Search

It is now established that Bcl11b specifies T cell fate. Here, we show that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. Our search for factors that relocalized the Bcl11b enhancer identified a non-coding RNA named ThymoD (thymocyte differentiation factor). ThymoD-deficient mice displayed a block at the onset of T cell development and developed lymphoid malignancies. We found that ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain. These large-scale changes in nuclear architecture were associated with the deposition of activating epigenetic marks across the loop domain, plausibly facilitating phase separation. These data indicate how, during developmental progression and tumor suppression, non-coding transcription orchestrates chromatin folding and compartmentalization to direct with high precision enhancer-promoter communication.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal autosomal recessive immune disorder characterized by uncontrolled activation of T and NK cells, macrophages, and overproduction of inflammatory cytokines. Early hematopoietic cell transplantation (HCT) is required for long-term survival. Current therapy is based on the HLH-94/2004 protocol, but is insufficient to fully control disease activity. This case report describes an infant with FHL type 3 who, despite initial therapy with dexamethasone and etoposide, showed aberrant cytokine levels, including interleukin-18 (IL-18), chemokine ligand 9 (CXCL9), soluble interleukin-2 receptor (sIL-2R), and soluble tumor necrosis factor receptor type II (sTNF-RII). The Janus kinase inhibitor ruxolitinib was therefore coadministered. The patient was treated with dose-adjusted ruxolitinib guided by cytokine profiles, and was successfully prepared for HCT. The results demonstrate the effectiveness and safety of dose-adjusted ruxolitinib as a bridging therapy for FHL, and the value of monitoring cytokine levels, especially IL-18, CXCL9, sIL-2R, and sTNF-RII, as disease-activity markers for FHL.

White-tailed sea eagle (Haliaeetus albicilla), a regionally rare species of raptor, is threatened in several countries. To assess the risk of H5 high pathogenicity avian influenza (HPAI) viral infection in rare bird species, we performed experimental infections with a GS/GD96-lineage H5N6 HPAI virus of clade 2.3.4.4e in white-tailed sea eagles. Additionally, during the winter of 2020–2021 in Japan, we accidentally encountered a white-tailed sea eagle that had a fatal outcome due to natural infection with a GS/GD96-lineage H5N8 HPAI virus of clade 2.3.4.4b, allowing us to compare experimental and natural infections in the same rare raptor species. Our experiments demonstrated the susceptibility of white-tailed sea eagles to the GS/GD96-lineage H5 HPAI virus with efficient replication in systemic organs. The potential for the viruses to spread within the white-tailed sea eagle population through indirect transmission was also confirmed. Comprehensive comparisons of both viral distribution and histopathological observations between experimentally and naturally infected white-tailed sea eagles imply that viral replication in the brain is responsible for the disease severity and mortality in this species. These findings provide novel insights into the risk assessment of H5 HPAI viral infection in white-tailed sea eagles, proper diagnostic procedures, potential risks to artificially fed eagle populations and persons handling superficially healthy eagles, potential impact of intragastric infection on eagle outcomes, and possibility of severity of the disease being attributed to viral replication in the brain.

Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive inborn error of immunity (IEI) caused by the defects in CD18, encoded by the ITGB2 gene. LAD-I is characterized by defective leukocyte adhesion to the vascular endothelium and impaired migration of leukocytes. Allogeneic hematopoietic cell transplant (HCT) is the only curative treatment for LAD-I. In an absence of ideal donor for HCT, human leukocyte antigen (HLA)-haploidentical HCT is performed. Posttransplant cyclophosphamide (PT-CY) is a relatively new graft-versus-host disease (GVHD) prophylactic measure and has been increasingly used in HLA-haploidentical HCT for malignant and nonmalignant diseases. However, experience in using PT-CY for rare IEIs, such as LAD-I, is very limited. We report a case of LAD-I successfully treated with HLA-haploidentical HCT with PT-CY. Complete chimerism was achieved, and the patient was cured. Her transplant course was complicated by mild GVHD, cytomegalovirus reactivation and veno-occlusive disease/sinusoidal obstruction syndrome, which were successfully treated. HLA-haploidentical HCT with PT-CY is a safe and effective option for patients with LAD-I when HLA-matched donors are unavailable.

Abstract Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.

Abstract To determine whether temporal subtraction (TS) CT obtained with non-rigid image registration improves detection of various bone metastases during serial clinical follow-up examinations by numerous radiologists. Six board-certified radiologists retrospectively scrutinized CT images for patients with history of malignancy sequentially. These radiologists selected 50 positive and 50 negative subjects with and without bone metastases, respectively. Furthermore, for each subject, they selected a pair of previous and current CT images satisfying predefined criteria by consensus. Previous images were non-rigidly transformed to match current images and subtracted from current images to automatically generate TS images. Subsequently, 18 radiologists independently interpreted the 100 CT image pairs to identify bone metastases, both without and with TS images, with each interpretation separated from the other by an interval of at least 30 days. Jackknife free-response receiver operating characteristics (JAFROC) analysis was conducted to assess observer performance. Compared with interpretation without TS images, interpretation with TS images was associated with a significantly higher mean figure of merit (0.710 vs. 0.658; JAFROC analysis, P = 0.0027). Mean sensitivity at lesion-based was significantly higher for interpretation with TS compared with that without TS (46.1% vs. 33.9%; P = 0.003). Mean false positive count per subject was also significantly higher for interpretation with TS than for that without TS (0.28 vs. 0.15; P

Non-human primate models of autism spectrum disorder (ASD) are few and not well characterised. Here, the authors describe synaptic function and gene expression changes in a marmoset model of ASD from birth to juvenile, highlighting its similarity to features observed in human ASD.

Case Presentation: We report a case of a male patient with rheumatoid arthritis (RA) diagnosed during treatment with a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist (once-weekly dulaglutide injection). At 3 months after dulaglutide initiation, he began experiencing left shoulder pain that continued despite treatment by an acupuncturist, indicating that the pain was not due to periarthritis scapulohumeralis. His HbA1c level was 7.3% at the 3-month follow-up. At the 6-month follow-up visit, the HbA1c level was 8.2%, the low-density lipoprotein cholesterol level was 132 mg/dL, and he expressed right shoulder pain. After 3 months, the HbA1c level was 9.0%, and his bilateral shoulder pain worsened, due to which he could not use his arms well. Routine laboratory testing revealed no other abnormalities at that time. However, several inflammatory and serological RA markers were detected, including an erythrocyte sedimentation rate of 73 (normal range,

Abstract The effect of the skin–capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan®. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p

In the fall of 2022, high pathogenicity avian influenza viruses (HPAIVs) were detected from raptors and geese in Japan, a month earlier than in past years, indicating a shift in detection patterns. In this study, we conducted a phylogenetic analysis on H5N1 HPAIVs detected from six wild birds during the 2022/2023 season to determine their genetic origins. Our findings revealed that these HPAIVs belong to the G2 group within clade 2.3.4.4b, with all isolates classified into three subgroups: G2b, G2d, and G2c. The genetic background of the G2b virus (a peregrine falcon-derived strain) and G2d viruses (two raptors and two geese-derived strains) were the same as those detected in Japan in the 2021/2022 season. Since no HPAI cases were reported in Japan during the summer of 2022, it is probable that migratory birds reintroduced the G2b and G2d viruses. Conversely, the G2c virus (a raptor-derived strain) was first recognized in Japan in the fall of 2022. This strain might share a common ancestor with HPAIVs from Asia and West Siberia observed in the 2021/2022 season. The early migration of waterfowl to Japan in the fall of 2022 could have facilitated the early invasion of HPAIVs.

A previous study proved that vGPE− mainly maintains the properties of classical swine fever (CSF) virus, which is comparable to the GPE− vaccine seed and is a potentially valuable backbone for developing a CSF marker vaccine. Chimeric viruses were constructed based on an infectious cDNA clone derived from the live attenuated GPE− vaccine strain as novel CSF vaccine candidates that potentially meet the concept of differentiating infected from vaccinated animals (DIVA) by substituting the glycoprotein Erns of the GPE− vaccine strain with the corresponding region of non-CSF pestiviruses, either pronghorn antelope pestivirus (PAPeV) or Phocoena pestivirus (PhoPeV). High viral growth and genetic stability after serial passages of the chimeric viruses, namely vGPE−/PAPeV Erns and vGPE−/PhoPeV Erns, were confirmed in vitro. In vivo investigation revealed that two chimeric viruses had comparable immunogenicity and safety profiles to the vGPE− vaccine strain. Vaccination at a dose of 104.0 TCID50 with either vGPE−/PAPeV Erns or vGPE−/PhoPeV Erns conferred complete protection for pigs against the CSF virus challenge in the early stage of immunization. In conclusion, the characteristics of vGPE−/PAPeV Erns and vGPE−/PhoPeV Erns affirmed their properties, as the vGPE− vaccine strain, positioning them as ideal candidates for future development of a CSF marker vaccine.

Electrochemical protonation provides ways to control physical properties and even explore unprecedented phases of solid‐state materials. While how proton accumulation changes materials' properties is investigated, how protonation of solids can be controlled and promoted remains an enigmatic puzzle. In the work reported here, the influence of electrochemical proton injection duration (tVg) is investigated on the protonation of SrCoO2.5 (SCO) films in electric‐field‐effect transistor structures with gate layers of the proton‐conducting electrolyte Nafion. The proton concentration accumulated in SCO films varies depending on the duration of the proton injection. When protons are injected in a relatively short tVg (≤ 600 s), the hydrogen concentration accumulated in SCO film increases with increasing tVg, reaching the maximum proton concentration of ≈1.9 per formula unit of SCO for the tVg = 600 s case. On the other hand, when tVg is longer than 900 s, the proton concentration decreases with tVg, implying the occurrence of counterreactions that extract protons from protonated SCO and oxidize the channel. These observations indicate that protons accumulated at the Nafion/SCO interface play a role in the protonation of SCO films and that suppressing the interfacial proton accumulation is the key to maximizing the proton concentration accumulated in SCO films. [ABSTRACT FROM AUTHOR]

The article explores the orientation-dependent electrochemical response of LaSrNiO4 (LSNO) epitaxial films by investigating the influence of growth orientation on electrochemical reactions. The study reveals that the resistance of (100)-oriented LSNO films can be modulated significantly by electrochemical reactions, while the resistance of (001)-oriented films remains largely unaffected. The results suggest that oxygen vacancies are produced in the NiO2 layer of LSNO during electrochemical reactions, with diffusion of oxygen ions occurring preferentially within the NiO2 layer. [Extracted from the article]

Background: Platelet-rich plasma (PRP) is a promising treatment for knee osteoarthritis (OA). However, exercise therapy and activities of daily living (ADL) guidance are recommended as core treatments in the Osteoarthritis Research Society International (OARSI) guidelines. However, the effects of PRP combined with exercise therapy are not fully understood. This study aimed to clarify the effectiveness of this treatment. Methods: We assigned patients diagnosed with knee OA and treated between January 2021 and December 2022 to groups who underwent PRP + exercise (PE), PRP (P), or exercise (E) therapy. Outcomes were evaluated using Knee Injury and Osteoarthritis Outcome Scores (KOOS) before, and 1, 3, and 12 months after treatment. Within-group comparisons according to the time of each score were statistically assessed using a one-way analysis of variance, then differences were analyzed using Bonferroni multiple comparisons p < 0.05). Treatment responses were determined using Outcome Measures in Rheumatology (OMERACT)-OARSI Responder criteria. Results: Pre-treatment KOOS did not significantly differ among the groups. Pain in the PE group improved within 1 month, symptoms, ADL, and quality of life (QOL) improved after 3, months and continued for 12 months. Pain and symptoms improved in the P group within 1 month, but ADLs and the QOL did not significantly change. Pain improved after 3 months in the E group and ADL, and QOL improved by 12 months. The response among the groups was the highest for the PE, with 50.0% at 1 and 3 months, and 65.0% at 12 months. Conclusions: Therapy with PRP immediately relieved pain, whereas exercise conferred late, but enduring effects. Combining PRP with exercise conferred synergistic advantages that persisted for up to 12 months. [ABSTRACT FROM AUTHOR]

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors often linked to underlying genetic variants. Genetic analysis can promote gene-adjusted, specific follow-up, and surveillance protocols for both patients and their families at risk. We report the case of a 7-yr-old boy with bilateral pheochromocytoma, which recurred a year after partial adrenalectomy. The patient's father developed bilateral pheochromocytomas at 25 yr of age. Both individuals possessed a novel heterogeneous in-frame duplication germline variant of VHL, yet neither exhibited other clinical manifestations of von Hippel--Lindau disease (VHL). Traditionally, VHL missense mutations have been associated with a higher risk of PPGL development, whereas truncating mutations typically confer a lower risk. In-frame duplication variants are rarely observed in patients with VHL but may lead to changes in the three-dimensional structure of the translated protein, similar to truncating variants. Our analysis suggests that these in-frame duplications of amino acids in specific regions may cause pheochromocytomas in a manner similar to missense variants. Further accumulation of VHL cases with various genotypes and standardized open-access worldwide databases, including longitudinal and specific clinical data linked to genotypes, is required. It is crucial to consider genetic analyses for pediatricians who may diagnose childhood-onset PPGL. [ABSTRACT FROM AUTHOR]

Abstract The number of isolated elderly people with few opportunities to talk to other people is currently increasing. Research is ongoing to develop talking robots for addressing the situation. The aim of the present study was to develop a talking robot that could converse with elderly people over an extended period. To enable long-duration conversation, we added a previously proposed active listening function for twining the robot dialogue system to prompt the user to say something. To verify the effectiveness of this function, a comparative experiment was performed using the proposed robot system and a control system with identical functions except the active listening function. The results showed that the conversation of the elderly subjects with the proposed robot system was significantly more than that with the control system. The capability of the developed robot system was further demonstrated in a nursing home for the elderly, where its conversation durations with different residents were measured. The results revealed that the robot could converse for more than 30 min with more than half of the elderly subjects. These results indicate that the additional function of the proposed talking robot system would enable elderly people to talk over longer periods of time.

Abstract Background This study aimed to clarify predictors of preterm birth in pregnancy of women with systemic lupus erythematosus (SLE). We investigated the predictors of preterm birth before pregnancy from the perspective of the importance of preconception care. Methods We analysed fetal outcomes of 108 pregnancies in 74 SLE patients in a retrospective study. We compared pre-pregnancy clinical characteristics and disease activity in these women between the preterm birth and full-term birth groups to select predictive factors for preterm birth before pregnancy. Results Eighty-three of 108 pregnancies resulted in live births, of which 27 (25.0%) were preterm births. Pre-pregnancy serum complement 3 (C3) level was significantly lower in the preterm birth group (77.0 mg/dl) than the full-term birth group (87.5 mg/dl) (P = 0.029). Multivariate analysis identified history of lupus nephritis (odds ratio: 5.734, 95% CI 1.568–21.010, P = 0.008) and low C3 level (< 85 mg/dl) at pre-pregnancy (odds ratio 4.498, 95% CI 1.296–15.616, P = 0.018) as risk factors for preterm birth. The greater the number of these risk factors, the higher was the preterm birth rate (P = 0.0007). In the case of SLEDAI score ≤ 4, the preterm birth rate was higher in the pre-pregnancy low C3 group (< 85 mg/dl) (42.1%) than in the high C3 group (C3 ≥ 85 mg/dl) (14.7%) (P = 0.018). Conclusion For patients with a history of LN, treatment management focusing on pre-pregnancy serum complement levels is very important.

The 70% ethanol extract of Artemisia campestris was screened to find PPARγ ligands using the PPARγ ligand-responsive chimera luciferase reporter system. Capillartemisin B was identified as a PPARγ ligand that stimulated lipid accumulation in 3T3-L1 cells. By further purification of PPARγ ligands from a large-scale preparation of the methanol extract of Artemisia campestris, we isolated and identified eupatilin and santaflavone as PPARγ ligands. Weak PPARγ ligand activity of eupatilin or santaflavone in reporter assay was enhanced by a PPARγ antagonist, GW9662, suggesting that santaflavone or eupatilin and GW9662 bound simultaneously to the multiple sub-pockets of the PPARγ ligand-binding domain (LBD) and cooperatively activated PPARγ. Docking simulation suggested that eupatilin binds to the Ω-pocket but not to the AF-2 pocket of Y-shaped PPARγ LBD where artepillin C that differs from capillartemisin B at the C-5′ position without hydroxy group binds. Eupatilin or santaflavone with or without GW9662 did not stimulate lipid accumulation in differentiated 3T3-L1 cells, suggesting that binding of each compound alone or with GW9662 to the Ω-pocket which stimulated the PPARγ-responsive reporter expression was not enough to stimulate lipid accumulation. The PPARγ ligands found in this study have a potential to design the fragment-based drug design of a novel PPARγ ligand that cover the Y-shaped PPARγ LBD.

Melting permafrost mounds in subarctic palsa mires are thawing under climate warming and have become a substantial source of N2O emissions. However, mechanistic insights into the permafrost thaw-induced N2O emissions in these unique habitats remain elusive. We demonstrated that N2O emission potential in palsa bogs was driven by the bacterial residents of two dominant Sphagnum mosses especially of Sphagnum capillifolium (SC) in the subarctic palsa bog, which responded to endogenous and exogenous Sphagnum factors such as secondary metabolites, nitrogen and carbon sources, temperature, and pH. SC's high N2O emission activity was linked with two classes of distinctive hyperactive N2O emitters, including Pseudomonas sp. and Enterobacteriaceae bacteria, whose hyperactive N2O emitting capability was characterized to be dominantly pH-responsive. As the nosZ gene-harboring emitter, Pseudomonas sp. SC-H2 reached a high level of N2O emissions that increased significantly with increasing pH. For emitters lacking the nosZ gene, an Enterobacteriaceae bacterium SC-L1 was more adaptive to natural acidic conditions, and N2O emissions also increased with pH. Our study revealed previously unknown hyperactive N2O emitters in Sphagnum capillifolium found in melting palsa mound environments, and provided novel insights into SC-associated N2O emissions.