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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.

Diego Novick,1 William Montgomery,2 Tamas Treuer,3 Ai Koyanagi,4 Jaume Aguado,4 Susanne Kraemer,5 Josep Maria Haro4 1Global Patient Outcomes and Real World Evidence (GPORWE), Eli Lilly and Company, Windlesham, Surrey, UK; 2Global Patient Outcomes and Real World Evidence (GPORWE), Eli Lilly Australia Pty Ltd, West Ryde, Australia; 3Global Patient Outcomes and Real World Evidence (GPORWE), Eli Lilly and Company, Budapest, Hungary; 4Parc Sanitari Sant Joan de Déu, CIBERSAM, Universitat de Barcelona, Barcelona, Spain; 5Medical Department, Eli Lilly and Company, Bad Homburg, Germany Purpose: Medication nonadherence is common in the treatment of patients with severe mental illness and is a frequent cause of relapse. Different formulations have been developed in an effort to improve medication adherence. The aim of this study was to explore whether there are differential clinical outcomes between two different formulations of olanzapine (orodispersible tablets [ODTs] vs standard oral tablets [SOT]) for the treatment of nonadherent patients with schizophrenia or bipolar disorder.Methods: Data for this analysis were from an observational study conducted in Europe (N=903). Adult schizophrenia and bipolar disorder patients in outpatient settings who initiated or changed to either olanzapine ODT or SOT according to physician decision within the last 45 days were eligible for enrollment. The follow-up period was 1 year. Of the 903 participants, 266 nonadherent patients (Medication Adherence Rating Scale score 0–4 at baseline) were included in the analysis. Clinical outcomes of interest were: 1) hospitalization and 2) relapse identified by the participating psychiatrist or hospitalization. An adjusted logistic regression model was fitted.Results: Patients taking ODT had more severe illness at baseline (P

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.