X-ray pumping of the 229Th nuclear clock isomer.

The metastable first excited state of thorium-229, 229mTh, is just a few electronvolts above the nuclear ground state1-4 and is accessible by vacuum ultraviolet lasers. The ability to manipulate the 229Th nuclear states with the precision of atomic laser spectroscopy5 opens up several prospects6, from studies of fundamental interactions in physics7,8 to applications such as a compact and robust nuclear clock5,9,10. However, direct optical excitation of the isomer and its radiative decay to the ground state have not yet been observed, and several key nuclear structure parameters-such as the exact energies and half-lives of the low-lying nuclear levels of 229Th-remain unknown11. Here we present active optical pumping into 229mTh, achieved using narrow-band 29-kiloelectronvolt synchrotron radiation to resonantly excite the second excited state of 229Th, which then decays predominantly into the isomer. We determine the resonance energy with an accuracy of 0.07 electronvolts, measure a half-life of 82.2 picoseconds and an excitation linewidth of 1.70 nanoelectronvolts, and extract the branching ratio of the second excited state into the ground and isomeric state. These measurements allow us to constrain the 229mTh isomer energy by combining them with γ-spectroscopy data collected over the past 40 years.

Myelination by signaling through Arf guanine nucleotide exchange factor.

During myelination, large quantities of proteins are synthesized and transported from the endoplasmic reticulum (ER)-trans-Golgi network (TGN) to their appropriate locations within the intracellular region and/or plasma membrane. It is widely believed that oligodendrocytes uptake neuronal signals from neurons to regulate the endocytosis- and exocytosis-mediated intracellular trafficking of major myelin proteins such as myelin-associated glycoprotein (MAG) and proteolipid protein 1 (PLP1). The small GTPases of the adenosine diphosphate (ADP) ribosylation factor (Arf) family constitute a large group of signal transduction molecules that act as regulators for intracellular signaling, vesicle sorting, or membrane trafficking in cells. Studies on mice deficient in Schwann cell-specific Arfs-related genes have revealed abnormal myelination formation in peripheral nerves, indicating that Arfs-mediated signaling transduction is required for myelination in Schwann cells. However, the complex roles in these events remain poorly understood. This review aims to provide an update on signal transduction, focusing on Arf and its activator ArfGEF (guanine nucleotide exchange factor for Arf) in oligodendrocytes and Schwann cells. Future studies are expected to provide important information regarding the cellular and physiological processes underlying the myelination of oligodendrocytes and Schwann cells and their function in modulating neural activity.

Hypomyelination Leukodystrophy 16 (HLD16)-Associated Mutation p.Asp252Asn of TMEM106B Blunts Cell Morphological Differentiation.

Transmembrane protein 106B (TMEM106B), which is a type II transmembrane protein, is believed to be involved in intracellular dynamics and morphogenesis in the lysosome. TMEM106B is known to be a risk factor for frontotemporal lobar degeneration and has been recently identified as the receptor needed for the entry of SARS-CoV-2, independently of angiotensin-converting enzyme 2 (ACE2). A missense mutation, p.Asp252Asn, of TMEM106B is associated with hypomyelinating leukodystrophy 16 (HLD16), which is an oligodendroglial cell-related white matter disorder causing thin myelin sheaths or myelin deficiency in the central nervous system (CNS). However, it remains to be elucidated how the mutated TMEM106B affects oligodendroglial cells. Here, we show that the TMEM106B mutant protein fails to exhibit lysosome distribution in the FBD-102b cell line, an oligodendroglial precursor cell line undergoing differentiation. In contrast, wild-type TMEM106B was indeed localized in the lysosome. Cells harboring wild-type TMEM106B differentiated into ones with widespread membranes, whereas cells harboring mutated TMEM106B failed to differentiate. It is of note that the output of signaling through the lysosome-resident mechanistic target of rapamycin (mTOR) was greatly decreased in cells harboring mutated TMEM106B. Furthermore, treatment with hesperetin, a citrus flavonoid known as an activator of mTOR signaling, restored the molecular and cellular phenotypes induced by the TMEM106B mutant protein. These findings suggest the potential pathological mechanisms underlying HLD16 and their amelioration.

Autism Spectrum Disorder- and/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which Dock5 Signalosome Molecules Control Cell Shape.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger's syndrome, and pervasive developmental disorder. Individuals with ASD may exhibit difficulties in social interactions, communication challenges, repetitive behaviors, and restricted interests. While genetic mutations in individuals with ASD can either activate or inactivate the activities of the gene product, impacting neuronal morphogenesis and causing symptoms, the underlying mechanism remains to be fully established. Herein, for the first time, we report that genetically conserved Rac1 guanine-nucleotide exchange factor (GEF) Dock5 signalosome molecules control process elongation in the N1E-115 cell line, a model line capable of achieving neuronal morphological changes. The increased elongation phenotypes observed in ASD and intellectual disability (ID)-associated Semaphorin-5A (Sema5A) Arg676-to-Cys [p.R676C] were also mediated by Dock5 signalosome molecules. Indeed, knockdown of Dock5 using clustered regularly interspaced short palindromic repeat (CRISPR)/CasRx-based guide(g)RNA specifically recovered the mutated Sema5A-induced increase in process elongation in cells. Knockdown of Elmo2, an adaptor molecule of Dock5, also exhibited similar recovery. Comparable results were obtained when transfecting the interaction region of Dock5 with Elmo2. The activation of c-Jun N-terminal kinase (JNK), one of the primary signal transduction molecules underlying process elongation, was ameliorated by either their knockdown or transfection. These results suggest that the Dock5 signalosome comprises abnormal signaling involved in the process elongation induced by ASD- and ID-associated Sema5A. These molecules could be added to the list of potential therapeutic target molecules for abnormal neuronal morphogenesis in ASD at the molecular and cellular levels.

Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr.

Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B protein displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that the expression of CHMP2B with the Asp148Tyr (D148Y) mutation, which preferentially displays FTD phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed in the N1E-115 cell line, a model that undergoes neurite elongation. Second, these effects were also accompanied by changes in neuronal differentiation marker protein expression. Third, wild-type CHMP2B protein was indeed localized in the endosomal sorting complexes required to transport (ESCRT)-like structures throughout the cytoplasm. In contrast, CHMP2B with the D148Y mutation exhibited aggregation-like structures and accumulated in the Golgi body. Fourth, among currently known Golgi stress regulators, the expression levels of Hsp47, which has protective effects on the Golgi body, were decreased in cells expressing CHMP2B with the D148Y mutation. Fifth, Arf4, another Golgi stress-signaling molecule, was increased in mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 with small interfering (si)RNA, cellular phenotypes in mutant-expressing cells were recovered. These results suggest that CHMP2B with the D148Y mutation, acting through Golgi stress signaling, is negatively involved in the regulation of neuronal cell morphological differentiation, providing evidence that a molecule controlling Golgi stress may be one of the potential FTD therapeutic targets at the molecular and cellular levels.

Association of depressive symptoms with incidence and mortality rates of COVID-19 over 2 years among healthcare workers in 20 countries: multi-country serial cross-sectional study.

BACKGROUND: Long-term deterioration in the mental health of healthcare workers (HCWs) has been reported during and after the COVID-19 pandemic. Determining the impact of COVID-19 incidence and mortality rates on the mental health of HCWs is essential to prepare for potential new pandemics. This study aimed to investigate the association of COVID-19 incidence and mortality rates with depressive symptoms over 2 years among HCWs in 20 countries during and after the COVID-19 pandemic. METHODS: This was a multi-country serial cross-sectional study using data from the first and second survey waves of the COVID-19 HEalth caRe wOrkErS (HEROES) global study. The HEROES study prospectively collected data from HCWs at various health facilities. The target population included HCWs with both clinical and non-clinical roles. In most countries, healthcare centers were recruited based on convenience sampling. As an independent variable, daily COVID-19 incidence and mortality rates were calculated using confirmed cases and deaths reported by Johns Hopkins University. These rates represent the average for the 7 days preceding the participants' response date. The primary outcome was depressive symptoms, assessed by the Patient Health Questionnaire-9. A multilevel linear mixed model (LMM) was conducted to investigate the association of depressive symptoms with the average incidence and mortality rates. RESULTS: A total of 32,223 responses from the participants who responded to all measures used in this study on either the first or second survey, and on both the first and second surveys in 20 countries were included in the analysis. The mean age was 40.1 (SD = 11.1), and 23,619 responses (73.3%) were from females. The 9323 responses (28.9%) were nurses and 9119 (28.3%) were physicians. LMM showed that the incidence rate was significantly and positively associated with depressive symptoms (coefficient = 0.008, standard error 0.003, p = 0.003). The mortality rate was significantly and positively associated with depressive symptoms (coefficient = 0.049, se = 0.020, p = 0.017). CONCLUSIONS: This is the first study to show an association between COVID-19 incidence and mortality rates with depressive symptoms among HCWs during the first 2 years of the outbreak in multiple countries. This study's findings indicate that additional mental health support for HCWs was needed when the COVID-19 incidence and mortality rates increase during and after the early phase of the pandemic, and these findings may apply to future pandemics. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04352634.

Analysis on high-resolution spectrum of the S1-S0 transition of free-base phthalocyanine.

A high-resolution absorption spectrum of the S1-S0 transition of free-base phthalocyanine was observed and analyzed with improved reliability. The spectrum, with a partially resolved rotational structure, was obtained by using the buffer-gas cooling technique and a single-mode tunable laser. Our new analysis reveals that the S1←S0000 band belongs to the a-type transition, where the electronic transition moment aligns parallel to the NH-HN direction, allowing the assignment of the S1 state to 1B3u. These results agree with a prior study using supersonic expansion and are well supported by theoretical calculations. Interestingly, the rotational constant B in the S1 state, which is often smaller than that in the ground state for typical molecules, was found to be slightly larger than that in the S01Ag state. This suggests a change in the character of π bonds with the electronic excitation.

Newly observed low-lying Ω = 1 state of PbO.

High-resolution spectroscopy of lead monoxide was performed in a range of 22 400-25 300 cm-1. A new Ω = 1 state located between the a1 and A0+ states was observed, and it is labeled c1. Spectroscopic constants, including the hyperfine interaction coefficient, were determined for the a1 and c1 states. The vibrational levels of these two electronic states are located closely to each other, and the interaction between them causes gradual exchange of electronic state properties in our observation wave number range. Our observation poses a question for the band assignment for the b0- state, which has some resemblance with this c1 state.

Supplementation with autologous adipose stem cell-derived mitochondria can be a safe and promising strategy for improving oocyte quality.

PURPOSE: In our previous study, we confirmed that the supplementation of vitrified-warmed murine oocytes with autologous adipose stem cell (ASC)-derived mitochondria during intracytoplasmic sperm injection enhances post-fertilization developmental competence in mice. To ensure the safety of this technology, we conducted a thorough study in mice to investigate the potential presence of specific malformations in offspring developed from this approach. METHODS: A transgenerational comparative analysis was conducted on founder mice from embryos that developed after mitochondrial supplementation, and two subsequent generations. Reproductive performance, body growth rate, histopathological parameters, hematological parameters, daily activity patterns, and daily body temperature changes in male and female mice across these three generations were assessed in comparison to wild-type mice of the same age. RESULTS: Both male and female animals in all three generations showed comparable reproductive performance to the control group. Additionally, body growth rate by the age of 8 weeks were found to be comparable to controls across all three generations. Notably, no significant histopathological abnormalities were detected in vital organs, including the brain, heart, liver, kidneys, lungs, ovaries, and testes, in any individuals from the studied cohorts. The blood parameters were consistent with the control data. The continuous monitoring of activity and body temperature changes (both day and night) over a 1-week period revealed a pattern closely resembling that observed in the control animals. CONCLUSION: Injection of ASC-mitochondria into oocytes may be a promising technique to support developmental potential without causing adverse epigenetic events in the offspring in mice. However, before considering clinical application, additional safety screening using larger animals or non-human primates is essential.

Identification of Tau protein as a novel marker for maturation and pathological changes of oligodendrocytes.

Microtubule-associated protein Tau is primarily expressed in axons of neurons, but also in Olig2-positive oligodendrocytes in adult rodent and monkey brains. In this study, we sought to determine at what cell stage Tau becomes expressed in the oligodendrocyte lineage. We performed immunostaining of adult mouse brain sections using well-known markers of oligodendrocyte lineage and found that Tau is expressed in mature oligodendrocytes, but not in oligodendrocyte progenitors and immature pre-oligodendrocytes. We also investigated Tau expression in developing mouse brain. Surprisingly, Tau expression occurred after the peak of myelination and even exceeded GSTπ expression, which has been considered as a marker of myelinating oligodendrocytes. These results suggest Tau as a novel marker of oligodendrocyte maturation. We then investigated whether Tau is important for oligodendrocyte development and/or myelination and how Tau changes in demyelination. First, we found no changes in myelination and oligodendrocyte markers in Tau knockout mice, suggesting that Tau is dispensable. Next, we analyzed the proteolipid protein 1 transgenic model of Pelizaeus-Merzbacher disease, which is a rare leukodystrophy. In hemizygous transgenic mice, the number of Tau-positive cells were significantly increased as compared with wild type mice. These cells were also positive for Olig2, CC1, and GSTπ, but not PDGFRα and GPR17. In stark contrast, the expression level of Tau, as well as GSTπ, was dramatically decreased in the cuprizone-induced model of multiple sclerosis. Taken together, we propose Tau as a new marker of oligodendrocyte lineage and for investigating demyelination lesions.

Extracellular HSPA5 is autocrinally involved in the regulation of neuronal process elongation.

The molecular mechanisms by which neuronal processes grow are extremely complicated, involving fine-tuned regulation of extracellular and intracellular signals. It remains to be elucidated which molecules are contained in the regulation. Herein, we report for the first time that heat shock protein family A member 5 (HSPA5, also called immunoglobulin heavy chain binding endoplasmic reticulum [ER] protein [BiP]) is secreted from mouse primary dorsal neuronal ganglion (DRG) cells or neuronal cell line N1E-115, a frequently used neuronal differentiation model. Supporting these results, HSPA5 protein was co-localized not only with ER antigen KDEL but also with intracellular vesicles such as Rab11-positive secretory vesicles. Unexpectedly, addition of HSPA5 inhibited elongation of neuronal processes, whereas neutralization of extracellular HSPA5 with the antibodies elongated processes, characterizing extracellular HSPA5 as a negative regulator of neuronal differentiation. Treatment of cells with neutralizing antibodies for low-density lipoprotein receptor (LDLR) did not have significant effects on process elongation, whereas LDLR-related protein 1 (LRP1) antibodies promoted differentiation, implying that LRP1 may act as a receptor candidate for HSPA5. Interestingly, extracellular HSPA5 was greatly decreased following treatment with tunicamycin, an ER stress inducer, illustrating that the ability to form neuronal processes could be preserved, even under stress. These results suggest that neuronal HSPA5 itself is secreted to contribute to inhibitory effects on neuronal cell morphological differentiation and can be included on the list of extracellular signaling molecules negatively controlling differentiation.

One-Year Functional Outcomes After Invasive Mechanical Ventilation for Older Adults With Preexisting Long-Term Care-Needs.

OBJECTIVES: To examine 1-year functional outcomes after invasive mechanical ventilation for adults greater than or equal to 65 years with preexisting long-term care-needs. DESIGN: We used medical and long-term care administrative databases. The database included data on functional and cognitive impairments that were assessed with the national standardized care-needs certification system and were categorized into seven care-needs levels based on the total daily estimated care minutes. Primary outcome was mortality and care-needs at 1 year after invasive mechanical ventilation. Outcome was stratified by preexisting care-needs at the time of invasive mechanical ventilation: no care-needs, support level 1-2 and care-needs level 1 (estimated care time 25-49 min), care-needs level 2-3 (50-89 min), and care-needs level 4-5 (≥90 min). SETTING: A population-based cohort study in Tochigi Prefecture, one of 47 prefectures in Japan. PATIENTS: Among people greater than or equal to 65 years old registered between June 2014 and February 2018, patients who received invasive mechanical ventilation were identified. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 593,990 eligible people, 4,198 (0.7%) received invasive mechanical ventilation. The mean age was 81.2 years, and 55.5% were male. The 1-year mortality rates after invasive mechanical ventilation in patients with no care-needs, support level 1-2 and care-needs level 1, care-needs level 2-3, and care-needs level 4-5 at the time of invasive mechanical ventilation were 43.4%, 54.9%, 67.8%, and 74.1%, respectively. Similarly, those with worsened care-needs were 22.8%, 24.2%, 11.4%, and 1.9%, respectively. CONCLUSIONS: Among patients in preexisting care-needs levels 2-5 who received invasive mechanical ventilation, 76.0-79.2% died or had worsened care-needs within 1 year. These findings may aid shared decision-making among patients, their families, and heath care professionals on the appropriateness of starting invasive mechanical ventilation for people with poor functional and cognitive status at baseline.

Doppler-free Spectroscopy of Buffer-Gas-Cooled Calcium Monohydroxide.

In this study, we report the Doppler-free spectra of buffer-gas-cooled CaOH. We observed five Doppler-free spectra containing low-J Q1 and R12 transitions, which were only partially resolved by previous Doppler-limited spectroscopies. The spectra frequencies were corrected using the Doppler-free spectra of iodine molecules; accordingly, the uncertainty was estimated to be below 10 MHz. We determined the spin-rotation constant in the ground state, which agrees with the values reported in the literature obtained based on millimeter-wave data within 1 MHz. This suggests that the relative uncertainty is much smaller. The present study demonstrates the Doppler-free spectroscopy of a polyatomic radical and the broad applicability of the buffer gas cooling method to molecular spectroscopy. CaOH is the only polyatomic molecule that can be directly laser-cooled and trapped in a magneto-optical trap. High-resolution spectroscopy of such molecules is useful for establishing efficient laser cooling schemes of polyatomic molecules.

1-year functional outcomes after cardiopulmonary resuscitation for older adults with pre-existing long-term care needs.

OBJECTIVE: To investigate the 1-year functional outcomes after cardiopulmonary resuscitation (CPR) in adults aged ≥65 years with pre-existing long-term care needs. METHODS: This population-based cohort study was conducted in Tochigi Prefecture, one of 47 prefectures in Japan. We used medical and long-term care administrative databases, which included data on functional and cognitive impairment that were assessed with the nationally standardised care-needs certification system. Among individuals aged ≥65 years registered between June 2014 and February 2018, patients who underwent CPR were identified. The primary outcome was mortality and care needs at 1 year after CPR. The outcome was stratified by pre-existing care needs before CPR based on the total daily estimated care minutes: no care needs, support levels 1 and 2 and care-needs level 1 (estimated care time 25-49 min), care-needs levels 2 and 3 (50-89 min) and care-needs levels 4 and 5 (≥90 min). RESULTS: Among 594,092 eligible individuals, 5,086 (0.9%) underwent CPR. The 1-year mortalities after CPR in patients with no care needs, support levels 1 and 2 and care-needs level 1, care-needs levels 2 and 3 and care-needs levels 4 and 5 were 94.6% (n = 2,207/2,332), 96.1% (n = 736/766), 94.5% (n = 930/984) and 95.9% (n = 963/1,004), respectively. Among survivors, most patients had no change in care needs before and at 1 year after CPR. There was no significant association between pre-existing functional and cognitive impairment and 1-year mortality and care needs after adjusting for potential confounders. CONCLUSION: Healthcare providers need to discuss poor survival outcomes after CPR with all older adults and their families in shared decision making.

Outcomes in novel hospital-at-home model for patients with COVID-19: a multicentre retrospective cohort study.

BACKGROUND: Hospital-at-home (HaH) care has been proposed as an alternative to inpatient care for patients with coronavirus disease (COVID-19). Previous reports were hospital-led and involved patients triaged at the hospitals. To reduce the burden on hospitals, we constructed a novel HaH care model organized by a team of local primary care clinics. METHODS: We conducted a multicentre retrospective cohort study of the COVID-19 patients who received our HaH care from 1 January to 31 March 2022. Patients who were not able to be triaged for the need for hospitalization by the Health Center solely responsible for the management of COVID-19 patients in Osaka city were included. The primary outcome was receiving medical care beyond the HaH care defined as a composite outcome of any medical consultation, hospitalization, or death within 30 days from the initial treatment. RESULTS: Of 382 eligible patients, 34 (9%) were triaged for hospitalization immediately after the initial visit. Of the remaining 348 patients followed up, 37 (11%) developed the primary outcome, while none died. Obesity, fever, and gastrointestinal symptoms at baseline were independently associated with an increased risk of needing medical care beyond the HaH care. A further 129 (37%) patients were managed online alone without home visit, and 170 (50%) required only 1 home visit in addition to online treatment. CONCLUSIONS: The HaH care model with a team of primary care clinics was able to triage patients with COVID-19 who needed immediate hospitalization without involving hospitals, and treated most of the remaining patients at home.

Outcomes after early versus delayed antibiotic treatment of liver abscess in Japan: A nationwide retrospective cohort study.

BACKGROUND: The optimal timing of antibiotic administration in patients with a liver abscess undergoing liver aspiration or drainage is unknown. METHODS: This was a retrospective cohort study using the Diagnosis Procedure Combination database, a national inpatient database in Japan. RESULTS: A total of 34,424 patients who were emergently hospitalized due to liver abscess between July 2010 and March 2020 were included. Of these, 31,248 (90.8%) received antibiotics on the day of admission (early antibiotics group), and 3176 (9.2%) did not (delayed antibiotics group). Multivariable logistic regression analyses showed that in-hospital mortality of patients in the early antibiotics group was significantly lower than that in the delayed antibiotics group (odds ratio, 0.61; 95% confidence interval, 0.52-0.72; p <0.001). Patients in the early antibiotics group had a significantly lower proportion of clinical deterioration (odds ratio, 0.73; 95% confidence interval, 0.63-0.84; p <0.001) and shorter length of stay (adjusted difference, -5.2 days; 95% confidence interval, -6.2 to -4.1 days; p <0.001) than those in the delayed antibiotics group. CONCLUSIONS: Starting antibiotic treatment on the day of admission was associated with lower mortality, a lower proportion of clinical deterioration, and a shorter length of hospital stay.

Effectiveness of early colonoscopy in patients with colonic diverticular hemorrhage: Nationwide inpatient analysis in Japan.

OBJECTIVES: Current guidelines recommend colonoscopy within 24 h for acute lower gastrointestinal bleeding; however, the evidence in support for colonic diverticular hemorrhage (CDH) indications remains insufficient. We use a nationwide database to investigate the effectiveness of early colonoscopy for CDH. METHODS: We conducted a retrospective cohort study using the Japanese Diagnosis Procedure Combination inpatient database and identified patients who were admitted for CDH from 2010 to 2017. Patients who underwent colonoscopy on the same day of admission (early group) were compared with those who underwent colonoscopy on the next day of admission (elective group). The primary outcome was in-hospital mortality, and secondary outcomes were length of hospital stay, total hospitalization cost, fasting period, and the prevalence of re-colonoscopy, interventional radiology or abdominal surgery. Propensity score matching was used to adjust for confounders. RESULTS: We identified 74,569 eligible patients. Patients were divided into the early (n = 46,759) and elective (n = 27,810) groups. After propensity score matching, 27,696 pairs were generated. In-hospital mortality did not significantly differ between the two groups (0.49% in the early group vs. 0.41% in the elective group; risk difference 0.08%; 95% confidence interval -0.02 to 0.19; P = 0.14). The early group had a significantly longer length of hospital stay, higher total hospitalization cost, longer fasting period, and higher prevalence of re-colonoscopy and abdominal surgery. CONCLUSIONS: The effectiveness of early colonoscopy conducted on the same day of admission for CDH could not be confirmed. Early colonoscopy may not result in favorable outcomes in CDH patients.

Mitochondrial Transfer into Human Oocytes Improved Embryo Quality and Clinical Outcomes in Recurrent Pregnancy Failure Cases.

One of the most critical issues to be solved in reproductive medicine is the treatment of patients with multiple failures of assisted reproductive treatment caused by low-quality embryos. This study investigated whether mitochondrial transfer to human oocytes improves embryo quality and provides subsequent acceptable clinical results and normality to children born due to the use of this technology. We transferred autologous mitochondria extracted from oogonia stem cells to mature oocytes with sperm at the time of intracytoplasmic sperm injection in 52 patients with recurrent failures (average 5.3 times). We assessed embryo quality using the following three methods: good-quality embryo rates, transferable embryo rates, and a novel embryo-scoring system (embryo quality score; EQS) in 33 patients who meet the preset inclusion criteria for analysis. We also evaluated the clinical outcomes of the in vitro fertilization and development of children born using this technology and compared the mtDNA sequences of the children and their mothers. The good-quality embryo rates, transferable embryo rates, and EQS significantly increased after mitochondrial transfer and resulted in 13 babies born in normal conditions. The mtDNA sequences were almost identical to the respective maternal sequences at the 83 major sites examined. Mitochondrial transfer into human oocytes is an effective clinical option to enhance embryo quality in recurrent in vitro fertilization-failure cases.

Hyaluronic acid and its receptor CD44, acting through TMEM2, inhibit morphological differentiation in oligodendroglial cells.

Hyaluronic acid is a main extracellular matrix component in the central nervous system (CNS), which provides structural support under physical and physiological conditions to maintain cellular homeostasis. However, hyaluronic acid and its degradation products are present within focal demyelinating lesions in multiple sclerosis (MS) patients and autoimmune encephalomyelitis (EAE) mouse models. Differentiated plasma membranes called myelin membranes are generated by oligodendrocytes (also called oligodendroglial cells), which are glial cells that wrap neuronal axons in the CNS. Despite these positive or negative relationships of hyaluronic acid with oligodendroglial cell differentiation and/or myelination, it remains unclear whether and how hyaluronic acid affects oligodendroglial cells. Here, we showed that hyaluronic acid and the cognate receptor CD44 are directly involved in inhibiting morphological differentiation in FBD-102b cells, which are differentiation models of oligodendroglial precursor cells, and primary oligodendroglial precursor cells. Their phenotype changes were supported by decreased oligodendroglial cell differentiation, myelin marker protein expression levels, and Akt kinase phosphorylation levels as a marker kinase. Furthermore, the effects of hyaluronic acid required transmembrane protein 2 (TMEM2), a cell surface hyaluronidase. These results suggest that hyaluronic acid and the CD44 receptor, acting through TMEM2, contribute to inhibiting morphological differentiation of oligodendroglial cells, providing a mechanism underlying cell physiological and possible pathological effects responsible for hyaluronic acid.

Varicella-zoster virus meningitis coincident with bacteremia caused by liver abscess: a case report.

Varicella-zoster virus (VZV) meningitis is sometimes associated with herpes zoster, which is also associated with various other infectious diseases. However, there are limited case reports of VZV meningitis with concomitant infectious diseases. Herein, we report a unique case of VZV meningitis concomitant with a pyogenic liver abscess. VZV meningitis was associated with herpes zoster ophthalmicus, Klebsiella pneumoniae bacteremia, and liver abscess. When VZV meningitis is suspected, clinicians should be aware of its relatively rare epidemiology, nonspecific presentation, and many background risks shared with other infections and should never omit thorough examinations to rule out other infectious causes.