Lipids Extracted from Mycobacterial Membrane and Enveloped PLGA Nanoparticles for Encapsulating Antibacterial Drugs Elicit Synergistic Antimicrobial Response against Mycobacteria.

Tuberculosis (TB) is a chronic disease caused byMycobacterium tuberculosis (Mtb), which shows a long treatment cycle often leads to drug resistance, making treatment more difficult. Immunogens present in the pathogen's cell membrane can stimulate endogenous immune responses. Therefore, an effective lipid-based vaccine or drug delivery vehicle formulated from the pathogen's cell membrane can improve treatment outcomes. Herein, we extracted and characterized lipids fromMycobacterium smegmatis, and the extracts contained lipids belonging to numerous lipid classes and compounds typically found associated with mycobacteria. The extracted lipids were used to formulate biomimetic lipid reconstituted nanoparticles (LrNs) and LrNs-coated poly(lactic-co-glycolic acid) nanoparticles (PLGA-LrNs). Physiochemical characterization and results of morphology suggested that PLGA-LrNs exhibited enhanced stability compared with LrNs. And both of these two types of nanoparticles inhibited the growth of M. smegmatis. After loading different drugs, PLGA-LrNs containing berberine or coptisine strongly and synergistically prevented the growth of M. smegmatis. Altogether, the bacterial membrane lipids we extracted with antibacterial activity can be used as nanocarrier coating for synergistic antibacterial treatment of M. smegmatis─an alternative model of Mtb, which is expected as a novel therapeutic system for TB treatment.

RPEM: Randomized Monte Carlo parametric expectation maximization algorithm.

Inspired from quantum Monte Carlo, by sampling discrete and continuous variables at the same time using the Metropolis-Hastings algorithm, we present a novel, fast, and accurate high performance Monte Carlo Parametric Expectation Maximization (MCPEM) algorithm. We named it Randomized Parametric Expectation Maximization (RPEM). We compared RPEM with NONMEM's Importance Sampling Method (IMP), Monolix's Stochastic Approximation Expectation Maximization (SAEM), and Certara's Quasi-Random Parametric Expectation Maximization (QRPEM) for a realistic two-compartment voriconazole model with ordinary differential equations using simulated data. We show that RPEM is as fast and as accurate as the algorithms IMP, QRPEM, and SAEM for the voriconazole model in reconstructing the population parameters, for the normal and log-normal cases.

Pterostilbene Protects against Osteoarthritis through NLRP3 Inflammasome Inactivation and Improves Gut Microbiota as Evidenced by In Vivo and In Vitro Studies.

Osteoarthritis (OA) is a persistent inflammatory disease, and long-term clinical treatment often leads to side effects. In this study, we evaluated pterostilbene (PT), a natural anti-inflammatory substance, for its protective effects and safety during prolonged use on OA. Results showed that PT alleviated the loss of chondrocytes and widened the narrow joint space in an octacalcium phosphate (OCP)-induced OA mouse model (n = 3). In vitro experiments demonstrate that PT reduced NLRP3 inflammation activation (relative protein expression: C: 1 ± 0.09, lipopolysaccharide (LPS): 1.14 ± 0.07, PT: 0.91 ± 0.07, LPS + PT: 0.68 ± 0.04) and the release of inflammatory cytokines through NF-κB signaling inactivation (relative protein expression: C: 1 ± 0.03, LPS: 3.49 ± 0.02, PT: 0.66 ± 0.08, LPS + PT: 2.78 ± 0.05), ultimately preventing cartilage catabolism. Interestingly, PT also altered gut microbiota by reducing inflammation-associated flora and increasing the abundance of healthy bacteria in OA groups. Collectively, these results suggest that the PT can be considered as a protective strategy for OA.

Adipose-derived stem cell modulate tolerogenic dendritic cell-induced T cell regulation is correlated with activation of Notch-NFκB signaling.

BACKGROUND: Adipose-derived stem cells (ASCs) are recognized for their potential immunomodulatory properties. In the immune system, tolerogenic dendritic cells (DCs), characterized by an immature phenotype, play a crucial role in inducing regulatory T cells (Tregs) and promoting immune tolerance. Notch1 signaling has been identified as a key regulator in the development and function of DCs. However, the precise involvement of Notch1 pathway in ASC-mediated modulation of tolerogenic DCs and its impact on immune modulation remain to be fully elucidated. This study aims to investigate the interplay between ASCs and DCs, focusing the role of Notch1 signaling and downstream pathways in ASC-modulated tolerogenic DCs. METHODS: Rat bone marrow-derived myeloid DCs were directly co-cultured with ASCs to generate ASC-treated DCs (ASC-DCs). Notch signaling was inhibited using DAPT, while NFκB pathways were inhibited by NEMO binding domain peptide and si-NIK. Flow cytometry assessed DC phenotypes. Real-time quantitative PCR, Western blotting and immunofluorescence determined the expression of Notch1, Jagged1 and the p52/RelB complex in ASC- DCs. RESULTS: Notch1 and Jagged1 were highly expressed on both DCs and ASCs. ASC-DCs displayed significantly reduced levels of CD80, CD86 and MHC II compared to mature DCs. Inhibiting the Notch pathway with DAPT reversed the dedifferentiation effects. The percentage of induced CD25+/FOXP3+/CD4+ Tregs decreased when ASC-DCs were treated with DAPT (inhibition of the Notch pathway) and si-NIK (inhibition of the non-canonical NFκB pathway). CONCLUSIONS: ASCs induce DC tolerogenicity by inhibiting maturation and promoting downstream Treg generation, involving the Notch and NFκB pathways. ASC-induced tolerogenic DCs can be a potential immunomodulatory tool for clinical application.

Enhanced ammonia oxidation by a photoelectrocatalysis­chlorine system: The role of ClO• and free chlorine.

The decomposition of ammonia-N to environmental-friendly N2 remains a fundamental problem for water treatment. We proposed a way to selectively and efficiently oxidize ammonia to N2 through an integrated photoeletrocatalysis­chlorine reactions (PECCl) system based on a bifunctional TiO2 nanotube photoanode. The ·OH and HClO can be simultaneously generated on the TiO2 nanotube photoanode in this system, which can in situ form ClO· for efficient ammonia removal. Compared with electrochemical­chlorine (EC-Cl), photocatalysis­chlorine (PC-Cl) and photoelectrocatalysis (PEC) systems, the PEC-Cl system exhibited much higher electrocatalytic activity due to the synergetic effect of photoelectrocatalyst and electrocatalyst in bifunctional TiO2 nanotube electrode. The removal efficiency of ammonia-N and total-N reached 100.0 % and 93.3 % at 0.3 V (vs Ag/AgCl) in the PEC-Cl system. Moreover, the system was efficient under various pH conditions. The reactions between ClO-/ClO· and the N-containing intermediates contributed to the high performance of the system, which expanded the reactions from the electrode surface to the electrolyte. Furthermore, radical scavenging and free chlorine determination experiments confirmed that ClO· and free chlorine were the main active species that enabled the ammonia oxidation. This study presents new understanding on the role of active species for ammonia removal in wastewater.

Prediction model and its application of helium extraction OPEX based on response surface methodology.

Focusing on the situation of the low helium content in natural gas resource in China and the high cost of helium extraction, the OPEX prediction model of helium extraction that based on the Response Surface Methodology (RSM) is proposed. This method applies ASPEN-HYSYS software to simulate the helium extraction process flow for a given product composition, pressure, and temperature; Applying the Design Expert module for Response Surface Methodology(RSM) parameter design, combined with OPEX of existing projects, determine the key influencing factors and upper and lower limits of OPEX, and obtaining the corresponding OPEX for different parameter values; Applying the Box Behnken Design (BBD) principle to optimize the helium extraction process parameters of RSM, based on fitting results and parameter significance verification of second-order regression function, the OPEX prediction model is built.This method is applied to a domestic helium extraction project, and the unit helium extraction cost is between 100 and 119.52 yuan/m3, IRR is 13.37%. The result shows the project has economic benefit, and the method presents a good perspective application.

Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels.

Taxol (paclitaxel) is the first approved microtubule-stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first-line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer-associated missence mutations in ß-tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol-resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol-resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug-susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6-fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 µM.

Metal organic frameworks as polysulfide reaction modulators for lithium sulfur batteries: advances and perspectives.

Currently, lithium sulfur (Li-S) battery with high theoretical energy density has attracted great research interest. However, the diffusion and loss process of intermediate lithium polysulfide during charge-discharge hindered the application of the Li-S batteryin modern life. To overcome this issue, metal organic frameworks (MOFs) and their composites have been regarded as effective additions to restrain the LiPS diffusion process for Li-S battery. Benefiting from the unique structure with rich active sites to adsorb LiPS and accelerate the LiPS redox, the Li-S batteries with MOFs modified exhibit superior electrochemical performance. Considering the rapid development of MOFs in Li-S battery, this review summarizes the recent researches of MOFs and their composites as the sulfur host materials, functional interlayer, separator coating layer, and separator/solid electrolyte for Li-S batteries in detail. In addition, the promising design strategies of functional MOF materials are proposed to improve the electrochemical performance of Li-S battery.

A bionic self-driven retinomorphic eye with ionogel photosynaptic retina.

Bioinspired bionic eyes should be self-driving, repairable and conformal to arbitrary geometries. Such eye would enable wide-field detection and efficient visual signal processing without requiring external energy, along with retinal transplantation by replacing dysfunctional photoreceptors with healthy ones for vision restoration. A variety of artificial eyes have been constructed with hemispherical silicon, perovskite and heterostructure photoreceptors, but creating zero-powered retinomorphic system with transplantable conformal features remains elusive. By combining neuromorphic principle with retinal and ionoelastomer engineering, we demonstrate a self-driven hemispherical retinomorphic eye with elastomeric retina made of ionogel heterojunction as photoreceptors. The receptor driven by photothermoelectric effect shows photoperception with broadband light detection (365 to 970 nm), wide field-of-view (180°) and photosynaptic (paired-pulse facilitation index, 153%) behaviors for biosimilar visual learning. The retinal photoreceptors are transplantable and conformal to any complex surface, enabling visual restoration for dynamic optical imaging and motion tracking.

Correction: Lonicera japonica Thunb. as a promising antibacterial agent for Bacillus cereus ATCC14579 based on network pharmacology, metabolomics, and in vitro experiments.

[This corrects the article DOI: 10.1039/D3RA00802A.].

Initial Oxidation Behavior of AlCoCrFeNi High-Entropy Coating Produced by Atmospheric Plasma Spraying in the Range of 650 °C to 1000 °C.

As protective coatings for the thermal parts of aero-engines, AlCoCrFeNi coatings have good application prospects. In this study, atmospheric plasma spraying (APS) was used to prepare AlCoCrFeNi high-entropy coatings (HECs), which were oxidized from 650 °C to 1000 °C. The mechanism of the oxide layer formation and the internal phase transition were systematically investigated. The results show that a mixed oxide scale with a laminated structure was formed at the initial stage of oxidation. The redistribution of elements and phase transition occurred in the HECs' matrix; the BCC/B2 structure transformed to Al-Ni ordered B2 phase and Fe-Cr disordered A2 phase.

Novel targets and their functions in the prognosis of uterine corpus endometrial cancer patients.

Aberrant mRNA expression is implicated in uterine corpus endometrial carcinoma (UCEC) oncogenesis and progression. However, effective prognostic biomarkers for UCEC remain limited. We aimed to construct a reliable multi-gene risk model using gene expression profiles. Utilizing TCGA data (543 UCEC samples, 35 controls), we identified 1517 differentially acting genes. Weighted gene co-expression complex analysis (WGCCA), hub gene screening, and risk regression analysis (RRA) were employed to determine prognosis-related genes and construct the risk model. Nomograms visualized risk scores and receiver operator characteristic (ROC) curves assessed model performance. Seven novel prognosis-related hub genes (ANGPT1, ASB2, GAL, GDF7, ONECUT2, SV2B, TRPC6) were identified. The model's concordance index (C index) by multivariate Cox regression analysis was 0.79. ROC curves yielded AUCs of 0.811 (3-year) and 0.79 (5-year), demonstrating the model's efficacy in predicting UCEC survival. Our study proposes a promising seven-biomarker risk model for predicting UCEC prognosis, offering potential clinical utility.

Effects of ambient temperature on growth performance, slaughter traits, meat quality and serum antioxidant function in Pekin duck.

The present study investigated the effects of temperature on growth performance, slaughtering traits, meat quality and antioxidant function of Pekin ducks from 21-42 d of age. Single factor analysis of variance was used in this experiment, 144 21 d-old Pekin ducks were randomly allotted to 4 environmentally controlled chambers: T20 (20°C), T23 (23°C), T26 (26°C) and T29 (29°C), with 3 replicates in each group (12 ducks in each replicate), the relative humidity of all groups is 74%. During the 21-day trial period, feed and water were freely available. At 42 d, the BW (body weight) and ADG (average daily gain) of T26 were significantly lower than T20 (p < 0.05), and the T29 was significantly lower than T20 and T23 (p < 0.05). The ADFI (average daily feed intake) of T26 and T29 were significantly lower than T20 and T23 (p < 0.05). Compared to the T29, the T20 showed a significant increase oblique body length and chest width, and both the keel length and thigh muscle weight significantly increased in both the T20 and T23, while the pectoral muscle weight increased significantly in other groups (p < 0.05). The cooking loss of the T29 was the lowest (p < 0.05). The T-AOC (total antioxidant capacity) of T29 was significantly higher than the other groups (p < 0.05), the SOD (superoxide dismutase) in the T29 was significantly higher than the T23 and T26 (p < 0.05). In conditions of 74% relative humidity, the BW and ADFI of Pekin ducks significantly decrease when the environmental temperature exceeds 26°C, and the development of body size and muscle weight follows this pattern. The growth development and serum redox state of Pekin ducks are more ideal and stable at temperatures of 20°C and 23°C.

A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer.

BACKGROUND: Although there is evidence that ribonucleotide reductase subunit M2 (RRM2) is associated with numerous cancers, pan-cancer analysis has seldom been conducted. This study aimed to explore the potential carcinogenesis of RRM2 in pan-cancer using datasets from The Cancer Genome Atlas (TCGA). METHODS: Data from the UCSC Xena database were analyzed to investigate the differential expression of RRM2 across multiple cancer types. Clinical data such as age, race, sex, tumor stage, and status were acquired to analyze the influence of RRM2 on the clinical characteristics of the patients. The role of RRM2 in the onset and progression of multiple cancers has been examined in terms of genetic changes at the molecular level, including tumor mutational burden (TMB), microsatellite instability (MSI), biological pathway changes, and the immune microenvironment. RESULTS: RRM2 was highly expressed in most cancers, and there was an obvious correlation between RRM2 expression and patient prognosis. RRM2 expression is associated with the infiltration of diverse immune and endothelial cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). Moreover, the cell cycle is involved in the functional mechanisms of RRM2. CONCLUSIONS: Our pan-cancer study provides a comprehensive understanding of the carcinogenesis of RRM2 in various tumors.

A new substrate equalization method for optimizing the influent conditions and fluid flow patterns of a multifed upflow anaerobic sludge blanket reactor with mature anammox granules.

To improve nitrogen removal efficiency (NRE) and achieve homogenous distribution of anammox sludge and substrate, a new substrate equalization theory and a cumulative overload index was proposed for multifed upflow anaerobic sludge bed (MUASB) reactors with mature anammox granules. The performance and flow patterns of MUASB reactors were investigated under various influent conditions. The results showed that the nitrogen removal performance and stability of MUASB reactors could be optimized by minimizing the cumulative load. The NRE gradually increased from 83.3 ± 2.2 %, 86.8 ± 4.2 % to 89.3 ± 4.1 % and 89.7 ± 1.6 % in feeding flow tests and feeding port tests, respectively. Furthermore, the flow patterns were compared based on residence time distribution and computational fluid dynamics, indicating that a better equilibrium distribution of microorganisms and substrates could be achieved in the MUASB reactors under the lowest cumulative load. Therefore, substrate equalization theory can be used to optimize the nitrogen removal performance of MUASB reactors with low-carbon footprints.

Salidroside promotes angiogenesis after cerebral ischemia in mice through Shh signaling pathway.

AIMS: The purpose of this study was to explore the impacts of salidroside on vascular regeneration, vascular structural changes and long-term neurological recuperation following cerebral ischemia and its possible mechanism. MAIN METHODS: From Day 1 to Day 28, young male mice with middle cerebral artery blockage received daily doses of salidroside and measured neurological deficits. On the 7th day after stroke, the volume of cerebral infarction was determined using TTC and HE staining. Microvascular density, astrocyte coverage, angiogenesis and the expression of the Shh signaling pathway were detected by IF, qRTPCR and WB at 7, 14 and 28 days after stroke. Changes in blood flow, blood vessel density and diameter from stroke to 28 days were measured by the LSCI and TPMI. KEY FINDINGS: Compared with the dMACO group, the salidroside treatment group significantly promoted the recovery of neurological function. Salidroside was found to enhance cerebral blood flow perfusion and reduce the infarct on the 7th day after stroke. From the 7th to the 28th day after stroke, salidroside treatment boosted the expression of CD31, CD31+/BrdU+, and GFAP in the cortex around the infarction site. On the 14th day after stroke, salidroside significantly enhanced the width and density of blood vessels. Salidroside increased the expression of histones and genes in the Shh signaling pathway during treatment, and this effect was weakened by the Shh inhibitor Cyclopamine. SIGNIFICANCE: Salidroside can restore nerve function, improve cerebral blood flow, reduce cerebral infarction volume, increase microvessel density and promote angiogenesis via the Shh signaling pathway.

Removal of RNA viruses from swine wastewater using anaerobic membrane bioreactor: Performance and mechanisms.

The effective removal of viruses from swine wastewater using anaerobic membrane bioreactor (AnMBR) is vital to ecological safety. However, most studies have focused only on disinfectants, whereas the capabilities of the treatment process have not been investigated. In this study, the performance and mechanism of an AnMBR in the removal of porcine hepatitis E virus (HEV), porcine kobuvirus (PKoV), porcine epidemic diarrhea virus (PEDV), and transmissible gastroenteritis coronavirus (TGEV) are systematically investigated. The results show that the AnMBR effectively removes the four viruses, with average removal efficiencies of 1.62, 3.05, 2.41, and 1.34 log for HEV, PKoV, PEDV and TGEV, respectively. Biomass adsorption contributes primarily to the total virus removal in the initial stage of reactor operation, with contributions to HEV and PKoV removal exceeding 71.7 % and 68.2 %, respectively. When the membrane is fouled, membrane rejection dominated virus removal. The membrane rejection contribution test shows the significant contribution of membrane pore foulants (23-76 %). Correlation analysis shows that the surface characteristics and size differences of the four viruses contribute primarily to their different effects on biomass adsorption and membrane rejection. This study provides technical guidance for viral removal during the treatment of high-concentration swine wastewater using an AnMBR.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma: A case report.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited effective treatment especially after first-line chemotherapy. The human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC) positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC. CASE SUMMARY: We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn't have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment. A novel combination therapy PRaG 3.0 of RC48 (HER2-antibody-drug conjugate), radiotherapy, PD-1 inhibitor, granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month. She had not developed any grade 2 or above treatment-related adverse events at any point. Percentage of peripheral CD8+Temra and CD4+Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy. CONCLUSION: PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Promoting good mental health over the menopause transition.

The potential risk for mental health conditions over the menopause transition shapes women's expectations and informs putative physiological mechanisms regulating women's mental health. We review evidence from prospective studies reporting on associations between mental health conditions and the menopause transition. Major depressive disorder and the more prevalent subthreshold depressive symptoms are the most common conditions studied. We reviewed 12 prospective studies reporting depressive symptoms, major depressive disorder, or both over the menopause transition and found no compelling evidence for a universal increased risk for either condition. However, specific subgroups of participants, primarily defined by menopause-related risk factors (ie, vasomotor symptoms that are severe or disturb sleep, a long duration of the transition, or reproductive hormone dynamics) and psychosocial risk factors (eg, stressful life events), were vulnerable to depressive symptoms. The increased risk of major depressive disorder over the menopause transition appears predominantly in individuals with previous major depressive disorder. Greater focus on recognising risk factors in primary care is warranted. On the basis of scarce data, we found no compelling evidence that risk of anxiety, bipolar disorder, or psychosis is universally elevated over the menopause transition. Potential misattribution of psychological distress and psychiatric disorders to menopause could harm women by delaying accurate diagnosis and the initiation of effective psychotropic treatments, and by creating negative expectations for people approaching menopause. A paradigm shift is needed. We conclude with recommendations for the detection and treatment of depressive symptoms or major depressive disorder and strategies to promote good mental health over the menopause transition, while responsibly preparing and supporting those at risk.