The ordered lattice host framework induced guest Li+ disordering in high performance cobalt-free Ni-rich cathode materials.

Recently, due to high price, resource shortage and unstable supply of cobalt, the development of low-cost cobalt-free Ni-rich cathodes has attracted extensive attention with the ever-increasing lithium-ion batteries (LIBs) industry. Selecting cost-effective elements to replace cobalt in Ni-rich cathodes is urgent. However, the principle of structural design of Ni-rich cathode remains unclear, hampering the selection of alternative elements. Herein, the cobalt-free cathodes of LiNi0.95Mg0.05O2 (NiMg) and LiNi0.95Mn0.05O2 (NiMn) are designed as alternatives to LiNi0.96Co0.04O2 (NiCo). NiMg has comparable cycle stability with NiCo, while NiMn has inferior cycle performance. Reverse Monte Carlo modelling was used to generate structural model and uncover local structure by fitting pair distribution function. It reveals Mn causes more severe Jahn-Teller distortions and disordered lattice host framework (Ni0.95M0.05O2, M = Co/Mn/Mg) than Co and Mg due to the strong size effect and coulomb interactions of Mn in Ni0.95Mn0.05O2 layer. The outstanding cycle stability of NiMg and NiCo originates from the ordered lattice host frameworks, which relieve stress and inhibit particle breakage during cycle. Meanwhile, the ordered lattice host framework induced guest Li+ disordering reduces Li+ diffusion energy barrier, improving the rate capability. This study provides a new perspective for the structural design of cobalt-free Ni-rich cathodes.

Determinants of respectful maternity care among women who gave childbirth in Southern Ethiopia.

BACKGROUND: Having a good provision of respectful maternity care (RMC) to a woman who gives childbirth is a crucial component of maternal health care to result in positive maternal and neonatal outcomes. Disrespect and lack of women-centered care in birth discourage a woman from seeking healthcare during childbirth contributing to poor healthcare-seeking behaviour and dissatisfaction with the maternity service. The current study aimed to assess key determinants of RMC during childbirth at selected public health facilities of the Gofa zone, Southern Ethiopia. METHODS: A cross-sectional study design was conducted from March to April 2021 among 390 women who gave birth in eight randomly selected public health facilities of Gofa zone, Southern Ethiopia. The level of RMC was measured using structured exit interview items. A structured-interviewer-administered questionnaire was used to collect data and then entered into Epi-data version 4.6 and exported to SPSS version 25 for further analysis. Bivariate and multivariate logistic regression analyses were used to identify determinants of RMC among women. RESULTS: A total of 390 women responded to the exit interview making a response rate of 100%. The mean (± SD) age of the 390 women was 27.9 (± 4.85) years. The overall prevalence of women who received RMC was 40.5%, 95% CI (36-45%). Two hundred and ninety-seven (76.2%; n = 297/390) women had antenatal care (ANC) attendance in the index pregnancy. A woman who had planned pregnancy (AOR = 1.72, CI: 1.04, 2.85), planned to deliver in a health facility (AOR = 1.68, CI: 1.00, 2.81), presence of familial support (AOR = 2.04, CI: 1.20, 3.48), and had information about service availability (AOR = 4.44, CI: 2.09, 9.42) were associated with RMC among women. CONCLUSION: The provision of respectful maternity care in the study area was low when compared with local studies. Planned pregnancy, plan to deliver in a health facility, family support, and presence of information about service availability were factors associated with RMC among women. More attention should be given to training and supportive supervision of health care professionals on respectful maternity care and its standards to increase service uptake and make service more women-centred.

FTY720 Suppresses Pathogenic Retinal Müller Cell Activation and Chronic Progression by Inhibiting the mTOR/NF-κB Signaling Pathway and Regulating Autophagy.

PURPOSE: FTY720 is an agonist of the Sphingosine-1-phosphate (S1P) receptor 1, 3, 4, and 5 and a functional antagonist of the S1P1 receptor; it can inhibit the activation of mTOR/NF-κB and has therapeutic potential in inflammatory disease. This study was designed to determine the role of the inflammatory process in diabetic retinopathy and investigate the effect of FTY720 on high glucose (HG)-induced rat retinal Müller cells (rMC-1 cells). METHODS: In the present study, the role of FTY720 in inhibiting inflammation and its underlying mechanism were investigated. rMC-1 cells were treated without or with HG, FTY720, CQ, or RAP. Cell viability was examined by CCK-8 assay; cell activation was assessed by western blot analysis and IF staining; and cell migration was evaluated by a scratch wound healing assay. The expression of inflammation-associated proteins and autophagy-related proteins was evaluated by transmission electron microscopy, AO staining, MDC-labeled autophagic vacuoles, western blot analysis and ELISA. RESULTS: Western blot analysis and IF staining showed that the level of the rMC-1 cell marker GFAP was decreased, while GS was increased in FTY720 groups compared to that in the HG group. The healing assay results showed that compared with HG treatment, FTY720 treatment significantly reduced cell migration. Western blot analysis, ELISA and IF staining showed that compared with HG, FTY720 reduced proinflammatory proteins by inhibiting the mechanistic target of the mTOR/NF-κB signaling pathway and regulating autophagy. CONCLUSIONS: This study suggests that in an HG-induced rMC-1 cell model, FTY720 significantly inhibited the production of inflammatory cytokines by inhibiting mTOR/NF-κB signaling and regulating autophagy. These findings were associated with a decrease in rMC-1 cell injury, suggesting that FTY720 or related compounds may be valuable modulators of HG-induced retinal injury.

Preclinical evaluation of the third-generation, bi-steric mechanistic target of rapamycin complex 1-selective inhibitor RMC-6272 in NF2-deficient models.

Background: NF2-associated meningiomas are progressive, highly morbid, and nonresponsive to chemotherapies, highlighting the need for improved treatments. We have established aberrant activation of the mechanistic target of rapamycin (mTOR) signaling in NF2-deficient tumors, leading to clinical trials with first- and second-generation mTOR inhibitors. However, results have been mixed, showing stabilized tumor growth without shrinkage offset by adverse side effects. To address these limitations, here we explored the potential of third-generation, bi-steric mTOR complex 1 (mTORC1) inhibitors using the preclinical tool compound RMC-6272. Methods: Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose-response testing, cell-cycle analysis, and immunoblotting. Furthermore, the efficacy of RMC-6272 was assessed in NF2-null 3D-spheroid meningioma models, and its in vivo potential was evaluated in 2 orthotopic meningioma mouse models. Results: Treatment of meningioma cells revealed that, unlike rapamycin, RMC-6272 demonstrated superior growth inhibitory effects, cell-cycle arrest, and complete inhibition of phosphorylated 4E-BP1 (mTORC1 readout). Moreover, RMC-6272 had a longer retention time than INK128 and inhibited the expression of several eIF4E-sensitive targets on the protein level. RMC-6272 treatment of NF2 spheroids showed significant shrinkage in size as well as reduced proliferation. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls. Conclusions: Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.

Determinants of respectful maternity care at a tertiary care teaching institute in South India: A mixed-methods study.

OBJECTIVE: To determine the proportion of women who experienced disrespect and abuse (D&A) and the type of D&A during labor and postpartum, and to determine the factors significantly associated with D&A. METHODS: A cross-sectional mixed-methods study undertaken in tertiary care teaching institute South India. After ethical approval, 380 postpartum women within 72 h of delivery were recruited for the study. The determinants of respectful maternity care (RMC) were assessed quantitatively and qualitatively. For quantitative assessment, they were interviewed using questionnaires adopted from the United States Agency for International Development- Maternal and Child Health Integrated Program (USAID-MCHIP) protocol, which has verification criteria for RMC. As a second method for quantitative assessment, they were asked to rate the care from their perspective on a 10-point score. For the qualitative component, they were asked to identify the healthcare workers associated with D&A by their designation and to answer three open-ended questions. IBM SPSS Statistics 25 (IBM Corporation, Statistical Package for Social Sciences, version 25) was used for analysis. D&A as per RMC standards I-VII and its severity were expressed as frequencies and percentages with 95% confidence interval. Univariate analysis was used to determine the associated factors, and severity was determined by χ2 test. RESULTS: The prevalence of D&A was high (85%) according to the RMC standards of the USAID-MCHIP questionnaire, whereas it was only 33% according to women's perspective. The most common type of D&A was non-dignified care. The factors significantly associated with D&A were women over 25 years, those admitted as an emergency referral, having a recommendation letter, and relatives working at the same healthcare facility. CONCLUSION: The prevalence of D&A was high as measured by the USAID-MCHIP questionnaire, and the most common type was non-dignified care followed by physical abuse.

Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.

BACKGROUND: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin. METHODS: Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272. RESULTS: Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin. CONCLUSIONS: Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.

A randomized controlled trial of recovery management checkups for primary care patients: Twelve-month results.

BACKGROUND: Primary care settings like federally qualified health centers (FQHC) are optimal locations to identify individuals with substance use disorders (SUD) and link them to SUD treatment, yet successful linkage has proven difficult. Recovery management checkups for primary care (RMC-PC) is a promising method for increasing linkage to care, engagement in treatment, and reducing substance use. METHODS: Participants (n = 266) who received screening, brief intervention, and referral to treatment (SBIRT) at four FQHC sites and needed SUD treatment were randomized to receive SBIRT only or SBIRT+RMC-PC. All participants received SBIRT prior to randomization as part of usual care while those in the experimental group also received quarterly checkups. All participants completed research interviews at enrollment and 3, 6, 9, and 12 months post-enrollment. The primary outcome was whether participants received any days of SUD treatment. Key secondary outcomes were days of SUD treatment (total and by SUD level of care), days of alcohol or drug abstinence, and a reduction in days of specific substance use, all based on self-report. RESULTS: Relative to participants receiving SBIRT only, participants assigned to SBIRT+RMC-PC were significantly more likely to have received any SUD treatment over 12 months (adjusted odds ratio [AOR] = 3.85) and more days of SUD treatment over 12 months (Cohen's effect size d = +0.41). The SBIRT+RMC-PC group also reported significantly more days of abstinence over 12 months (d = +0.30), fewer days of alcohol use (d = -0.20) and cannabis use (d = -0.20), and lower combined substance use frequency (d = -0.25). Days of treatment were found to positively mediate the direct effect of SBIRT+RMC-PC on days of abstinence. CONCLUSION: This study provides further evidence of the effectiveness of the "referral to treatment" component of SBIRT when combined with RMC for patients in primary care settings, including those with drug use problems. Moreover, results demonstrate the value of repeated checkups on longer-term treatment and substance use outcomes.

Structure determination in a new type of amorphous molecular solids with different nonlinear optical properties: a comparative structural analysis.

The microscopic structures of two amorphous molecular solids with extremely nonlinear optical properties have been studied. They consist of organotetrel chalcogenide clusters with the chemical formula [(RSn)4S6]. The basic molecular building blocks are adamantane-like {Sn4S6} cores with organic ligands R attached to the Sn atoms. While the material equipped with R=naphthyl generates frequency doubling upon irradiation with a simple infrared laser diode, the material decorated with R=phenyl responds by emitting brilliant white light. The structural differences were investigated using x-ray scattering and extended x-ray absorption fine structure combined with molecular Reverse Monte Carlo. Transmission electron microscopy and scanning precession electron diffraction were used to examine structural differences from mesoscopic down to microscopic scales. Characteristic differences were found on all scales. While close core-to-core distances between {Sn4S6} cluster cores and molecular distortions are found in the white light emitting material, undistorted molecules and significantly larger core distances characterize the material showing frequency doubling. Here however, results of scanning precession electron diffraction reveal the formation of nanocrystalline structures in the amorphous matrix, which we identify as cause for the suppression of white light emission.

Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24).

BACKGROUND: Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) are rare entities with a poor outcome. First-line metastatic treatment is based on gemcitabine + platinum chemotherapy (GC) regimen but retrospective data suggest enhanced anti-tumour activity with the addition of bevacizumab. Therefore, we performed a prospective assessment of the safety and efficacy of GC + bevacizumab in metastatic RMC/CDC. METHODS: We conducted a phase 2 open-label trial in 18 centres in France in patients with metastatic RMC/CDC and no prior systemic treatment. Patients received bevacizumab plus GC up to 6 cycles followed, for non-progressive disease, by maintenance therapy with bevacizumab until progression or unacceptable toxicity. The co-primary end-points were objective response rates (ORRs) and progression-free survival (PFS) at 6 months (ORR-6; PFS-6). PFS, overall survival (OS) and safety were secondary end-points. At interim analysis, the trial was closed due to toxicity and lack of efficacy. RESULTS: From 2015 to 2019, 34 of the 41 planned patients have been enroled. After a median follow-up of 25 months, ORR-6 and PFS-6 were 29.4% and 47.1%, respectively. Median OS was 11.1 months (95% confidence interval [CI]: 7.6-24.2). Seven patients (20.6%) discontinued bevacizumab because of toxicities (hypertension, proteinuria, colonic perforation). Grade 3-4 toxicities were reported in 82% patients, the most common being haematologic toxicities and hypertension. Two patients experienced grade 5 toxicity (subdural haematoma related to bevacizumab and encephalopathy of unknown origin). CONCLUSION: Our study showed no benefit for bevacizumab added to chemotherapy in metastatic RMC and CDC with higher than expected toxicity. Consequently, GC regimen remains a therapeutic option for RMC/CDC patients.

Combining reverse Monte Carlo analysis of X-ray scattering and extended X-ray absorption fine structure spectra of very small nanoparticles.

Finite size effects in partial pair distribution functions generate artefacts in the scattering structure factor and scattering intensity. It is shown how they can be overcome using a binned version of the Debye scattering equation. Accordingly, reverse Monte Carlo simulations are used for very small nanoparticles of LaFeO3 with diameters below 10 nm to simultaneously analyse X-ray scattering data and extended X-ray absorption fine structure spectra at the La K and Fe K edges. The structural information obtained is consistent regarding local structure and long-range order.

Using recovery management checkups for primary care to improve linkage to alcohol and other drug use treatment: a randomized controlled trial three month findings.

BACKGROUND AND AIMS: Recovery management checkups (RMC) have established efficacy for linking patients to substance use disorder (SUD) treatment. This study tested whether using RMC in combination with screening, brief intervention, and referral to treatment (SBIRT), versus SBIRT alone, can improve linkage of primary care patients referred to SUD treatment. DESIGN: A randomized controlled trial of SBIRT as usual (n = 132) versus SBIRT plus recovery management checkups for primary care (RMC-PC) (n = 134) with follow-up assessments at 3 months post-baseline. SETTING: Four federally qualified health centers in the United States serving low-income populations. PARTICIPANTS: Primary care patients (n = 266, 64% male, 80% Black, mean age, 48.3 [range, 19-53]) who were referred to SUD treatment after SBIRT. INTERVENTIONS: SBIRT alone (control condition) compared with SBIRT + RMC-PC (experimental condition). MEASUREMENT: The primary outcome was any days of SUD treatment in the past 3 months. Key secondary outcomes were days of SUD treatment overall and by level of care, days of alcohol and other drug (AOD) abstinence, and days of using specific substances, all based on self-report. FINDINGS: At 3-month follow-up, those assigned to SBIRT + RMC-PC (n = 134) had higher odds of receiving any SUD treatment (46% vs 20%; adjusted odds ratio = 4.50 [2.49, 8.48]) compared with SBIRT only, including higher rates of entering residential and intensive outpatient treatment. They also reported more days of treatment (14.45, vs 7.13; d = +0.26), more days abstinent (41.3 vs 31.9; d = +0.22), and fewer days of using alcohol (27.14, vs 36.31; d = -0.25) and cannabis (19.49, vs 28.6; d = -0.20). CONCLUSIONS: Recovery management checkups in combination with screening, brief intervention, and referral to treatment are an effective strategy for improving linkage of primary care patients in need to substance use disorder treatment over 3 months.

Implementing the Practice of Birth Companion in Labor During the COVID-19 Pandemic: A Quality Improvement Endeavor in India.

Objective We aim to implement the practice of birth companions (BC) (from 0% to 90%) during labor to provide respectful maternity care (RMC) during the coronavirus disease 2019 (COVID-19) pandemic. Methods This was a prospective quality improvement (QI) study conducted in the Department of Obstetrics and Gynecology at All India Institute of Medical Sciences (AIIMS), Rishikesh, India. The methodology given by the World Health Organization (WHO)'s Point of Care Continuous Quality Improvement (POCQI) manual was followed, and standard tools of quality improvement were used to attain the objective. Results The QI team conducted a cause and effect analysis to understand the reasons why birth companions were not allowed during childbirth. The Pareto principle derived at three most important causes of the problem: absence of a defined policy, ignorance of guidelines promoting BC even during the pandemic, and relatives could enter wards only after a negative reverse transcriptase polymerase chain reaction (RTPCR) report, which could take up to 48 hours. Multiple change ideas were tested by means of Plan-Do-Study-Act (PDSA) cycles that were successful in bringing about desired change and improvement in the delivery of quality healthcare. Conclusion QI methodology was effective in promoting and achieving more than 90% birth companionship in labor and thus helpful in providing respectful maternity care even during the COVID-19 pandemic.

Ferroelectric Ordering in Nanosized PbTiO3.

The insight into the three-dimensional configuration of ferroelectric ordering in ferroelectric nanomaterials is motivated by the application of the development of functional nanodevices and the structural designing. However, the atomic deciphering of the spatial distribution of ordered structure remains challenging for the limitation of dimension and probing techniques. In this paper, a neutron pair distribution function (nPDF) was utilized to analyze the spontaneous polarization distribution of zero-dimensional PbTiO3 nanoparticles in three dimensions, via the application of reverse Monte Carlo (RMC) modeling. The comprehensive identification with transmission electron microscopy verified the linear characteristics of polarization along the c-axis in the main body, while electric polarization distribution on the surface was enhanced abnormally. In addition, the correlation of dipole vectors extending to three unit cells below the surface is retained. This work shows an application of the micro/macroscale information to effectively decode the polarization structure of nanoferroelectrics, providing new views of designing nanoferroelectric devices.

Exposing Obstetric Violence in the Eastern Mediterranean Region: A Review of Women's Narratives of Disrespect and Abuse in Childbirth.

Background: Obstetric violence (OV) threatens the provision of dignified, rights-based, high-quality, and respectful maternal care (RMC). The dearth of evidence on OV in the Eastern Mediterranean Region poses a knowledge gap requiring research to improve rights-based and respectful health practice and policy. While efforts to improve the quality of maternal health have long-existed, women's experiences of childbirth and perceptions of dignity and respect are not adequately or systematically recorded, especially in the said region. Aim: This study centered on the experiences of women's mistreatment in childbirth to provide an overview of OV and offer recommendations to improve RMC. Methods: A scoping review was conducted, and a total of 38 articles met the inclusion criteria and were analyzed using Bowser and Hill's framework of the seven typologies of Disrespect and Abuse (D&A) in childbirth. D&A in childbirth (or violations to RMC) is a manifestation of OV and served as a proxy to analyze its prevalence in the EMR. Findings and Discussion: This study indicated that across the EMR, women experienced every type of D&A in childbirth. This happens regardless of health systems' strength or country's income, with 6 out of 7 types of D&A found in almost two-thirds of included countries. In the EMR, the most common types of D&A in childbirth are physical abuse (especially overused routine interventions) and non-dignified care (embedded in patriarchal socio-cultural norms). The intersections of these abuses enable the objectification of women's bodies and overuse of unconsented routine interventions in a hierarchical and patriarchal system that regards the power and autonomy of doctors above birthing women. If unchecked, the implications include acceptance, continuation, and underreporting of D&A in childbirth, as well as passivity toward human-rights violations, which all further cause the continuing the cycle of OV. Conclusion: In order to eliminate OV, a paradigm shift is required involving infrastructure changes, education, empowerment, advocacy, a women-centered and gender-sensitive approach to health system strengthening, and policy development. Recommendations are given at individual, community, health systems, and policy levels to ensure that every woman achieves her right to health and birth in a dignified, respectful, and empowered manner.

An exploratory study of client and provider experience and perceptions of facility-based childbirth care in Quiché, Guatemala.

INTRODUCTION: Respectful maternity care (RMC) is fundamental to women's and families' experience of care and their decision about where to give birth. Studies from multiple countries describe the mistreatment of women during facility-based childbirth, though only a small number of studies from Guatemala have been published. Less information is available on women's negative and positive experiences of childbirth care and health workers' perceptions and experiences of providing maternity care. METHODS: As part of a program implemented in the Western Highlands of Guatemala to improve quality of reproductive maternal newborn and child health care, a mixed methods assessment was conducted in three hospitals and surrounding areas to understand women's and health workers' experience and perceptions of maternity care. The quantitative component included a survey of 31 maternity health workers and 140 women who had recently given birth in these hospitals. The qualitative component included in-depth interviews (IDIs) and focus group discussions (FGDs) with women and maternity health workers and managers. RESULTS: Women reported a mix of positive and negative experiences of childbirth care related to interpersonal and health system factors. 81% of surveyed women reported that health workers had treated them with respect while 21.4% of women reported verbal abuse. Fifty-five percent and 12% of women, respectively, reported not having access to a private toilet and bath or shower. During IDIs and FGDs, many women described higher rates of verbal abuse directed at women who do not speak Spanish. A regression analysis of survey results indicated that speaking Ixil or K'iche at home was associated with a higher likelihood of women being treated negatively during childbirth in a facility. Health worker survey results corroborated negative aspects of care described by women and also reported mistreatment of health workers by clients and families (70.9%) and colleagues (48.2%). CONCLUSIONS: This study adds to the literature on women's experience of institutional childbirth and factors that influence this experience by triangulating experience and perceptions of both women and health workers. This assessment highlights opportunities to address mistreatment of both women and health workers and to build on positive care attributes to strengthen RMC for all women.

FGF10 Triggers De Novo Alveologenesis in a Bronchopulmonary Dysplasia Model: Impact on Resident Mesenchymal Niche Cells.

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX-PBS, or HYX-FGF10. scRNAseq between rMC-Sca1Pos isolated from NOX and HYX-PBS was also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1Pos niche cells potentially representing its cellular target.

Bicalutamide may enhance kidney injury in diabetes by concomitantly damaging energy production from OXPHOS and glycolysis.

Bicalutamide (Bic), frequently used in androgen-deprivation therapy for treating prostate cancer, was demonstrated to induce multiple apoptosis and fibrosis pathways and mitochondrial dysfunction in renal mesangial cells. Whether Bic also damages the glycolytic pathway has never been cited. To investigate this, we performed an in vitro model study with mesangial cells, and at the same time, collected data from an in vivo experiment. Bic induced hypoxia-inducible factor (HIF)-1 which upregulates phosphorylated-5'-AMP-activated protein kinase (p-AMPK) and severely suppresses the rate of adenosine triphosphate (ATP) production in both the oxidative phosphorylation and glycolysis pathways. Bic suppressed the oxygen consumption rate, extracellular acidification rate, and mitochondrial proton efflux rate, downregulated in vivo but upregulated in vitro glucose transporter (GLUT)-1, reduced glucose uptake, inhibited key glycolytic enzymes, including phosphofructokinase (PFK), pyruvate kinase (PK), and pyruvate dehydrogenase (PDH), and upregulated hexokinase II (HKII) and lactic dehydrogenase A (LDHA). In vivo, Bic downregulated renal cubilin levels, thereby disrupting the glomerular reabsorption function. Conclusively, Bic can damage bioenergenesis from both mitochondria and glycolysis. It was suggested that long-term administration of Bic can initiate renal damage depending on the duration and dose of treatment, which requires cautious follow-up.

rmc-discord: reverse Monte Carlo refinement of diffuse scattering and correlated disorder from single crystals.

A user-friendly program has been developed to analyze diffuse scattering from single crystals with the reverse Monte Carlo method. The approach allows for refinement of correlated disorder from atomistic supercells with magnetic or structural (occupational and/or displacive) disorder. The program is written in Python and optimized for performance and efficiency. Refinements of two user cases obtained with legacy neutron-scattering data demonstrate the effectiveness of the approach and the developed program. It is shown with bixbyite, a naturally occurring magnetic mineral, that the calculated three-dimensional spin-pair correlations are resolved with finer real-space resolution compared with the pair distribution function calculated directly from the reciprocal-space pattern. With the triangular lattice Ba3Co2O6(CO3)0.7, refinements of occupational and displacive disorder are combined to extract the one-dimensional intra-chain correlations of carbonate molecules that move toward neighboring vacant sites to accommodate strain induced by electrostatic interactions. The program is packaged with a graphical user interface and extensible to serve the needs of single-crystal diffractometer instruments that collect diffuse-scattering data.