Transcriptomic and functional screening of weapon formation genes implies significance of cell adhesion molecules and female-biased genes in broad-horned flour beetle.

For understanding the evolutionary mechanism of sexually selected exaggerated traits, it is essential to uncover its molecular basis. By using broad-horned flour beetle that has male-specific exaggerated structures (mandibular horn, head horn and gena enlargement), we investigated the transcriptomic and functional characters of sex-biased genes. Comparative transcriptome of male vs. female prepupal heads elucidated 673 sex-biased genes. Counter-intuitively, majority of them were female-biased (584 genes), and GO enrichment analysis showed cell-adhesion molecules were frequently female-biased. This pattern motivated us to hypothesize that female-biased transcripts (i.e. the transcripts diminished in males) may play a role in outgrowth formation. Potentially, female-biased genes may act as suppressors of weapon structure. In order to test the functionality of female-biased genes, we performed RNAi-mediated functional screening for top 20 female-biased genes and 3 genes in the most enriched GO term (cell-cell adhesion, fat1/2/3, fat4 and dachsous). Knockdown of one transcription factor, zinc finger protein 608 (zfp608) resulted in the formation of male-like gena in females, supporting the outgrowth suppression function of this gene. Similarly, knockdown of fat4 induced rudimental, abnormal mandibular horn in female. fat1/2/3RNAi, fat4RNAi and dachsousRNAi males exhibited thick and/or short mandibular horns and legs. These cell adhesion molecules are known to regulate tissue growth direction and known to be involved in the weapon formation in Scarabaeoidea beetles. Functional evidence in phylogenetically distant broad-horned flour beetle suggest that cell adhesion genes are repeatedly deployed in the acquisition of outgrowth. In conclusion, this study clarified the overlooked functions of female-biased genes in weapon development.

Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis.

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.

A Case of Coronary Artery Perforation Caused by Manual Cardiopulmonary Resuscitation in the Catheterization Laboratory.

Cardiopulmonary resuscitation (CPR) is essential for the survival of cardiac arrest patients, but it can cause severe traumatic complications. In the catheterization laboratory, various physical constraints complicate the appropriate performance of CPR. However, we are not aware of reports of CPR complications in this setting. Here, we report a case of coronary artery perforation (CAP) caused by manual CPR in the catheterization laboratory. The patient, a 68-year-old woman, initially underwent successful percutaneous coronary intervention (PCI) for unstable angina. Back in the ward, the patient experienced acute stent thrombosis, which resulted in cardiac arrest, and another PCI was performed under ongoing manual CPR. Although revascularization was successful, sudden CAP occurred, leading to cardiac tamponade. Despite extensive treatment efforts, the patient died 18 hours later.Initially, the compression site of CPR was on the midline of the sternum; however, the compression site shifted to the left, to just above the left anterior descending artery, by the time that CAP was detected via angiography. This corresponded to the area where rib fractures were observed upon computed tomography, suggesting the possibility of traumatic CAP due to manual CPR. The physical constraints in the catheterization laboratory can lead to an inappropriate CPR technique and severe traumatic complications.

A specific type of insulin-like peptide regulates the conditional growth of a beetle weapon.

Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) has been identified as a major physiological mechanism underlying the nutrient-dependent regulation of sexually selected weapon growth in animals. However, the molecular mechanisms that couple nutritional state with weapon growth remain largely unknown. Here, we show that one specific subtype of insulin-like peptide (ILP) responds to nutrient status and thereby regulates weapon size in the broad-horned flour beetle Gnatocerus cornutus. By using transcriptome information, we identified five G. cornutus ILP (GcorILP1-5) and two G. cornutus insulin-like receptor (GcorInR1, -2) genes in the G. cornutus genome. RNA interference (RNAi)-mediated gene silencing revealed that a certain subtype of ILP, GcorILP2, specifically regulated weapon size. Importantly, GcorILP2 was highly and specifically expressed in the fat body in a condition-dependent manner. We further found that GcorInR1 and GcorInR2 are functionally redundant but that the latter is partially specialized for regulating weapon growth. These results strongly suggest that GcorILP2 is an important component of the developmental mechanism that couples nutritional state to weapon growth in G. cornutus. We propose that the duplication and subsequent diversification of IIS genes played a pivotal role in the evolution of the complex growth regulation of secondary sexual traits.

Linear Ballistic Accumulator Item Response Theory Model for Multidimensional Multiple-Alternative Forced-Choice Measurement of Personality.

There has been a growing interest in psychological measurements that use the multiple-alternative forced-choice (MAFC) response format for its resistance to response biases. Although several models have been proposed for the data obtained from such measurements, none have succeeded in incorporating the response time information. Given that currently, many psychological measurements are performed via computers, it would be beneficial to develop a joint model involving an MAFC item response and response time. The present study proposes the first model that combines a cognitive process model that underlies the observed response time and the forced-choice item response model. Specifically, the proposed model is based on the linear ballistic accumulator model of response time, which is substantially extended by reformulating its parameters so as to incorporate the MAFC item responses. The model parameters are estimated by the Markov chain Monte Carlo (MCMC) algorithm. A simulation study confirmed that the proposed approach could appropriately recover the parameters. Two empirical applications are reported to demonstrate the use of the proposed model and compare it with existing models. The results showed that the proposed model could be a useful tool for jointly modeling the MAFC item responses and response times.

Assessing the hierarchy of personal values among adolescents: A comparison of rating scale and paired comparison methods.

INTRODUCTION: For assessing personal values, the rating scale method may not adequately reflect the hierarchical structure of personal values and tends to be influenced by response style bias. The paired comparison method is considered a promising alternative approach, because it engages comparative judgment and may reduce response style biases. The present study aimed to compare these two methods for assessing the hierarchy of personal values among adolescents. METHODS: A total of 191 community-dwelling adolescents aged 12-15 years old completed the rating scale and paired comparison version of the Brief Personalized Value Inventory. Descriptive statistics and latent class analyses were used to assess the difference between the rating scale and paired comparison methods. RESULTS: The two methods yielded similar rankings and means for personal values. The number of subgroups identified by latent class analysis was higher in the paired comparison method than in the rating scale method (10-class vs. 5-class). In the results using the rating scale method, there was a subgroup with high scores on all personal values items. CONCLUSIONS: The paired comparison method captured substantially more heterogeneity in the hierarchy of personal values among adolescents compared to the rating scale, which may be influenced by response style bias.

Joint modeling of the two-alternative multidimensional forced-choice personality measurement and its response time by a Thurstonian D-diffusion item response model.

The two-alternative multidimensional forced-choice measurement of personality has attracted researchers' attention for its tolerance to response bias. Moreover, the response time can be collected along with the item response when personality measurement is conducted with computers. In view of this situation, the objective of this study is to propose a Thurstonian D-diffusion item response theory (IRT) model, which combines two key existing frameworks: the Thurstonian IRT model for forced-choice measurement and the D-diffusion IRT model for the response time in personality measurement. The proposed model reflects the psychological theories behind the data-generating mechanism of the item response and response time. A simulation study reveals that the proposed model can successfully recover the parameters and factor structure in typical application settings. A real data application reveals that the proposed model estimates similar but still different parameter values compared to the original Thurstonian IRT model, and this difference can be explained by the response time information. In addition, the proposed model successfully reflects the distance-difficulty relationship between the response time and the latent relative respondent position.

Loser-effect duration evolves independently of fighting ability.

Winning or losing contests can impact subsequent competitive behaviour and the duration of these effects can be prolonged. While it is clear effects depend on social and developmental environments, the extent to which they are heritable, and hence evolvable, is less clear and remains untested. Furthermore, theory predicts that winner and loser effects should evolve independently of actual fighting ability, but again tests of this prediction are limited. Here we used artificial selection on replicated beetle populations to show that the duration of loser effects can evolve, with a realized heritability of about 17%. We also find that naive fighting ability does not co-evolve with reductions in the duration of the loser effect. We discuss the implications of these findings and how they corroborate theoretical predictions.

Histone deacetylases control module-specific phenotypic plasticity in beetle weapons.

Nutritional conditions during early development influence the plastic expression of adult phenotypes. Among several body modules of animals, the development of sexually selected exaggerated traits exhibits striking nutrition sensitivity, resulting in positive allometry and hypervariability distinct from other traits. Using de novo RNA sequencing and comprehensive RNA interference (RNAi) for epigenetic modifying factors, we found that histone deacetylases (HDACs) and polycomb group (PcG) proteins preferentially influence the size of mandibles (exaggerated male weapon) and demonstrate nutrition-dependent hypervariability in the broad-horned flour beetle, Gnatocerus cornutus RNAi-mediated HDAC1 knockdown (KD) in G. cornutus larvae caused specific curtailment of mandibles in adults, whereas HDAC3 KD led to hypertrophy. Notably, these KDs conferred opposite effects on wing size, but little effect on the size of the core body and genital modules. PcG RNAi also reduced adult mandible size. These results suggest that the plastic development of exaggerated traits is controlled in a module-specific manner by HDACs.

Two Medullary Hemorrhage Cases Complicated by Respiratory Distress in the Early Phase.

Medullary hemorrhage is quite rare among brain stem hemorrhage cases, thus the clinical course remains unclear. In the medulla oblongata, respiratory centers are located and previous reports indicate that medullary lesions have possible relationship with acute respiratory distress syndrome. This kind of respiratory failure is commonly caused by neurogenic pulmonary edema (NPE), which is defined as noncardiac noninfectious acute respiratory distress syndrome with changes in intracranial condition including cerebrovascular events. However, to date, very few reports have described cases with medullary hemorrhage accompanied by NPE. We experienced 2 patients with medullary hemorrhages. A 65-year-old man presented with sudden onset of headache, whose head computed tomography showed right medullary hemorrhage. Another 76-year-old woman was transferred because of sudden limb weakness and diagnosed with left medullary hemorrhage. Digital subtraction angiography showed the presence of arteriovenous fistula in the medulla oblongata and drainer veins in the second case. Both cases were complicated by acute pulmonary edema in the early phase, suggesting the possible association of the medullary hemorrhage with NPE.

Software for the data analysis of the arrival-timing monitor at SACLA.

X-ray free-electron laser (XFEL) pulses from SPring-8 Ångstrom Compact free-electron LAser (SACLA) with a temporal duration of <10 fs have provided a variety of benefits in scientific research. In a previous study, an arrival-timing monitor was developed to improve the temporal resolution in pump-probe experiments at beamline 3 by rearranging data in the order of the arrival-timing jitter between the XFEL and the synchronized optical laser pulses. This paper presents Timing Monitor Analyzer (TMA), a software package by which users can conveniently obtain arrival-timing data in the analysis environment at SACLA. The package is composed of offline tools that pull stored data from cache storage, and online tools that pull data from a data-handling server in semi-real time during beam time. Users can select the most suitable tool for their purpose, and share the results through a network connection between the offline and online analysis environments.

Modeling when people quit: Bayesian censored geometric models with hierarchical and latent-mixture extensions.

People often interact with environments that can provide only a finite number of items as resources. Eventually a book contains no more chapters, there are no more albums available from a band, and every Pokémon has been caught. When interacting with these sorts of environments, people either actively choose to quit collecting new items, or they are forced to quit when the items are exhausted. Modeling the distribution of how many items people collect before they quit involves untangling these two possibilities, We propose that censored geometric models are a useful basic technique for modeling the quitting distribution, and, show how, by implementing these models in a hierarchical and latent-mixture framework through Bayesian methods, they can be extended to capture the additional features of specific situations. We demonstrate this approach by developing and testing a series of models in two case studies involving real-world data. One case study deals with people choosing jokes from a recommender system, and the other deals with people completing items in a personality survey.

Negative estimate of variance-accounted-for effect size: How often it is obtained, and what happens if it is treated as zero.

Researchers recommend reporting of bias-corrected variance-accounted-for effect size estimates such as omega squared instead of uncorrected estimates, because the latter are known for their tendency toward overestimation, whereas the former mostly correct this bias. However, this argument may miss an important fact: A bias-corrected estimate can take a negative value, and of course, a negative variance ratio does not make sense. Therefore, it has been a common practice to report an obtained negative estimate as zero. This article presents an argument against this practice, based on a simulation study investigating how often negative estimates are obtained and what are the consequences of treating them as zero. The results indicate that negative estimates are obtained more often than researchers might have thought. In fact, they occur more than half the time under some reasonable conditions. Moreover, treating the obtained negative estimates as zero causes substantial overestimation of even bias-corrected estimators when the sample size and population effect are not large, which is often the case in psychology. Therefore, the recommendation is that researchers report obtained negative estimates as is, instead of reporting them as zero, to avoid the inflation of effect sizes in research syntheses, even though zero can be considered the most plausible value when interpreting such a result. R code to reproduce all of the described results is included as supplemental material.

Data acquisition system for X-ray free-electron laser experiments at SACLA.

A data acquisition system for X-ray free-electron laser experiments at SACLA has been developed. The system has been designed for reliable shot-to-shot data storage with a high data stream greater than 4 Gbps and massive data analysis. Configuration of the system and examples of prompt data analysis during experiments are presented. Upgrade plans for the system to extend flexibility are described.

Environmental Factors Affecting Pupation Decision in the Horned Flour Beetle Gnatocerus cornutus.

Social environments often affect the development of organisms. In Tenebrionidae beetles, larval development can be arrested at the final instar stage in the presence of conspecific larvae. This developmental plasticity is considered to be an anti-cannibalistic strategy but the critical environmental determinants and actual effects remain to be elucidated. In this study, we examined the effects of the heterospecific environment, conspecific sexual environment (i.e., presence of conspecific male or female), and abiotic physical stimulation on the pupation decision of the sexually dimorphic horned-flour beetle Gnatocerus cornutus. Additionally, actual anti-cannibalistic or antipredatory effects of developmental arrest were evaluated by analyzing stage-dependent vulnerabilities. When G. cornutus larvae were maintained with a G. cornutus larva, a G. cornutus adult, or T. castaneum adult, the developmental period up to the prepupal stage was significantly elongated, suggesting that the cue is not species-specific. Sexual environment did not affect the timing of pupation in G. cornutus; however, we found that abiotic tactile stimulations by glass beads could repress pupation. We also discovered that prepupal and pupal stages were more vulnerable to cannibalism and predation than the larval stage. These data suggest that G. cornutus larvae use non-species specific tactile stimulation as a decision cue for pupation and it has broader defensive effects against heterospecific predation as well as conspecific cannibalism.

Sexual conflict over mating in Gnatocerus cornutus? Females prefer lovers not fighters.

Female mate choice and male-male competition are the typical mechanisms of sexual selection. However, these two mechanisms do not always favour the same males. Furthermore, it has recently become clear that female choice can sometimes benefit males that reduce female fitness. So whether male-male competition and female choice favour the same or different males, and whether or not females benefit from mate choice, remain open questions. In the horned beetle, Gnatocerus cornutus, males have enlarged mandibles used to fight rivals, and larger mandibles provide a mating advantage when there is direct male-male competition for mates. However, it is not clear whether females prefer these highly competitive males. Here, we show that female choice targets male courtship rather than mandible size, and these two characters are not phenotypically or genetically correlated. Mating with attractive, highly courting males provided indirect benefits to females but only via the heritability of male attractiveness. However, mating with attractive males avoids the indirect costs to daughters that are generated by mating with competitive males. Our results suggest that male-male competition may constrain female mate choice, possibly reducing female fitness and generating sexual conflict over mating.

Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.

BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

Morphological and functional analyses for investigation of sexually selected legs in the frog legged beetle Sagra femorata (Coleoptera: Chrysomelidae).

Mate choice and male-male combat over successful mating often cause disproportionate exaggeration of male trait relative to body size. However, the exaggeration is often not the only trait involved with male-male combat and mate choice: suites of co-expressed traits may function together as a coordinated unit. When this occurs, dimorphism may be expected for these additional, non-exaggerated, structures. S. femorata males have disproportionately large hind-legs used in male-male combat over females. During the fights, fore- and mid-legs are used to keep males in positions where advantageous for leverage. Because use of the exaggerated hind-legs is coordinated with the other legs, they will coevolve as a functional unit. Here, we show that 1) S. femorata has sexual size differences in all three legs; 2) males show positive allometry in the relative sizes of all three legs; and 3) microstructures of tarsi on the fore- and mid-legs are also sexually dimorphic. Despite these differences in the tarsal microstructure, 4) adhesion forces of the tarsi had no sexual difference in flat surface. The microstructure would be specialized on attaching elytra surface. These results suggest that the three pairs of legs function together during fighting behavior, with hind-legs employed primarily for fighting, and the fore- and mid-legs functioning to grip females, keeping males positioned on the back of the female during combat.

Phenotypic Insights Into Anti-IgLON5 Disease in IgLON5-Deficient Mice.

BACKGROUND AND OBJECTIVES: Anti-IgLON5 disease is an autoimmune neurodegenerative disorder characterized by various phenotypes, notably sleep and movement disorders and tau pathology. Although the disease is known to be associated with the neuronal cell adhesion protein IgLON5, the physiologic function of IgLON5 remains elusive. There are conflicting views on whether autoantibodies cause loss of function, activation of IgLON5, or inflammation-associated neuronal damage, ultimately leading to the disease. We generated IgLON5 knockout (-/-) mice to investigate the functions of IgLON5 and elucidate the pathomechanism of anti-IgLON5 disease. METHODS: IgLON5 knockout (-/-) mice underwent behavioral tests investigating motor function, psychiatric function (notably anxiety and depression), social and exploratory behaviors, spatial learning and memory, and sensory perception. Histologic analysis was conducted to investigate tau aggregation in mice with tauopathy. RESULTS: IgLON5-/- mice had poorer performance in the wire hang and rotarod tests (which are tests for motor function) than wild-type mice. Moreover, IgLON5-/- mice exhibited decreased anxiety-like behavior and/or hyperactivity in behavior tests, including light/dark transition test and open field test. IgLON5-/- mice also exhibited poorer remote memory in the contextual fear conditioning test. However, neither sleeping disabilities assessed by EEG nor tau aggregation was detected in the knockout mice. DISCUSSION: These results suggest that IgLON5 is associated with activity, anxiety, motor ability, and contextual fear memory. Comparing the various phenotypes of anti-IgLON5 disease, anti-IgLON5 disease might partially be associated with loss of function of IgLON5; however, other phenotypes, such as sleep disorders and tau aggregation, can be caused by gain of function of IgLON5 and/or neuronal damage due to inflammation. Further studies are needed to elucidate the role of IgLON5 in the pathogenesis of anti-IgLON5 diseases.

High-speed classification of coherent X-ray diffraction patterns on the K computer for high-resolution single biomolecule imaging.

Single-particle coherent X-ray diffraction imaging using an X-ray free-electron laser has the potential to reveal the three-dimensional structure of a biological supra-molecule at sub-nanometer resolution. In order to realise this method, it is necessary to analyze as many as 1 × 10(6) noisy X-ray diffraction patterns, each for an unknown random target orientation. To cope with the severe quantum noise, patterns need to be classified according to their similarities and average similar patterns to improve the signal-to-noise ratio. A high-speed scalable scheme has been developed to carry out classification on the K computer, a 10PFLOPS supercomputer at RIKEN Advanced Institute for Computational Science. It is designed to work on the real-time basis with the experimental diffraction pattern collection at the X-ray free-electron laser facility SACLA so that the result of classification can be feedback for optimizing experimental parameters during the experiment. The present status of our effort developing the system and also a result of application to a set of simulated diffraction patterns is reported. About 1 × 10(6) diffraction patterns were successfully classificatied by running 255 separate 1 h jobs in 385-node mode.