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Abstract Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field, due in part to low local blood flow and poor interactions between drug carriers and bone material. Here we report bone‐targeting ionizable lipids incorporating a piperazine backbone and bisphosphate moieties, which bind tightly with hydroxyapatite ([Ca₅(PO₄)₃OH]), a key component of mineralized tissues. These lipids demonstrate biocompatibility and low toxicity in both vitro and in vivo studies. LNP formulated with these lipids facilitated efficient cellular transfection and improved binding to hydroxyapatite in vitro, and targeted delivery to the bone microenvironment in vivo following systemic administration. Overall, our findings demonstrate the critical role of the piperazine backbone in a novel ionizable lipid, which incorporates a bisphosphonate group to enable efficient bone‐targeted delivery, highlighting the potential of rational design of ionizable lipids for next‐generation bone‐targeting delivery systems. 

Cryptographic Self-Selection is a common primitive underlying leader-selection for Proof-of-Stake blockchain protocols. The concept was first popularized in Algorand [Jing Chen and Silvio Micali, 2019], who also observed that the protocol might be manipulable. [Matheus V. X. Ferreira et al., 2022] provide a concrete manipulation that is strictly profitable for a staker of any size (and also prove upper bounds on the gains from manipulation). Separately, [Maryam Bahrani and S. Matthew Weinberg, 2024; Aviv Yaish et al., 2023] initiate the study of undetectable profitable manipulations of consensus protocols with a focus on the seminal Selfish Mining strategy [Eyal and Sirer, 2014] for Bitcoin’s Proof-of-Work longest-chain protocol. They design a Selfish Mining variant that, for sufficiently large miners, is strictly profitable yet also indistinguishable to an onlooker from routine latency (that is, a sufficiently large profit-maximizing miner could use their strategy to strictly profit over being honest in a way that still appears to the rest of the network as though everyone is honest but experiencing mildly higher latency. This avoids any risk of negatively impacting the value of the underlying cryptocurrency due to attack detection). We investigate the detectability of profitable manipulations of the canonical cryptographic self-selection leader selection protocol introduced in [Jing Chen and Silvio Micali, 2019] and studied in [Matheus V. X. Ferreira et al., 2022], and establish that for any player with α < (3-√5)/2 ≈ 0.38 fraction of the total stake, every strictly profitable manipulation is statistically detectable. Specifically, we consider an onlooker who sees only the random seed of each round (and does not need to see any other broadcasts by any other players). We show that the distribution of the sequence of random seeds when any player is profitably manipulating the protocol is inconsistent with any distribution that could arise by honest stakers being offline or timing out (for a natural stylized model of honest timeouts). 

Abstract Soft robots have attracted increasing attention due to their excellent versatility and broad applications. In this article, we present a minimally designed soft crawling robot (SCR) capable of robust locomotion in unstructured pipes with various geometric/material properties and surface topology. In particular, the SCR can squeeze through narrow pipes smaller than its cross section and propel robustly in spiked pipes. The gait pattern and locomotion mechanism of this robot are experimentally investigated and analysed by the finite element analysis, revealing that the resultant forward frictional force is generated due to the asymmetric mechanical properties along the length direction of the robot. The proposed simple yet working SCR could inspire novel designs and applications of soft robots in unstructured narrow canals such as large intestines or industrial pipelines. 

BackgroundAnalyses of microbial evolution often use reconciliation methods. However, the standard duplication-transfer-loss (DTL) model does not account for the fact that species trees are often not fully sampled and thus, from the perspective of reconciliation, a gene family may enter the species tree from the outside. Moreover, within the genome, genes are often rearranged, causing them to move to new syntenic regions. ResultsWe extend the DTL model to account for two events that commonly arise in the evolution of microbes:originof a gene from outside the sampled species tree andrearrangementof gene syntenic regions. We describe an efficient algorithm for maximum parsimony reconciliation in this new DTLOR model and then show how it can be extended to account for non-binary gene trees to handle uncertainty in gene tree topologies. Finally, we describe preliminary experimental results from the integration of our algorithm into the existing xenoGI tool for reconstructing the histories of genomic islands in closely related bacteria. ConclusionsReconciliation in the DTLOR model can offer new insights into the evolution of microbes that is not currently possible under the DTL model. 

Abstract Summary We describe eMPRess, a software program for phylogenetic tree reconciliation under the duplication-transfer-loss model that systematically addresses the problems of choosing event costs and selecting representative solutions, enabling users to make more robust inferences. Availability and implementation eMPRess is freely available at http://www.cs.hmc.edu/empress. Supplementary information Supplementary data are available at Bioinformatics online. 

ABSTRACT The fecal indicator bacterial species Escherichia coli is an important measure of water quality and a leading cause of impaired surface waters. We investigated the impact of the filter-feeding metazooplankton Daphnia magna on the inactivation of E. coli . The E. coli clearance rates of these daphnids were calculated from a series of batch experiments conducted under variable environmental conditions. Batch system experiments of 24 to 48 h in duration were completed to test the impacts of bacterial concentration, organism density, temperature, and water type. The maximum clearance rate for adult D. magna organisms was 2 ml h −1 organism −1 . Less than 5% of E. coli removed from water by daphnids was recoverable from excretions. Sorption of E. coli on daphnid carapaces was not observed. As a comparison, the clearance rates of the freshwater rotifer Branchionus calyciflorus were also calculated for select conditions. The maximum clearance rate for B. calyciflorus was 6 × 10 −4  ml h −1 organism −1 . This research furthers our understanding of the impacts of metazooplankton predation on E. coli inactivation and the effects of environmental variables on filter feeding. Based on our results, metazooplankton can play an important role in the reduction of E. coli in natural treatment systems under environmentally relevant conditions. IMPORTANCE Escherichia coli is a fecal indicator bacterial species monitored by the U.S. Environmental Protection Agency to assess microbial water quality. Due to the potential human health implications linked to high levels of E. coli , it is important to understand the inactivation or reduction mechanisms in surface waters. Our research examines the capacities of two types of widespread filter-feeding freshwater metazooplankton, Daphnia magna and Brachionus calyciflorus , to reduce E. coli concentrations. We examine the impacts of different environmentally relevant conditions on the clearance rates. Our results contribute to a better understanding of the importance of metazooplankton in controlling E. coli concentrations and what conditions will reduce or increase grazing. These results provide baseline data to support future efforts to develop a quantitative model relating zooplankton uptake rates to relevant environmental variables.