Identification of the core rumen bacterial taxa and their population dynamics during the fattening period in Japanese Black cattle.

The rumen microbiota comprises a vast range of bacterial taxa, which may affect the production of high-quality meat in Japanese Black cattle. The aim of this study was to identify core rumen microbiota in rumen fluid samples collected from 74 Japanese Black cattle raised under different dietary conditions using 16S rRNA gene amplicon sequencing. In the rumen of fattening Japanese Black cattle, 10 bacterial taxa, showing >1% average relative abundance and >95% prevalence, irrespective of the dietary conditions and the fattening periods, were identified as the core rumen bacterial taxa, which accounted for approximately 80% of the rumen microbiota in Japanese Black cattle. Additionally, population dynamics of the core rumen bacterial taxa revealed two distinct patterns: Prevotella spp. and unclassified Bacteroidales decreased in the mid-fattening period, whereas unclassified Clostridiales, unclassified Ruminococcaceae, Ruminococcus spp., and unclassified Christensenellaceae increased during the same period. Therefore, the present study reports the wide distribution of the core rumen bacterial taxa in Japanese Black cattle, and the complementary nature of the population dynamics of these core taxa, which may ensure stable rumen fermentation during the fattening period.

Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment.

The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity.

CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation.

Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (e.g., L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild type. Furthermore, crystal structure analysis suggested that CH7233163 is a noncovalent ATP-competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib-resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

Observing the Kinetic Pathway of Nanotube Formation from Bolaamphiphiles by Time-Resolved Small-Angle X-ray Scattering.

We investigated the formation kinetics of a single monolayer nanotube from bolaamphiphiles (consisting of a sugar residue, an alkyl chain, and an amino group) in solution. In this bolaamphiphile, a transition from a monomerically dispersed state to the nanotube takes place by changing the solvent condition. This transition was induced by fast mixing with a stopped-flow apparatus. From just after the mixing, this transition process was monitored in situ by time-resolved small-angle X-ray scattering. In this manner, we were able to derive the direct structural information as a function of time during the nanotube formation. The results revealed that disklike aggregates initially formed, which then grew and closed to produce a tubular structure.

Encapsulation of Albumin in Organic Nanotube Channel: Structural Investigation by Small-Angle X-ray Scattering.

Rationally designed bolaamphiphiles are known to self-assemble into nanotube structures. Herein, we report the formation of an inclusion complex between a nanotube and bovine serum albumin (BSA). This complex formation was confirmed by ultraviolet (UV) absorbance and electrophoretic light scattering (ELS). The structure for different mixing ratios of BSA to the nanotube was also investigated by transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS). The structural analysis with our proposed model has revealed that the BSA molecules were contained within the internal space of the nanotube with maintenance of its tubular structure.

Human NAT10 is an ATP-dependent RNA acetyltransferase responsible for N4-acetylcytidine formation in 18 S ribosomal RNA (rRNA).

Human N-acetyltransferase 10 (NAT10) is known to be a lysine acetyltransferase that targets microtubules and histones and plays an important role in cell division. NAT10 is highly expressed in malignant tumors, and is also a promising target for therapies against laminopathies and premature aging. Here we report that NAT10 is an ATP-dependent RNA acetyltransferase responsible for formation of N(4)-acetylcytidine (ac(4)C) at position 1842 in the terminal helix of mammalian 18 S rRNA. RNAi-mediated knockdown of NAT10 resulted in growth retardation of human cells, and this was accompanied by high-level accumulation of the 30 S precursor of 18 S rRNA, suggesting that ac(4)C1842 formation catalyzed by NAT10 is involved in rRNA processing and ribosome biogenesis.