A community cluster of influenza A(H3N2) virus infection with reduced susceptibility to baloxavir due to a PA E199G substitution in Japan, February to March 2023.

A community cluster of influenza A(H3N2) caused by viruses with an E199G substitution in PA was detected in Nara, Japan, between February and March 2023. The three patients with these mutant viruses had not received antiviral treatment before specimen collection but patients in the same hospital had. The sequences of the mutant viruses were closely related, suggesting clonal spread in Nara. They showed reduced susceptibility to baloxavir in vitro; however, the clinical significance of the PA E199G substitution remains unclear.

The Potential of Heart Rate Variability Monitoring for Mental Health Assessment in Top Wheel Gymnastics Athletes: A Single Case Design.

The assessment of heart rate variability (HRV) upon waking has been proposed as a method to evaluate mental health; however, owing to large individual differences among athletes, it is unclear whether HRV is adequate to predict mental health decline. In this study, we sought to establish this by evaluating HRV upon awakening in one athlete over 20 months. We assessed mental health once a month by calculating the depression index. In addition, self-reported training load and psychological fatigue index were assessed as psychological indices for athletes. Heart rate and HRV were each measured three days per week in both resting (supine) and standing (upright) positions. The results showed that orthostatic HRV upon waking had moderate linear relationships with the scores on the depression index and psychological fatigue index. By contrast, self-reported training load, a measure of physical stressor, was not associated with HRV. The findings suggest that the repeated assessment of HRV upon waking and mental health indicators may be useful in preventing mental health decline in athletes.

Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle.

The ZFP36 family is a prototypical member of a highly conserved group of proteins with CCCH-type RNA-binding domains, whose functional role and regulatory mechanism in mitotic cells remain obscure. In this study, we provide the first evidence that ZFP36L1 phosphorylation is modulated in a cell cycle-dependent manner. The C-terminal region of ZFP36L1 is critical for its cell cycle-dependent phosphorylation of this protein. We also suggest that the phosphorelay-dependent regulation of ZFP36L1 influences mitotic spindle organization. Thus, our data demonstrate a new class of regulatory mechanism for CCCH-type zinc-finger proteins in cell cycle control.

Casein kinase 2 phosphorylates and stabilizes C/EBPß in pancreatic ß cells.

During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to pancreatic ß cell failure. CCAAT/enhancer-binding protein (C/EBP) ß is highly induced by ER stress and AMP-activated protein kinase (AMPK) suppression in pancreatic ß cells, and its accumulation reduces pancreatic ß cell mass. We investigated the phosphorylation state of C/EBPß under these conditions. Casein kinase 2 (CK2) was found to co-localize with C/EBPß in MIN6 cells. It phosphorylated S222 of C/EBPß, a previously unidentified phosphorylation site. We found that C/EBPß is phosphorylated by CK2 under AMPK suppression and ER stress, which are important from the viewpoint of the worsening pathological condition of type 2 diabetes, such as decreased insulin secretion and apoptosis of pancreatic ß cells.

BEN3/BIG2 ARF GEF is Involved in Brefeldin A-Sensitive Trafficking at the trans-Golgi Network/Early Endosome in Arabidopsis thaliana.

Membrane traffic at the trans-Golgi network (TGN) is crucial for correctly distributing various membrane proteins to their destination. Polarly localized auxin efflux proteins, including PIN-FORMED1 (PIN1), are dynamically transported between the endosomes and the plasma membrane (PM) in the plant cells. The intracellular trafficking of PIN1 protein is sensitive to the fungal toxin brefeldin A (BFA), which is known to inhibit guanine nucleotide exchange factors for ADP ribosylation factors (ARF GEFs) such as GNOM. However, the molecular details of the BFA-sensitive trafficking pathway have not been fully revealed. In a previous study, we identified an Arabidopsis mutant BFA-visualized endocytic trafficking defective 3 (ben3) which exhibited reduced sensitivity to BFA in terms of BFA-induced intracellular PIN1 agglomeration. Here, we show that BEN3 encodes a member of BIG family ARF GEFs, BIG2. BEN3/BIG2 tagged with fluorescent proteins co-localized with markers for the TGN/early endosome (EE). Inspection of conditionally induced de novo synthesized PIN1 confirmed that its secretion to the PM is BFA sensitive, and established BEN3/BIG2 as a crucial component of this BFA action at the level of the TGN/EE. Furthermore, ben3 mutation alleviated BFA-induced agglomeration of another TGN-localized ARF GEF, BEN1/MIN7. Taken together, our results suggest that BEN3/BIG2 is an ARF GEF component, which confers BFA sensitivity to the TGN/EE in Arabidopsis.

Do Combined Oculomotor and Bimanual Coordination Exercises Instantly Stabilize Balance in Athletes?

Purpose: This study examined the immediate effects of oculomotor and bimanual coordination exercises, as well as a combination of the two, on stability of balance in athletes. Patients and Methods: Changes in center-of-gravity sway were measured in 30 college student athletes before and after the following three exercise conditions: 1) oculomotor exercises, 2) bimanual coordination exercises, and 3) a combination of oculomotor and bimanual coordination exercises (1+2). The order of these exercises was counterbalanced. Results: The combination of exercises (condition 3) reduced large swaying during balancing and immediately increased postural stability. Moreover, the oculomotor and bimanual coordination exercises (conditions 1 and 2) immediately reduced large sway during balancing when performed independently. Thus, the present study revealed that the combination of oculomotor and bimanual coordination exercises immediately reduced accidental swaying during balancing and also improved postural stability. Conclusion: This combination could be effective as an immediate balance adjustment method for athletes.

Severe Thrombocytopenia Secondary to Systemic Lupus Erythematosus With Antiphospholipid Antibodies in a Middle-Aged Woman.

Thrombocytopenia is a common hematological complication of systemic lupus erythematosus (SLE). However, severe thrombocytopenia is a relatively rare presentation, accounting for only 3-10% of cases. A 52-year-old woman was being treated with 4 mg/day of prednisolone for 12 years for SLE-induced autoimmune hemolytic anemia. She presented to her family physician with nasal bleeding and purpura, which required more than two hours to control. She had bruises on her legs and mild multiple arthralgia. The platelet count was 19,000/µL. She was suspected to have developed immune thrombocytopenia as an exacerbation of SLE. Thus, she was referred to our hospital. Laboratory examination revealed thrombocytopenia, hypocomplementemia, and a positive result for anti-cardiolipin (CL) and anti-ß2-glycoprotein (GP) I IgG antibodies. The patient was diagnosed with thrombocytopenic purpura, complicated by SLE. Methylprednisolone pulse therapy, followed by 60 mg/day of prednisolone and 200/400 mg of hydroxychloroquine on alternate days, was initiated. The platelet count increased from 5,000/µl to 50,000/µl, and the immature platelet fraction (IPF) decreased from 14.9% to 6.3%. Anti-CL and anti-ß2-GPI IgG antibodies were considered to be associated with thrombocytopenia and a risk of thrombotic events after normalization of her platelet counts. Therefore, aspirin therapy was initiated to prevent thrombosis. As an episode of acute thrombocytopenia occurred without other clinical findings indicating active SLE, it was important to determine the exact cause of thrombocytopenia in this situation. Immediate recovery of thrombocytopenia with high-dose prednisolone reduced the risk of bleeding that could have otherwise been fatal.

Augmented-reality-based multi-person exercise has more beneficial effects on mood state and oxytocin secretion than standard solitary exercise.

BACKGROUND: Exercise has positive effects on psychological well-being, with team sports often associated with superior mental health compared to individual sports. Augmented reality (AR) technology has the potential to convert solitary exercise into multi-person exercise. Given the role of oxytocin in mediating the psychological benefits of exercise and sports, this study aimed to investigate the impact of AR-based multi-person exercise on mood and salivary oxytocin levels. METHODS: Fourteen participants underwent three distinct regimens: non-exercise (Rest), standard solitary cycling exercise (Ex), and AR-based multi-person cycling exercise (Ex+AR). In both Ex and Ex+AR conditions, participants engaged in cycling at a self-regulated pace to maintain a Rating of Perceived Exertion of 10. In the Ex+AR condition, participants' avatars were projected onto a tablet screen, allowing them to cycle alongside ten other virtual avatars in an AR environment. Mood states and saliva samples were collected before and immediately after each 10-minute regimen. Subsequently, salivary oxytocin levels were measured. RESULTS: Notably, only the Ex+AR condition significantly improved mood states associated with depression-dejection and exhibited a non-significant trend toward suppressing anger-hostility in participants. Moreover, the Ex+AR condition led to a significant elevation in salivary oxytocin levels, while the Ex condition showed a non-significant trend toward an increase. However, changes in salivary oxytocin did not show a significant correlation with changes in mood states. CONCLUSIONS: These findings suggest that Ex+AR enhances mood states and promotes oxytocin release. AR-based multi-person exercise may offer greater psychological benefits compared to standard solitary exercise, although the relationship between oxytocin and mood changes remains inconclusive.

Multiple Retroperitoneal Abscesses Caused by Citrobacter koseri are Associated with a Poor Prognosis: A Case Report.

Citrobacter koseri causes opportunistic infections in various organs. We herein report an 84-year-old man with diabetes mellitus who presented to our hospital with left hip pain and walking difficulty. Computed tomography showed an extensive abscess with gas production, mainly in the left retroperitoneal space, caused by C. koseri infection. Despite daily cleaning of the wound and antimicrobial therapy (with surgical drainage), the patient developed repeated pneumonia and small bowel hemorrhaging caused by disseminated intravascular coagulation and died on day 65 of hospitalization. Overall, retroperitoneal abscesses caused by C. koseri are rare, and multiple abscesses may show a poor prognosis.

A case of plastic bronchitis with a remarkable response to steroids.

Plastic bronchitis can cause fatal airway obstruction. An 85-year-old woman with no medical history presented to the emergency department of our hospital with progressing respiratory failure and hemoptysis. Bronchoscopy revealed a fibrin-type cast thrombus in the trachea, and plastic bronchitis was diagnosed. Initial treatment involved airway thrombus removal, and the patient survived. However, bleeding persisted for 6 days, and respiratory status showed slight improvement despite ventilatory management. Steroids were administered for concomitant acute respiratory distress syndrome, and there was marked improvement in both airway hemorrhage and respiratory failure. The patient was extubated, the steroid dose was reduced, and no rebleeding was observed. The patient was discharged from the hospital 1 month after the onset of symptoms. Blood tests were positive for the myeloperoxidase-anti-neutrophil cytoplasmic antibody; however, no biopsy was performed, and no specific symptoms were observed. A definitive diagnosis was therefore not reached. The causes of plastic bronchitis are numerous, and there are no standardized diagnostic criteria or treatment guidelines for this condition. The present case suggests that steroids may be effective in some patients with plastic bronchitis.

Effects of Versatile Kinesthetic Experiences on Balance Ability and Interpersonal Relationships.

The study aimed to investigate the effects of kinesthetic experiences on balance ability (using exercise balls for gymnastics) and on interpersonal relationships by comparing two different learning methods. Participants learning gymnastics during physical education classes at university were randomly allocated to a kinesthetic-experiential learning (KEL) group (n = 20) or a model-mastery learning (MML) group (n = 22). Both groups practiced a balancing exercise on an exercise ball. In the KEL group, participants were asked to pay attention to the sensations of their body on the ball in a variety of movements, whereas the MML group was asked to reproduce the instructions of the ideal model provided by an instructor. The results showed that the participants in the KEL group had longer balancing time on the exercise ball, higher self-evaluation scores, and higher interpersonal relationship scores than those in the MML group, although the objective evaluations of postural stability were better in the MML group than in the KEL group. These findings suggest that methods that provide learners with versatile kinesthetic experiences through a variety of movements are more effective for enhancing balance ability and interpersonal relationships.

Improvement of the ability to recover balance through versatile kinesthetic learning experiences.

The purpose of the present study was to compare learners' movement variability while maintaining balance and the ability to recover balance using the kinesthetic-experiential learning (KEL) method of implicit learning and the model-mastery learning (MML) method of explicit learning. The participants were 29 healthy university students. They were randomly divided into two groups (KEL and MML). They were required to balance both knees on an exercise ball. The balancing time and the ability to recover their balance were measured using motion capture. Results indicated that balancing time was significantly improved for both learning methods. Regarding the learners' movements while maintaining balance, they maintained balance while moving in the KEL method, whereas they maintained balance by keeping the entire body stationary in the MML method. Concerning the ability to recover, the KEL method improved the balance recovery ability more effectively than the MML method. Therefore, we concluded that using the KEL method at the initial stage of learning improves learners' balance recovery ability and increases movement variability.

Case report: Posterior reversible encephalopathy syndrome, an adverse effect of lenvatinib and pembrolizumab combination therapy, in a patient with advanced endometrial cancer.

Background: Lenvatinib-pembrolizumab combination (LEAP) is an approved therapy in Japan for advanced endometrial cancer, based on the data from the KEYNOTE-775 clinical trial. We report a case of posterior reversible encephalopathy syndrome (PRES) in a patient who received LEAP therapy for advanced endometrial cancer. Case presentation: A 53-year-old patient with stage IVB endometrial cancer having rectal metastases, after four cycles of paclitaxel-carboplatin therapy, was found to have increased rectal invasion, peritoneal dissemination, and multiple paraaortic lymph node metastases. She was treated with LEAP therapy and discharged on day 12 without adverse events, except for mild anemia on day 11 of treatment. She was carefully managed in the outpatient department, but on day 18, she was admitted to the emergency department with severely impaired consciousness and generalized seizures. Computed tomography of the head and lumbar tap showed no abnormal findings, and the seizures resolved with anticonvulsant medication alone. Based on a thorough physical examination and findings on magnetic resonance imaging (MRI), which showed high signal intensity in the left occipital lobe, encephalopathy, rather than encephalitis, was the likely diagnosis. Symptomatic improvement was observed, and pembrolizumab monotherapy was resumed. Conclusions: If consciousness is impaired during LEAP treatment, it is necessary to differentiate between immunogenic encephalitis caused by pembrolizumab or encephalopathy caused by lenvatinib. MRI and lumbar tap can help in distinguishing between the two and diagnosing the responsible drug.

First case report of monoclonal IgG3-heavy-chain glomerulonephritis with microtubular structures.

Our patient was a 69-year-old woman admitted to our hospital for heavy proteinuria and hematuria. A renal biopsy showed findings similar to those of membranoproliferative glomerulonephritis associated with nodular lesions, and immunofluorescence showed marked deposits of IgG, C1q, and C3 on the peripheral capillary walls. IgG3 alone was observed on IgG subclass staining with no κ or λ light chains, and Congo red staining was negative. These findings suggested IgG3-heavy-chain deposition disease (HCDD). However, we did not find a deletion of the first heavy-chain constant domain, which is commonly observed in HCDD. Electron microscopy showed randomly arranged subendothelial microtubular structures with diameters of 70-90 nm. Altogether, the diagnosis of HCDD could not be made, although monoclonal IgG3 deposits in glomeruli were observed. This is the first case report of monoclonal IgG3-heavy-chain glomerulonephritis with subendothelial-based, randomly arranged microtubular structures with diameters of 70-90 nm.

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish.

Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones.

Nuclear accumulation of ZFP36L1 is cell cycle-dependent and determined by a C-terminal serine-rich cluster.

ZFP36L1 is an RNA-binding protein responsible for mRNA decay in the cytoplasm. ZFP36L1 has also been suggested as a nuclear-cytoplasmic shuttling protein because it contains a potential nuclear localization signal and a nuclear export signal. However, it remains unclear how the nuclear localization of ZFP36L1 is controlled. In this study, we provide evidence that the nuclear accumulation of ZFP36L1 protein is modulated in a cell cycle-dependent manner. ZFP36L1 protein accumulation in fractionated nuclei was particularly prominent in cells arrested at G1-/S-phase boundary, while it was downregulated in S-phase cells, and eventually disappeared in G2-phase nuclei. Moreover, forced nuclear targeting of ZFP36L1 revealed marked downregulation of this protein in S- and G2-phase cells, suggesting that ZFP36L1 can be eliminated in the nucleus. The C-terminal serine-rich cluster of ZFP36L1 is critical for the regulation of its nuclear accumulation because truncation of this probable disordered region enhanced the nuclear localization of ZFP36L1, increased its stability and abolished its cell cycle-dependent fluctuations. These findings provide the first hints to the question of how ZFP36L1 nuclear accumulation is controlled during the course of the cell cycle.

Early Endosomal Trafficking Component BEN2/VPS45 Plays a Crucial Role in Internal Tissues in Regulating Root Growth and Meristem Size in Arabidopsis.

Polar auxin transport is involved in multiple aspects of plant development, including root growth, lateral root branching, embryogenesis, and vasculature development. PIN-FORMED (PIN) auxin efflux proteins exhibit asymmetric distribution at the plasma membrane (PM) and collectively play pivotal roles in generating local auxin accumulation, which underlies various auxin-dependent developmental processes. In previous research, it has been revealed that endosomal trafficking components BEN1/BIG5 (ARF GEF) and BEN2/VPS45 (Sec1/Munc 18 protein) function in intracellular trafficking of PIN proteins in Arabidopsis. Mutations in both BEN1 and BEN2 resulted in defects in polar PIN localization, auxin response gradients, and in root architecture. In this study, we have attempted to gain insight into the developmental roles of these trafficking components. We showed that while genetic or pharmacological disturbances of auxin distribution reduced dividing cells in the root tips and resulted in reduced root growth, the same manipulations had only moderate impact on ben1; ben2 double mutants. In addition, we established transgenic lines in which BEN2/VPS45 is expressed under control of tissue-specific promoters and demonstrated that BEN2/VPS45 regulates the intracellular traffic of PIN proteins in cell-autonomous manner, at least in stele and epidermal cells. Furthermore, BEN2/VPS45 rescued the root architecture defects when expressed in internal tissues of ben1; ben2 double mutants. These results corroborate the roles of the endosomal trafficking component BEN2/VPS45 in regulation of auxin-dependent developmental processes, and suggest that BEN2/VPS45 is required for sustainable root growth, most likely through regulation of tip-ward auxin transport through the internal tissues of root.

Evaluation of the Relationship Between Cognitive Impairment, Glycometabolism, and Nicotinic Acetylcholine Receptor Deficits in a Mouse Model of Alzheimer's Disease.

PURPOSE: In patients with Alzheimer's disease (AD), the loss of cerebral nicotinic acetylcholine receptors (nAChRs) that are implicated in higher brain functions has been reported. However, it is unclear if nAChR deficits occur in association with cognitive impairments. The purpose of this study was to assess the relationship between nAChR deficits and cognitive impairments in a mouse model of AD (APP/PS2 mice). PROCEDURES: The cognitive abilities of APP/PS2 and wild-type mice (aged 2-16 months) were evaluated using the novel object recognition test. Double-tracer autoradiography analyses with 5-[125I]iodo-A-85380 ([125I]5IA: α4ß2 nAChR imaging probe) and 2-deoxy-2-[18F]fluoro-D-glucose were performed in both mice of different ages. [123I]5IA-single-photon emission tomography (SPECT) imaging was also performed in both mice at 12 months of age. Furthermore, each age cohort was investigated for changes in cognitive ability and expression levels of α7 nAChRs and N-methyl-D-aspartate receptors (NMDARs). RESULTS: No significant difference was found between the APP/PS2 and wild-type mice at 2-6 months of age in terms of novel object recognition memory; subsequently, however, APP/PS2 mice showed a clear cognitive deficit at 12 months of age. [125I]5IA accumulation decreased in the brains of 12-month-old APP/PS2 mice, i.e., at the age at which cognitive impairments were first observed; this result was supported by a reduction in the protein levels of α4 nAChRs using Western blotting. nAChR deficits could be noninvasively detected by [123I]5IA-SPECT in vivo. In contrast, no significant changes in glycometabolism, expression levels of α7 nAChRs, or NMDARs were associated with cognitive impairments in APP/PS2 mice. CONCLUSION: A decrease in cerebral α4ß2 nAChR density could act as a biomarker reflecting cognitive impairments associated with AD pathology.

Docosahexaenoic Acid Reduces Palmitic Acid-Induced Endoplasmic Reticulum Stress in Pancreatic Β Cells.

Endoplasmic reticulum (ER) stress leads to peripheral insulin resistance and the progression of pancreatic beta cell failure in type 2 diabetes. Although ER stress plays an important role in the pathogenesis of diabetes, it is indispensable for cellular activity. Therefore, when assessing the pathological significance of ER stress, it is important to monitor and quantify ER stress levels. Here, we have established a novel system to monitor ER stress levels quickly and sensitively, and using this method, we have clarified the effect of differences in glucose concentration and various fatty acids on the ER of pancreatic ß cells. First, we developed a cell system that secretes Gaussia luciferase in culture medium depending on the activation of the GRP78 promoter. This system could sensitively monitor ER stress levels that could not be detected with real-time RT-PCR and immunoblotting. This system revealed that hyperglycemia does not induce unfolded protein response (UPR) in a short period of time in MIN6 cells, a mouse pancreatic ß cell line. Physiological concentrations of palmitic acid, a saturated fatty acid, induced ER stress quickly, while physiological concentrations of oleic acid, an unsaturated fatty acid, did not. Docosahexaenoic acid, an n-3 unsaturated fatty acid, inhibited palmitic acid-induced ER stress. In this study, we have established a system that can sensitively detect ER stress levels of living cells in a short period of time. This system can be used to monitor the state of the ER in living cells and lead to the investigation of the significance of physiological or pathological ER stress levels.

HSF1 and HSF3 cooperatively regulate the heat shock response in lizards.

Cells cope with temperature elevations, which cause protein misfolding, by expressing heat shock proteins (HSPs). This adaptive response is called the heat shock response (HSR), and it is regulated mainly by heat shock transcription factor (HSF). Among the four HSF family members in vertebrates, HSF1 is a master regulator of HSP expression during proteotoxic stress including heat shock in mammals, whereas HSF3 is required for the HSR in birds. To examine whether only one of the HSF family members possesses the potential to induce the HSR in vertebrate animals, we isolated cDNA clones encoding lizard and frog HSF genes. The reconstructed phylogenetic tree of vertebrate HSFs demonstrated that HSF3 in one species is unrelated with that in other species. We found that the DNA-binding activity of both HSF1 and HSF3 in lizard and frog cells was induced in response to heat shock. Unexpectedly, overexpression of lizard and frog HSF3 as well as HSF1 induced HSP70 expression in mouse cells during heat shock, indicating that the two factors have the potential to induce the HSR. Furthermore, knockdown of either HSF3 or HSF1 markedly reduced HSP70 induction in lizard cells and resistance to heat shock. These results demonstrated that HSF1 and HSF3 cooperatively regulate the HSR at least in lizards, and suggest complex mechanisms of the HSR in lizards as well as frogs.