Hokkaido Research Organization

Abstract Cyclic peptides have emerged as a pivotal modality for next-generation therapeutics, due to their superior biocompatibility, high selectivity, and structural stability. While AI-driven peptide design has advanced rapidly, conventional optimization algorithms are often constrained by initialization biases, which impede the efficient exploration of the vast chemical space. Here, we propose a novel methodology that integrates the protein language model ESM-2 with cyclic permutation averaging of embeddings to resolve this bottleneck. This approach establishes a comprehensive "peptide space", a high-dimensional vector representation that encapsulates the physicochemical and structural attributes of cyclic peptides. Our analysis reveals that random sequence selection results in a heterogeneous distribution within this space, potentially underrepresenting specific functional regions. Conversely, navigating this defined peptide space enables the selection of libraries that uniformly span diverse molecular properties. In a proof-of-concept study designing binders for β2-microglobulin (β2m), we demonstrate that initial sequences uniformly sampled from our peptide space yield superior candidates more efficiently than those derived from random selection. Furthermore, this framework facilitates the quantitative assessment of mutational perturbations on global peptide properties, supporting rational decision-making for both broad exploration and local optimization. This "peptide space" concept provides a foundational framework for defining appropriate search boundaries and enhancing computational efficiency in AI-mediated drug discovery. Graphic Abstract

ABSTRACT In Hokkaido, Japan, various management measures are being implemented to mitigate human‐brown bear conflicts. To evaluate the effectiveness of these measures, we aimed to estimate the number of nuisance bears as an indicator of conflict based on damage and occurrence reports. For the estimation, we assessed the harmfulness level (Conditions 0–3) of the bears based on information provided in the reports and developed a method to remove duplicate or substantial overcounts of a bear resulting from multiple reports on the same individual. The specified criteria based on the difference in dates and distance were established to identify a single bear associated with multiple reports. By establishing two sets of criteria, one relaxed and one stringent, we estimated the minimum and maximum numbers of nuisance bears. We estimated the number of nuisance individuals annually based on the reports collected from 2009 to 2023 in the Oshima Peninsula, Hokkaido. The total number of nuisance individuals fluctuated between 362 and 495 (maximum) and 163 and 214 (minimum) in the first half of the 2010s. Thereafter, the maximum number of individuals in Condition 0/1 (lower harmfulness) continued to increase, reaching 504 in 2023, whereas the number of individuals in Conditions 2 and 3 remained relatively stable, ranging from 153 in 2015 to 261 in 2018. Establishing a specific criterion to estimate the number of nuisance individuals involved in conflict provides a more valuable evaluation indicator for adaptive management than one that solely relies on the number of occurrences.

Integrating electric vehicles (EVs) into microgrids offers a promising solution to enhance renewable energy utilization, especially in cold regions where EV adoption remains challenging. This paper determines operational data using telematics devices over one year from six municipal vehicles, which include EV and conventional vehicles. The data includes key parameters, such as initial state of charge (SOC) and parking ratio, for evaluating power supply and demand balancing. This paper analyzes the temperature dependence of key parameters and the daily operation patterns of vehicles using the GPS data. This paper also evaluates the correlation between facility demand and weather conditions to realize weather-linked simulations.

皆さんには，心を惹かれる何かがありますか？今回は，私がなぜ「プロセス」に魅力を感じ，なぜ水文研究を続けてきたのか，私の人となりや研究を振り返りながら紐解いていきます．

Coxiella-like endosymbionts (CLEs) are obligate nutritional mutualistsof ticks that are thought to supplement B vitamins and other essential metabolites thatare deficient in the tick’s blood meal. Extensive colonization of CLEs has been observedin the ovaries and Malpighian tubules of several tick species, includingHaemaphysalis longicornis. Despite experimental evidence linkingsymbionts to host fitness, their roles in blood feeding remain poorly understood. Here, weconducted a comparative transcriptomic analysis of CLE genes in adult female H.longicornis ticks before and two days after feeding. CLE genes were identifiedby mapping RNA-seq data onto the putative CLE genomes derived from the draft genomeassembly of H. longicornis. Our analysis explored the potential functionof CLEs during the early stage of blood feeding. The results revealed abundant expressionof genes involved in B vitamin biosynthesis and enrichment of Gene Ontology termsassociated with biotin and ubiquinone biosynthesis. Although most expressed CLE genes wereshared between the two organs, gene expression patterns in response to blood feedingdiffered between the Malpighian tubules and ovaries. These findings suggest that CLEs inthe Malpighian tubules and ovaries exhibit distinct functions during the early stage ofblood feeding. Overall, this study provides a fundamental basis for identifying potentialtargets in anti-tick control strategies and enhances our understanding of how bloodfeeding impacts tick physiology.

In this study, to minimize the degradation caused by pasteurization in processed foods, pasteurization conditions of 98 °C were determined for the preservation of curry sauces inoculated with psychrotrophic Paenibacillus spores for 12 weeks at 10 °C, leading to a proposed approach. Paenibacillus spores underwent vegetative growth in some samples heated for 25 min. Probabilistic analysis predicted that 16–51 of the spores survived in those samples. The number of surviving spores that did not exhibit vegetative growth during 12-weeks of storage was estimated by comparing the ratio of the samples without vegetative growth to the cumulative probability of spore survival, with this number, estimated to be below 43 spores per sample. Theoretically, this value could be achieved by heating for 27.1 min at 98 °C equivalent. For challenge tests alone, samples should be heated for at least 31 min; however, combining challenge tests with probabilistic analysis could shorten the pasteurization time.

Understanding the interactions among hosts, vectors, and pathogens is essential for elucidating the ecology of tick-borne diseases. However, studies on tick fauna and pathogenic infections in large mammals in Hokkaido, Japan remain limited. We examined the spatial and temporal (region and season) and host factors (sex and age) affecting pathogen prevalence and tick infestation in sika deer (Cervus nippon yesoensis) and brown bears (Ursus arctos yesoensis) in Hokkaido. We selected Anaplasma and Hepatozoon, two prevalent pathogens in sika deer and brown bears, respectively, to analyze host-vector-pathogen relationships. Between 2021 and 2024, we tested samples from 223 deer and 437 bears for these pathogens and examined tick infestation patterns in 157 deer and 255 bears across four regions. Anaplasma infection prevalence was high in deer from South and East Hokkaido but low in those from North Hokkaido. Hepatozoon infection in bears was high in South and Central Hokkaido, and low in the East and North. Generalized linear mixed models (GLMMs) indicated that Anaplasma prevalence was determined by regional factors, whereas Hepatozoon infection was influenced by region and host age, with adults showing lower infection rates. Six tick species were identified: Ixodes ovatus, Ixodes persulcatus, Haemaphysalis japonica, Haemaphysalis megaspinosa, Haemaphysalis flava, and Haemaphysalis longicornis. The GLMMs revealed that I. ovatus was more prevalent on male deer than females. Conversely, I. persulcatus nymphs were less prevalent male bears than females. Older hosts showed higher levels of infestation across multiple tick species. These findings reveal the complex interplay shaping tick-borne disease ecology in wildlife.

Coastal geothermal saline groundwater (SGW) in Quaternary volcanic regions represents an important geothermal resource, but its complex chemical compositions often obscure its origin and dynamics. This study aims to elucidate the SGW in the coastal plain of Hakodate, Hokkaido, in Japan using the B-Li-Cl dynamics to delineate water-rock interactions and diagenesis, and to classify SGW types. Major dissolved components and stable isotopes (δD, δ 18 O) are susceptible to freshwater dilution, limiting their diagnostic utility. The B-Li-Cl composition allowed for the classification of SGW into three types (Type 1, 2, and 3). Types 1 and 2 were influenced by direct seawater contributions and other origins such as diagenesis and volcanic gas, respectively. Type 3, with higher B (Boron) and Li (Lithium) concentrations than the other SGW, is distributed in the geothermal region, and reflects seawater modified by interaction with volcanic rocks at 175±25°C. Integration of chemical equilibrium modeling and geothermometer supports this geochemical evolution of the SGWs. Additionally, hydrogeological analyses have estimated that the flow dynamics of Type 3 waters are recharged through fractures near offshore submarine volcanic vents that migrate to deeper subsurface regions. These findings offer new insights into coastal hydrothermal systems in the study area. The Li and B concentrations serve as effective tracers for elucidating the origin of SGW in coastal geothermal regions, and their application is expected to lead to a more comprehensive understanding of SGW flow dynamics. • Saline groundwater (SGW) in the Hakodate area, Japan, can be classified into three types using B–Li–Cl geochemical signatures • Type 3 SGW enriched in B and Li linked to volcanic water–rock interaction • Type3 have undergone water-rock-interaction at 175±25°C using combination of multiple geothermometer. • Modelling reveals recharge via fractures near offshore volcanic vents • B and Li serve as effective tracers for SGW evolution in volcanic coastal zones