Characteristic phenotypes of ADH5/ALDH2 deficiency during childhood.

ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.

Physician characteristics associated with antiviral prescriptions for older adults with COVID-19 in Japan: an observational study.

OBJECTIVES: Although guidelines recommend antiviral therapy for outpatients with COVID-19 who are at high risk of progressing to severe conditions, such as older adults, many patients do not receive appropriate treatment. Little is known, however, about the physician factors associated with the prescription of guideline-recommended antiviral therapy for patients with COVID-19. DESIGN: A cross-sectional study. SETTING: Data including outpatient visits in primary care clinics in Japan from April to August 2023. PARTICIPANTS: We analysed 30 953 outpatients aged ≥65 years treated with COVID-19 (mean (SD) age, 75.0 (7.6) years; 17 652 women (57.0%)) in 1394 primary care clinics. OUTCOME MEASURES: The primary outcome was the prescription of guideline-recommended antivirals (ie, nirmatrelvir-ritonavir or molnupiravir), adjusted for patient characteristics, months of visits and regions. RESULTS: Antiviral prescriptions were concentrated among a small proportion of physicians; for example, the top 10% of physicians that had the largest number of nirmatrelvir-ritonavir prescriptions accounted for 92.4% of all nirmatrelvir-ritonavir prescriptions. After adjusting for potential confounders, physicians with higher patient volumes were more likely to prescribe guideline-recommended antivirals to their patients (adjusted OR (aOR) for high vs low volume, 1.76; 95% CI 1.31 to 2.38; adjusted p<0.001). We found no evidence that the likelihood of guideline-recommended antiviral prescription differed based on physicians' gender (aOR for women vs men, 1.24; 95% CI 0.88 to 1.74; adjusted p=0.48) or age (aOR for 45-59 vs <45 years, 1.16; 95% CI 0.87 to 1.54; adjusted p=0.48; aOR for ≥60 vs <45 years, 0.88; 95% CI 0.66 to 1.16; adjusted p=0.48). These patterns were similar when examining nirmatrelvir-ritonavir and molnupiravir separately. CONCLUSIONS: Our findings suggest that provider-level factors, such as the clinical experience of treating the patients with COVID-19, play an important role in the appropriate prescription of antiviral medications for COVID-19 in the primary care setting.

Antibiotic Prescription for Outpatients With COVID-19 in Primary Care Settings in Japan.

This cross-sectional study assesses the characteristics of patients and physicians associated with antibiotic prescription for COVID-19.

Perceived Exertion Correlates with Multiple Physiological Parameters During Cardiopulmonary Exercise Testing.

The purpose of this study was to investigate the relationship of the Borg scale score with leg-muscle oxygenated haemoglobin (O2Hb) and deoxygenated haemoglobin (HHb) levels on near infrared spectroscopy (NIRS) and the work rate, heart rate (HR), oxygen uptake (VO2) and minute ventilation (VE) during supine cardiopulmonary exercise testing (CPET) in healthy adult men. We also investigated the relationships between the leg-muscle O2Hb and HHb levels and the work rate during supine CPET. Fifteen healthy male volunteers (mean age, 20.7 ± 0.6 years; mean height, 172.1 ± 5.7 cm; mean body weight, 61.7 ± 6.6 kg) participated in this study. The cardiopulmonary and NIRS parameters were assessed during each minute of supine CPET and at the end of the test. The Borg scale score significantly correlated with the work rate, HR, VO2, and VE during supine CPET (Rs = 0.86-0.94, p < 0.05). Furthermore, the Borg scale score significantly correlated with the leg-muscle O2Hb and HHb levels during supine CPET (Rs = -0.6, and 0.8, respectively; p < 0.05). The leg-muscle O2Hb and HHb levels had significant correlations with the work rate (R = -0.62 and 0.8, respectively; p < 0.05). The Borg scale score may be used to determine the rating of perceived exertion, whole-body fatigue and local-muscle fatigue during supine exercise. Moreover, leg-muscle oxygenation is associated with the work rate in supine exercise, similar to that observed in upright exercise.

Neural basis for anxiety and anxiety-related physiological responses during a driving situation: an fMRI study.

Although the exteroceptive and interoceptive prediction of a negative event increases a person's anxiety in daily life situations, the relationship between the brain mechanism of anxiety and the anxiety-related autonomic response has not been fully understood. In this functional magnetic resonance imaging (fMRI) study, we examined the neural basis of anxiety and anxiety-related autonomic responses in a daily driving situation. Participants viewed a driving video clip in the first-person perspective. During the video clip, participants were presented with a cue to indicate whether a subsequent crash could occur (attention condition) or not (safe condition). Enhanced activities in the anterior insula, bed nucleus of the stria terminalis, thalamus, and periaqueductal gray, and higher sympathetic nerve responses (pupil dilation and peripheral arterial stiffness) were triggered by the attention condition but not with the safe condition. Autonomic response-related functional connectivity was detected in the visual cortex, cerebellum, brainstem, and MCC/PCC with the right anterior insula and its adjacent regions as seed regions. Thus, the right anterior insula and adjacent regions, in collaboration with other regions play a role in eliciting anxiety based on the prediction of negative events, by mediating anxiety-related autonomic responses according to interoceptive information.

Refractory T-cell/histiocyte-rich large B-cell lymphoma in a patient with ataxia-telangiectasia caused by novel compound heterozygous variants in ATM.

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ATM (A-T mutated) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. Approximately, 10% of A-T patients develop lymphoid malignancies. Deaths caused by extreme sensitivity to chemotherapy for malignancy have been reported, and cancer treatment in A-T is extraordinarily difficult, needing careful monitoring and individualized protocols. We report the case of a 12-year-old girl with A-T diagnosed at the age of 3 in association with IgA deficiency and recurrent pulmonary infections. Sanger sequencing revealed compound heterozygosity of the ATM gene, which bore two novel mutations. At the age of 12, she developed stage IV T-cell/histiocyte-rich large B-cell lymphoma. The tumor was resistant to chemotherapy, and she unfortunately died of cardiac insufficiency and multiple organ failure induced by rapid progression of the disease. The treatment approach for children with A-T and advanced-stage B-non-Hodgkin lymphoma must be refined.

Relationship Between the Borg Scale Rating of Perceived Exertion and Leg-Muscle Deoxygenation During Incremental Exercise in Healthy Adults.

INTRODUCTION: The Borg scale rating of perceived exertion is a reliable indicator and widely used to monitor and guide exercise intensity. We aimed to evaluate the relationships between the Borg scale score and oxygenated hemoglobin (O2Hb) and deoxygenated hemoglobin (HHb) concentrations in the leg muscle as measured by near-infrared spectroscopy (NIRS) during cardiopulmonary exercise testing (CPET) in healthy adult men. We also investigated the relationships between the Borg scale score and the work rate (WR), heart rate (HR), oxygen uptake (VO2), and minute ventilation (VE). METHODS: Participants comprised 12 healthy men. Cardiopulmonary and NIRS parameters were assessed during each minute of CPET and at the end of the test. RESULTS: The Borg scale score was significantly correlated with cardiopulmonary parameters including WR, HR, VO2, and VE during CPET (Rs = 0.87-0.95; p < 0.05). Furthermore, the Borg scale score was significantly correlated with NIRS parameters including O2Hb and HHb levels during CPET (Rs = -0.48 and 0.45, respectively; p < 0.05). DISCUSSION: The Borg scale score is significantly correlated with cardiopulmonary parameters (WR, HR, VO2, and VE), as well as with leg-muscle oxygenation parameters as assessed by NIRS, during CPET in healthy adults. The correlation coefficients obtained from NIRS parameters were lower than those of cardiopulmonary parameters. CONCLUSIONS: The Borg scale score might better reflect cardiopulmonary responses than muscle deoxygenation during exercise. These results can aid in the planning of rehabilitation programs for healthy adults.

Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous LRBA Variants.

Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was LRBA. We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the LRBA gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.

Effective Stabilization of Perovskite Cesium Lead Bromide Nanocrystals through Facile Surface Modification by Perfluorocarbon Acid.

CsPbX3 (X = Cl, Br, I) perovskite nanocrystals (NCs) have attracted much attention as promising materials for next-generation optoelectronic applications. However, improvement of their low stabilities against heating and humidity is needed for practical use. In this work, we focused on perfluorodecanoic acid (PFDA) as a surface ligand and investigated the thermal and chemical stabilities of the photoluminescence (PL) properties of CsPbBr3 NCs. Oleic acid (OA) adsorbed on the NCs was exchanged for decanoic acid (DA) and PFDA. OA-modified and DA-modified NCs exhibited drastic fluorescence quenching to 12.9 and 21.1% of their initial PL intensities, respectively, after heating at 100 °C for 4 h. In contrast, the PFDA-modified NCs maintained 92.1% of their PL intensity after the same heating. Furthermore, the polar solvent resistance was also improved by PFDA modification. These improvements can be attributed to the strong adsorptivity and high chemical stability of the PFDA ligand.

Aqueous Two-Phase System Formation in Small Droplets by Shirasu Porous Glass Membrane Emulsification Followed by Water Extraction.

By utilizing water transport phenomena between two different water-in-oil (W/O) emulsion droplets through continuous oil phase, we developed a novel method of aqueous two-phase system (ATPS) formation in small droplets prepared by Shirasu porous glass (SPG) membrane emulsification technique. When we mixed W/O emulsion droplets containing poly(ethylene glycol) (PEG) and dextran (DEX) at concentrations below the threshold of the phase separation, with droplets containing other solutes at high concentrations, water extraction from the droplets containing PEG and DEX to those containing the other solutes occurred, owing to the osmotic pressure difference. This effect increased the concentrations of PEG and DEX in the droplets above the phase separation threshold. We demonstrated the feasibility of the preparation method by varying the pore sizes of the SPG membranes, the solutes, and their concentrations. Only when the concentration of the solute was high enough to extract sufficient amounts of water did the homogeneous disperse phase consisting of PEG and DEX in droplets turn into a PEG-rich phase and DEX-rich phase, showing ATPS. This result was irrespective of the solute itself and pore size of the SPG membrane. In particular, we successfully demonstrated monodisperse ATPS droplets with diameters of approximately 10 µm under a certain condition.

The C-terminal region of the yeast monocarboxylate transporter Jen1 acts as a glucose signal-responding degron recognized by the α-arrestin Rod1.

In response to changes in nutrient conditions, cells rearrange the composition of plasma membrane (PM) transporters to optimize their metabolic flux. Not only transcriptional gene regulation, but also inactivation of specific transporters is important for fast rearrangement of the PM. In eukaryotic cells, endocytosis plays a role in transporter inactivation, which is triggered by ubiquitination of these transporters. The Nedd4 family E3 ubiquitin ligase is responsible for ubiquitination of the PM transporters and requires that a series of α-arrestin proteins are targeted to these transporters. The mechanism by which an α-arrestin recognizes its cognate transporters in response to environmental signals is of intense scientific interest. Excess substrates or signal transduction pathways are known to initiate recognition of transporters by α-arrestins. Here, we identified an endocytic-sorting signal in the monocarboxylate transporter Jen1 from yeast (Saccharomyces cerevisiae), whose endocytic degradation depends on the Snf1-glucose signaling pathway. We found that the C-terminal 20-amino acid-long region of Jen1 contains an amino acid sequence required for association of Jen1 to the α-arrestin Rod1, as well as lysine residues important for glucose-induced Jen1 ubiquitination. Notably, fusion of this region to the methionine permease, Mup1, whose endocytosis is normally induced by excess methionine, was sufficient for Mup1 to undergo glucose-induced, Rod1-mediated endocytosis. Taken together, our results demonstrate that the Jen1 C-terminal region acts as a glucose-responding degron for α-arrestin-mediated endocytic degradation of Jen1.

Importance of the High-Expression of Proline Transporter PutP to the Adaptation of Escherichia coli to High Salinity.

　The effect of the amount of the proline transporter PutP expression on the mechanism of adaptation of E. coli cells to high salinity was analyzed. The PutP gene derived from the E. coli expression plasmid was introduced into the E. coli cell, and a high PutP expression strain was developed. At 1.2 M NaCl culture condition, the growth of normal E. coli cells was inhibited, whereas high ProP expression cells showed growth under 2.5 M NaCl conditions. The uptake of proline by E. coli as a compatible solute and substrate for metabolization was in good accordance with those seen in cell growth. These data suggested that the amount of the proline transporter PutP expression played an important role in the adaptation of E. coli cells to high saline conditions.

The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine.

The excision of 8-oxoguanine (oxoG) by the human 8-oxoguanine DNA glycosylase 1 (hOGG1) base-excision repair enzyme was studied by using the QM/MM (M06-2X/6-31G(d,p):OPLS2005) calculation method and nuclear magnetic resonance (NMR) spectroscopy. The calculated glycosylase reaction included excision of the oxoG base, formation of Lys249-ribose enzyme-substrate covalent adduct and formation of a Schiff base. The formation of a Schiff base with ΔG# = 17.7 kcal/mol was the rate-limiting step of the reaction. The excision of the oxoG base with ΔG# = 16.1 kcal/mol proceeded via substitution of the C1΄-N9 N-glycosidic bond with an H-N9 bond where the negative charge on the oxoG base and the positive charge on the ribose were compensated in a concerted manner by NH3+(Lys249) and CO2-(Asp268), respectively. The effect of Asp268 on the oxoG excision was demonstrated with 1H NMR for WT hOGG1 and the hOGG1(D268N) mutant: the excision of oxoG was notably suppressed when Asp268 was mutated to Asn. The loss of the base-excision function was rationalized with QM/MM calculations and Asp268 was confirmed as the electrostatic stabilizer of ribose oxocarbenium through the initial base-excision step of DNA repair. The NMR experiments and QM/MM calculations consistently illustrated the base-excision reaction operated by hOGG1.

Optimal densities of alkali metal atoms in an optically pumped K-Rb hybrid atomic magnetometer considering the spatial distribution of spin polarization.

An optically pumped K-Rb hybrid atomic magnetometer can be a useful tool for biomagnetic measurements due to the high spatial homogeneity of its sensor property inside a cell. However, because the property varies depending on the densities of potassium and rubidium atoms, optimization of the densities is essential. In this study, by using the Bloch equations of K and Rb and considering the spatial distribution of the spin polarization, we confirmed that the calculation results of spin polarization behavior are in good agreement with the experimental data. Using our model, we calculated the spatial distribution of the spin polarization and found that the optimal density of K atoms is 3 × 1019 m-3 and the optimal density ratio is nK/nRb ~ 400 to maximize the output signal and enhance spatial homogeneity of the sensor property.

Feasibility and efficacy of high-speed gait training with a voluntary driven exoskeleton robot for gait and balance dysfunction in patients with chronic stroke: nonrandomized pilot study with concurrent control.

The aim of this pilot study was to investigate the feasibility of high-speed gait training with an exoskeleton robot hybrid assistive limb (HAL) in patients with chronic stroke, and to examine the efficacy of eight sessions (8 weeks) of gait training with a HAL compared with conventional physical therapy. Eighteen patients with chronic stroke were included in this study (nine each in the HAL and control groups). The HAL group underwent high-speed gait training with the HAL once a week for 8 weeks (20 min/session). The control group underwent conventional physical therapy for gait disturbance. Outcome measures were walking speed, number of steps, and cadence during a 10 m walking test, a timed up and go test, a functional reach test, and the Berg Balance Scale. Assessments were performed in the absence of the HAL before training and after the fourth and eighth training sessions. All patients in the HAL group completed the high-speed gait training without adverse events. The HAL group improved significantly in walking speed (55.9% increase, P<0.001), number of steps (17.6% decrease, P<0.01), and cadence (32.8% increase, P<0.001) during the 10 m walking test. The patients also exhibited significant improvements in the timed up and go test, the functional reach test, and the Berg Balance Scale after HAL training (P<0.01 in all). No statistical time-dependent changes were observed in any parameter in the control group. For chronic stroke patients, high-speed gait training with a HAL appears to be feasible and effective in improving gait and balance dysfunction despite the limitations of this nonrandomized pilot study.

Relationship between mitochondrial DNA copy number and SIRT1 expression in porcine oocytes.

The present study assessed the effect of resveratrol on the expression of SIRT1 and mitochondrial quality and quantity in porcine oocytes. Supplementing the maturation medium with 20 µM resveratrol increased the expression of SIRT1, and enhanced mitochondrial functions, as observed from the increased ATP content and mitochondrial membrane potential. Addition of resveratrol also improved the ability of oocytes to develop into the blastocyst stage following activation. The effects of resveratrol on mitochondrial number were examined by comparing the mitochondrial DNA copy number (Mt number) between group of oocytes collected from the same donor gilt ovaries. Supplementing the maturation medium with only resveratrol did not affect the Mt number in the oocytes. However, supplementing the maturation medium with 10 µM MG132, a proteasome inhibitor, significantly increased the amount of ubiquitinated proteins and Mt number by 12 and 14%, respectively. In addition, when resveratrol was added to the medium containing MG132, the Mt number increased significantly by 39%, this effect was diminished by the addition of the SIRT1 inhibitor EX527. Furthermore, supplementing the medium with MG132 and EX527 did not affect Mt number. The mean SIRT1 expression in 20 oocytes was significantly and positively correlated with the Mt number in oocytes collected from the same donor. This study suggests that the expression of SIRT1 is associated with the Mt number in oocytes. In addition, activation of SIRT1 by resveratrol enhances the biosynthesis and degradation of mitochondria in oocytes, thereby replenishing and improving mitochondrial function and the developmental ability of oocytes.

Resveratrol improves the mitochondrial function and fertilization outcome of bovine oocytes.

The aim of the present study was to address the effect of resveratrol-mediated upregulation of sirtuin 1 (SIRT1) during oocyte maturation on mitochondrial function, the developmental ability of oocytes and on mechanisms responsible for blockage of polyspermic fertilization. Oocytes collected from slaughterhouse-derived ovaries were cultured in TCM-199 medium supplemented with 10% FCS and 0 or 20 µM resveratrol (Res). We examined the effect of Res on SIRT1 expression in in vitro-matured oocytes (Exp 1); fertilization and developmental ability (Exp 2); mitochondrial DNA copy number (Mt number), ATP content and mitochondrial membrane potential in matured oocytes (Exp 3); and the time required for proteinase to dissolve the zona pellucida following in vitro fertilization (as a marker of zona pellucida hardening), as well as on the distribution of cortical granules before and after fertilization (Exp 4). In Exp 1, the 20 µM Res treatment upregulated protein expression of SIRT1 in oocytes. In Exp 2, Res treatment improved the ratio of normal fertilization and the total cell number of blastocysts. In Exp 3, Res treatment significantly increased the ATP content in matured oocytes. Additionally, Res increased the overall Mt number and mitochondrial membrane potential, but the effect was donor-dependent. In Exp 4, Res-induced zona hardening improved the distribution and exocytosis of cortical granules after in vitro fertilization. In conclusion, Res improved the quality of oocytes by improving mitochondrial quantity and quality. In addition, Res added to the maturation medium enhanced SIRT1 protein expression in oocytes and improved fertilization via reinforcement of the mechanisms responsible for blockage of polyspermic fertilization.