Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model.

In women, stress urinary incontinence (SUI), leakage of urine from increased abdominal pressure, is correlated with pudendal nerve (PN) injury during childbirth. Expression of brain-derived neurotrophic factor (BDNF) is dysregulated in a dual nerve and muscle injury model of childbirth. We aimed to use tyrosine kinase B (TrkB), the receptor of BDNF, to bind free BDNF and inhibit spontaneous regeneration in a rat model of SUI. We hypothesized that BDNF is essential for functional recovery from the dual nerve and muscle injuries that can lead to SUI. Female Sprague-Dawley rats underwent PN crush (PNC) and vaginal distension (VD) and were implanted with osmotic pumps containing saline (Injury) or TrkB (Injury + TrkB). Sham Injury rats received sham PNC + VD. Six weeks after injury, animals underwent leak-point-pressure (LPP) testing with simultaneous external urethral sphincter (EUS) electromyography recording. The urethra was dissected for histology and immunofluorescence. LPP after injury and TrkB was significantly decreased compared to Injury rats. TrkB treatment inhibited reinnervation of neuromuscular junctions in the EUS and promoted atrophy of the EUS. These results demonstrate that BDNF is essential to neuroregeneration and reinnervation of the EUS. Treatments aimed at increasing BDNF periurethrally could promote neuroregeneration to treat SUI.

Therapeutic potential of muscle growth promoters in a stress urinary incontinence model.

Weakness of urinary sphincter and pelvic floor muscles can cause insufficient urethral closure and lead to stress urinary incontinence. Bimagrumab is a novel myostatin inhibitor that blocks activin type II receptors, inducing skeletal muscle hypertrophy and attenuating muscle weakness. ß2-Adrenergic agonists, such as 5-hydroxybenzothiazolone derivative (5-HOB) and clenbuterol, can enhance muscle growth. We hypothesized that promoting muscle growth would increase leak point pressure (LPP) by facilitating muscle recovery in a dual-injury (DI) stress urinary incontinence model. Rats underwent pudendal nerve crush (PNC) followed by vaginal distension (VD). One week after injury, each rat began subcutaneous (0.3 mL/rat) treatment daily in a blinded fashion with either bimagrumab (DI + Bim), clenbuterol (DI + Clen), 5-HOB (DI + 5-HOB), or PBS (DI + PBS). Sham-injured rats underwent sham PNC + VD and received PBS (sham + PBS). After 2 wk of treatment, rats were anesthetized for LPP and external urethral sphincter electromyography recordings. Hindlimb skeletal muscles and pelvic floor muscles were dissected and stained. At the end of 2 wk of treatment, all three treatment groups had a significant increase in body weight and individual muscle weight compared with both sham-treated and sham-injured rats. LPP in DI + Bim rats was significantly higher than LPP of DI + PBS and DI + Clen rats. There were more consistent urethral striated muscle fibers, elastin fibers in the urethra, and pelvic muscle recovery in DI + Bim rats compared with DI + PBS rats. In conclusion, bimagrumab was the most effective for increasing urethral pressure and continence by promoting injured external urethral sphincter and pelvic floor muscle recovery.

Artesunate interrupts the self-transcriptional activation of MarA to inhibit RND family pumps of Escherichia coli.

Resistance-Nodulation-Division (RND) family pumps are responsible for producing multidrug resistance in Escherichia coli; however, there has been little study of targeted inhibitors of RNDs. In the present study, we investigated the inhibition of RND pumps by artesunate (AS) in E. coli, and further investigated the mechanism with respect to MarA, a regulator of RNDs. Although AS had no direct antibacterial effect, it showed a synergistic effect in combination with ß-lactams against E. coli ATCC35218 in vitro and in vivo, suggesting it possesses antibacterial enhancement activity. Notably, AS, alone or in combination with ß-lactams, downregulated the mRNA expression levels of marA, soxS, and rob, known as the marA-soxS-rob regulon, which then decreased the expression levels of RNDs, thereby increased ampicillin accumulation within ATCC35218. Using gene-deletion strains, we found that the antibacterial sensitization effect of AS persisted in wildtype bacteria, but was completely lost in the strain lacking marA, and decreased in the strain lacking soxS or rob, suggesting marA plays a crucial role in the sensitization of AS. Critically, we showed that AS inhibited the binding of MarA to the promoter of marA itself, not acrB, resulting in decreased mRNA expression of both acrB and marA. Mechanistically, we found AS directly bound to the central cavity of MarA through the R59 and K62 residues, and thus altered the charge distribution of MarA to interrupt the recognition between MarA and its promoter. We concluded that AS interrupts the self-transcriptional activation of MarA, thereby inhibits MarA-dependent mRNA expression of marA, acrAB, and tolC, and also certain other RNDs and regulatory genes related to MarA. Therefore, AS is a novel inhibitor of RND pumps that acts on the regulator MarA.

Role of lysyl oxidase like 1 in regulation of postpartum connective tissue metabolism in the mouse vagina†.

Pelvic organ prolapse (POP) in lysyl oxidase like-1 knockout (Loxl1 KO) mice occurs primarily in parous mice and is rare in nulliparous mice. We determined the effect of Loxl1 deficiency on postpartum regulation of connective tissue metabolism genes and degradative enzyme activity in the vagina at 20 days gestation or 4 h, 48 h, 7 days, 15 days, 25 days, 7 weeks, or 12 weeks postpartum. Nulliparous Loxl1 KO and wildtype (WT) mice aged 11, 18, or 23 weeks were controls. Gene expression and enzyme activity were assessed using real-time quantitative reverse transcription PCR and fluorescein conjugated gelatin zymography, respectively. Parity, but not aging, had a significant influence on gene expression both with time postpartum and between KO and WT mice. Mmp2, Timp1, Timp2, Timp3, Timp4, Col1a1, Col3a1, Acta2, and Bmp1 were differentially expressed between KO and WT mice. Correlational analysis of gene-gene pairs revealed 10 significant differences between parous KO and WT groups, 5 of which were due to lack of co-expression of Bmp1 in KO mice. The overall enzyme activity that could be attributed to MMPs was significantly higher in WT compared to KO mice both 25 days and 12 weeks postpartum, and MMP activity was significantly lower 15 days and 25 days postpartum compared to KO nulliparous controls, but not WT. These findings suggest that Loxl1 deficiency combined with parity has a significant impact on postpartum regulation of connective tissue metabolism, particularly as it relates to co-expression of Bmp1 and altered proteolytic activity.

Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway.

BACKGROUND/AIMS: Lipopolysaccharide (LPS) plays a critical role in excessive inflammatory cytokine production during sepsis. Previously, artesunate (AS) was reported to protect septic mice by reducing LPS-induced pro-inflammatory cytokine release. In the present study, the possible mechanism of the anti-inflammatory effect of AS was further investigated. METHODS: An enzyme-linked immunosorbent assay was used to detect TNF-α and IL-6 release from macrophages. Specific small interfering RNAs (siRNAs) were used to knockdown the mRNA expression of target genes. Transmission electron microscopy and laser confocal microscopy were used to observe changes in autophagy. Western blotting was performed to detect the protein levels of tumor necrosis factor receptor-associated factor6 (TRAF6), Beclin1, phosphatidylinositol 3-kinase class III (PI3KC3), autophagy-related protein 5 (ATG5), and sequestosome 1. Immunoprecipitation (IP) and fluorescent co-localization were used to detect the interactions between TRAF6-Beclin1 and Beclin1-PI3KC3, and the ubiquitination of Beclin1. RESULTS: AS inhibited TNF-α and IL-6 release from RAW264.7 cells, mouse bone marrow-derived monocytes (BMDMs) and peritoneal macrophages (PMs) induced by LPS. However, the inhibition by AS of LPS-induced cytokine release decreased when autophagy was inhibited using 3-MA, bafilomycin A1, or a siRNA targeting the Atg5 gene. Notably, AS showed an inhibition of LPS-induced autophagic activation not degradation. Whereas, these effects of AS were lost in macrophages lacking TLR4 and decreased in macrophages with down-regulated TRAF6, indicating that AS inhibited LPS-induced cytokine release and autophagic activation via TLR4-TRAF6 signaling. Western blotting results showed AS could reduce the levels of TRAF6, Beclin1, and PI3KC3. Importantly, the IP results showed AS only inhibited K63-linked ubiquitylation not total ubiquitylation of Beclin1 by acting on TRAF6. This interrupted the TRAF6-Beclin1 interaction and subsequent the formation of Beclin1- PI3KC3 core complex of the PI3K-III complex. CONCLUSION: AS inhibited LPS-induced cytokine release from macrophages by inhibiting autophagic activation. This effect was tightly related to blockade of the TRAF6-Beclin1-PI3KC3 pathway via decreasing K63-linked ubiquitination of Beclin1 and then interrupting the formation of Beclin1-PI3KC3 core complex of the PI3K-III complex. Our findings reveal the mechanism of AS's anti-inflammatory effect and is significant for future targeted investigations of sepsis treatment.

Stromal Cell-Derived Factor 1 Plasmid Regenerates Both Smooth and Skeletal Muscle After Anal Sphincter Injury in the Long Term.

BACKGROUND: Regenerating muscle at a time remote from injury requires re-expression of cytokines to attract stem cells to start and sustain the process of repair. OBJECTIVE: We aimed to evaluate the sustainability of muscle regeneration after treatment with a nonviral plasmid expressing stromal cell-derived factor 1. DESIGN: This was a randomized study. SETTINGS: The study was conducted with animals in a single research facility. INTERVENTIONS: Fifty-six female age-/weight-matched Sprague-Dawley rats underwent excision of the ventral half of the anal sphincter complex. Three weeks later, rats were randomly allocated (n = 8) to one of the following groups: no treatment, 100 µg of plasmid encoding stromal cell-derived factor 1 injected locally, local injection of plasmid and 8 × 10 bone marrow-derived mesenchymal stem cells, and plasmid encoding stromal cell-derived factor 1 injected locally with injection of a gelatin scaffold mixed with bone marrow-derived mesenchymal stem cells. MAIN OUTCOME MEASURES: Anal manometry, histology, immunohistochemistrym and morphometry were performed 8 weeks after treatment. Protein expression of cytokines CXCR4 and Myf5 was investigated 1 week after treatment (n = 6 per group). ANOVA was used, with p < 0.0083 indicating significant differences for anal manometry and p < 0.05 for all other statistical analysis. RESULTS: Eight weeks after treatment, all of the groups receiving the plasmid had significantly higher anal pressures than controls and more organized muscle architecture in the region of the defect. Animals receiving plasmid alone had significantly greater muscle in the defect (p = 0.03) than either animals with injury alone (p = 0.02) or those receiving the plasmid, cells, and scaffold (p = 0.03). Both smooth and skeletal muscles were regenerated significantly more after plasmid treatment. There were no significant differences in the protein levels of CXCR4 or Myf5. LIMITATIONS: The study was limited by its small sample size and because stromal cell-derived factor 1 was not blocked. CONCLUSIONS: A plasmid expressing stromal cell-derived factor 1 may be sufficient to repair an injured anal sphincter even long after the injury and in the absence of mesenchymal stem cell or scaffold treatments. See Video Abstract at http://links.lww.com/DCR/A451.

Regenerating the Anal Sphincter: Cytokines, Stem Cells, or Both?

BACKGROUND: Healing of an anal sphincter defect at a time distant from injury is a challenge. OBJECTIVE: We aimed to investigate whether re-establishing stem cell homing at the site of an anal sphincter defect when cytokine expression has declined using a plasmid engineered to express stromal derived factor 1 with or without mesenchymal stem cells can improve anatomic and functional outcome. DESIGN: This was a randomized animal study. SETTINGS: Thirty-two female age- and weight-matched Sprague Dawley rats underwent 50% excision of the anal sphincter complex. Three weeks after injury, 4 interventions were randomly allocated (n = 8), including no intervention, 100-µg plasmid, plasmid and 800,000 cells, and plasmid with a gelatin scaffold mixed with cells. MAIN OUTCOME MEASURES: The differences in anal sphincter resting pressures just before and 4 weeks after intervention were used for functional analysis. Histology was analyzed using Masson staining. One-way ANOVA followed by the Tukey post hoc test was used for pressure and histological analysis. RESULTS: All 3 of the intervention groups had a significantly greater change in resting pressure (plasmid p = 0.009; plasmid + cells p = 0.047; plasmid + cells in scaffold p = 0.009) compared with the control group. The plasmid-with-cells group showed increased organization of muscle architecture and increased muscle percentage, whereas the control group showed disorganized architecture at the site of the defect. Histological quantification revealed significantly more muscle at the site of defect in the plasmid-plus-cells group compared with the control group, which had the least muscle. Quantification of connective tissue revealed significantly less fibrosis at the site of defect in the plasmid and plasmid-plus-cells groups compared with the control group. LIMITATIONS: Midterm evaluation and muscle morphology were not defined. CONCLUSIONS: At this midterm follow-up, local delivery of a stromal derived factor 1 plasmid with or without local mesenchymal stem cells enhanced anal sphincter muscle regeneration long after an anal sphincter injury, thereby improving functional outcome. See Video Abstract at http://links.lww.com/DCR/A324.

Temporal regulation of extracellular signal-regulated kinase 1/2 phosphorylation, heat shock protein 70 and activating transcription factor 3 during prostaglandin F-induced luteal regression in pseudopregnant rats following heat stress.

The aim of the present study was to investigate the effects of heat stress on heat shock protein (HSP) 70 expression and mitogen-activated protein kinase (MAPK) and protein kinase (PK) B signalling during prostaglandin F (PGF)-induced luteal regression. During pseudopregnancy, rats were exposed to heat stress (HS, 40°C, 2h) for 7 days and treated with PGF or physiological saline on Day 7; serum and ovaries were collected 0, 1, 2, 8 or 24h after PGF treatment. The early inhibitory effect of PGF on progesterone was reduced in HS rats. HSP70 expression in response to PGF was significantly enhanced in HS rats. PGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was significantly greater in the HS group; however, HS rats exhibited elevated basal levels of phosphorylation of p38 MAPK, but not ERK1/2. PGF treatment increased expression of activating transcription factor (ATF) 3 at 2h, which was inhibited by heat stress. Evaluating PKB signalling revealed that phosphorylation of p-Akt (Thr308 and Ser473) was reduced at 8 and 24h after PGF treatment in both non-heat stress (NHS) and HS groups, but there were no significant differences between the HS and NHS groups at any of the time points. In conclusion, the present study provides further evidence that heat stress may enhance HSP70 and affect ERK1/2 and ATF3 expression, but not Akt activation, during PGF-induced luteal regression in pseudopregnant rats.

Electrical Stimulation Followed by Mesenchymal Stem Cells Improves Anal Sphincter Anatomy and Function in a Rat Model at a Time Remote From Injury.

BACKGROUND: We have explored cell-based therapy to aid anal sphincter repair, but a conditioning injury is required to direct stem cells to the site of injury because symptoms usually manifest at a time remote from injury. OBJECTIVE: We aimed to investigate the effect of local electrical stimulation followed by mesenchymal stem cell delivery on anal sphincter regeneration at a time remote from injury. DESIGN AND MAIN OUTCOME MEASURES: With the use of a rat model, electrical stimulation parameters and cell delivery route were selected based on in vivo cytokine expression and luciferase-labeled cell imaging of the anal sphincter complex. Three weeks after a partial anal sphincter excision, rats were randomly allocated to 4 groups based on different local interventions: no treatment, daily electrical stimulation for 3 days, daily stimulation for 3 days followed by stem cell injection on the third day, and daily electrical stimulation followed by stem cell injection on the first and third days. Histology-assessed anatomy and anal manometry evaluated physiology 4 weeks after intervention. RESULTS: The electrical stimulation parameters that significantly upregulated gene expression of homing cytokines also achieved mesenchymal stem cell retention when injected directly in the anal sphincter complex in comparison with intravascular and intraperitoneal injections. Four weeks after intervention, there was significantly more new muscle in the area of injury and significantly improved anal resting pressure in the group that received daily electrical stimulation for 3 days followed by a single injection of 1 million stem cells on the third day at the site of injury. LIMITATION: This was a pilot study and therefore was not powered for functional outcome. CONCLUSIONS: In this rat injury model with optimized parameters, electrical stimulation with a single local mesenchymal stem cell injection administered 3 weeks after injury significantly improved both new muscle formation in the area of injury and anal sphincter pressures.

Synthetic Human TLR9-LRR11 Peptide Attenuates TLR9 Signaling by Binding to and thus Decreasing Internalization of CpG Oligodeoxynucleotides.

Toll-like receptor (TLR) 9 is an endosomal receptor recognizing bacterial DNA/CpG-containing oligodeoxynucleotides (CpG ODN). Blocking CpG ODN/TLR9 activity represents a strategy for therapeutic prevention of immune system overactivation. Herein, we report that a synthetic peptide (SP) representing the leucine-rich repeat 11 subdomain of the human TLR9 extracellular domain could attenuate CpG ODN/TLR9 activity in RAW264.7 cells by binding to CpG ODN and decreasing its internalization. Our results demonstrate that preincubation with SP specifically inhibited CpG ODN- but not lipopolysaccharide (LPS)- and lipopeptide (PAM3CSK4)-stimulated TNF-α and IL-6 release. Preincubation of SP with CpG ODN dose-dependently decreased TLR9-driven phosphorylation of IκBα and ERK and activation of NF-κB/p65. Moreover, SP dose-dependently decreased FAM-labeled CpG ODN internalization, whereas non-labeled CpG ODN reversed the inhibition. The KD value of SP-CpG ODN binding was within the micromolar range. Our results demonstrated that SP was a specific inhibitor of CpG ODN/TLR9 activity via binding to CpG ODN, leading to reduced ODN internalization and decreased activation of subsequent pathways within cells. Thus, SP could be used as a potential CpG ODN antagonist to block TLR9 signaling.

Natural Image Reconstruction from fMRI Based on Node-Edge Interaction and Multi-Scale Constraint.

Reconstructing natural stimulus images using functional magnetic resonance imaging (fMRI) is one of the most challenging problems in brain decoding and is also the crucial component of a brain-computer interface. Previous methods cannot fully exploit the information about interactions among brain regions. In this paper, we propose a natural image reconstruction method based on node-edge interaction and a multi-scale constraint. Inspired by the extensive information interactions in the brain, a novel graph neural network block with node-edge interaction (NEI-GNN block) is presented, which can adequately model the information exchange between brain areas via alternatively updating the nodes and edges. Additionally, to enhance the quality of reconstructed images in terms of both global structure and local detail, we employ a multi-stage reconstruction network that restricts the reconstructed images in a coarse-to-fine manner across multiple scales. Qualitative experiments on the generic object decoding (GOD) dataset demonstrate that the reconstructed images contain accurate structural information and rich texture details. Furthermore, the proposed method surpasses the existing state-of-the-art methods in terms of accuracy in the commonly used n-way evaluation. Our approach achieves 82.00%, 59.40%, 45.20% in n-way mean squared error (MSE) evaluation and 83.50%, 61.80%, 46.00% in n-way structural similarity index measure (SSIM) evaluation, respectively. Our experiments reveal the importance of information interaction among brain areas and also demonstrate the potential for developing visual-decoding brain-computer interfaces.

Contribution of pudendal nerve injury to stress urinary incontinence in a male rat model.

Urinary incontinence is a common complication following radical prostatectomy, as the surgery disturbs critical anatomical structures. This study explored how pudendal nerve (PN) injury affects urinary continence in male rats. In an acute study, leak point pressure (LPP) and external urethral sphincter electromyography (EMG) were performed on six male rats with an intact urethra, the urethra exposed (UE), the PN exposed (NE), and after PN transection (PNT). In a chronic study, LPP and EMG were tested in 67 rats 4 days, 3 weeks, or 6 weeks after sham PN injury, PN crush (PNC), or PNT. Urethras were assessed histologically. Acute PNT caused a significant decrease in LPP and EMG amplitude and firing rate compared to other groups. PNC resulted in a significant reduction in LPP and EMG firing rate 4 days, 3 weeks, and 6 weeks later. EMG amplitude was also significantly reduced 4 days and 6 weeks after PNC. Neuromuscular junctions were less organized and less innervated after PNC or PNT at all timepoints compared to sham injured animals. Collagen infiltration was significantly increased after PNC and PNT compared to sham at all timepoints. This rat model could facilitate preclinical testing of neuroregenerative therapies for post-prostatectomy incontinence.

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.

Impact of parturition on chemokine homing factor expression in the vaginal distention model of stress urinary incontinence.

PURPOSE: Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. MATERIALS AND METHODS: We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. RESULTS: Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1α and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. CONCLUSIONS: Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1α and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia.

The Anima as an Archetype of Human Resilience in the Face of Calamity.

This paper will provide a theoretical basis for looking at a dream in the analysis of a client during a calamity. Finding the archetype of the anima is a way of responding to a crisis, in this case to the COVID-19 pandemic period. With all the basic instincts disrupted by a catastrophe, the emergence of the anima, as archetype of life, is there to remind us how to survive and recover. The anima archetype, often representing psychological resilience in ancient myths, shows up in dreams to guide human transformation from the struggle to survive trauma to the art of living a full life.

Cet article fournira un fondement théorique pour l'exploration d'un rêve dans l'analyse d'un client durant un désastre. Trouver l'archétype de l'anima est une manière de répondre à une crise, ici à la période de pandémie. Lorsque que tous les instincts fondamentaux sont perturbés par la catastrophe, l'émergence de l'anima en tant qu'archétype de la vie vient nous rappeler comment survivre et se remettre. L'archétype de l'anima, qui représente souvent la résilience psychologique dans les mythes anciens, apparait dans les rêves pour guider la transformation humaine dans la lutte pour survivre au traumatisme et pour aller vers l'art de vivre une vie pleine.

Este artículo ofrece una base teórica para observar un sueño en el análisis de un cliente durante una calamidad. Encontrar el arquetipo del ánima es una forma de responder a una crisis, en este caso al periodo pandémico. Con todos los instintos básicos perturbados por una catástrofe, la aparición del ánima como arquetipo de la vida está ahí para recordarnos cómo sobrevivir y recuperarnos. El arquetipo del ánima, que a menudo representa la resiliencia psicológica en los mitos antiguos, aparece en los sueños para guiar la transformación humana en la lucha por sobrevivir al trauma hacia el arte de vivir una vida plena.

Status and correlates of children's exposure to secondhand smoke at home: A survey in Chongqing, China.

INTRODUCTION: The home is the primary source of children's exposure to secondhand smoke. This study investigated the status and influencing factors of child exposure to secondhand smoke at home when people smoke in the household. METHODS: Participants with at least one child living in their household from 10 communities in Chongqing were recruited and provided a self-administered questionnaire using a multistage proportional random sampling design from June to August 2021. The chi-squared test and binary logistic regression analyses were used to identify influencing factors. RESULTS: The questionnaire completed by 1345 families showed that 631 (46.9%) families lived with smokers in their household, and 509 (80.7%) of those families reported that smoking occurred within the home while the children were present. Binary logistic regression analyses demonstrated that the time between waking up and household smokers having the first cigarette of the day (OR=0.44; 95% CI: 0.22-0.85), changes to smoking habits and behaviors within the last six months (OR=1.76; 95% CI: 1.06-2.90), attitudes towards tobacco control in the household (OR=2.91; 95% CI: 1.72-4.92), self-efficacy in maintaining a smoke-free home (OR=2.27; 95% CI: 1.36-3.79), having rules to maintain a smoke-free home (OR=3.25; 95% CI: 1.68-6.29), and the status of providing cigarettes to guests at home (OR=11.0; 95% CI: 1.33-90.8) were associated with exposure to SHS. CONCLUSIONS: Education focusing on the impact of smoking on children's health should be encouraged. Smoke-free homes should be established, and smoking restrictions in the household should be enacted. Therefore, information about the available tobacco-control services should be given to family members and be used properly. It is an effective way to decrease the risk of at-home exposure to SHS for children, to overcome any obstacles in tobacco control.

Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells.

Alkbh5 is one of the primary demethylases responsible for reversing N6-methyladenosine (m6A) modifications on mRNAs, and it plays a crucial role in many physiological and pathological processes. Previous studies have shown that Alkbh5 is required for maintaining the function of leukemia stem cells but is dispensable for normal hematopoiesis. In this study, we found that Alkbh5 deletion led to a moderate increase in the number of multiple progenitor cell populations while compromising the long-term self-renewal capacity of hematopoietic stem cells (HSCs). Here, we used RNA-seq and m6A-seq strategies to explore the underlying molecular mechanism. At the molecular level, Alkbh5 may regulate hematopoiesis by reducing m6A modification of Cebpa and maintaining gene expression levels. Overall, our study unveiled an essential role for Alkbh5 in regulating HSC homeostasis and provides a reference for future research in this area.

Status and correlates of home smoking bans after the implementation of the smoke-free legislation in public places: A survey in Chongqing.

INTRODUCTION: Secondhand smoke exposure in many countries decreased dramatically after the implementation of smoke-free legislation in public places, but the exposure at home did not change to the same degree. The aim of this study was to describe the status and correlates of a home smoking ban in Chongqing, China. METHODS: From June to August 2021, we selected two healthcare centers in the East, West, North, South and Middle regions of Chongqing. We investigated the family smoke-free situation in the selected region using a stratified random sampling method. A chi-squared test was performed to compare the totally and partially smoke-free homes, and a binary logistic regression model was used to analyze the correlates of smoke-free rules at home. RESULTS: The study investigated 2121 families, among which 884 (41.7%) implemented a total ban on smoking at home. The covariates included age (OR=1.54; 95% CI: 1.18-2.01), living with children aged <14 years (OR=1.51; 95% CI: 1.20-1.90), no smokers in the family (OR=2.37; 95% CI: 1.78-3.17), awareness of the hazards of secondhand smoke (OR=1.30; 95% CI: 1.07-1.59), worrying about the impact of smoking in the presence of children on health (OR=1.92; 95% CI: 1.25-2.95), no difficulty (OR=1.34; 95% CI: 1.07-1.67) and confidence (OR=1.73; 95% CI: 1.41-2.13) in stopping others from smoking, no smoking rules in cars (OR=3.67; 95% CI: 2.58-5.22), and frequency of entertaining guests with cigarettes (OR=0.41; 95% CI: 0.28-0.59). CONCLUSIONS: It is common for households in Chongqing to have smoking bans, especially those with children. If a family has members that are smokers, education researchers should pay more attention to the hazards of secondhand smoke on the health of family members, and to adopt more tobacco control measures and enhance the self-efficacy of implementing a home smoking ban. Helping smokers to quit is a vital way to decrease the hazards of cigarettes.

Brain-Derived Neurotrophic Factor Is an Important Therapeutic Factor in Mesenchymal Stem Cell Secretions for Treatment of Traumatic Peripheral Pelvic Injuries.

Traumatic neuromuscular injury to the pudendal nerve and urethra during childbirth does not regenerate well and contributes to stress urinary incontinence in women. Mesenchymal stem cells (MSCs) can improve neuroregeneration via their secretions, or secretome, which includes brain-derived neurotrophic factor (BDNF). In this study, we investigated whether BDNF is a key factor in the secretome of MSCs for the facilitation of functional recovery following a dual simulated childbirth injury. BDNF knockdown (KD) MSCs were created using an anti-BDNF shRNA lentivirus vector. A scrambled sequence was used as a transduction control (scrambled). Cells were cultured for 24 h before media was concentrated 50x to create concentrated conditioned media (CCM) containing MSC secretome. CCM of unmanipulated MSCs was screened for high BDNF expression (high BDNF CCM). Concentrated control media (CM) was created by concentrating media not conditioned by cells. Female Sprague-Dawley rats underwent bilateral pudendal nerve crush and vaginal distension (Injury) or sham injury. One hour and 1 week after injury, sham injured rats received CM, and injured rats received CM, high BDNF CCM, KD CCM, or scrambled CCM (300 µl intraperitoneally). Three weeks after injury, rats underwent leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings. The urethra and pudendal nerve were harvested for anatomical assessment. ANOVA followed by the Student-Newman-Keuls test determined significant differences between groups (p < 0.05). BDNF KD CCM had significantly decreased BDNF concentration compared to scrambled CCM, while the concentration in high BDNF CCM was significantly increased. LPP was significantly decreased in CM and KD CCM treated animals compared to sham injury, but not with scrambled or high BDNF CCM. PNSBP firing rate showed a significant decrease with CM treatment compared to sham injury. Neuromuscular junctions in the urethral sphincter in KD CCM, scrambled CCM, and high BDNF CCM were healthier than CM treated rats. While anatomical and nerve function tests demonstrate regeneration of the pudendal nerve with any CCM treatment, LPP results suggest it takes longer to recover continence with reduced BDNF in CCM. BDNF in MSC CCM is an important factor for the acceleration of recovery from a dual nerve and muscle injury.

Insufficiency of FZR1 disturbs HSC quiescence by inhibiting ubiquitin-dependent degradation of RUNX1 in aplastic anemia.

FZR1 has been implicated as a master regulator of the cell cycle and quiescence, but its roles and molecular mechanisms in the pathogenesis of severe aplastic anemia (SAA) are unclear. Here, we report that FZR1 is downregulated in SAA HSCs compared with healthy control and is associated with decreased quiescence of HSC. Haploinsufficiency of Fzr1 shows impaired quiescence and self-renewal ability of HSC in two Fzr1 heterozygous knockout mouse models. Mechanistically, FZR1 insufficiency inhibits the ubiquitination of RUNX1 protein at lysine 125, leading to the accumulation of RUNX1 protein, which disturbs the quiescence of HSCs in SAA patients. Moreover, downregulation of Runx1 reversed the loss of quiescence and impaired long-term self-renew ability in Fzr1+/- HSCs in vivo and impaired repopulation capacity in BM from SAA patients in vitro. Our findings, therefore, raise the possibility of a decisive role of the FZR1-RUNX1 pathway in the pathogenesis of SAA via deregulation of HSC quiescence.