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Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

Objectives: We aimed to determine (1) the prevalence of constipation among inpatients, (2) the prevalence and symptoms of difficult defecation among constipated inpatients, and (3) the factors associated with constipation. Methods: We performed a retrospective cohort study over a single day at one university hospital. We analyzed the nursing records for inpatients who had been hospitalized for at least 3 days. The survey items included the symptoms associated with defecation difficulty and nutritional intake. The symptoms of difficult defecation were defined as (1) fewer than three spontaneous bowel movements per week; (2) lumpy or hard stools (Bristol stool form scale types 1–2); (3) straining during defecation; and (4) the sensation of incomplete evacuation during defecation, based on the Roma-IV diagnostic criteria. Constipation was defined as the presence of two or more symptoms of defecation difficulty. Univariate and multivariate analyses were performed to determine the constipation status of the patients. Results: The prevalence of constipation in the university hospital was 12.2%, and the department with the highest prevalence of difficulty with defecation was the Psychiatry Department (64.1%). Of the patients with constipation, 36.8% exhibited symptoms of defecation difficulty other than low frequency of defecation. The factor that was significantly associated with constipation after admission was pre-admission constipation (odds ratio=8.92, p

Introduction: Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality and underlying mechanisms remain unknown. Objectives: To investigate the potential association between slow gut transit and AD using epidemiological data and a murine model. Methods: We conducted a bi-national cohort study in South Korea (discovery cohort, N=3,130,193) and Japan (validation cohort, N=4,379,285) during the pre-observation period to determine the previous diagnostic history (2009–2010) and the follow-up period (2011–2021). To evaluate the causality, we induced slow gut transit using loperamide in 5xFAD transgenic mice. Changes in amyloid-beta (Aβ) and other markers were examined using ELISA, qRT-PCR, RNA-seq, and behavioral tests. Results: Constipation was associated with an increased risk of AD in the discovery cohort (hazard ratio, 2.04; 95% confidence interval [CI], 2.01–2.07) and the validation cohort (hazard ratio; 2.82; 95% CI, 2.61–3.05). We found that loperamide induced slower gut transit in 5xFAD mice, increased Aβ and microglia levels in the brain, increased transcription of genes related to norepinephrine secretion and immune responses, and decreased the transcription of defense against bacteria in the colonic tissue. Conclusion: Impaired gut transit may contribute to AD pathogenesis via the gut-brain axis, thus suggesting a cyclical relationship between intestinal barrier disruption and Aβ accumulation in the brain. We propose that gut transit or motility may be a modifiable lifestyle factor in the prevention of AD, and further clinical investigations are warranted.

A 29-year-old man with diabetic nephropathy presented with fever and chills 4 days postdischarge following hospitalization for hyperglycemia. Abdominal computed tomography revealed a splenic abscess. Percutaneous drainage was performed, and intravenous meropenem was administered. Subsequent culture of the drained abscess identified Lancefieldella rimae. Based on the antimicrobial susceptibility results, the patient was switched to oral levofloxacin. This combined treatment led to the resolution of the abscess, with no recurrence after 6 months. This is the first case of a splenic abscess caused by L. rimae successfully managed by prompt percutaneous drainage and appropriate antibiotics.

Abstract The phenotypes of RP1-related inherited retinal dystrophies (RP1-IRD), causing autosomal dominant (AD) and autosomal recessive (AR) diseases, vary depending on specific RP1 variants. A common nonsense mutation near the C-terminus, c.5797 C > T (p.Arg1933*), is associated with RP1-IRD, but the exact role of this mutation in genotype-phenotype correlation remains unclear. In this study, we retrospectively analyzed patients with RP1-IRD (N = 42) from a single center in Japan. AR RP1-IRD patients with the c.5797 C > T mutation (N = 14) mostly displayed macular dystrophy but rarely retinitis pigmentosa or cone-rod dystrophy. Conversely, AR RP1-IRD patients without the c.5797 C > T mutation, including those with other pathogenic RP1 variants, were mostly diagnosed with severe retinitis pigmentosa. Full-field electroretinograms were significantly better in patients homozygous or compound heterozygous for the c.5797 C > T mutation than in those without this mutation, corresponding to their milder phenotypes. Clinical tests also revealed a slower onset of age and a better mean deviation value with the static visual field in AR RP1-IRD patients with the c.5797 C > T mutation compared to those without. Therefore, the presence of c.5797 C > T may partly account for the phenotypic variety of RP1-IRD and may yield milder phenotypes. These findings may be useful for predicting the prognosis of RP1-IRD patients.

Abstract Opsins are G protein-coupled receptors (GPCRs) that have evolved to detect light stimuli and initiate intracellular signaling cascades. Their role as signal transducers is critical to light perception across the animal kingdom. Opsins covalently bind to the chromophore 11-cis retinal, which isomerizes to the all-trans isomer upon photon absorption, causing conformational changes that result in receptor activation. Monostable opsins, responsible for vision in vertebrates, release the chromophore after activation and must bind another retinal molecule to remain functional. In contrast, bistable opsins, responsible for non-visual light perception in vertebrates and for vision in invertebrates, absorb a second photon in the active state to return the chromophore and protein to the inactive state. Structures of bistable opsins in the activated state have proven elusive, limiting our understanding of how they function as bidirectional photoswitches. Here we present active state structures of a bistable opsin, jumping spider rhodopsin isoform-1 (JSR1), in complex with its downstream signaling partners, the Gi and Gq heterotrimers. These structures elucidate key differences in the activation mechanisms between monostable and bistable opsins, offering essential insights for the rational engineering of bistable opsins into diverse optogenetic tools to control G protein signaling pathways.

Aneurysmal subarachnoid hemorrhage (aSAH) is a critical condition with high in-hospital mortality rates. Delayed cerebral ischemia (DCI), a secondary complication associated with aSAH, can also contribute to morbidity and mortality. Although draining the hematoma from the subarachnoid space has been considered effective in preventing DCI, the placement of a drainage system could increase the risk of bacterial meningitis and ventriculitis. This study aimed to examine the association between meningitis following aSAH and the occurrence of DCI, focusing on the role of cerebral vasospasm. Patients who underwent endovascular coiling or surgical clipping for aSAH from April 2001 to March 2022 were included in this study, while those who did not undergo postoperative drainage were excluded. The patient's clinical characteristics, treatment modalities, and outcomes were then analyzed, after which logistic regression was used to assess the odds ratios (OR) for DCI. A total of 810 patients with aSAH were included in this study. Meningitis following aSAH was identified as an independent factor associated with DCI (odds ratio 5.0 [95% confidence intervals (CI) 2.3-11]). Other significant factors were female sex (odds ratio 1.5 [95% CI 0.89-2.5]) and surgical clipping (odds ratio 2.1 [95% CI 1.3-3.4]). This study demonstrated a significant association between meningitis following aSAH and the development of DCI, suggesting that the inflammatory environment associated with meningitis may contribute to cerebral vasospasm. Early recognition and treatment of meningitis in patients with aSAH could reduce the risk of DCI and improve patient outcomes.

Objective: The aim of the study was to evaluate the efficacy and safety of teriparatide compared to other treatments for postmenopausal osteoporosis. Methods: A review of studies from 2000 to January 2023 analyzed randomized controlled trials on postmenopausal women treated with teriparatide (PTH 1–34), comparing it to placebo or other osteoporosis treatments. The analysis focused on bone mineral density (BMD), bone turnover markers, and clinical outcomes, employing Review Manager 5.4.1 and the RoB 2 tool for bias assessment. Results: Our analysis of 23 randomized controlled trials (RCTs) found that PTH (134) treatment significantly increased lumbar spine BMD (mean difference (MD) = 0.02, 95% CI: 0.01–0.03) and femoral neck BMD (MD = 0.01, 95% CI: 0.00–0.01). However, there were no significant changes in total hip and radial bone BMD among the 3536 and 2046 participants, respectively. We also found that PTH (1–34) increased P1NP in a larger cohort (n = 1415) when compared to osteocalcin (n = 206). Although the risk of adverse events increased (relative risk (RR) = 1.65, 95% CI: 1.32–2.07), the incidence of fractures decreased significantly (RR = 0.57, 95% CI: 0.45–0.072), with no significant difference observed in mortality rates between treatment and control groups. Conclusion: Teriparatide improves lumbar spine and femoral neck BMD in postmenopausal women. Particularly notable is the novel finding regarding its effect on radius BMD, an area less explored in previous research. Despite an uptick in adverse events, the marked decrease in fracture incidence confirms its clinical utility for high-risk osteoporosis patients, highlighting the necessity for ongoing investigations into its full skeletal effects.

Abstract Background Pediatric patients with eating disorders in a multicenter joint study on 11 facilities were enrolled and prospectively investigated to determine whether improvement in body weight, eating attitudes, and psychosocial factors in children with eating disorders would also improve depressive symptoms. Methods In this study, 91 patients were enrolled between April 2014 and March 2016. The severity of underweight was assessed using the body mass index-standard deviation score (BMI-SDS), eating behavior was assessed using the children's eating attitude test (ChEAT26), the outcome of childhood eating disorders was assessed using the childhood eating disorder outcome scale, and depressive symptoms were assessed using the Children's Depression Inventory (CDI) score. Results After 12 months of treatment, depressive symptoms were evaluated in 62 of the 91 cases where it was evaluated at the initial phase. There was no difference in background characteristics between the included patients and the 29 patients who dropped out. A paired-sample t-test revealed a significant decrease in CDI scores after 12 months of treatment (p

Many older adults are increasingly embracing digital technology in the Republic of Korea. This study investigated the relationship between the digital skills of Korean older adults and their perceived health status and digital technology application for health promotion. This mixed-method study comprised a community survey of 434 older adults aged ≥65 in two cities in South Korea, followed by focus group interviews. Five types of digital skills, ‘operational internet skills’, ‘information navigation skills’, ‘social skills’, ‘creative skills’, and ‘mobile skills’, were measured using the LSE digital skill measurement instrument. Multivariable analysis identified the influence of digital skills on health-related outcomes. Among them, ‘social skills’ associated positively with self-rated health (β 0.37, 95%CI 0.08, 0.65). ‘Information navigation skills’ contributed positively to the use of digital technology and the internet for a healthy lifestyle in terms of improving eating habits (β 0.43, 95%CI 0.09, 0.77), accessing healthcare (β 0.53, 95%CI 0.21, 0.85), and accessing long-term care services (β 0.45, 95%CI 0.11, 0.79). Thematic analysis revealed that the study participants use Korean language-based resources such as Naver and Kakao Talk for social connection to promote a healthy lifestyle. This study concludes that encouraging initial and sustained use of the internet and enhancing digital skills among Korean older adults can promote active and healthy aging.

Abstract Immunoglobulin E (IgE) plays pivotal roles in allergic diseases through interaction with a high-affinity receptor (FcεRI). We established that Fab fragments of anti-IgE antibodies (HMK-12 Fab) rapidly dissociate preformed IgE-FcεRI complexes in a temperature-dependent manner and inhibit IgE-mediated anaphylactic reactions, even after allergen challenge. X-ray crystallographic studies revealed that HMK-12 Fab interacts with each of two equivalent epitopes on the Cε2 homodimer domain involved in IgE F(ab’)2. Consequently, HMK-12 Fab-mediated targeting of Cε2 reduced the binding affinity of Fc domains and resulted in rapid removal of IgE from the receptor complex. This unexpected finding of allosteric inhibition of IgE-FcεRI interactions by simultaneous targeting of two epitope sites on the Cε2 homodimer domain of IgE F(ab’)2 may have implications for the development of novel therapies for allergic disease.

Abstract Melanopsin is a photopigment belonging to the G Protein-Coupled Receptor (GPCR) family expressed in a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) and responsible for a variety of processes. The bistability and, thus, the possibility to function under low retinal availability would make melanopsin a powerful optogenetic tool. Here, we aim to utilize mouse melanopsin to trigger macrophage migration by its subcellular optical activation with localized blue light, while simultaneously imaging the migration with red light. To reduce melanopsin’s red light sensitivity, we employ a combination of in silico structure prediction and automated quantum mechanics/molecular mechanics modeling to predict minimally invasive mutations to shift its absorption spectrum towards the shorter wavelength region of the visible spectrum without compromising the signaling efficiency. The results demonstrate that it is possible to achieve melanopsin mutants that resist red light-induced activation but are activated by blue light and display properties indicating preserved bistability. Using the A333T mutant, we show that the blue light-induced subcellular melanopsin activation triggers localized PIP3 generation and macrophage migration, which we imaged using red light, demonstrating the optogenetic utility of minimally engineered melanopsins.

Abstract Background The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells. Methods RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma. Results Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice. Conclusions Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.

Background: Reproductive factors, such as age at menarche, are known to be associated with disease risk, but data on trends in these factors in Japan are limited. In this study, we investigated secular trends in reproductive factors and explored their potential association with socioeconomic and historical events. Methods: We conducted a retrospective analysis of 62,005 Japanese women born between 1890 and 1991 using a survey conducted over 25 years. Trends in reproductive factors were analyzed using linear and joinpoint regression models, and their associations with major historical events involving Japan were evaluated. Results: We found that the age at menarche showed a significant downward trend (P < 0.001) over the century. Three joinpoints were identified, in 1932 (15.23 years old), 1946 (13.48 years old), and 1959 (12.71 years old), which indicated that average age at menarche decreased by approximately 0.8% per year between 1932 and 1946, and then by 0.4% per year between 1946 and 1959, both of which were statistically significant. However, after 1959, age of menarche remained stable. Analyses of other reproductive factors found significant changes, including a decrease in parity and the number of babies breastfed, and an increase in age at first birth. Conclusion: Age at menarche showed a long-term downward trend in Japan, with significant change points in annual percent change. Other factors showed secular changes in trends as well. These change points were observed at the same time as historical events, namely wars and economic development, suggesting that socioeconomic and environmental changes at the population level affect reproductive factors in females.

Introduction While immune checkpoint inhibitors represent the mainstream treatment for metastatic renal cell carcinoma, a standardized approach following immune checkpoint inhibitors remains unclear. We report a case of metastatic renal cell carcinoma treated with nivolumab rechallenge. Case presentation A 60‐year‐old male with metastatic melanoma was referred to the urology division due to right renal cancer. He was undergoing nivolumab treatment for metastatic melanoma. Radical nephrectomy revealed clear cell renal cell carcinoma, pT3a. Two months post‐surgery, multiple metastases were identified. Despite subsequent administration of interferon‐α, axitinib, and temsirolimus, the metastases progressed. Consequently, nivolumab rechallenge and palliative radiotherapy were initiated, resulting in a durable response for 20 months. However, disease progression occurred, and he died of cancer 4 years after nephrectomy. Conclusion This is the first report of nivolumab rechallenge in metastatic renal cell carcinoma. Although the utility remains unclear, this case suggests that some patients may benefit from nivolumab rechallenge.

Introduction: In human placental development, the trophectoderm (TE) appears in blastocysts on day 5 post-fertilization and develops after implantation into three types of trophoblast lineages: cytotrophoblast (CT), syncytiotrophoblast (ST), and extravillous trophoblast (EVT). CDX2/Cdx2 is expressed in the TE, and Cdx2 expression is upregulated by knockdown of Foxo1 in mouse ESCs. However, the significance of FOXO1 in trophoblast lineage differentiation during the early developmental period remains unclear. In this study, we examined the effect of FOXO1 inhibition on the differentiation of naive human induced pluripotent stem cells (iPSCs) into TE and trophoblast lineages. Methods: We induced TE differentiation from naive iPSCs in the presence or absence of a FOXO1 inhibitor, and the resulting cells were subjected to trophoblast differentiation procedures without the FOXO1 inhibitor. The cells obtained in these processes were assessed for morphology, gene expression, and hCG secretion using phase-contrast microscopy, reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR (RT-qPCR), RNA-seq, immunochromatography, and a chemiluminescent enzyme immunoassay. Results: In the induction of trophoblast differentiation from naive iPSCs, treatment with a FOXO1 inhibitor resulted in the enhanced expression of TE markers, CDX2 and HAND1, but conversely decreased the expression of ST markers, such as ERVW1 (Syncytin-1) and GCM1, and an EVT marker, HLA-G. The proportion of cells positive for an early TE marker TACSTD2 and negative for a late TE marker ENPEP was higher in FOXO1 inhibitor-treated cells than in non-treated cells. The expressions of ERVW1 (Syncytin-1), ERVFRD-1 (Syncytin-2), and other endogenous retrovirus (ERV)-associated genes that have been reported to be expressed in trophoblasts were suppressed in the cells obtained by differentiating the TE cells treated with FOXO1 inhibitor. Conclusions: Treatment with a FOXO1 inhibitor during TE induction from naive iPSCs promotes early TE differentiation but hinders the progression of differentiation into ST and EVT. The suppression of ERV-associated genes may be involved in this process.

Abstract This study aimed to develop and validate a machine learning (ML) model tailored to the Korean population with type 2 diabetes mellitus (T2DM) to provide a superior method for predicting the development of cardiovascular disease (CVD), a major chronic complication in these patients. We used data from two cohorts, namely the discovery (one hospital; n = 12,809) and validation (two hospitals; n = 2019) cohorts, recruited between 2008 and 2022. The outcome of interest was the presence or absence of CVD at 3 years. We selected various ML-based models with hyperparameter tuning in the discovery cohort and performed area under the receiver operating characteristic curve (AUROC) analysis in the validation cohort. CVD was observed in 1238 (10.2%) patients in the discovery cohort. The random forest (RF) model exhibited the best overall performance among the models, with an AUROC of 0.830 (95% confidence interval [CI] 0.818–0.842) in the discovery dataset and 0.722 (95% CI 0.660–0.783) in the validation dataset. Creatinine and glycated hemoglobin levels were the most influential factors in the RF model. This study introduces a pioneering ML-based model for predicting CVD in Korean patients with T2DM, outperforming existing prediction tools and providing a groundbreaking approach for early personalized preventive medicine.

Abstract Background The economic crisis that began in 2008 has severely affected Southern (Greece, Italy, Portugal, Spain) Western European (SWE) countries of Western Europe (WE) and may have affected ongoing efforts to eliminate viral hepatitis. This study was conducted to investigate the impact of the economic crisis on the burden of HBV and HCV disease. Methods Global Burden of Diseases 2019 data were used to analyse the rates of epidemiological metrics of HBV and HCV acute and chronic infections in SWE and WE. Time series modelling was performed to quantify the impact of healthcare expenditure on the time trend of HBV and HCV disease burden in 2000–2019. Results Declining trends in incidence and prevalence rates of acute HBV (aHBV) and chronic HBV were observed in SWE and WE, with the pace of decline being slower in the post-austerity period (2010–2019) and mortality due to HBV stabilised in SWE. Acute HCV (aHCV) metrics and chronic HCV incidence and mortality showed a stable trend in SWE and WE, whereas the prevalence of chronic HCV showed an oscillating trend, decreasing in WE in 2010–2019 (p