Blending and separating dynamics of RNA-binding proteins develop architectural splicing networks spreading throughout the nucleus.

The eukaryotic nucleus has a highly organized structure. Although the spatiotemporal arrangement of spliceosomes on nascent RNA drives splicing, the nuclear architecture that directly supports this process remains unclear. Here, we show that RNA-binding proteins (RBPs) assembled on RNA form meshworks in human and mouse cells. Core and accessory RBPs in RNA splicing make two distinct meshworks adjacently but distinctly distributed throughout the nucleus. This is achieved by mutual exclusion dynamics between the charged and uncharged intrinsically disordered regions (IDRs) of RBPs. These two types of meshworks compete for spatial occupancy on pre-mRNA to regulate splicing. Furthermore, the optogenetic enhancement of the RBP meshwork causes aberrant splicing, particularly of genes involved in neurodegeneration. Genetic mutations associated with neurodegenerative diseases are often found in the IDRs of RBPs, and cells harboring these mutations exhibit impaired meshwork formation. Our results uncovered the spatial organization of RBP networks to drive RNA splicing.

Investigation of optimal weight gain during pregnancy: A retrospective analysis of the Japanese perinatal registry database.

AIM: This study aimed to determine the weight gain during pregnancy that minimizes the predicted probability of various perinatal adverse events according to the pre-pregnancy body mass index (BMI) and make recommendations for optimal weight gain in Japan. METHODS: The Japan Society of Obstetrics and Gynecology perinatal database for 2015-2017 was used. From the 719 723 deliveries included in this database, parturients with underlying diseases or missing data were excluded, and 419 114 deliveries were analyzed. A questionnaire survey was also conducted to weigh each perinatal adverse event. For each of the nine outcomes, a restricted cubic spline model was made to estimate the association between the "expected gestational weight gain at 40 weeks" and the outcome risk. RESULTS: Since the classes of medical facilities were generally the same, weights were assigned according to the mean of the questionnaires rather than by the class of the facility. For each pre-pregnancy BMI, the weight gains during pregnancy that minimized the predicted probability of various adverse perinatal events were 12-15, 10-13, 7-10, and upper limit of 5 kg for the underweight, normal-weight, obese 1, and obese ≥2 groups, respectively. CONCLUSIONS: The weight gain during pregnancy that minimizes the predicted probability of various perinatal adverse events according to the pre-pregnancy BMI was established.

Association between smoking and duration of regional anesthesia - A propensity score matching study.

BACKGROUND: Previous studies have shown shorter duration of general anesthesia in smokers but it is unclear in regional anesthesia among smokers. We investigated the association between smoking status and the duration of regional anesthesia. METHODS: A total of 77 patients with a mean age of 47.3 years who underwent lower extremity orthopaedic surgery under regional anesthesia between January 2021 and June 2022 were enrolled. Sixteen patients were smokers and 57 patients were non-smokers. Propensity score matching was performed to balance patient characteristics. Our primary outcome was the time to onset of motor or sensory blockade and the duration required for full recovery of motor or sensory function. RESULTS: The time to sensory loss was 43.4 (SD 35.9) minutes in the smoking group and 39.6 (SD 31.7) minutes in the non-smoking group (p = 0.69), and the time to motor blockade was 37.0 (SD 28.4) minutes in the smoking group and 30.1 (SD 24.1) minutes in the non-smoking group (p = 0.35). The time for recovery of sensory function was 1146.7 (SD 197.8) minutes in the smoking group and 1024.6 (SD 177.9) minutes in the non-smoking group (p = 0.024). The time to recovery of motor function was 978.3 (SD 220.5) minutes in the smoking group and 1090.9 (SD 222.8) minutes in the non-smoking group (p = 0.08). The duration of sensory effect was significantly longer in the smoking group than in the non-smoking group. CONCLUSIONS: We found no significant association in the onset of regional anesthesia, but the duration of sensory blockade was significantly longer in the smoking group than in the non-smoking group. Hence, attention should be paid to the risks of the insensate limb in smokers due to prolonged sensory blockade as compared to non-smokers, rather than be concerned about delays in the onset of anesthesia.

Risk factors for resignation from work during pregnancy among Japanese women: a cross-sectional, multicenter questionnaire survey.

This study was to investigate the employment status of pregnant women in Japan and identify risk factors associated with resigning from work during pregnancy. We conducted a cross-sectional survey with 975 postpartum women in Tokyo and its suburbs, focusing on those who were employed during pregnancy. Women who were employed when they became pregnant were selected and divided into two groups: those who did not resign and those who resigned; the groups were analyzed separately. Multiple logistic regression analyses were performed to examine associations between employment resignation and risk factors. The analysis revealed that 79% continued working, while 8.1% resigned. Risk factors for resignation included non-regular employment (OR: 13.1, 95% CI: 6.6-25.9), fewer employees (OR: 3.4, 95% CI: 1.8-6.4), and shorter employee tenure (OR: 2.4, 95% CI: 1.1-5.2). Non-regular employment status, a smaller number of employees, and shorter employee tenure were identified as risk factors for working women resigning from their job during pregnancy. In work situations and work environments that encourage pregnant women to leave the workforce, developing systems to improve these conditions for pregnant employees may help women to progress in the labor force.

Tokophobia: Psychopathology and Diagnostic Consideration of Ten Cases.

Tokophobia is regarded as the intensive fear of childbirth that some pregnant women have. However, little is known about the psychopathological details of tokophobia (fear of childbirth). Between 2020 and 2021, a total of 10 pregnant women (nine nulliparae and one multipara) with a strong fear of childbirth were referred by obstetricians. Semi-structured psychopathological interviews were conducted, and two cases were judged to have obsession, three an overvalued idea, and one secondary delusion. Three were characterised by both obsession and overvalued idea and one by both obsession and secondary delusion. In total, six cases had features of an overvalued idea. All of the participants except one had a lifetime history of a specific phobia. In addition, their history included social phobia in two cases, panic disorder in one case, obsessive-compulsive disorder (other than tokophobia) in two cases, depressive disorder in two cases, bipolar disorder in two cases, and PTSD in six cases. To conclude, this study showed that tokophobia was not a phobic disorder but a kind of overvalued idea that requires specific assessment and treatment.

Effectiveness, reliability, and validity of new Japanese diagnostic criteria for obstetrical disseminated intravascular coagulation.

Since July 2022, obstetrical disseminated intravascular coagulation (DIC) in Japan has been diagnosed based on the new criteria (tentative version), which assesses the main underlying disease, fibrinogen level, and fibrin/fibrinogen degradation products or D-dimer level. In June 2024, the tentative version underwent minor revision and the final version was released. The previous Japanese criteria assessed underlying disease, clinical symptoms, and various laboratory findings. This study aimed to prove the effectiveness, reliability, and validity of the new criteria (final version). We analyzed 212 women with singleton pregnancies who delivered after 22 gestational weeks and experienced blood loss ≥ 1000 mL during vaginal delivery or ≥ 2000 mL during cesarean section. Those with missing laboratory findings before receiving blood transfusion at delivery were excluded. In the obstetrical DIC group, the frequency of fibrinogen levels < 150 mg/dL was significantly higher than in the control group (90% vs. 5%, p < 0.0001), as was the frequency of scores ≥ 8 according to the previous Japanese criteria (100% vs. 10%, p < 0.0001). Cronbach alpha was 0.757 and Spearman's rank-order correlation was 0.558 between the new and previous criteria. In conclusion, we proved the effectiveness, reliability, and validity of the Japanese new criteria (final version) to diagnose obstetrical DIC.

Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2.

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons. RNA-seq analysis of co-cultured cells showed that calcitriol increased the expressions of Rspo2, Rapsn, and Dusp6. ChIP-seq of VDR revealed that VDR binds to a region approximately 15 â€‹kbp upstream to Rspo2. Biallelic deletion of the VDR-binding site of Rspo2 by CRISPR/Cas9 in C2C12 myoblasts/myotubes nullified the calcitriol-mediated induction of Rspo2 expression and MuSK phosphorylation. We generated Chrne knockout (Chrne KO) mouse by CRISPR/Cas9. Intraperitoneal administration of calcitriol markedly increased the number of AChR clusters, as well as the area, the intensity, and the number of synaptophysin-positive synaptic vesicles, in Chrne KO mice. In addition, calcitriol ameliorated motor deficits and prolonged survival of Chrne KO mice. In the skeletal muscle, calcitriol increased the gene expressions of Rspo2, Rapsn, and Dusp6. We propose that calcitriol is a potential therapeutic agent for CMS and other diseases with defective neuromuscular signal transmission.

Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation.

Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9, simulating that found in a patient with CMS. As Gfpt1 exon 9 is exclusively expressed in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (1) UDP-HexNAc, CMP-NeuAc and protein O-GlcNAcylation were reduced in skeletal muscles; (2) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (3) markers of the unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of endoplasmic reticulum (ER) stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis.

Observation of interplay between phonon chirality and electronic band topology.

The recently demonstrated chiral modes of lattice motion carry angular momentum and therefore directly couple to magnetic fields. Notably, their magnetic moments are predicted to be strongly influenced by electronic contributions. Here, we have studied the magnetic response of transverse optical phonons in a set of Pb1-xSnxTe films, which is a topological crystalline insulator for x > 0.32 and has a ferroelectric transition at an x-dependent critical temperature. Polarization-dependent terahertz magnetospectroscopy measurements revealed Zeeman splittings and diamagnetic shifts, demonstrating a large phonon magnetic moment. Films in the topological phase exhibited phonon magnetic moment values that were larger than those in the topologically trivial samples by two orders of magnitude. Furthermore, the sign of the effective phonon g-factor was opposite in the two phases, a signature of the topological transition according to our model. These results strongly indicate the existence of interplay between the magnetic properties of chiral phonons and the topology of the electronic band structure.