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Undergraduate mentoring and research internships promote entry into graduate training, academic success, research productivity, and greater career satisfaction. Most pathway programs to enhance representation within academia and health care intervene at the graduate level, leaving a critical gap in undergraduate training. The Veterans Health Administration's (VHA's) national network of clinicians and researchers is uniquely suited to provide equitable access to quality mentorship and education for undergraduates interested in health care careers. We present a program evaluation case study of a VHA undergraduate training program incorporating empirically supported components that promote success and transition to graduate school, including tiered mentorship, a didactic-preceptor model, hands-on experience, and interdisciplinary work. We describe participant characteristics and consider the program elements that may contribute to trainees' success, highlighting the importance of undergraduate training within a health care system like VHA. We found that all program completers attained their bachelor's degree and nearly 70% advanced to graduate studies. Despite some differences based on participant characteristics, all program components were deemed useful preparation for professional success, with hands-on research experience and mentoring cited as the most helpful. The promising results of our case study demonstrate the feasibility of successfully implementing an undergraduate training program to provide a pathway to advanced careers in health care within the VHA. We posit that programs like ours can serve as a framework for creating pathway training programs that target undergraduates traditionally underrepresented, subsequently empowering them to pursue health care careers, and ultimately increasing diversity by training professionals who are better prepared to assist with diverse patient needs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Autoimmune blistering diseases (AIBDs), including pemphigoid and pemphigus, are intractable dermatological disorders clinically characterized by blistering and erosion affecting mucosal membranes and the skin. Due to their rarity and the limited coverage for less severe cases under Japanese medical subsidies, comprehensive epidemiological analyses encompassing less severe cases have not been conducted in Japan. In this study, we analyzed the epidemiology of AIBDs in Japan, utilizing data from a Japanese nationwide database. We identified 9796 cases of bullous pemphigoid (BP), 62 cases of epidermolysis bullosa acquisita (EBA), 871 cases of pemphigus vulgaris (PV), and 578 cases of pemphigus foliaceous (PF). BP patients exhibited an older age distribution compared to EBA, PV, and PF, with median ages of 81, 72, 65, and 70 years, respectively. Higher rates of comorbidities such as Alzheimer's disease, spondylopathies, and extrapyramidal and movement disorders were observed only in BP cases, while other neurodegenerative disorders such as polyneuropathies, unspecified dementia, and schizophrenia were frequent in both BP and EBA. Dipeptidyl peptidase-4 inhibitors were more commonly prescribed before the onset of BP and EBA compared to PV and PF. Treatment patterns indicated that PV patients were more frequently administered higher doses of oral corticosteroids compared to other AIBDs. Additionally, aggressive therapies, including steroid pulse, intravenous immunoglobulin, and plasmapheresis therapies, were more frequently applied in PV cases. In-hospital mortality rates were higher in BP and EBA at 8.0% and 11.3%, respectively, compared to PV and PF at 2.8% and 5.9%, respectively. Kaplan-Meier analysis indicated that BP and EBA reached a 5-year in-hospital mortality rate of approximately 0.21 and 0.34, while PV and PF rates were approximately 0.07 and 0.11, respectively. The Cox hazard model revealed that higher age is the risk factor for in-hospital mortality in all diseases. Kaplan-Meier analysis indicated a cumulative steroid cessation probability of 0.25 at 3 years for BP, and at 6 and 5 years for PV and PF, respectively. The Cox hazard model revealed that higher age and lower maximum corticosteroid dose contribute to the steroid cessation probability in BP, PV, and PF. This study provides insights into the epidemiology, treatment patterns, comorbidities, and outcomes of AIBDs in Japan., (© 2024 Japanese Dermatological Association.)

Ecdysone-induced protein 93 (E93), known as the 'adult-specifier' transcription factor in insects, triggers metamorphosis in both hemimetabolous and holometabolous insects. Although E93 is conserved in ametabolous insects, its spatiotemporal expression and physiological function remain poorly understood. In this study, we first discover that, in the ametabolous firebrat Thermobia domestica, the previtellogenic ovary exhibits cyclically high E93 expression, and E93 mRNA is broadly distributed in previtellogenic ovarioles. E93 homozygous mutant females of T. domestica exhibit severe fecundity deficiency due to impaired previtellogenic development of the ovarian follicles, likely because E93 induces the expression of genes involved in ECM (extracellular matrix)-receptor interactions during previtellogenesis. Moreover, we reveal that in the hemimetabolous cockroach Blattella germanica, E93 similarly promotes previtellogenic ovarian development. In addition, E93 is also essential for vitellogenesis that is necessary to guarantee ovarian maturation and promotes the vitellogenesis-previtellogenesis switch in the fat body of adult female cockroaches. Our findings deepen the understanding of the roles of E93 in controlling reproduction in insects, and of E93 expression and functional evolution, which are proposed to have made crucial contributions to the origin of insect metamorphosis., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Juvenile hormone (JH) is an insect-exclusive hormone involved in regulating diverse aspects of insect physiology, and the evolution of its diverse function is widely interesting. Studying embryogenesis in basal wingless insects is important to understand the functional evolution of JH; however, experimental studies in this regard are scarce. In this study, we conducted CRISPR/Cas9-mediated knockout (KO) of genes involved in JH biosynthesis and signaling cascades in the ametabolous firebrat, Thermobia domestica. Additionally, we investigated whether the primitive action of JH is conserved in the hemimetabolous cricket, Gryllus bimaculatus., Results: We observed that KO of JHAMT, CYP15A1, Met, and Kr-h1 resulted in embryonic lethality in T. domestica. Deprivation of JH or JH signaling arrested the progression of extraembryonic fluid resorption after dorsal closure and hatching, which is consistent with the gene expression pattern showing high Kr-h1 expression in the late embryos of T. domestica. The embryos deficient in JH signaling displayed wrinkled and weak legs. Comparative transcriptome analysis revealed that JH signaling promotes embryonic leg maturation through inducing energy supply and muscle activity, as validated by transmission electron microscopy (TEM). In addition, JH signaling exhibited similar embryonic effects in G. bimaculatus., Conclusions: This study reveals the indispensable role of JH signaling in facilitating the maturation of terminal tissues during late embryogenesis, as demonstrated by the regulation of leg development, in ametabolous and hemimetabolous insects. These findings further indicate that the embryonic functions of JH evolved earlier than its anti-metamorphic functions during postembryonic development., (© 2024. The Author(s).)

Approximately 40% of the mammalian proteome undergoes N-terminal methionine excision and acetylation, mediated sequentially by methionine aminopeptidase (MetAP) and N-acetyltransferase A (NatA), respectively 1 . Both modifications are strictly cotranslational and essential in higher eukaryotic organisms 1 . The interaction, activity and regulation of these enzymes on translating ribosomes are poorly understood. Here we perform biochemical, structural and in vivo studies to demonstrate that the nascent polypeptide-associated complex 2,3 (NAC) orchestrates the action of these enzymes. NAC assembles a multienzyme complex with MetAP1 and NatA early during translation and pre-positions the active sites of both enzymes for timely sequential processing of the nascent protein. NAC further releases the inhibitory interactions from the NatA regulatory protein huntingtin yeast two-hybrid protein K 4,5 (HYPK) to activate NatA on the ribosome, enforcing cotranslational N-terminal acetylation. Our results provide a mechanistic model for the cotranslational processing of proteins in eukaryotic cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Veterans with posttraumatic stress disorder (PTSD) or moral injury are at risk of maladaptive response styles to positive emotions, such as emotional numbing. A potential pathway to target problematic responses to positive affect is a positive psychology intervention that elicits moral elevation-feeling inspired after witnessing someone perform a virtuous act. This study aims to examine responses to positive affect in a pilot trial of a web-based moral elevation intervention titled, MOVED: Moral Elevation Online Intervention for Veterans Experiencing Distress Related to PTSD and Moral Injury. Method: Veterans who reported moral injury distress and probable PTSD were randomized into an intervention or control condition ( n = 48). We examined repeated measures data during the trial and focused on three subscales of the Response to Positive Affect Questionnaire: rumination on positive mood and somatic experiences (emotion-focus), rumination on positive aspects of the self and pursuit of relevant goals (self-focus), and efforts to dampen positive moods (dampening). Three multilevel models were fitted with time and condition as predictors and subscale scores as outcomes. Qualitative data reported at intervention sessions was also reviewed and coded based on the three subscales., Results: Veterans in the MOVED condition reported more positive rumination than the control condition for both emotion-focus ( b = 2.70, p = .023) and self-focus styles ( b = 2.90, p = .003). There was no group difference in the dampening style. Qualitative responses after elevation-eliciting exercises and session-based goals were most frequently coded as including emotion-focused positive rumination, followed by dampening, then self-focused rumination., Conclusion: These results provide preliminary evidence that a moral elevation intervention might contribute to positive responses to positive affect in a sample predisposed to emotional numbing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objectives: The objectives were to investigate the clinical characteristics and course of long COVID, defined as the persistence of symptoms at least one month after the onset of COVID-19, in outpatients and to clarify differences in symptoms between SARS CoV-2 mutant strains. Methods: Our observational study in a primary care institution in Japan included 1053 patients with long COVID who visited our outpatient clinic between April 2021 and March 2023. Symptom distribution, performance status, and patient background at the time of the first outpatient visit were compared between infectious strains (Delta and before group and Omicron group). Background factors and symptoms related to time to remission were also analyzed. Results: The severity of COVID-19 in the acute phase was mild, moderate, and severe in 82.2%, 14.9%, and 2.9% in the Delta and before group; and in 97.6%, 1.7%, and 0.4% in the Omicron group, respectively. Vaccination coverage was significantly different between the Delta and before (37.1%) and Omicron groups (73.1%) ( p < 0.001), probably due to the period of vaccine unavailability in the former group. Symptoms of fatigue and headache occurred most frequently, irrespective of infectious strain. The mean number of symptoms per patient was significantly higher in the Delta and before group than the Omicron group (3.4 vs. 2.7, p < 0.0001). The median time overall to remission of long COVID was 169 days. Cox hazard model analysis identified female sex, high body mass index, and dyspnea (but not infectious strain) as significant factors prolonging the time to remission ( p < 0.05). Conclusions: Differences in the number of symptoms between infectious strains may be related to differences in viral virulence and/or vaccination coverage. However, the clinical course was found to be minimally influenced by the infectious strain. The present results should improve the understanding of prognosis in patients with long COVID from both the clinical and social perspectives.

Although patients with hyperuricemia and gout often have dyslipidemia, the effects of febuxostat, a xanthine oxidase inhibitor, on their lipid profiles are unclear. Thus, we performed a sub-analysis of the randomized PRIZE study in which the effects of febuxostat on carotid atherosclerosis were investigated in patients with hyperuricemia. The participants were randomized to the febuxostat or control group. The primary endpoint of this sub-analysis was changes in the patients' non-high-density lipoprotein cholesterol (HDL-C) levels from baseline to 6-month follow-up. Correlations between the changes in lipid profiles and cardiometabolic parameters were also evaluated. In total, 456 patients were included. From baseline to 6 months, non-HDL-C levels were significantly reduced in the febuxostat group (-5.9 mg/dL, 95% confidence interval [CI]: -9.1 to -2.8 mg/dL, p < 0.001), but not in the control group (-1.3 mg/dL, 95% CI: -4.4 to 1.8, p = 0.348). The reduction in non-HDL-C levels was more pronounced in women and correlated with changes in serum uric acid and estimated glomerular filtration rate levels only in the febuxostat group. In patients with hyperuricemia, febuxostat treatment was associated with reduced non-HDL-C levels from baseline to the 6-month follow-up compared to the control treatment, suggesting that the lipid-lowering effect of febuxostat should be considered when targeting dyslipidemia.

Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. In the past, many researchers have focused on drusen and tried to elucidate the pathophysiology of AMD because they believed that disease progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD. In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number. However, the existence of advanced AMD without drusen has long been recognized. For example, polypoidal choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD. Now is the time to reconsider the relationship between AMD and drusen. In this review, we focus on early AMD pathogenesis based on basic research from the perspective of cholesterol metabolism and hypoxic response in the retina, and we discuss the role of drusen.

Eukaryotic ribosome assembly is an intricate process that involves four ribosomal RNAs, 80 ribosomal proteins, and over 200 biogenesis factors that take part in numerous interdependent steps. This complexity creates a large genetic space in which pathogenic mutations can occur. Dead-end ribosome intermediates that result from biogenesis errors are rapidly degraded, affirming the existence of quality control pathway(s) that monitor ribosome assembly. However, the factors that differentiate between on-path and dead-end intermediates are unknown. We engineered a system to perturb ribosome assembly in human cells and discovered that faulty ribosomes are degraded via the ubiquitin proteasome system. We identified ZNF574 as a key component of a novel quality control pathway, which we term the Ribosome Assembly Surveillance Pathway (RASP). Loss of ZNF574 results in the accumulation of faulty biogenesis intermediates that interfere with global ribosome production, further emphasizing the role of RASP in protein homeostasis and cellular health.

In vitro translation is an important method for studying fundamental aspects of co- and post-translational gene regulation, as well as for protein expression in the laboratory and on an industrial scale. Here, by re-examining and improving a human in vitro translation system (HITS), we were able to develop a minimal system where only four components are needed to supplement human cell lysates. Functional characterization of our improved HITS revealed the synergistic effect of mRNA capping and polyadenylation. Furthermore, we found that mRNAs are translated with an efficiency equal to or higher than existing state-of-the-art mammalian in vitro translation systems. Lastly, we present an easy preparation procedure for cytoplasmic extracts from cultured HeLa cells, which can be performed in any cell culture laboratory. These methodological advances will allow HITSs to become a widespread tool in basic molecular biology research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The burden of ocular diseases has been gradually increasing worldwide. Various factors are suggested for the development and progression of ocular diseases, such as ocular inflammation, oxidative stress, and complex metabolic dysregulation. Thus, managing ocular diseases requires the modulation of pathologic signaling pathways through many mechanisms. Nicotinamide mononucleotide (NMN) is a bioactive molecule naturally found in life forms. NMN is a direct precursor of the important molecule nicotinamide adenine dinucleotide (NAD + ), an essential co-enzyme required for enormous cellular functions in most life forms. While the recent experimental evidence of NMN treatment in various metabolic diseases has been well-reviewed, NMN treatment in ocular diseases has not been comprehensively summarized yet. In this regard, we aimed to focus on the therapeutic roles of NMN treatment in various ocular diseases with recent advances., Methods: How we came to our current opinion with a recent summary was described based on our own recent reports as well as a search of the related literature., Results: We found that NMN treatment might be available for the prevention of and protection from various experimental ocular diseases, as NMN treatment modulated ocular inflammation, oxidative stress, and complex metabolic dysregulation in murine models for eye diseases such as ischemic retinopathy, corneal defect, glaucoma, and age-related macular degeneration., Conclusion: Our current review suggests and discusses new modes of actions of NMN for the prevention of and protection from various ocular diseases and can urge future research to obtain more solid evidence on a potential future NMN treatment in ocular diseases at the preclinical stages., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Task Group 115 of the International Commission on Radiological Protection is focusing on mission-related exposures to space radiation and concomitant health risks for space crew members including, among others, risk of cancer development. Uncertainties in cumulative radiation risk estimates come from the stochastic nature of the considered health outcome (i.e., cancer), uncertainties of statistical inference and model parameters, unknown secular trends used for projections of population statistics and unknown variability of survival properties between individuals or population groups. The variability of survival is usually ignored when dealing with large groups, which can be assumed well represented by the statistical data for the contemporary general population, either in a specific country or world averaged. Space crew members differ in many aspects from individuals represented by the general population, including, for example, their lifestyle and health status, nutrition, medical care, training and education. The individuality of response to radiation and lifespan is explored in this modelling study. Task Group 115 is currently evaluating applicability and robustness of various risk metrics for quantification of radiation-attributed risks of cancer for space crew members. This paper demonstrates the impact of interpopulation variability of survival curves on values and uncertainty of the estimates of the time-integrated radiation risk of cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

AMP-activated protein kinase (AMPK) plays a crucial role in maintaining ATP homeostasis in photoreceptor neurons. AMPK is a heterotrimeric protein consisting of α, β, and γ subunits. The independent functions of the 2 isoforms of the catalytic α subunit, PRKAA1 and PRKAA2, are uncharacterized in specialized neurons, such as photoreceptors. Here, we demonstrate in mice that rod photoreceptors lacking PRKAA2, but not PRKAA1, showed altered levels of cGMP, GTP, and ATP, suggesting isoform-specific regulation of photoreceptor metabolism. Furthermore, PRKAA2-deficient mice displayed visual functional deficits on electroretinography and photoreceptor outer segment structural abnormalities on transmission electron microscopy consistent with neuronal dysfunction, but not neurodegeneration. Phosphoproteomics identified inosine monophosphate dehydrogenase (IMPDH) as a molecular driver of PRKAA2-specific photoreceptor dysfunction, and inhibition of IMPDH improved visual function in Prkaa2 rod photoreceptor-knockout mice. These findings highlight a therapeutically targetable PRKAA2 isoform-specific function of AMPK in regulating photoreceptor metabolism and function through a potentially previously uncharacterized mechanism affecting IMPDH activity.

Background: The unplanned and intensified use of insecticides to control mosquito-borne diseases has led to an upsurge of resistance to commonly used insecticides. Aedes aegypti, the main vector of dengue, chikungunya, and Zika virus, is primarily controlled through the application of adulticides (pyrethroid insecticides) and larvicides (temephos). Fine spatial-scale analysis of resistance may reveal important resistance-related patterns, and the application of mathematical models to determine the phenotypic resistance status lessens the cost and usage of resources, thus resulting in an enhanced and successful control program., Methods: The phenotypic resistance for permethrin, deltamethrin, and malathion was monitored in the Ae. aegypti populations using the World Health Organization (WHO) adult bioassay method. Mosquitoes' resistance to permethrin and deltamethrin was evaluated for the commonly occurring base substitutions in the voltage-gated sodium channel (vgsc) gene. Rational functions were used to determine the relationship between the kdr alleles and the phenotypic resistant percentage of Ae. aegypti in Sri Lanka., Results: The results of the bioassays revealed highly resistant Ae. aegypti populations for the two pyrethroid insecticides (permethrin and deltamethrin) tested. All populations were susceptible to 5% malathion insecticide. The study also revealed high frequencies of C1534 and G1016 in all the populations studied. The highest haplotype frequency was detected for the haplotype CC/VV, followed by FC/VV and CC/VG. Of the seven models obtained, this study suggests the prediction models using rational approximation considering the C allele frequencies and the total of C, G, and P allele frequencies and phenotypic resistance as the best fits for the area concerned., Conclusions: This is the first study to our knowledge to provide a model to predict phenotypic resistance using rational functions considering kdr alleles. The flexible nature of the rational functions has revealed the most suitable association among them. Thus, a general evaluation of kdr alleles prior to insecticide applications would unveil the phenotypic resistance percentage of the wild mosquito population. A site-specific strategy is recommended for monitoring resistance with a mathematical approach and management of insecticide applications for the vector population., (© 2023. The Author(s).)

Coronaviruses are a group of related RNA viruses that cause respiratory diseases in humans and animals. Understanding the mechanisms of translation regulation during coronaviral infections is critical for developing antiviral therapies and preventing viral spread. Translation of the viral single-stranded RNA genome in the host cell cytoplasm is an essential step in the life cycle of coronaviruses, which affects the cellular mRNA translation landscape in many ways. Here we discuss various viral strategies of translation control, including how members of the Betacoronavirus genus shut down host cell translation and suppress host innate immune functions, as well as the role of the viral non-structural protein 1 (Nsp1) in the process. We also outline the fate of viral RNA, considering stress response mechanisms triggered in infected cells, and describe how unique viral RNA features contribute to programmed ribosomal -1 frameshifting, RNA editing, and translation shutdown evasion., (© 2024. The Author(s).)

Abstract: A promising approach to enhancing trauma-focused treatment is moral elevation-feeling inspired by witnessing a virtuous act. This study explored potential links between eliciting elevation and relevant outcomes in a series of case examples. Veterans with probable posttraumatic stress disorder completed experimental tasks including a written trauma narrative exercise and watching elevation-eliciting videos. Participants also completed baseline assessments, repeated measures of trauma-related cognitions, emotions, elevation, and saliva sample collection. Four cases were identified and reviewed: two positive responders (high elevation after videos) and two nonresponders (restricted elevation response). Positive responder cases reported decreased cognitions, emotions, and moral injury distress from after the trauma narrative to after elevation exercises, whereas nonresponders reported minimal to no changes. Positive responders also demonstrated decreases in cortisol, whereas nonresponders demonstrated increases in cortisol. Future work should examine whether elevation contributes to changes in biopsychosocial outcomes and identify individual factors that indicate who might benefit from elevation-based interventions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Preserving core body temperature across a wide range of ambient temperatures requires adaptive changes of thermogenesis that must be offset by corresponding changes of energy intake if body fat stores are also to be preserved. Among neurons implicated in the integration of thermoregulation with energy homeostasis are those that express both neuropeptide Y (NPY) and agouti-related protein (AgRP) (referred to herein as AgRP neurons). Specifically, cold-induced activation of AgRP neurons was recently shown to be required for cold exposure to increase food intake in mice. Here, we investigated how consuming a high-fat diet (HFD) impacts various adaptive responses to cold exposure as well as the responsiveness of AgRP neurons to cold., Methods: To test this, we used immunohistochemistry, in vivo fiber photometry and indirect calorimetry for continuous measures of core temperature, energy expenditure, and energy intake in both chow- and HFD-fed mice housed at different ambient temperatures., Results: We show that while both core temperature and the thermogenic response to cold are maintained normally in HFD-fed mice, the increase of energy intake needed to preserve body fat stores is blunted, resulting in weight loss. Using both immunohistochemistry and in vivo fiber photometry, we show that although cold-induced AgRP neuron activation is detected regardless of diet, the number of cold-responsive neurons appears to be blunted in HFD-fed mice., Conclusions: We conclude that HFD-feeding disrupts the integration of systems governing thermoregulation and energy homeostasis that protect body fat mass during cold exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objectives: Despite the involvement of B cells in the pathogenesis of immune-mediated diseases (IMDs), biological mechanisms underlying their function are scarcely understood. To overcome this gap, here we constructed and investigated a large-scale repertoire catalogue of five B cell subsets of patients with IMDs., Methods: We mapped B cell receptor regions from RNA sequencing data of sorted B cell subsets. Our dataset consisted of 595 donors under IMDs and health. We characterised the repertoire features from various aspects, including their association with immune cell transcriptomes and clinical features and their response to belimumab treatment., Results: Heavy-chain complementarity-determining region 3 (CDR-H3) length among naïve B cells was shortened among autoimmune diseases. Strong negative correlation between interferon signature strength and CDR-H3 length was observed in naïve B cells and suggested the role for interferon in premature B cell development. VDJ gene usage was skewed especially in plasmablasts and unswitched-memory B cells of patients with systemic lupus erythematosus (SLE). We developed a scoring system to quantify this skewing, and it positively correlated with peripheral helper T cell transcriptomic signatures and negatively correlated with the amount of somatic hyper mutations in plasmablasts, suggesting the association of extrafollicular pathway. Further, this skewing led to high usage of IGHV4-34 gene with 9G4 idiotypes in unswitched-memory B cells, which showed a prominent positive correlation with disease activity in SLE. Gene usage skewing in unswitched-memory B cells was ameliorated after belimumab treatment., Conclusions: Our multimodal repertoire analysis enabled us the system-level understanding of B cell abnormality in diseases., Competing Interests: Competing interests: MO, YN, TI, and TO belonged to the Social Cooperation Program, Department of functional genomics and immunological diseases, supported by Chugai Pharmaceutical. NB is an employee of Chugai Pharmaceutical. KF receives consulting honoraria and research support from Chugai Pharmaceutical., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Nonstructural protein 1 (Nsp1) produced by coronaviruses inhibits host protein synthesis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp1 C-terminal domain was shown to bind the ribosomal mRNA channel to inhibit translation, but it is unclear whether this mechanism is broadly used by coronaviruses, whether the Nsp1 N-terminal domain binds the ribosome, or how Nsp1 allows viral RNAs to be translated. Here, we investigated Nsp1 from SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), and Bat-Hp-CoV coronaviruses using structural, biophysical, and biochemical experiments, revealing a conserved role for the C-terminal domain. Additionally, the N-terminal domain of Bat-Hp-CoV Nsp1 binds to the decoding center of the 40S subunit, where it would prevent mRNA and eIF1A accommodation. Structure-based experiments demonstrated the importance of decoding center interactions in all three coronaviruses and showed that the same regions of Nsp1 are necessary for the selective translation of viral RNAs. Our results provide a mechanistic framework to understand how Nsp1 controls preferential translation of viral RNAs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

DNA-encoded chemical libraries (DELs) consist of large chemical compound collections individually linked to DNA barcodes, facilitating pooled construction and screening. However, screening campaigns often fail if the molecular arrangement of the building blocks is not conducive to an efficient interaction with a protein target. Here we postulated that the use of rigid, compact and stereo-defined central scaffolds for DEL synthesis may facilitate the discovery of very specific ligands capable of discriminating between closely related protein targets. We synthesized a DEL comprising 3,735,936 members, featuring the four stereoisomers of 4-aminopyrrolidine-2-carboxylic acid as central scaffolds. The library was screened in comparative selections against pharmaceutically relevant targets and their closely related protein isoforms. Hit validation results revealed a strong impact of stereochemistry, with large affinity differences between stereoisomers. We identified potent isozyme-selective ligands against multiple protein targets. Some of these hits, specific to tumour-associated antigens, demonstrated tumour-selective targeting in vitro and in vivo. Collectively, constructing DELs with stereo-defined elements contributed to high library productivity and ligand selectivity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Segmentation of tumor regions in H &E-stained slides is an important task for a pathologist while diagnosing different types of cancer, including oral squamous cell carcinoma (OSCC). Histological image segmentation is often constrained by the availability of labeled training data since labeling histological images is a highly skilled, complex, and time-consuming task. Thus, data augmentation strategies become essential to train convolutional neural networks models to overcome the overfitting problem when only a few training samples are available. This paper proposes a new data augmentation strategy, named Random Composition Augmentation (RCAug), to train fully convolutional networks (FCN) to segment OSCC tumor regions in H &E-stained histological images. Given the input image and their corresponding label, a pipeline with a random composition of geometric, distortion, color transfer, and generative image transformations is executed on the fly. Experimental evaluations were performed using an FCN-based method to segment OSCC regions through a set of different data augmentation transformations. By using RCAug, we improved the FCN-based segmentation method from 0.51 to 0.81 of intersection-over-union (IOU) in a whole slide image dataset and from 0.65 to 0.69 of IOU in a tissue microarray images dataset., (© 2023. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Introduction: Chronic limb-threatening ischemia (CLTI) is the end stage of peripheral arterial disease (PAD) and is associated with high amputation rates, mortality and disease-related health care costs. In infrapopliteal arterial disease (IPAD), endovascular revascularization should be considered for the majority of anatomical and clinical subgroups of CLTI. However, a gap of high-quality evidence exists in this field. The aim of the Dutch Chronic Lower Limb-Threatening Ischemia Registry (THRILLER) is to collect real world data on popliteal and infrapopliteal endovascular interventions., Methods: THRILLER is a clinician-driven, prospective, multicenter, observational registry including all consecutive patients that undergo a popliteal or infrapopliteal endovascular intervention in seven Dutch hospitals. We estimate that THRILLER will include 400-500 interventions annually. Standardized follow-up visits with wound monitoring, toe pressure measurement and duplex ultrasonography will be scheduled at 6-8 weeks and 12 months after the intervention. The independent primary endpoints are primary patency, limb salvage and amputation free survival. Patients must give informed consent before participation and will be included according to predefined reporting standards. A data log of patients who meet the inclusion criteria but are not included in the registry will be maintained. We intend to conduct the first interim analysis two years after the start of inclusion. The results will be published in a scientific journal., Discussion: Despite innovations in medical therapy and revascularization techniques, patients with CLTI undergoing endovascular revascularization still have a moderate prognosis. Previous prospective cohort studies were hampered by small sample sizes or heterogeneous reporting. Randomized controlled trials (RCTs) have high costs, potential conflicts of interest and give a limited reflection of daily practice. THRILLER aims to provide the largest prospective well phenotyped up-to-date dataset on treatment outcomes in CLTI patients to answer multiple underexplored research questions regarding diagnostics, medication, patient selection, treatment strategies and post intervention follow-up., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nugteren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

N-terminal methionine excision from newly synthesized proteins, catalyzed cotranslationally by methionine aminopeptidases (METAPs), is an essential and universally conserved process that plays a key role in cell homeostasis and protein biogenesis. However, how METAPs interact with ribosomes and how their cleavage specificity is ensured is unknown. We discovered that in eukaryotes the nascent polypeptide-associated complex (NAC) controls ribosome binding of METAP1. NAC recruits METAP1 using a long, flexible tail and provides a platform for the formation of an active methionine excision complex at the ribosomal tunnel exit. This mode of interaction ensures the efficient excision of methionine from cytosolic proteins, whereas proteins targeted to the endoplasmic reticulum are spared. Our results suggest a broader mechanism for how access of protein biogenesis factors to translating ribosomes is controlled.

The translocon-associated protein (TRAP) complex resides in the endoplasmic reticulum (ER) membrane and interacts with the Sec translocon and the ribosome to facilitate biogenesis of secretory and membrane proteins. TRAP plays a key role in the secretion of many hormones, including insulin. Here we reveal the molecular architecture of the mammalian TRAP complex and how it engages the translating ribosome associated with Sec61 translocon on the ER membrane. The TRAP complex is anchored to the ribosome via a long tether and its position is further stabilized by a finger-like loop. This positions a cradle-like lumenal domain of TRAP below the translocon for interactions with translocated nascent chains. Our structure-guided TRAP mutations in Caenorhabditis elegans lead to growth deficits associated with increased ER stress and defects in protein hormone secretion. These findings elucidate the molecular basis of the TRAP complex in the biogenesis and translocation of proteins at the ER., (© 2023. The Author(s).)

The genetic code that specifies the identity of amino acids incorporated into proteins during protein synthesis is almost universally conserved. Mitochondrial genomes feature deviations from the standard genetic code, including the reassignment of two arginine codons to stop codons. The protein required for translation termination at these noncanonical stop codons to release the newly synthesized polypeptides is not currently known. In this study, we used gene editing and ribosomal profiling in combination with cryo-electron microscopy to establish that mitochondrial release factor 1 (mtRF1) detects noncanonical stop codons in human mitochondria by a previously unknown mechanism of codon recognition. We discovered that binding of mtRF1 to the decoding center of the ribosome stabilizes a highly unusual conformation in the messenger RNA in which the ribosomal RNA participates in specific recognition of the noncanonical stop codons.

Mycobacterium virginiense, a species of the Mycobacterium terrae complex, was first identified in 2016. Although M. virginiense has only been reported to cause tenosynovitis, there have been only a few reports. Moreover, there is no established standard treatment, and no cases of M. virginiense infection have been reported in Japan. A 70-year-old Japanese man with a history of hand injury and wound contamination was diagnosed with synovitis and tenosynovitis of the left flexor digitorum superficialis and profundus muscles. M. virginiense was detected in perisynovial reservoirs and surgically removed synovium and was identified by hsp65 and rpoB sequencing. Postoperative chemotherapy with clarithromycin, rifabutin, and ethambutol was administered. Infection with M. virginiense can occur in patients with synovitis and tenosynovitis who have experienced injury or wound contamination, requiring surgery and long-term treatment with multiple antibiotics., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The green peach aphid, Myzus persicae (Sulzer), is a significant global pest in horticultural and field crops. Afidopyropen is a novel systemic insecticide with high efficacy against sucking pests, and it is suitable for the management of M. persicae. However, the persistent toxicity and dissipation dynamics of afidopyropen in vegetables remain unknown. In this study, we determined the residual activity and dissipation dynamics of afidopyropen against M. persicae on cabbage and chili. The data showed that the toxicity of afidopyropen against M. persicae lasted more than 30 days; the corrected mortality was greater than 80% 10 days after application and was 50-60% 30 days post-application. The afidopyropen residues on cabbage and chili plants were quantified using ultrahigh-pressure liquid chromatography-tandem mass spectrometry. The dissipation half-lives of afidopyropen on cabbage and chili plants ranged from 1.45 to 2.34 days and 3.98-5.98 days at different recommended dosages, respectively. Our findings provide valuable data for the maximum residue limits of afidopyropen on vegetables and will help growers determine the frequency and timing of its application on cabbage and chili., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response against three SARS-CoV-2 proteins. We used TRABI for continuous seromonitoring of hospital patients and blood donors (n = 72'250) in the canton of Zurich from December 2019 to December 2020 (pre-vaccine period). We found that antibodies waned with a half-life of 75 days, whereas the cumulative incidence rose from 2.3% in June 2020 to 12.2% in mid-December 2020. A follow-up health survey indicated that about 10% of patients infected with wildtype SARS-CoV-2 sustained some symptoms at least twelve months post COVID-19. Crucially, we found no evidence of a difference in long-term complications between those whose infection was symptomatic and those with asymptomatic acute infection. The cohort of asymptomatic SARS-CoV-2-infected subjects represents a resource for the study of chronic and possibly unexpected sequelae., Competing Interests: TPJK is a member of the board of directors of Fluidic Analytics. AA is a member of the board of directors of Mabylon AG which has funded antibody-related work in the Aguzzi lab in the past. All other authors declare no competing interests., (© 2023 The Authors.)

[Purpose] This study aimed to examine the validity and reproducibility of a new quantitative method for measuring spinal kyphosis using computed tomography (CT), and to investigate its relationship with reflux esophagitis. [Method] Using a new method to measure the index of kyphosis in CT images (IKCT), 10 examiners evaluated 10 cases of spinal kyphosis. One examiner measured 47 cases twice and 20 cases were examined to assess the validity with the kyphosis index. A case-control study was conducted on 303 cases of reflux esophagitis, of which 241 were mild and 62 severe. [Results] Regarding IKCT reproducibility, the inter-rater intraclass correlation coefficient was 0.977. The intra-rater intraclass correlation coefficient was 0.974. The correlation index with the kyphosis index was 0.731. A greater IKCT value, not contracting serious atrophic gastritis, and severe hiatal hernia were identified as risk factors for severe reflux esophagitis. [Conclusion] IKCT is a simple and useful method for measuring kyphosis. The prevention of kyphosis can help suppress severe reflux esophagitis.

A brain-computer interface (BCI) is a non-muscular communication technology that provides an information exchange channel for our brains and external devices. During the decades, BCI has made noticeable progress and has been applied in many fields. One of the most traditional BCI applications is the BCI speller. This article primarily discusses the progress of research into P300 BCI spellers and reviews four types of P300 spellers: single-modal P300 spellers, P300 spellers based on multiple brain patterns, P300 spellers with multisensory stimuli, and P300 spellers with multiple intelligent techniques. For each type of P300 speller, we further review several representative P300 spellers, including their design principles, paradigms, algorithms, experimental performance, and corresponding advantages. We particularly emphasized the paradigm design ideas, including the overall layout, individual symbol shapes and stimulus forms. Furthermore, several important issues and research guidance for the P300 speller were identified. We hope that this review can assist researchers in learning the new ideas of these novel P300 spellers and enhance their practical application capability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pan, Chen, Ban, He, Chen and Huang.)

The green peach aphid, Myzus persicae (Sulzer) is a generalist pest of various host plants, whose feeding preference and growth performance mainly depends on the quantity and quality of nutrients and defensive metabolites in host plants. Here, we studied the preference and performance of M. persicae on three major Brassicaceae vegetables in China and measured nutrient (amino acids) and defensive metabolites (glucosinolates) in these plants. We found that M. persicae preferred and performed better on Chinese cabbage than cabbage and radish, which may be due to the relatively higher concentration of amino acids and lower levels of indole glucosinolates in their leaves. The glucosinolates level in cabbage leaves was ten times higher than the other two plants, while the amino acid concentration in radish was only half of the cabbage or Chinese cabbage. The higher concentration of indole glucosinolates in cabbage and lower levels of amino acids in radish may account for the poorer preference and growth of M. persicae on these two plants. These results suggest that both amino acids and glucosinolates in plants may play important roles in the preference and performance of M. persicae, which provide new knowledge for the cultivation and breeding of Brassicaceae vegetables., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Ahmed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD + ) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD + levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2 ) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction.

Background: The Consultation and Relational Empathy (CARE) measure is a patient-reported measure of physician empathy which is widely used internationally. The Japanese version of the CARE measure has very high internal reliability, suggesting that a shorter version may have adequate validity and reliability., Objective: To investigate a valid shorter version of the Japanese CARE measure., Methods: We conducted a pilot study using secondary analysis of previous data obtained from 9 general practitioners and 252 patients and used to develop the Japanese CARE measure. All 1,023 possible combinations of the Japanese CARE items (n = 1-10) were candidates for the short measure. The internal consistency (Cronbach's alpha) and the correlations between candidate short questionnaires and the original questionnaire were calculated. After selecting the most valid short questionnaire, inter-rater reliability was determined using generalizability theory, and construct validity (Spearman's rho) was determined using patient satisfaction., Results: Two items were selected for a pilot shorter version: item 6 "Showing care and compassion" and item 9 "Helping you to take control." These showed high internal consistency and correlations with the 10-item measure (Cronbach's alpha = 0.920, correlation = 0.979). Forty-five questionnaires per doctor allowed us to reliably differentiate between practitioners. The construct validity for the pilot short measure was high (Spearman's rho 0.706, P < 0.001)., Conclusion: We generated a pilot 2-item version of the Japanese CARE measure. This pilot 2-item version provides a basis for future validation studies of short CARE measures in other languages., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The very-low-voltage (VLV) mode in electrosurgery can stably and deeply energize tissues even if the local electrical resistance changes with energization. Therefore, in electrosurgical hemostasis, the VLV mode is more reliable than other coagulation modes. In clinical practice, the appropriate use of combined saline drip and blood suction under the VLV mode can further enhance coagulation ability. However, the detailed mechanism is not known. The current study aimed to evaluate the association between electrosurgical activation time (ET) and hemostatic tissue effect (HTE) under the VLV mode. Further, the effect of saline drip and suction on power consumption and HTE was validated., Methods: Twelve female pigs weighing 35 kg were included in the experiment. A liver hemorrhage model was established via an open abdominal procedure, and hemostasis in the hemorrhagic lesion was attempted using the VLV mode under different conditions (ET: 3, 6, 9, and 12 s, with/without saline drip and/or continuous suction). Electrical data (such as voltage, current, and resistance) during coagulation were extracted. Then, the vertical/horizontal extent of HTE was assessed, and the hemostasis outcome (successful or failed) was recorded., Results: The vertical/horizontal HTE, power consumption, and integrated current value were positively correlated with the ET. The coagulation depth deepened with saline drip (p < 0.01). However, it was not affected by continuous suction (p = 0.20). The HTE area increased with saline drip (p < 0.01) and decreased with suction (p < 0.01). The power consumption and integrated current increased with saline drip (p < 0.01) and decreased with suction (p < 0.01). The success rate of hemostasis decreased with saline drip alone (31of 48 trials [success rate = 64.5%] in the saline drip group and 44/48 trials (success rate = 91.7%) in the control group). However, it improved with continuous suction (46/48 trials [success rate = 95.8%])., Conclusion: The electrosurgical activation time was positively correlated with hemostatic tissue effect. Saline drip increased heat transfer efficiency but decreased the success rate of hemostasis. Therefore, the use of continuous suction in addition to saline drip increased hemostatic efficiency., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Brownian particles placed sequentially in contact with distinct thermal reservoirs and subjected to external driving forces are promising candidates for the construction of reliable engine setups. In this contribution, we address the role of driving forces for enhancing the collisional machine performance. Analytical expressions for thermodynamic quantities such as power output and efficiency are obtained for general driving schemes. A proper choice of these driving schemes substantially increases both power output and efficiency and extends the working regime. Maximizations of power and efficiency, whether with respect to the strength of the force, driving scheme, or both have been considered and exemplified for two kind of drivings: generic power-law and harmonic (sinusoidal) drivings.

Retinal ischemia/reperfusion (I/R) injury can cause severe vision impairment. Retinal I/R injury is associated with pathological increases in reactive oxygen species and inflammation, resulting in retinal neuronal cell death. To date, effective therapies have not been developed. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD + ) intermediate, has been shown to exert neuroprotection for retinal diseases. However, it remains unclear whether NMN can prevent retinal I/R injury. Thus, we aimed to determine whether NMN therapy is useful for retinal I/R injury-induced retinal degeneration. One day after NMN intraperitoneal (IP) injection, adult mice were subjected to retinal I/R injury. Then, the mice were injected with NMN once every day for three days. Electroretinography and immunohistochemistry were used to measure retinal functional alterations and retinal inflammation, respectively. The protective effect of NMN administration was further examined using a retinal cell line, 661W, under CoCl 2 -induced oxidative stress conditions. NMN IP injection significantly suppressed retinal functional damage, as well as inflammation. NMN treatment showed protective effects against oxidative stress-induced cell death. The antioxidant pathway ( Nrf2 and Hmox-1 ) was activated by NMN treatment. In conclusion, NMN could be a promising preventive neuroprotective drug for ischemic retinopathy.

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here, we show that FGF1 inhibited ARC NPY/AgRP neuron activity, both after intracerebroventricular injection in vivo and when applied ex vivo in a slice preparation; we also showed that the underlying mechanism involved increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons was also highly durable, lasting for at least 2 weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by intracerebroventricular FGF1 injection in rodent models of T2D.

Isoleucyl-tRNA synthetase (IleRS) is an essential enzyme that covalently couples isoleucine to the corresponding tRNA. Bacterial IleRSs group in two clades, ileS1 and ileS2, the latter bringing resistance to the natural antibiotic mupirocin. Generally, bacteria rely on either ileS1 or ileS2 as a standalone housekeeping gene. However, we have found an exception by noticing that Bacillus species with genomic ileS2 consistently also keep ileS1, which appears mandatory in the family Bacillaceae. Taking Priestia (Bacillus) megaterium as a model organism, we showed that PmIleRS1 is constitutively expressed, while PmIleRS2 is stress-induced. Both enzymes share the same level of the aminoacylation accuracy. Yet, PmIleRS1 exhibited a two-fold faster aminoacylation turnover (k cat ) than PmIleRS2 and permitted a notably faster cell-free translation. At the same time, PmIleRS2 displayed a 10 4 -fold increase in its K i for mupirocin, arguing that the aminoacylation turnover in IleRS2 could have been traded-off for antibiotic resistance. As expected, a P. megaterium strain deleted for ileS2 was mupirocin-sensitive. Interestingly, an attempt to construct a mupirocin-resistant strain lacking ileS1, a solution not found among species of the family Bacillaceae in nature, led to a viable but compromised strain. Our data suggest that PmIleRS1 is kept to promote fast translation, whereas PmIleRS2 is maintained to provide antibiotic resistance when needed. This is consistent with an emerging picture in which fast-growing organisms predominantly use IleRS1 for competitive survival., (© 2022 The Protein Society.)

In insects, the loss of flight typically involves a dispersal-reproduction transition, but the underlying molecular mechanisms remain poorly understood. In the parthenogenetic pea aphid Acyrthosiphon pisum, winged females undergo flight-muscle degeneration after flight and feeding on new host plants. Similarly, topical application of a juvenile hormone (JH) mimic to starved aphids also induces flight-muscle degeneration. We found that feeding preferentially upregulated the expression of the JH receptor gene Met and a JH-inducible gene, Kr-h1, in the flight muscles, and, thus, enhanced tissue-specific JH sensitivity and signaling. RNAi-mediated knockdown of Kr-h1 prevented flight-muscle degeneration. Likewise, blocking nutritional signals by pharmacological inhibition of the target of rapamycin complex 1 (TORC1) impaired JH sensitivity of the flight muscles in feeding aphids and subsequently delayed muscle degeneration. RNA-sequencing analysis revealed that enhanced JH signaling inhibited the transcription of genes involved in the tricarboxylic acid cycle, likely resulting in reduction of the energy supply, mitochondrial dysfunction and muscle-fiber breakdown. This study shows that nutrient-dependent hormone sensitivity regulates developmental plasticity in a tissue-specific manner, emphasizing a relatively underappreciated mechanism of hormone sensitivity in modulating hormone signaling., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Judgements on tolerability and reasonableness are central to the optimisation of protection. There are currently several international developments regarding these key considerations which will contribute to the review and evolution of the system of radiological protection. The IRPA15 International Congress brought together the principal issues currently under discussion, and the outcome of these discussions is presented., (© 2022 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Radiation detriment is a concept to quantify the burden of stochastic effects from exposure of the human population to low-dose and/or low-dose-rate ionising radiation. As part of a thorough review of the system of radiological protection, the International Commission on Radiological Protection (ICRP) has compiled a report on radiation detriment calculation methodology as Publication 152. It provides a historical review of the detriment calculation with details of the procedure used in ICRP Publication 103. A selected sensitivity analysis was conducted to identify the parameters and calculation conditions that can be major sources of variation and uncertainty. It has demonstrated that sex, age at exposure, dose and dose-rate effectiveness factor, dose assumption in the lifetime risk calculation, and lethality fraction have a substantial impact on the calculated values of radiation detriment. Discussions are also made on the issues to be addressed and possible ways for improvement toward the revision of general recommendations. These include update of the reference population data and cancer severity parameters, revision of cancer risk models, and better handling of the variation with sex and age. Finally, emphasis is placed on transparency and traceability of the calculation, along with the need to improve the way of expressing and communicating the detriment., (© 2022 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Abstract: Although research in general medicine is diverse, it has not been compared with research in a different medical specialty. The study aim was to understand the characteristics of research produced at Japanese university departments of general medicine and published in English-language journals, via comparison with another academic specialty, cardiology.In this cross-sectional study, a nationwide survey of the official websites of 82 university-affiliated medical schools in Japan was conducted in April 2020 to identify the heads of general medicine departments. We then surveyed the research output of these individuals in terms of original article output and research field diversity for journals listed in the Web of Science Core Collection of journals from 2010 to 2019. A similar survey of cardiology department publications was also conducted to provide a reference for intergroup comparisons and analysis of covariance.The analysis included 128 researchers from 78 general medicine departments and 96 researchers from 81 cardiology departments. The dominant research field of general medicine was general and internal medicine; that of cardiology was cardiac/cardiovascular systems. Data stratification by research field showed that general medicine researchers published significantly more articles than researchers in cardiology, a field that contains relatively few researchers. Furthermore, a comparison of individual researchers with the same number of published articles showed that researchers in general medicine departments published across a significantly wider range of fields than those in cardiology.This is the first study to describe the research characteristics of general medicine university departments in Japan through comparison with research in a different academic specialty. General medicine researchers in Japan comprise a heterogeneous group that mainly publishes research on general and internal medicine. Some general medicine researchers take a multidisciplinary approach to research and publishing., Competing Interests: The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The dose of intrathecal morphine is important because of its narrow therapeutic range. Due to a compounding error, pharmacy-compounded, ready-to-use syringes contained 1 mg ml -1 morphine instead of the intended 50 mcg ml -1 . Six patients consequently received this twenty-fold dose. This study aims to describe the serious adverse events in these six patients and a systematic review is added to describe the characteristics of serious adverse events after intrathecal morphine., Methods: A retrospective case series described all six patients that received the erroneous morphine intrathecally for analgesia after laparoscopic segmental colonic resections. The patients' charts were reviewed for the occurrence, timing, duration and management of adverse events, the vital signs at the night after surgery, and length of hospital stay. A systematic review investigated characteristics of serious adverse events after intrathecal morphine in a perioperative setting., Results: Four patients had a serious adverse event, which was respiratory depression combined with somnolence ( n  = 3) and hypotension ( n  = 1). The review yielded 63 cases with serious adverse events, predominantly somnolence and/or respiratory depression. The onset occurred between 2 and 24 hours after injection. The severity of symptoms varied and life-threatening respiratory depression only occurred after a dose >900 mcg or when potentiating medication was used. Naloxone did not affect analgesia. No prolonged sequalae occurred., Conclusion: This study reveals that respiratory depression and somnolence are the predominant serious adverse events after intrathecal morphine in a perioperative setting and demonstrated a large variation in the presentation of symptoms., Competing Interests: The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Mark V. Koning et al.)

Although the methods for medical education continue to evolve due to the development of medicines, the cadaver dissection course still plays a fundamental role. The cadaver dissection course allows students to learn to handle instruments correctly while actively exploring three-dimensional anatomy. However, dissection comes with the risk of accidental injury. In recent years, the number of classes offered for the cadaver dissection course has decreased while the amount of knowledge required in clinical medicine has increased. Simulation-based education (SBE) has been proven to be an effective educational method that enhances the development of practical skills by integrating learners' knowledge and skills. This study aimed to investigate the effect of SBE as a preparatory education course when taken prior to a medical student's enrollment in the cadaver dissection course. In the present study, an SBE assuming practical cadaver dissection course was performed in the Clinical Simulation Center. The frequency of injury rates per 1000 h of cadaver dissection course was significantly less in 2017 and 2018 compared to that in 2016. Two years after the implementation of the SBE, average student self-efficacy scores and written examination scores significantly increased, whereas self-contentment scores were relatively unchanged. The results showed that the implementation of SBE decreased the incidence of injuries and improved students' overall self-efficacy scores and increased acquisition of knowledge evident on written examination score. Therefore, SBE as a preparatory education course may effectively promote the combined development of dissection skills and anatomical knowledge in the subsequent fundamental cadaver dissection course., (© 2021 American Association for Anatomy.)

Background: Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes., Methods: In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed., Results: The median plasma XOR activity level was 64.3 pmol/h/mL (33.3-147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055)., Conclusions: Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction., Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The nascent polypeptide-associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC's globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization.