels (∼10 kPa), photo-cross-linkable
HA hydrogels (∼13 kPa), or commercially available fibrin glues
(2–40 kPa). At the same time, their maximum adhesion energy
is 384.6 ± 26.0 J m–2, which also is 40–400-fold,
2–40-fold, and ∼8-fold higher than those of the mussel-based
adhesive, cyanoacrylate, and fibrin glues, respectively. Moreover,
the hydrogels can gel rapidly within 60 s and have a tunable degradation
suitable for tissue regeneration. Together with their cytocompatibility
and good cell adhesion, they are promising materials as new biological
adhesives.
Assembly of eukaryotic ribosome is a complicated and dynamic process that involves a series of intermediates. It is unknown how the highly intertwined structure of 60S large ribosomal subunits is established. Here, we report the structure of an early nucleolar pre-60S ribosome determined by cryo-electron microscopy at 3.7 Å resolution, revealing a half-assembled subunit. Domains I, II and VI of 25S/5.8S rRNA pack tightly into a native-like substructure, but domains III, IV and V are not assembled. The structure contains 12 assembly factors and 19 ribosomal proteins, many of which are required for early processing of large subunit rRNA. The Brx1-Ebp2 complex would interfere with the assembly of domains IV and V. Rpf1, Mak16, Nsa1 and Rrp1 form a cluster that consolidates the joining of domains I and II. Our structure reveals a key intermediate on the path to establishing the global architecture of 60S subunits.
Ribonuclease-A (RNase-A) encapsulated
PbS quantum dots (RNase-A@PbS
Qdots) which emit in the second near-infrared biological window (NIR-II, ca. 1000–1400 nm) are rapidly synthesized under microwave
heating. Photoluminescence (PL) spectra of the Qdots can be tuned
across the entire NIR-II range by simply controlling synthesis temperature.
The size and morphology of the Qdots are examined by transmission
electron microscopy (TEM), atomic force microscopy (AFM), and dynamic
light scattering (DLS). Quantum yield (Φf) measurement
confirms that the prepared Qdots are one of the brightest water-soluble
NIR-II emitters for in vivo imaging. Their high Φf (∼17.3%) and peak emission at ∼1300 nm ensure
deep optical penetration to muscle tissues (up to 1.5 cm) and excellent
imaging contrast at an extremely low threshold dose of ∼5.2
pmol (∼1 μg) per mouse. Importantly, this protein coated
Qdot displays no signs of toxicity toward model neuron, normal, and
cancer cells in vitro. In addition, the animal’s
metabolism results in thorough elimination of intravenously injected
Qdots from the body within several days via the reticuloendothelial
system (RES), which minimizes potential long-term toxicity in vivo from possible release of lead content. With a combination
of attractive properties of high brightness, robust photostability,
and excellent biocompatibility, this new NIR-II emitting Qdot is highly
promising in accurate disease screening and diagnostic applications.
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