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Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the on-target knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs., (© 2023. The Author(s).)

We formulate a theory for the phase reduction of a beating flagellum. The theory enables us to describe the dynamics of a beating flagellum in a systematic manner using a single variable called the phase. The theory can also be considered as a phase reduction method for the limit-cycle solutions in infinite-dimensional dynamical systems, namely, the limit-cycle solutions to partial differential equations representing beating flagella. We derive the phase sensitivity function, which quantifies the phase response of a beating flagellum to weak perturbations applied at each point and at each time. Using the phase sensitivity function, we analyze the phase synchronization between a pair of beating flagella through hydrodynamic interactions at a low Reynolds number.

A new tellinid species, Pharaonella amanyu sp. n. , is described from sand banks around Amami Islands, the Ryukyu Archipelago, in southern Japan. A molecular phylogenetic analysis suggests that this new species is closely related to P. sieboldii . This species has long siphons and lives buried deep in well-sorted white sand syntopically with Tonganaella tongana . These rare, large tellinid species are indicators of unspoiled tidal/subtidal sand flats, which should receive the highest priority conservation in the Ryukyu Archipelago.

Many insects utilize substrate-borne vibrations as a source of information for recognizing mates or predators. Among various substrates, plant leaves are commonly used for transmitting and receiving vibrational information. However, little is known about the utilization of vibrations by leaf-dwelling insects, especially coleopteran beetles. We conducted two experiments to examine the response of the leaf-dwelling cerambycid beetle, Paraglenea fortunei, to substrate-borne vibrations. We recorded and analyzed vibrations of host plant leaves from four different sources: wind (0.5 m/s), a beetle during landing, a walking beetle, and a beetle walking in the wind (0.5 m/s). We then measured the behavioral thresholds, the lowest amplitudes that induce behavioral responses, from beetles walking and resting on horizontal and vertical substrates with pulsed vibrations ranging from 20 Hz to 1 kHz. The vibrational characteristics of biotic and abiotic stimuli clearly differed. Beetle-generated vibrations (landing, walking, and walking in the wind) were broadly high in the low-frequency components above ∼30 Hz, while wind-generated vibrations showed a dominant peak at ∼30 Hz and a steep decrease thereafter. Among four situations, beetles walking on horizontal substrates showed lowest thresholds to vibrations of 75-500 Hz, which are characteristic of beetle-generated vibrations. Given that P. fortunei beetles are found on horizontal leaf surfaces of the host plant, vibrations transmitted though horizontal substrates may induce a strong freeze response in walking beetles to detect conspecifics or heterospecifics. Our findings provide evidence that leaf-dwelling beetles can discriminate among biotic and abiotic factors via differences in vibrational characteristics.

Sponges, porous filter-feeding organisms consisting of vast canal systems, provide unique substrates for diverse symbiotic organisms. The Spongia (Spongia) sp. massive sponge is obligately inhabited by the host-specific endosymbiotic bivalve Vulsella vulsella, which benefits from this symbiosis by receiving protection from predators. However, whether the host sponge gains any benefit from this association is unclear. Considering that the bivalves exhale filtered water into the sponge body rather than the ambient environment, the sponge is hypothesized to utilize water exhaled by the bivalves to circulate water around its body more efficiently. We tested this hypothesis by observing the sponge aquiferous structure and comparing the pumping rates of sponges and bivalves. Observations of water currents and the sponge aquiferous structure revealed that the sponge had a unique canal system enabling it to inhale water exhaled from bivalves, indicating that the host sponge adapted morphologically to receive water from the bivalves. In addition, the volume of water circulating in the sponge body was dramatically increased by the water exhaled from bivalves. Therefore, this sponge-bivalve association can be regarded as a novel mutualism in which two filter-feeding symbionts promote mutual filtering rates. This symbiotic association should be called a "filtering mutualism".

We assessed the host-use pattern of the sponge-endosymbiotic bivalve Vulsella vulsella and its demographic consequences in an inland sea in Okinawa Island, Japan. Vulsella vulsella utilized only one massive globular sponge species Spongia sp. as a host, and no Spongia sp. without V. vulsella were found. Individual sponges contained 9-248 live bivalves and 0-222 dead bivalves. The densities of live and dead bivalves in individual sponges were approximately constant irrespective of sponge size, indicating that available space is very scarce inside each sponge. The size distribution of bivalves was skewed to small, young individuals less than 30 mm in shell height, although the estimated largest possible size was 106 mm. The bivalve population at each sampling date was composed of three yearly cohorts, and recruitment of juveniles occurred in the summer. The bivalves became sexually mature as males within one year after recruitment and changed sex from male to female as they grew. The size and sex distributions of the bivalve were largely similar among sponges regardless of sponge size, suggesting that the recruitment, growth, longevity, and sex change of the bivalve were strictly regulated, probably by the high water temperature and strong waves generated by typhoons in summer months.

The pterioid bivalves (superfamily Pterioidea) are epifaunal filter feeders that attach to various substrata, including rocks, corals, gorgonians, and sponges. An intriguing question is how different substratum types have affected the diversification of pterioid bivalves. To elucidate the evolutionary pathway of Pterioidea, we conducted a phylogenetic analysis of 49 individuals belonging to 18 pterioid and 5 outgroup species using 18S and 28S ribosomal RNA genes. The results supported the monophyly of superfamily Pterioidea and recovered three major clades within Pterioidea: Malleus, Pteria and Electroma (Pterelectroma) zebra and the rest. This result contradicts the current circumscription of the pterioid families, Pteriidae, Malleidae, and Isognomonidae, and suggests that hinge morphology, which has long been used as a diagnostic character, does not reflect phylogenetic relationships. The monophyly of most genera, however, was confirmed. Mapping substrata types on the phylogenetic tree indicated that the ancestors of pterioid bivalves were epifaunal on rocks, and that epizoic life on sessile cnidarians had a single origin. Although we could not ascertain whether endozoic life in sponges evolved once or twice, our results suggest that colonization of biotic substrata resulted in diversification and morphological and ecological adaptation to epi-/endozoic life. We estimated that the genus Pteria has diversified since the late Cretaceous in response to gorgonian diversification. These results emphasize the importance of substratum shifts in speciation and diversification of pterioid bivalves., (Copyright © 2010 Elsevier Inc. All rights reserved.)