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The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca 2+ /high Mg 2+ synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100 µM), or a persistent sodium channel blocker, riluzole (20 µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions., Competing Interests: Declarations. Ethical approval: The experimental protocols were approved by the Animal Research Committee of Showa University (approval nos. 03066, 05075, 04057) in accordance with Law No. 105 for the care and use of laboratory animals of the Japanese Government. Human and animal ethics: This study was performed with animal experiments. All efforts were made to minimize the number of animals used and their suffering. Consent for publication: All authors consent to publication of this manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The SPRED family proteins act as negative regulators of the Ras-ERK pathway: the N-terminal EVH1 domain interacts with the Ras-GAP domain (GRD) of the NF1 protein, while the C-terminal Sprouty-related (SPR) domain promotes membrane localization of SPRED, thereby recruiting NF-1 to Ras. Loss-of-function mutations in the hSPRED1 cause Legius syndrome in an autosomal dominant manner. In this study, we investigated the effects of missense mutations in the SPR domain identified in patients with Legius syndrome. Among the 18 mutations we examined, six (C368S, M369L, V408E, P415A, P415L, and P422R) have defects in the palmitoylation of the SPRED1 protein, losing plasma membrane localization and forming cytoplasmic granular aggregates. To evaluate the in vivo effects of SPR mutations, knock-in (KI) mice with P415A and P415V substitutions or M417Afs∗4, a C-terminal 28 amino acid deletion, were generated. All these KI mice exhibited cranial malformations, a characteristic feature of Legius syndrome. However, both P415A and P415V mutants formed granular aggregates, whereas M417Afs∗4 showed a diffuse cytoplasmic distribution, and Spred1 P415A and Spred1 P415V mice, but not Spred1 M417Afs∗4 mice, developed cerebellar ataxia and Purkinje cell loss with age. These data suggest that in addition to loss of palmitoylation, the C-terminal region is required for the granular aggregate formation and Purkinje cell loss. The autophagy inducer spermidine rescued the ataxia phenotypes and Purkinje cell loss in Spred1 P415A mice. These results suggest that some, but not all, SPR mutations that lose lipid modification induce abnormal cytoplasmic aggregation, which could be a target for autophagic clearance, and potentially cause neurodegenerative diseases., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : Caregivers experience high rates of occupational injuries, especially during wheelchair transfers, which often result in back pain and musculoskeletal disorders due to the physical demands of lifting and repositioning. While mechanical floor lifts, the current standard, reduce back strain, they are time-consuming and require handling techniques that subject caregivers to prolonged and repeated non-neutral trunk postures, increasing the risk of long-term back injuries. Aims : The aim was to assess the time efficiency and ergonomics of the powered personal transfer system (PPTS), a robotic transfer device designed for bed-to/from-wheelchair transfers. Methods : We evaluated transfers with the PPTS and mechanical lift with eight able-bodied participants who assisted with transfers between a bed and a wheelchair. Inertial measurement units (IMUs) were placed on participants to track their motion and assess trunk joint angles during transfers. Results : The PPTS significantly reduced the transfer time (144.31 s vs. 525.82 s, p < 0.001) and required significantly less range of motion for trunk flexion ( p < 0.001), lateral bending ( p = 0.008), and axial rotation ( p = 0.001), all of which have been associated with back injuries. Additionally, the PPTS significantly reduced the time caregivers spent in non-neutral trunk postures, potentially lowering injury risks. Conclusions : These findings suggest that the PPTS improves transfer efficiency and caregiver safety, offering a promising alternative to the current standard of care for wheelchair-to/from-bed transfers.

Background: Surgical site infections are common in spinal surgeries. It is uncertain whether outcomes in spine surgery patients with vs. without surgical site infection are equivalent. Therefore, we assessed the effects of surgical site infection on postoperative patient-reported outcomes., Methods: We enrolled patients who underwent elective spine surgery at 12 hospitals between April 2017 and February 2020. We collected data regarding the patients' backgrounds, operative factors, and incidence of surgical site infection. Data for patient-reported outcomes, namely numerical rating scale, Neck Disability Index/Oswestry Disability Index, EuroQol Five-Dimensional questionnaire, and 12-Item Short-Form Health Survey scores, were obtained preoperatively and 1 year postoperatively. We divided the patients into with and without surgical site infection groups. Multivariate logistic regression analyses were performed to identify the risk factors for surgical site infection. Using propensity score matching, we obtained matched surgical site infection-negative and -positive groups. Student's t-test was used for comparisons of continuous variables, and Pearson's chi-square test was used to compare categorical variables between the two matched groups and two unmatched groups., Results: We enrolled 8861 patients in this study; 74 (0.8 %) developed surgical site infections. Cervical spine surgery and American Society of Anesthesiologists physical status classification ≥3 were identified as risk factors; microendoscopy was identified as a protective factor. Using propensity score matching, we compared surgical site infection-positive and -negative groups (74 in each group). No significant difference was found in postoperative pain or dysesthesia of the lower back, buttock, leg, and plantar area between the groups. When comparing preoperative with postoperative pain and dysesthesia, statistically significant improvement was observed for both variables in both groups (p < 0.01 for all variables). No significant differences were observed in postoperative outcomes between the matched surgical site infection-positive and -negative groups., Conclusions: Patients with surgical site infections had comparable postoperative outcomes to those without surgical site infections., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Aging progresses through the interaction of metabolic processes, including changes in the immune and endocrine systems. Glucocorticoids (GCs), which are regulated by the hypothalamic-pituitary-adrenal (HPA) axis, play an important role in regulating metabolism and immune responses. However, the age-related changes in the secretion mechanisms of GCs remain elusive. Here, we found that corticosterone (CORT) secretion follows a circadian rhythm in young mice, whereas it oversecreted throughout the day in aged mice >18 months old, resulting in the disappearance of diurnal variation. Furthermore, senescent cells progressively accumulated in the zF of the adrenal gland as mice aged beyond 18 months. This accumulation was accompanied by an increase in the number of Ad4BP/SF1 (SF1), a key transcription factor, strongly expressing cells (SF1-high positive: HP). Removal of senescent cells with senolytics, dasatinib, and quercetin resulted in the reduction of the number of SF1-HP cells and recovery of CORT diurnal oscillation in 24-month-old mice. Similarly, administration of a neutralizing antibody against IL1β, which was found to be strongly expressed in the adrenocortical cells of the zF, resulted in a marked decrease in SF1-HP cells and restoration of the CORT circadian rhythm. Our findings suggest that the disappearance of CORT diurnal oscillation is a characteristic of aging individuals and is caused by the secretion of IL1β, one of the SASPs, from senescent cells that accumulate in the zF of the adrenal cortex. These findings provide a novel insight into aging. Age-related hypersecretory GCs could be a potential therapeutic target for aging-related diseases., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aim: Exclusion of polycystic ovarian morphology (PCOM) from the diagnostic criteria for adolescent polycystic ovary syndrome (PCOS) has been proposed. We analyzed the profiles of adolescent women with suspected PCOS based on the Japan Society of Obstetrics and Gynecology (JSOG) diagnostic and Rotterdam criteria, excluding those with PCOM., Methods: Thirteen- to twenty-one-year-old women with suspected or confirmed diagnosis of PCOS according to the JSOG and Rotterdam criteria were included in this study. Patient characteristics such as hormone levels and body mass index (BMI) were compared between the groups. Correlations between BMI and testosterone, and BMI and time to diagnosis were also analyzed., Results: Twenty-nine patients were diagnosed with adolescent PCOS according to the JSOG criteria, and 11 patients according to the Rotterdam criteria after excluding the patients fulfilling the PCOM criteria. Serum testosterone levels were significantly higher in adolescents diagnosed with PCOS using the Rotterdam criteria than in those diagnosed using the JSOG criteria (p < 0.001). The obese group had significantly higher testosterone levels and a longer time from menarche to PCOS diagnosis. A positive correlation was observed between BMI and testosterone levels (r = 0.318, p = 0.014)., Conclusion: Although adolescents with PCOS diagnosed using the Rotterdam criteria exhibited higher testosterone levels, which is a typical characteristic of this condition, the JSOG criteria may be useful for the early diagnosis of adolescent PCOS, including suspected cases. The differences between the two criteria may reflect the natural history of PCOS and its different reproductive and metabolic phenotypes., (© 2024 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Introduction: Anti-NMDA receptor encephalitis is an autoimmune disorder caused by autoantibodies (abs) against the conformational epitope on GluN1 subunits. GluN1-abs have been determined with cell-based assay (CBA) co-expressing GluN1/GluN2 subunits. However, commercial fixed CBA expressing only GluN1 subunit has increasingly been used in clinical practice. The ab titers can be determined with serial dilutions, but its clinical significance remains unclear. We aimed to develop an H-intensity scale (HIS) score to estimate GluN1-ab titers in cerebrospinal fluid (CSF) with one-time immunostaining using both commercial CBA and immunohistochemistry and report its usefulness. "H" is the initial of a patient with high CSF GluN1-ab titers (1:2,048)., Methods: We first determined the reliability of CBA in 370 patients with suspected autoimmune encephalitis by comparing the results between commercial CBA and established assay in Dalmau's Lab. Then, we made positive control panels using the patient H's CSF diluted in a fourfold serial dilution method (1:2, 1:8, 1:32, 1:128, 1:512, and 1:2,048). Based on the panels, we scored the intensity of ab reactivity of 79 GluN1-ab-positive patients' CSF (diluted at 1:2) on a scale from 0 to 6 (with ≥1 considered positive). To assess inter-assay reliability, we performed immunostaining twice in 21 patients' CSF. We investigated an association between the score of CSF obtained at diagnosis and the clinical/paraclinical features., Results: The sensitivity and specificity of CBA were 93.7% (95% CI: 86.0-97.3) and 98.6% (95% CI: 96.5-99.5), respectively. Linear regression analysis showed a good agreement between the scores of the first and second assays. Patients with a typical spectrum, need for mechanical ventilation support, autonomic symptoms/central hypoventilation, dyskinesias, speech dysfunction, decreased level of consciousness, preceding headache, ovarian teratoma, and CSF leukocyte count >20 cells/µL had a higher median HIS score than those without, but HIS score was not associated with sex, age at onset, or seizure. HIS score at diagnosis had a significant effect on 1-year functional status., Discussion: The severity of disease and four of the six core symptoms were associated with higher GluN1-ab titers in CSF at diagnosis, which may play a role in poor 1-year functional status. An incomplete phenotype can be attributed to low CSF GluN1-ab titers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Iizuka, Nagata, Kanazawa, Iwami, Nagashima, Nakamura, Kaneko, Kitamura, Nishiyama, Mamorita and Iizuka.)

Introduction: The association between postoperative patient-reported outcomes (PROs) and patient satisfaction remains poorly defined in patients undergoing surgery for thoracic myelopathy. This study aimed to investigate PROs and patient satisfaction following surgical intervention for thoracic myelopathy., Methods: A prospective cohort of 133 patients who underwent surgery for thoracic myelopathy at 13 hospitals between April 2017 and August 2021 was enrolled. Patient demographics and perioperative complications were recorded. PROs were assessed using questionnaires administered preoperatively and 1 year postoperatively, including the EuroQol-5 dimension, physical and mental component summaries of the 12-item Short-Form Health Survey, Oswestry Disability Index, and numerical rating scales for low back, lower extremity, and plantar pain. Patients were categorized into two groups: satisfied (very satisfied, satisfied, and slightly satisfied) and dissatisfied (neither satisfied nor dissatisfied, slightly dissatisfied, dissatisfied, and very dissatisfied)., Results: The mean age of the patients was 66.5 years, comprising 87 men and 46 women. The most common diagnoses were ossification of the ligamentum flavum (48.8%) and thoracic spondylotic myelopathy (26.3%). Seventy-four (55.6%) and 59 (44.3%) patients underwent decompression surgery and underwent decompression with fusion, respectively. Eight patients required reoperation due to postoperative surgical site infection, hematoma, and insufficient decompression in four, three, and one patient. Ninety (67.7%) patients completed both the preoperative and postoperative PRO questionnaires, all of which demonstrated significant improvement. Among them, 58 (64.4%) and 32 (35.6%) reported satisfaction and dissatisfaction with their treatment, respectively. The satisfied group showed superior improvement in PROs than the dissatisfied group, although there were no significant differences in complication rates between the two groups., Conclusions: The 64.4% satisfaction rate observed in patients undergoing surgery for thoracic myelopathy was lower than that reported in previous studies on cervical or lumbar spine surgery. The dissatisfied group exhibited significantly poorer quality of life (QOL) and higher pain scores than the satisfied group., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2024 The Japanese Society for Spine Surgery and Related Research.)

Bacterial meningitis is a life-threatening condition that is mainly caused by Streptococcus pneumoniae and Neisseria meningitis. Although Streptococcus gallolyticus subsp. pasteurianus (Sgp) is also known to cause meningitis, its frequency is quite low, especially in adults. We herein report the first immunocompetent Japanese adult patient (20-year-old woman) with bacterial meningitis caused by Sgp. The patient showed dramatic improvement after antibiotic treatment. Although previous reports have described an association between Sgp infection and an immunosuppressive status, bowel and hepatobiliary diseases, or strongyloidiasis, our case did not demonstrate any of these conditions, suggesting that Sgp can cause meningitis even in young immunocompetent adults.

This study aimed to clarify the differential exercise capacity between 2-month-old and 10-month-old mice using an incremental running test. Metabolic and ventilatory responses and blood lactate concentration were measured to evaluate exercise capacity. We examined whether incremental running test results reflected metabolic and ventilatory responses and blood lactate concentration observed during the steady-state running test. Metabolic response significantly declined with age, whereas ventilatory response was similar between the groups. A low-intensity/moderate exercise load of 10/min in an incremental running test was performed on both mice for 30 min. They showed a characteristic pattern in ventilatory response in 10-month mice. The results of incremental running tests didn't necessarily reflect the steady-state metabolic and ventilatory responses because some parameters showed an approximation and others did not in incremental and steady-state tests, which changed with age. Our study suggests metabolic and ventilatory responses depending on age and provides basic knowledge regarding the objective and quantitative assessment of treadmill running in an animal model., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Inebilizumab, an anti-CD19 B cell-depleting antibody, reduced the risk of a neuromyelitis optica spectrum disorder (NMOSD) attack, disability worsening, magnetic resonance imaging (MRI) lesion activity, and disease-related hospitalizations in participants with NMOSD in the N-MOmentum study (NCT02200770). However, the efficacy and safety outcomes of inebilizumab specific to an Asian population were not fully reported. Therefore, subgroup analyses of the N-MOmentum study were conducted post hoc to evaluate the efficacy and safety of inebilizumab in Asian participants with NMOSD., Methods: The N-MOmentum study was a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial with an open-label extension period (OLP). In the subgroup analyses, data from Asian participants from the N-MOmentum study were compared with those of non-Asian participants. Eligible participants were randomly allocated (3:1) to receive 300 mg intravenous (IV) inebilizumab or placebo on Days 1 and 15. Participants who had an NMOSD attack or completed the randomized controlled period (RCP) could enter the OLP, where they received inebilizumab for ≥2 years. All participants who entered the OLP received inebilizumab 300 mg IV every 6 months., Results: Overall, 230 participants received treatment (174 received inebilizumab and 56 received placebo), of whom 47 were Asian (39 received inebilizumab and 8 received placebo). Baseline characteristics were similar between the Asian and non-Asian subgroups, except for disease duration, annualized relapse rate prior to randomization in this study, and previous maintenance therapy. In the Asian subgroup, the risk of NMOSD attacks was reduced with inebilizumab versus placebo (hazard ratio, 0.202) and the attack-free rate at 28 weeks was 82.1% with inebilizumab versus 37.5% with placebo, in the 6-month RCP. NMOSD attack rates were comparable between the Asian and non-Asian subgroups. In the Asian subgroup, the rates of Expanded Disability Status Scale worsening from baseline, active MRI lesions, and disease-related hospitalizations tended to be lower in the inebilizumab group than in the placebo group; similar results were shown in the non-Asian subgroup. For long-term efficacy and safety (RCP and OLP), the annualized adjudicated NMOSD attack rate in Asian participants treated with inebilizumab was reduced (0.096) compared with that at baseline (1.04), with a mean follow-up period of inebilizumab treatment of 3.38 years, which was consistent with the results in the non-Asian subgroup. The risk of NMOSD attack decreased with prolonged duration of treatment in both the inebilizumab/inebilizumab and placebo/inebilizumab groups in the Asian and non-Asian subgroups. The incidence of treatment-emergent adverse events (TEAEs) was similar between the Asian and non-Asian subgroups. In the Asian and non-Asian subgroups, 15.2% and 35.2% of participants, respectively, had at least one serious TEAE and/or Grade ≥3 TEAE during long-term therapy. No deaths occurred in the Asian subgroup whereas three deaths occurred in the non-Asian subgroup., Conclusion: Inebilizumab reduced the risk of an NMOSD attack, progression of disability, MRI lesion activity, and disease-related hospitalizations in Asian participants with NMOSD. The efficacy of inebilizumab in reducing NMOSD attacks continued without any unexpected safety signals or concerns during long-term use in Asian participants., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Employees of MedImmune and Viela Bio (now Horizon Therapeutics) participated in the design and conduct of the study; and data collection, management, analysis, and interpretation. Kazuo Fujihara has received grants or contracts from the Ministry of Health, Labour and Welfare Japan; consulting fees from Merck Biopharma, Japan Tobacco Inc, and AbbVie; and payment or honoraria for lectures, presentations, manuscript writing, or educational events from Viela Bio/MedImmune, Biogen, Mitsubishi Tanabe Pharma, Novartis Pharma, Chugai Pharmaceutical, Eisai, Asahi Kasei Medical, Merck, and Takeda Pharmaceutical; has participated in a data safety monitoring board or advisory board of VielaBio/Horizon Therapeutics, Mitsubishi Tanabe Pharma, Novartis Pharma, Chugai Pharmaceutical, Alexion Pharmaceuticals, Biogen, and UCB; and has a leadership or fiduciary role in Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS), Japanese Society of Neuroimmunology, Japan Multiple Sclerosis Society, and European Charcot Foundation. Ho Jin Kim has received grants or contracts from the National Research Foundation of Korea, Aprilbio, Eisai, and UCB; consulting fees from Altos Biologics, Biogen, Daewoong Pharmaceutical, Handok, Horizon Therapeutics (formerly Viela Bio), Kaigene, Kolon Life Science, Mdimune, Merck, Roche, Sanofi Genzyme, and UCB; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen, Eisai, GC Pharma, Merck, Mitsubishi Tanabe Pharma, Roche, and Sanofi Genzyme. Takahiko Saida has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen, Eisai, Mitsubishi Tanabe Pharma, and Novartis Pharma. Tatsuro Misu has received grants or contracts from Cosmic Corporation and Medical and Biological Laboratories Co.; and speaker honoraria from Biogen Idec, Mitsubishi Tanabe Pharma, Novartis Pharma, Chugai Pharmaceutical, Alexion Pharmaceuticals, Teijin Pharma., and Viela Bio. Yoshito Nagano, Naoko Totsuka, Masato Iizuka, Shinsuke Kido, Ryuuji Terata, Kyoko Okumura, and Shinya Hirota are employees of Mitsubishi Tanabe Pharma Corporation. Bruce A. C. Cree has received grants or contracts from Genentech; consulting fees from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics, and Therini; has participated in a data safety monitoring board or advisory board of Immunic AG; and has stock options in Autobahn., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To compare the risk of ovarian malignancy algorithm (ROMA) and Copenhagen Index (CPH-I) in their ability to distinguish epithelial ovarian cancer (EOC) and malignant ovarian tumors (MLOT) from benign ovarian tumors (BeOT) in Japanese women., Methods: Patients with pathologically diagnosed ovarian tumors were included in this study. The study validated the diagnostic performance of ROMA and CPH-I., Results: Among the 463 Japanese women included in this study, 312 had BeOT, 99 had EOC, and 52 had other MLOT. The receiver-operator characteristic (ROC) area under the curve (AUCs) of ROMA (0.89) and CPH-I (0.89) for distinguishing EOC from BeOT were significantly higher than that of CA125 (0.82) (CA 125 vs. ROMA; p = 0.002, vs. CPH-I; p < 0.001). The ROC-AUCs of ROMA (0.82) and CPH-I (0.81) for distinguishing MLOT from BeOT were significantly higher than that of CA125 (0.75) (CA 125 vs. ROMA: p = 0.003, vs. CPH-I: p < 0.001). The sensitivity (SN)/specificity (SP) of ROMA and CPH-I for distinguishing EOC from BeOT at standard cut-off points were 69%/90%, and 69%/90%, respectively, those for distinguishing MLOT from BeOT were 54%/90%, and 55%/90%, respectively., Conclusion: ROMA and CPH-I performed comparably well and better than CA125 in distinguishing EOC from BeOT in Japanese women. ROMA and CHP-I should be used with caution in practical situations, where all histological possibilities for must be considered, because the SNs of ROMA and CPH-I were only 54% and 55%., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: The COVID-19 pandemic has transformed healthcare significantly and telepsychiatry is now the primary means of treatment in some countries., Aims: To compare the efficacy of telepsychiatry and face-to-face treatment., Method: A comprehensive meta-analysis comparing telepsychiatry with face-to-face treatment for psychiatric disorders. The primary outcome was the mean change in the standard symptom scale scores used for each psychiatric disorder. Secondary outcomes included all meta-analysable outcomes, such as all-cause discontinuation and safety/tolerability., Results: We identified 32 studies ( n = 3592 participants) across 11 mental illnesses. Disease-specific analyses showed that telepsychiatry was superior to face-to-face treatment regarding symptom improvement for depressive disorders ( k = 6 studies, n = 561; standardised mean difference s.m.d. = -0.325, 95% CI -0.640 to -0.011, P = 0.043), whereas face-to-face treatment was superior to telepsychiatry for eating disorder ( k = 1, n = 128; s.m.d. = 0.368, 95% CI 0.018-0.717, P = 0.039). No significant difference was seen between telepsychiatry and face-to-face treatment when all the studies/diagnoses were combined ( k = 26, n = 2290; P = 0.248). Telepsychiatry had significantly fewer all-cause discontinuations than face-to-face treatment for mild cognitive impairment ( k = 1, n = 61; risk ratio RR = 0.552, 95% CI 0.312-0.975, P = 0.040), whereas the opposite was seen for substance misuse ( k = 1, n = 85; RR = 37.41, 95% CI 2.356-594.1, P = 0.010). No significant difference regarding all-cause discontinuation was seen between telepsychiatry and face-to-face treatment when all the studies/diagnoses were combined ( k = 27, n = 3341; P = 0.564)., Conclusions: Telepsychiatry achieved a symptom improvement effect for various psychiatric disorders similar to that of face-to-face treatment. However, some superiorities/inferiorities were seen across a few specific psychiatric disorders, suggesting that its efficacy may vary according to disease type.

Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic mechanism that maintains chromatin states responsible for suppressing female sexual differentiation remains unclear. Here, we show that Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in postnatal Sertoli cells. We genetically disrupted PRC1 function in embryonic Sertoli cells after sex determination, and we found that PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed specific genes required for granulosa cells, thereby inactivating the female gene regulatory network. Chromatin regions associated with female-specific genes were marked by Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, this study identifies a critical Polycomb-based mechanism that suppresses ovarian differentiation and maintains Sertoli cell fate in adult testes., (© 2023. The Author(s).)

Background: The relationship between intraoperative lactate levels and prognosis after emergency gastrointestinal surgery remains unclear. The purpose of this study was to investigate the prognostic value of intraoperative lactate levels for predicting in-hospital mortality, and to examine intraoperative hemodynamic managements., Methods: We conducted a retrospective observational study of emergency GI surgeries performed at our institution between 2011 and 2020. The study group comprised patients admitted to intensive care units postoperatively, and whose intraoperative and postoperative lactate levels were available. Intraoperative peak lactate levels (intra-LACs) were selected for analysis, and in-hospital mortality was set as the primary outcome. The prognostic value of intra-LAC was assessed using logistic regression and receiver operating characteristic (ROC) curve analysis., Results: Of the 551 patients included in the study, 120 died postoperatively. Intra-LAC in the group who survived and the group that died was 1.80 [interquartile range [IQR], 1.19-3.01] mmol/L and 4.22 [IQR, 2.15-7.13] mmol/L (P < 0.001), respectively. Patients who died had larger volumes of red blood cell (RBC) transfusions and fluid administration, and were administered higher doses of vasoactive drugs. Logistic regression analysis showed that intra-LAC was an independent predictor of postoperative mortality (odds ratio [OR] 1.210, 95% CI 1.070 -1.360, P = 0.002). The volume of RBCs, fluids transfused, and the amount of vasoactive agents administered were not independent predictors. The area under the curve (AUC) of the ROC curve for intra-LAC for in-hospital mortality was 0.762 (95% confidence interval [CI], 0.711-0.812), with a cutoff value of 3.68 mmol/L by Youden index., Conclusions: Intraoperative lactate levels, but not hemodynamic management, were independently associated with increased in-hospital mortality after emergency GI surgery., (© 2023. The Author(s).)

T cells play important roles in autoimmune diseases, but it remains unclear how to optimally manipulate them. We focused on the T cell immunoreceptor with Ig and ITIM domains (TIGIT), a coinhibitory molecule that regulates and is expressed in T cells. In autoimmune diseases, the association between TIGIT-expressing cells and pathogenesis and the function of human-TIGIT (hu-TIGIT) signalling modification have not been fully elucidated. Here we generated anti-hu-TIGIT agonistic monoclonal antibodies (mAbs) and generated hu-TIGIT knock-in mice to accurately evaluate the efficacy of mAb function. Our mAb suppressed the activation of CD4 + T cells, especially follicular helper T and peripheral helper T cells that highly expressed TIGIT, and enhanced the suppressive function of naïve regulatory T cells. These results indicate that our mAb has advantages in restoring the imbalance of T cells that are activated in autoimmune diseases and suggest potential clinical applications for anti-hu-TIGIT agonistic mAbs as therapeutic agents., (© 2023. The Author(s).)

As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.

The Last Interglacial (LIG: 130,000-115,000 years ago) was a period of warmer global mean temperatures and higher and more variable sea levels than the Holocene (11,700-0 years ago). Therefore, a better understanding of Antarctic ice-sheet dynamics during this interval would provide valuable insights for projecting sea-level change in future warming scenarios. Here we present a high-resolution record constraining ice-sheet changes in the Wilkes Subglacial Basin (WSB) of East Antarctica during the LIG, based on analysis of sediment provenance and an ice melt proxy in a marine sediment core retrieved from the Wilkes Land margin. Our sedimentary records, together with existing ice-core records, reveal dynamic fluctuations of the ice sheet in the WSB, with thinning, melting, and potentially retreat leading to ice loss during both early and late stages of the LIG. We suggest that such changes along the East Antarctic Ice Sheet margin may have contributed to fluctuating global sea levels during the LIG., (© 2023. The Author(s).)

17α-ethinylestradiol (EE2), a derivative of 17β-estradiol (E2), is a potent estrogenic substance that is used as the estrogenic component of oral contraceptives (OCPs). However, women who take OCPs have an increased risk of cardiovascular events. Since few studies have examined EE2 endothelial effects, we explored the effects of EE2 on endothelial function in ovariectomized and isoflavone-free rats. After ovariectomy, 12-week-old female Sprague-Dawley rats were assigned to EE2, E2 or control groups. After 16 weeks, the EE2 and E2 groups were orally administered EE2 (8.3 μg/day) and E2 (12.6 μg/day) for 4 weeks, respectively. At 18 weeks, endothelial denudation of the left common carotid arteries was performed, and they were harvested at 20 weeks. The rats in the EE2 and E2 groups exhibited significantly decreased body weights and significantly increased uterine weights, respectively, but no differences were observed between the EE2 and E2 groups. The EE2 and E2 groups showed significantly enhanced acetylcholine-induced endothelium-dependent relaxation, with apamin plus charybdotoxin inhibiting only the EE2 group. Endothelial nitric oxide (NO) synthase expression was significantly higher in the EE2 group than in the control, but lower than in the E2 group. The intima-to-media ratio of denuded arteries was significantly lower in the E2 group than in the other groups, suggesting that NO decreased in the EE2 group compared to the E2 group. We conclude that EE2 has a weaker ability than E2 to produce NO and, for the first time, we demonstrate the ability of EE2 to enhance the activity of endothelial-derived hyperpolarizing factor., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A variety of neuronal surface (NS) antibodies (NS-Ab) have been identified in autoimmune encephalitis (AE). Tissue-based assay (TBA) using a rodent brain immunohistochemistry (IHC) is used to screen NS-Ab, while cell-based assay (CBA) to determine NS antigens. Commercial rat brain IHC is currently available but its clinical relevance remains unclear. Immunostaining patterns of NS antigens have not been extensively studied yet. To address these issues, we assessed a predictive value of "neuropil pattern" and "GFAP pattern" on commercial IHC in 261 patients, and characterized an immunostaining pattern of 7 NS antigens (NMDAR, LGI1, GABAaR, GABAbR, AMPAR, Caspr2, GluK2). Sensitivity and specificity of "neuropil pattern" for predicting NS-Ab were 66.0% (95% CI 55.7-75.3), and 98.2% (95% CI 94.8-99.6), respectively. False-positive rate was 1.8% (3/164) while false-negative rate was 34.0% (33/97). In all 3 false-positive patients, neuropil-like staining was attributed to high titers of GAD65-Ab. In 33 false-negative patients, NMDAR was most frequently identified (n=18 [54.5%], 16/18 [88.9%] had low titers [< 1:32]), followed by GABAaR (n=5). Of 261 patients, 25 (9.6%) had either GFAP (n=21) or GFAP-mimicking pattern (n=4). GFAP-Ab were identified in 21 of 31 patients examined with CBA (20 with GFAP pattern, 1 with GFAP-mimicking pattern). Immunostaining pattern of each NS antigen was as follows: 1) NMDAR revealed homogenous reactivity in the dentate gyrus molecular layer (DG-ML) with less intense dot-like reactivity in the cerebellar granular layer (CB-GL); 2) both GABAaR and GluK2 revealed intense dot-like reactivity in the CB-GL, but GABAaR revealed homogenous reactivity in the DG-ML while GluK2 revealed intense reactivity along the inner layer of the DG-ML; and 3) LGI1, Caspr2, GABAbR, and AMPAR revealed intense reactivity in the cerebellar ML (CB-ML) but LGI1 revealed intense reactivity along the middle layer of the DG-ML. Whereas, Caspr2, GABAbR, and AMPAR revealed similar reactivity in the DG-ML but some difference in other regions. TBA is useful not only for screening NS- or GFAP-Ab but also for estimating NS antigens; however, negative results should be interpreted cautiously because "neuropil pattern" may be missed on commercial IHC when antibody titers are low. Antigen-specific immunoreactivity is a useful biomarker of AE., Competing Interests: KN received research supports from Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., and Eisai Co., Ltd. TI received a research support from Astellas Pharma Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nagata, Kanazawa, Mitsuhata, Iizuka, Nagashima, Nakamura, Kaneko, Kitamura, Nishiyama and Iizuka.)

Seizure-like burst activities are induced by blockade of GABAA and/or glycine receptors in various spinal ventral roots of brainstem-spinal cord preparation from neonatal rodents. We found that this is not applicable to the phrenic nerve and that a new inhibitory descending pathway may suppress seizure-like activity in the phrenic nerve. Experiments were performed in brainstem-spinal cord preparation from newborn rats (age: 0-1 day). Left phrenic nerve and right C4 activities were recorded simultaneously. When GABAA and glycine receptors were blocked by 10 μM bicuculline and 10 μM strychnine (Bic+Str), seizure-like burst activities appeared in the fourth cervical ventral root (C4) but not the phrenic nerve. After making a transverse section at C1, the inspiratory burst activity disappeared from both C4 and the phrenic nerve, whereas seizure-like activity appeared in both nerves. We hypothesized that inhibitory descending pathways other than those via GABAA and/or glycine receptors (from the medulla to the spinal cord) work to avoid disturbance of regular respiratory-related diaphragm contraction by seizure-like activity. We found that cannabinoid receptor antagonist, AM251 was effective for the induction of seizure-like activity by Bic+Str in the phrenic nerve in brainstem-spinal cord preparation. Cannabinoid receptors may be involved in this descending inhibitory system.

Lubricant performance can be improved using additives such as organic friction modifiers (OFMs) and is influenced by their conformation and properties in the space confined between the substrate surfaces, rendering the detailed property analysis of confined OFMs and lubricants a matter of high practical significance. To date, studies on fatty acids as confined OFMs have mainly focused on linear- and unsaturated-chain molecules, leaving branched-chain structures underexplored. To bridge this gap, we used resonance shear measurements in this study to probe the viscosity of two branched-chain C 18 fatty acids (isostearic acid T and isostearic acid) confined between mica surfaces at different applied normal loads ( L ) and surface separation distances ( D ). The viscosity parameter ( b s ) of both acids significantly increased at D < ∼4 nm because of structuring and was lower for isostearic acid than that for isostearic acid T at L > ∼0.6 mN. This reversal of bulk viscosity order under nanoconfinement was ascribed to the ability of the bulky methyl-substituted side chain of isostearic acid to prevent ordering in the nanospace between the mica surfaces and thus preserve fluidlike properties. The obtained results provide fundamental insights into the lubricity of branched-chain fatty acids and are expected to promote the development of novel high-performance OFMs.

Background: Whether lumbar decompression with fusion surgery is effective against Meyerding grade 2 degenerative spondylolisthesis (DS) is unknown. Therefore, the current study aimed to compare the surgical outcomes between posterior decompression alone and posterior decompression with fusion surgery among patients with grade 2 DS with central canal stenosis., Methods: This retrospective cohort study included prospectively registered patients (n = 3863) who underwent surgery for degenerative lumbar spinal canal stenosis at nine high-volume spine centers from April 2017 to July 2019. Patients with grade 2 DS and central canal stenosis were included in the analysis. Patients with radiculopathy, including foraminal stenosis, degenerative scoliosis, and concomitant anterior spinal fusion, and those with a previous history of lumbar surgery were excluded. The participants were divided into the decompression alone group (group D) and decompression with fusion surgery group (group F). Data about patient-reported outcomes, including Numeric Rating Scale (low back pain, leg pain, leg numbness, and foot numbness), Oswestry Disability Index, EuroQol Five-Dimensional questionnaire, and 12-Item Short-Form Health Survey scores, were obtained preoperatively and 2 years postoperatively., Results: In total, 2354 (61%) patients, including 42 (1.8%) with grade 2 DS (n = 18 in group D and n = 24 in group F), completed the 2-year follow-up. Group D had a higher proportion of female patients than group F. However, the two groups did not significantly differ in terms of other baseline demographic characteristics. Group D had a significantly shorter surgical time and lower volume of intraoperative blood loss than group F. Postoperative patient-reported outcomes did not significantly differ between the two groups, although the preoperative degree of low back pain was higher in group F than in group D. The slip degree of group D did not worsen during the follow-up period., Conclusion: The surgical outcomes were similar regardless of the addition of fusion surgery among patients with grade 2 DS. Decompression alone was superior to decompression with fusion surgery as it was associated with a lower volume of intraoperative blood loss and shorter surgical time., (© 2022. The Author(s).)

We previously demonstrated that in an isolated brainstem-spinal cord preparation from neonatal rats, a local bath application of strychnine (a broad antagonist of glycine and GABA A receptors) to the spinal cord enhances thoracic inspiratory motor activity. Herein, to investigate the involvement of the inspiratory spinal interneurons that provide excitatory input to the motoneuron, we conducted calcium imaging using this preparation. Oregon Green 488 BAPTA-1 AM, a fluorescent calcium indicator, was injected into the ventromedial surface of the thoracic cord. In all cells that showed inspiratory-related fluorescence changes > 2% of the baseline fluorescence intensity, the inspiratory-related fluorescence change decreased when the focal depth was deepened. The application of strychnine to the spinal cord increased the inspiratory-related intracellular calcium rise in these cells. These results suggest that the enhancement of inspiratory interneuron activity could be involved in this enhancement of inspiratory motor activity., (© 2022. The Author(s).)

Antarctica is one of the most vulnerable regions to climate change on Earth and studying the past and present responses of this polar marine ecosystem to environmental change is a matter of urgency. Sedimentary ancient DNA (sedaDNA) analysis can provide such insights into past ecosystem-wide changes. Here we present authenticated (through extensive contamination control and sedaDNA damage analysis) metagenomic marine eukaryote sedaDNA from the Scotia Sea region acquired during IODP Expedition 382. We also provide a marine eukaryote sedaDNA record of ~1 Mio. years and diatom and chlorophyte sedaDNA dating back to ~540 ka (using taxonomic marker genes SSU, LSU, psbO). We find evidence of warm phases being associated with high relative diatom abundance, and a marked transition from diatoms comprising <10% of all eukaryotes prior to ~14.5 ka, to ~50% after this time, i.e., following Meltwater Pulse 1A, alongside a composition change from sea-ice to open-ocean species. Our study demonstrates that sedaDNA tools can be expanded to hundreds of thousands of years, opening the pathway to the study of ecosystem-wide marine shifts and paleo-productivity phases throughout multiple glacial-interglacial cycles., (© 2022. The Author(s).)

For the optimal management of refractory ulcerative colitis (UC), secondary loss of response (LOR) and primary non-response to biologics is a critical issue. This article aimed to summarize the current literature on the use of cytapheresis (CAP) in patients with UC showing a poor response or LOR to biologics and discuss its advantages and limitations. Further, we summarized the efficacy of CAP in patients with UC showing insufficient response to thiopurines or immunomodulators (IM). Eight studies evaluated the efficacy of CAP in patients with UC with inadequate responses to thiopurines or IM. There were no significant differences in the rate of remission and steroid-free remission between patients exposed or not exposed to thiopurines or IM. Three studies evaluated the efficacy of CAP in patients with UC showing an insufficient response to biologic therapies. Mean remission rates of biologics exposed or unexposed patients were 29.4 % and 44.2%, respectively. Fourteen studies evaluated the efficacy of CAP in combination with biologics in patients with inflammatory bowel disease showing a poor response or LOR to biologics. The rates of remission/response and steroid-free remission in patients with UC ranged 32%-69% (mean: 48.0%, median: 42.9%) and 9%-75% (mean: 40.7%, median: 38%), respectively. CAP had the same effectiveness for remission induction with or without prior failure on thiopurines or IM but showed little benefit in patients with UC refractory to biologics. Although heterogeneity existed in the efficacy of the combination therapy with CAP and biologics, these combination therapies induced clinical remission/response and steroid-free remission in more than 40% of patients with UC refractory to biologics on average. Given the excellent safety profile of CAP, this combination therapy can be an alternative therapeutic strategy for UC refractory to biologics. Extensive prospective studies are needed to understand the efficacy of combination therapy with CAP and biologics., Competing Interests: Conflict-of-interest statement: There is no conflicts of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Ice loss in the Southern Hemisphere has been greatest over the past 30 years in West Antarctica. The high sensitivity of this region to climate change has motivated geologists to examine marine sedimentary records for evidence of past episodes of West Antarctic Ice Sheet (WAIS) instability. Sediments accumulating in the Scotia Sea are useful to examine for this purpose because they receive iceberg-rafted debris (IBRD) sourced from the Pacific- and Atlantic-facing sectors of West Antarctica. Here we report on the sedimentology and provenance of the oldest of three cm-scale coarse-grained layers recovered from this sea at International Ocean Discovery Program Site U1538. These layers are preserved in opal-rich sediments deposited ∼1.2 Ma during a relatively warm regional climate. Our microCT-based analysis of the layer's in-situ fabric confirms its ice-rafted origin. We further infer that it is the product of an intense but short-lived episode of IBRD deposition. Based on the petrography of its sand fraction and the Phanerozoic 40 Ar/ 39 Ar ages of hornblende and mica it contains, we conclude that the IBRD it contains was likely sourced from the Weddell Sea and/or Amundsen Sea embayment(s) of West Antarctica. We attribute the high concentrations of IBRD in these layers to "dirty" icebergs calved from the WAIS following its retreat inland from its modern grounding line. These layers also sit at the top of a ∼366-m thick Pliocene and early Pleistocene sequence that is much more dropstone-rich than its overlying sediments. We speculate this fact may reflect that WAIS mass-balance was highly dynamic during the ∼41-kyr (inter)glacial world., (© 2022. The Authors.)

Long noncoding RNAs (lncRNAs) are important tissue-specific regulators of gene expression, and their dysregulation can induce aberrant gene expression leading to various pathological conditions, including cancer. Although many lncRNAs have been discovered by computational analysis, most of these are as yet unannotated. Herein, we describe the nature and function of a novel lncRNA detected downstream of the human parathyroid hormone (PTH) gene in both extremely rare ectopic PTH-producing retroperitoneal malignant fibrous histiocytoma and parathyroid tumors with PTH overproduction. This novel lncRNA, which we have named "PTH-AS," has never been registered in a public database, and here, we investigated for the first time its exact locus, length, transcription direction, polyadenylation, and nuclear localization. Microarray and Gene Ontology analyses demonstrated that forced expression of PTH-AS in PTH-nonexpressing human breast cancer T47D cells did not induce the ectopic expression of the nearby PTH gene but did significantly upregulate Janus kinase-signal transducer and activator of transcription pathway-related genes such as cancer-promoting interferon-related DNA damage resistance signature (IRDS) genes. Importantly, we show that PTH-AS expression not only enhanced T47D cell invasion and resistance to the DNA-damaging drug doxorubicin but also promoted lung metastasis rather than tumor growth in a mouse xenograft model. In addition, PTH-AS-expressing T47D tumors showed increased macrophage infiltration that promoted angiogenesis, similar to IRDS-associated cancer characteristics. Although the detailed molecular mechanism remains imperfectly understood, we conclude that PTH-AS may contribute to tumor development, possibly through IRDS gene upregulation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The Enhanced Permeability and Retention (EPR) effect is a golden strategy for the nanoparticle (NP)-based targeting of solid tumors, and the surface property of NPs might be a determinant on their targeting efficiency. Poly(ethylene glycol) (PEG) is commonly used as a shell material; however, it has been pointed out that PEG-coated NPs may exhibit accumulation near tumor vasculature rather than having homogenous intratumor distribution. The PEG shell plays a pivotal role on prolonged blood circulation of NPs but potentially impairs the intratumor retention of NPs. In this study, we report on a shell material to enhance tumor-targeted delivery of NPs by maximizing the EPR effect: polyzwitterion based on ethylenediamine-based carboxybetaine [PGlu(DET-Car)], which shows the changeable net charge responding to surrounding pH. The net charge of PGlu(DET-Car), is neutral at physiological pH 7.4, allowing it to exhibit a stealth property during the blood circulation; however, it becomes cationic for tissue-interactive performance under tumorous acidic conditions owing to the stepwise protonation behavior of ethylenediamine. Indeed, the PGlu(DET-Car)-coated NPs (i.e., gold NPs in the present study) exhibited prolonged blood circulation and remarkably enhanced tumor accumulation and retention than PEG-coated NPs, achieving 32.1% of injected dose/g of tissue, which was 4.2 times larger relative to PEG-coated NPs. Interestingly, a considerable portion of PGlu(DET-Car)-coated NPs clearly penetrated into deeper tumor sites and realized the effective accumulation in hypoxic regions, probably because the cationic net charge of PGlu(DET-Car) is augmented in more acidic hypoxic regions. This study suggests that the changeable net charge on the NP surface in response to tumorous acidic conditions is a promising strategy for tumor-targeted delivery based on the EPR effect., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The Southern Ocean paleoceanography provides key insights into how iron fertilization and oceanic productivity developed through Pleistocene ice-ages and their role in influencing the carbon cycle. We report a high-resolution record of dust deposition and ocean productivity for the Antarctic Zone, close to the main dust source, Patagonia. Our deep-ocean records cover the last 1.5 Ma, thus doubling that from Antarctic ice-cores. We find a 5 to 15-fold increase in dust deposition during glacials and a 2 to 5-fold increase in biogenic silica deposition, reflecting higher ocean productivity during interglacials. This antiphasing persisted throughout the last 25 glacial cycles. Dust deposition became more pronounced across the Mid-Pleistocene Transition (MPT) in the Southern Hemisphere, with an abrupt shift suggesting more severe glaciations since ~0.9 Ma. Productivity was intermediate pre-MPT, lowest during the MPT and highest since 0.4 Ma. Generally, glacials experienced extended sea-ice cover, reduced bottom-water export and Weddell Gyre dynamics, which helped lower atmospheric CO 2 levels., (© 2022. The Author(s).)