Amphiregulin secreted by umbilical cord Multipotent Stromal Cells protects against ferroptosis of macrophages via the Activating Transcription Factor 3-CD36 axis to alleviate endometrial fibrosis.

Endometrium fibrosis is the leading cause of uterine infertility. Macrophages participated in the occurrence and development of endometrial fibrosis. We previously reported that human umbilical cord multipotent stromal cells (hUC-MSCs) exerted their therapeutic effect in a macrophage-dependent manner in endometrial fibrosis. However precise mechanisms by which hUC-MSCs may influence macrophages in endometrial fibrosis remain largely unexplored. Here, we demonstrated that abnormal iron and lipid metabolism occurred in intrauterine adhesions (IUA) patients and murine models. Ferroptosis has been proven to contribute to the progression of fibrotic diseases. Our results revealed that pharmacological activation of ferroptosis by Erastin aggravated endometrial fibrosis, while inhibition of ferroptosis by Ferrostatin-1 ameliorated endometrial fibrosis in vivo. Moreover, ferroptosis of macrophages was significantly upregulated in endometria of IUA murine models. Of note, transcriptome profiles revealed that CD36 gene expression was significantly increased in IUA patients and immunofluorescence analysis showed CD36 protein was mainly located in macrophages. Silencing CD36 in macrophages could reverse cell ferroptosis. Dual luciferase reporter assay revealed that CD36 was the direct target of activation transcription factor 3 (ATF3). Furthermore, through establishing coculture system and IUA murine models, we found that hUC-MSCs had a protective role against macrophage ferroptosis and alleviated endometrial fibrosis related to decreased CD36 and ATF3. The effect of hUC-MSCs on macrophage ferroptosis was attributed to the upregulation of amphiregulin (AREG). Our data highlighted that macrophage ferroptosis occurred in endometrial fibrosis via the ATF3-CD36 pathway and hUC-MSCs protected against macrophage ferroptosis to alleviate endometrial fibrosis via secreting AREG. These findings provided a potential target for therapeutic implications of endometrial fibrosis.

Oroxylin A-induced Trained Immunity Promotes LC3-associated Phagocytosis in Macrophage in Protecting Mice Against Sepsis.

Sepsis is defined as a dysregulated host response to infection that leads to multiorgan failure. Innate immune memory, i.e., "trained immunity", can result in stronger immune responses and provide protection against various infections. Many biological agents, including ß-glucan, can induce trained immunity, but these stimuli may cause uncontrolled inflammation. Oroxylin A (OA) is an active flavonoid compound that is derived from Scutellaria baicalensis. OA is an agonist for inducing trained immunity in vivo and in vitro, and ß-glucan was used as a positive control. The protective effects of OA-induced trained immunity were evaluated in mouse models that were established by either lipopolysaccharide (LPS) administration or caecal ligation and puncture (CLP). The expression of inflammatory factors and signaling pathway components involved in trained immunity was evaluated in vitro using qRT‒PCR, western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). Flow cytometry and confocal microscopy were used to examine reactive oxygen species (ROS) levels and phagocytosis in trained macrophages. A PCR array was used to screen genes that were differentially expressed in trained macrophages. Here, we revealed that OA alleviated sepsis via trained immunity. OA-treated macrophages displayed increased glycolysis and mTOR phosphorylation, and mTOR inhibitors suppressed OA-induced trained immunity by effectively reprogramming macrophages. The PCR array revealed key genes in the mTOR signaling pathway in OA-treated macrophages. Furthermore, OA targeted the Dectin-1-syk axis to promote LC3-associated phagocytosis (LAP) by trained macrophages, thereby enhancing the ability of these macrophages to protect against infection. This ability could be transferred to a new host via the adoptive transfer of peritoneal macrophages. This study is the first to provide new insights into the potential of OA-induced trained immunity to be used as a strategy to protect mice against sepsis by promoting LAP by macrophages.

Real-time imaging reveal anisotropic dissolution behaviors of silver nanorods.

The morphology and size control of anisotropic nanocrystals are critical for tuning shape-dependent physicochemical properties. Although the anisotropic dissolution process is considered to be an effective means to precisely control the size and morphology of nanocrystals, the anisotropic dissolution mechanism remains poorly understood. Here, usingin situliquid cell transmission electron microscopy, we investigate the anisotropic etching dissolution behaviors of polyvinylpyrrolidone (PVP)-stabilized Ag nanorods in NaCl solution. Results show that etching dissolution occurs only in the longitudinal direction of the nanorod at low chloride concentration (0.2 mM), whereas at high chloride concentration (1 M), the lateral and longitudinal directions of the nanorods are dissolved. First-principles calculations demonstrate that PVP is selectively adsorbed on the {100} crystal plane of silver nanorods, making the tips of nanorods the only reaction sites in the anisotropic etching process. When the chemical potential difference of the Cl-concentration is higher than the diffusion barrier (0.196 eV) of Cl-in the PVP molecule, Cl-penetrates the PVP molecular layer of {100} facets on the side of the Ag nanorods. These findings provide an in-depth insight into the anisotropic etching mechanisms and lay foundations for the controlled preparation and rational design of nanostructures.

Alleviating Recombinant Tissue Plasminogen Activator-induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.

Co-Assembled Nanoparticles toward Multi-Target Combinational Therapy of Alzheimer's Disease by Making Full Use of Molecular Recognition and Self-Assembly.

The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single-target pharmic interventions, thus necessitating multi-pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi-target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking ß-amyloid (Aß) fibrillation and oxidative stress as model combination pattern, a supramolecular multifunctional integration is proposed by co-assembling guanidinium-modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including 1) inhibition of Aß production and aggregation, 2) disintegration of Aß fibrils, 3) acceleration of Aß metabolic clearance, and 4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aß plaque content, neuroinflammation, and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform.

Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner.

Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.

Radiologic, clinical, and functional evaluation of children with displaced T-condylar fractures treated by closed reduction and percutaneous fixation using the Mayo Elbow Performance Score.

PURPOSE: T-condylar (T-C) fractures of the distal humerus are rare in children. There is no accepted treatment for such an injury, and there is a lack of reports evaluating the outcome of T-C fractures treated by closed reduction and percutaneous fixation. The aim of this study was to evaluate the feasibility of closed reduction and percutaneous K-wire and screw (CRPKS) fixation in patients with type II and III T-C fractures according to the Toniolo-Wilkins classification modified by Canavese et al. (TWC classification). METHODS: The clinical data of 12 consecutive patients (8 males, 4 females) who were younger than 14 years of age and who had a T-C fracture that was managed by CRPKS were retrospectively evaluated. Fractures were classified according to the TWC classification. The baseline information of the patients, carrying angle (CA) and Mayo Elbow Performance Score (MEPS) were used to evaluate clinical and functional outcomes; related complications were recorded. Statistical analysis was performed. RESULTS: The mean age at the time of injury was 11.6 ± 1.8 years (range, 8-14). The time from injury to surgical treatment was 1.5 ± 1.0 days (range, 0-3), and the mean follow-up duration was 33.7 ± 12.3 months (range, 18-61). Surgery lasted 45.7 ± 7.6 min on average (range, 35-58). All fractures healed in 4.9 ± 1.0 weeks on average (range, 4-7). At the last follow-up visit, the CA was 12.6° ± 5.8° on the injured side and 13.8° ± 1.8° on the uninjured side (p=0.432). The MEPS was 100 (95, 100) on the injured side and 100 (100, 100) on the uninjured side (p=0.194). Three complications were recorded. CONCLUSION: Good functional and radiological outcomes can be expected in pediatric patients with type II and III T-C fractures treated by CRPKS. The technique is relatively simple to perform and has a lower rate of complications.

Molecular Recognition with Macrocyclic Receptors for Application in Precision Medicine.

ConspectusMacrocyclic receptors can serve as alternatives to natural recognition systems as recognition tools. They provide effectively preorganized cavities to encapsulate guests via host-guest interactions, thereby affecting the physiochemical properties of the guests. Macrocyclic receptors exhibit chemical and thermal stabilities higher than those of natural receptors and thus are expected to resist degradation inside the body. This reduces the risk of harmful degradation byproducts and ensures optimal levels of effectiveness. Macrocyclic receptors have precise molecular weights and well-defined structures; this ensures their batch-to-batch reproducibility, which is critical for ensuring quality and effectiveness levels. Moreover, macrocyclic receptors exhibit broad modification tunabilities, rendering them adaptable to various guests. Molecular recognition is the basis of numerous biological processes. Macrocyclic receptors may display considerable potential for application in diagnosing and treating diseases, depending on the host-guest recognition of bioactive molecules. However, the binding affinities and selectivities of macrocyclic receptors toward bioactive molecules are generally insufficient, which may lead to problems such as low diagnosis accuracies, off-target leaking, and interference with normal functions. Therefore, addressing the challenge of the strong and specific complexation of bioactive molecules and macrocyclic receptors is imperative.To overcome this challenge, we proposed the innovative strategies of longitudinal cavity extension and coassembled heteromultivalent recognition for application in the recognition of small molecules and biomacromolecules, respectively. The deepened cavity provides a stronger hydrophobic effect and a larger interaction area while maintaining the framework rigidity. By coassembling two macrocyclic amphiphiles into one ensemble, we achieved the desired heteromultivalent recognition. This strategy affords the necessary binding properties while preventing the requirement of tedious steps and site mismatch in covalent synthesis. Using these two strategies, we achieved specific and strong binding of macrocyclic receptors to various bioactive molecules including biomarkers, drugs, and disease-related peptides/proteins. We then applied these macrocyclic receptor-based recognition systems in biosensing and bioimaging, drug delivery, and therapeutics.In this Account, we summarize the strategies we used in the recognition of small molecules and biomacromolecules. Thereafter, we discuss their applications in precision medicine, involving the (1) sensing of biomarkers and imaging of lesion sites, which are critical in the early screening of diseases and accurate diagnoses; (2) precise loading and targeted delivery of drugs, which are crucial in improving their therapeutic efficacies and reducing their side effects; and (3) capture and removal of disease-related biomacromolecules, which are significant for precise intervention in life processes. Finally, we propose recommendations for the further development of macrocyclic receptor-based recognition systems in biomedicine. Macrocyclic receptors exhibit considerable potential for research, and continued investigation may not only expand the applications of supramolecular chemistry but also open novel avenues for the development of precision medicine.

Predictive value of hepatitis B serological indicators for mortality among cancer survivors and validation in a gastric cancer cohort.

Hepatitis B virus (HBV) infection has gradually been considered to associate with cancer development and progression. This study aimed to explore the associations of serological indicators of HBV infection with mortality risk among cancer survivors and further validated using a gastric cancer (GC) cohort from China, where HBV infection is endemic. National Center for Health Statistics' National Health and Nutrition Examination Survey (NHANES) data were used in this study. Individuals with positive results of hepatitis B core antigen (anti-HBc) were considered to have current or past HBV infection. Serological indicators were positive only for hepatitis B surface antibodies (anti-HBs), indicating vaccine-induced immunity, whereas negativity for all serologic indicators was considered to indicate the absence of HBV infection and immunity to HBV. The GC cohort included patients from the First Hospital of Jilin University, China. The median follow-up time of the NHANES was 10 years; during the follow-up, 1505 deaths occurred. The results revealed that anti-HBs-positive cancer survivors had a 39% reduced risk of mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.44-0.85). Men and individuals aged <65 years old with past exposure to HBV had higher mortality risk (HR 1.52, 95% CI 1.09-2.13; HR 2.07, 95% CI 1.13-3.83). In this GC cohort, individuals who were only anti-HBs-positive showed a reduced risk of mortality (HR 0.77, 95% CI 0.62-0.95). Thus, anti-HBs positivity was a significant factor of decreased mortality among cancer survivors. More rigorous surveillance is necessary for cancer survivors with anti-HBc positivity, particularly men, and younger individuals.

In situ rapid synthesis of ionic liquid/ionic covalent organic framework composites for CO2 fixation.

IL/ICOF composites were in situ synthesized via a one-pot route in half an hour under ambient conditions for catalytic cycloaddition of CO2 with epoxides into cyclic carbonates. The prepared composites feature a decent CO2 adsorption capacity of 1.63 mmol g-1 at 273 K and 1 bar and exhibit excellent catalytic performance in terms of yield and durability. This work may pave a new way to design and construct functionalized porous organic frameworks as heterogeneous catalysts for CO2 capture and conversion.

Calponin 2 regulates ketogenesis to mitigate acute kidney injury.

Calponin 2 (CNN2) is a prominent actin stabilizer. It regulates fatty acid oxidation (FAO) by interacting with estrogen receptor 2 (ESR2) to determine kidney fibrosis. However, whether CNN2 is actively involved in acute kidney injury (AKI) remains unclear. Here, we report that CNN2 was induced in human and animal kidneys after AKI. Knockdown of CNN2 preserved kidney function, mitigated tubular cell death and inflammation, and promoted cell proliferation. Distinct from kidney fibrosis, proteomics showed that the key elements in the FAO pathway had few changes during AKI, but we identified that 3-hydroxymethylglutaryl-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme of endogenous ketogenesis that promotes cell self-renewal, was markedly increased in CNN2-knockdown kidneys. The production of ketone body ß-hydroxybutyrate and ATP was increased in CNN2-knockdown mice. Mechanistically, CNN2 interacted with ESR2 to negatively regulate the activities of mitochondrial sirtuin 5. Activated sirtuin 5 subsequently desuccinylated Hmgcs2 to produce energy for mitigating AKI. Understanding CNN2-mediated discrete fine-tuning of protein posttranslational modification is critical to optimize organ performance after AKI.

Risk-stratified approach by aMAP score for community population infected with hepatitis B and C to guide subsequent liver cancer screening practice: A cohort study with 10-year follow-up.

The aim of this study was to determine whether the age-Male-ALBI-Platelet (aMAP) score is applicable in community settings and how to maximise its role in risk stratification. A total of thousand five hundred and three participants had an aMAP score calculated at baseline and were followed up for about 10 years to obtain information on liver cancer incidence and death. After assessing the ability of aMAP to predict liver cancer incidence and death in terms of differentiation and calibration, the optimal risk stratification threshold of the aMAP score was explored, based on absolute and relative risks. The aMAP score achieved higher area under curves (AUCs) (almost all above 0.8) within 10 years and exhibited a better calibration within 5 years. Regarding absolute risk, the risk of incidence of and death from liver cancer showed a rapid increase after an aMAP score of 55. The cumulative incidence (5-year: 8.3% vs. 1.3% and 10-year: 20.9% vs. 3.6%) and mortality (5-year: 6.7% vs. 1.1% and 10-year: 17.5% vs. 3.1%) of liver cancer in individuals with an aMAP score of ≥55 were significantly higher than in those with a score of <55 (Grey's test p < .001). In terms of relative risk, the risk of death from liver cancer surpassed that from other causes after an aMAP score of ≥55 [HR = 1.38(1.02-1.87)]. Notably, the two types of death risk had opposite trends between the subpopulation with an aMAP score of ≥55 and < 55. To conclude, this study showed the value of the aMAP score in community settings and recommends using 55 as a new risk stratification threshold to guide subsequent liver cancer screening.

Activating Selenium Cathode Chemistry for Aqueous Zinc-Ion Batteries.

Aqueous rechargeable zinc-ion batteries (ARZIBs) are a promising next-generation energy-storage device by virtue of the superior safety and low cost of both the aqueous electrolyte and zinc-metal anode. However, their development is hindered by the lack of suitable cathodes with high volumetric capacity that can provide both lightweight and compact size. Herein, a novel cathode chemistry based on amorphous Se doped with transition metal Ru that mitigates the resistive surface layer produced by the side reactions between the Se cathode and aqueous electrolyte is reported. This improvement can permit high volumetric capacity in this system. Distinct from the conventional conversion mechanisms between Se and ZnSe in Se||Zn cells, this strategy realizes synchronous proton and Zn2+ intercalation/deintercalation in the Ru-doped amorphous Se||Zn half cells. Moreover, an unanticipated Zn2+ deposition/stripping process in this system further contributes to the superior electrochemical performance of this new cathode chemistry. Consequently, the Ru-doped amorphous Se||Zn half cells are found to deliver a record-high capacity of 721 mAh g-1 /3472 mAh cm-3 , and superior cycling stability of over 800 cycles with only 0.015% capacity decay per cycle. This reported work opens the door for new chemistries that can further improve the gravimetric and volumetric capacity of ARZIBs.

Ultraviolet communication with a large scattering angle via artificial agglomerate fog.

Considering strong signal attenuation of the large-angle non-line-of-sight (NLOS) link achieved due to the ultraviolet (UV) scattering properties, we propose to increase the UV communication link gain under a large scattering angle via generating agglomerate fog within a certain range as a secondary light source. In this study, a channel model with locally strong scatterers from agglomerate fog is proposed based on Monte Carlo ray-tracing approaches. Mie theory is adopted to calculate the atmospheric channel parameters, to further evaluate the link gain of a channel under non-uniform atmosphere. The performance of scattering system in the presence of fog conditions depends on the relative positions of the light source to the fog and to the receiver. The link gain results reveal the transmission capabilities for different scattering channel geometries, and give the optimal spray point location within a 10 m communication range. We further establish a foggy NLOS system using an agglomerate fog generator to verify our research in the real environment. The results show that the received signal strength of the NLOS link can be effectively enhanced by constructing scatterers in the atmospheric channel, which significantly decreases the bit-error rate (BER).

Elder and booster vaccination associates with decreased risk of serious clinical outcomes in comparison of Omicron and Delta variant: A meta-analysis of SARS-CoV-2 infection.

Background: The COVID-19 pandemic brings great pressure to the public health systems. This meta-analysis aimed to compare the clinical outcomes among different virus variants, to clarify their impact on medical resources and to provide evidence for the formulation of epidemic prevention policies. Methods: A systematic literature search was performed in the PubMed, Embase, and Cochrane Library databases using the key words "Omicron" and "Delta." The adjusted Risk ratios (RRs), Odds ratios (ORs) and Hazard ratios (HRs) were extracted, and RRs and Rate difference % (RD%) were used to interpret the risk estimates of the outcomes ultimately. Results: Forty-three studies were included, with 3,812,681 and 14,926,841 individuals infected with SARS-CoV-2 Delta and Omicron variant, respectively. The relative risks of hospitalization, death, ICU admission, and mechanical ventilation use after infection with the Omicron variant were all significantly reduced compared those after infection with the Delta variant (RRhospitalization = 0.45, 95%CI: 0.40-0.52; RRdeath = 0.37, 95%CI: 0.30-0.45; RRICU = 0.35, 95%CI: 0.29-0.42; RRmechanical ventilation = 0.33, 95%CI: 0.25-0.44). The change of both absolute and relative risks for hospitalization was more evident (RR = 0.47, 95%CI: 0.42-0.53；RD% =10.61, 95%CI: 8.64-12.59) and a significant increase was observed for the absolute differences in death in the elderly (RD% = 5.60, 95CI%: 4.65-6.55); the change of the absolute differences in the risk of hospitalization and death were most markedly observed in the patients with booster vaccination (RD%hospitalization = 8.60, 95CI%: 5.95-11.24; RD%death = 3.70, 95CI%: 0.34-7.06). Conclusion: The ability of the Omicron variant to cause severe clinical events has decreased significantly, as compared with the Delta variant, but vulnerable populations still need to be vigilant. There was no interaction between the vaccination doses and different variants.

Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages.

Rationale: Platelets can influence the progression and prognosis of colorectal cancer (CRC) through multiple mechanisms, including crosstalk with tumor-associated macrophages (TAMs). However, the mechanisms underlying the crosstalk between platelets and TAMs remain unclear. The present study aimed to investigate the role of intratumoral platelets in regulating the function of TAMs and to identify the underlying mechanisms. Methods: The interaction of platelets with macrophages was assessed in the presence or absence of the indicated compounds in vivo. An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC mouse model was used to investigate the role of platelets in controlling CRC development. Multiplexed immunofluorescence staining, fluorescence-activated cell sorting (FACS), and RNA sequence analysis were used to examine the changes in TAMs. TAMs and bone marrow-derived macrophages (BMDMs) were treated with the indicated compounds or siRNA against specific targets, and the expression levels of signal transducer and activator of transcription 1 (STAT1), c-Jun N-terminal kinase (JNK), and P-selectin glycoprotein ligand-1 (PSGL-1) were measured by Western blotting. The mRNA expression levels of complement 5 (C5), complement 5a receptor 1 (C5ar1), Arginase 1 (Arg1) and Il10 were measured by real-time RT-PCR, and the complement 5a (C5a) concentration was measured by ELISA. The dual-luciferase reporter assay and ChIP assay were performed to examine the potential regulatory mechanisms of platelet induction of C5 transcription in TAMs. Results: In our study, we found that an increase in platelets exacerbated CRC development, while inhibiting platelet adhesion attenuated tumor growth. Platelets signal TAMs through P-selectin (CD62P) binding to PSGL-1 expressed on TAMs and activating the JNK/STAT1 pathway to induce the transcription of C5 and the release of C5a, shifting TAMs toward a protumor phenotype. Inhibiting the C5a/C5aR1 axis or PSGL-1 significantly reduced CRC growth. Conclusions: An increase in intratumoral platelets promoted CRC growth and metastasis by CD62P binding to PSGL-1 expressed on TAMs, leading to JNK/STAT1 signaling activation, which promoted C5 transcription and activated the C5a/C5aR1 axis in TAMs. Our study examined the mechanism of the crosstalk between platelets and TAMs to exacerbate CRC development and proposed a potential therapeutic strategy for CRC patients.

Analysis of Pathogenic Bacteria and Drug Resistance Among Girls with Bacterial Vaginitis.

Objective: The aim of this study was to analyze the prevalence of vaginal flora and drug resistance in bacterial vaginitis among girls. Methods: A total of 3099 girls (0-10 years old) with vaginitis who visited the Beijing Children's Hospital from January 2020 to December 2021 were included in the present study. The clinical data, results of bacterial culture of vaginal secretions, and drug sensitivity reports of the subjects were collected and analyzed. Results: Of the 3099 girls with vaginitis, 399 girls had a positive bacterial culture of vaginal secretions. Nineteen types of bacteria were cultured from the vaginal secretions of these 399 girls, with a total of 419 strains. The top three infective bacteria were Haemophilus influenzae (127 strains, 30.31%), Staphylococcus aureus (66 strains, 15.75%), and Streptococcus agalactiae (32 strains, 7.64%). Additionally, 20 girls were simultaneously infected with two types of bacteria. Staphylococcus aureus, Group G Streptococcus, Haemophilus parainfluenzae, and Pseudomonas aeruginosa more frequently occurred in mixed infections. The number and bacterial detection rate among school-age girls were higher than those of preschool-age girls. We found seasonal variation in infection rates, and vaginitis among girls was higher in summer. Recurrence of vaginitis in girls was not related to the type of pathogenic bacteria in the infection. Drug sensitivity analyses showed that the resistance rates of clindamycin and erythromycin were generally high, 70-100%. After the coronavirus disease 2019 outbreak, the resistance rates of some antibiotics had decreased to varying degrees. Conclusion: Improving the understanding of vaginal flora and drug resistance in girls with vaginitis will facilitate the selection of highly effective and sensitive antibacterial drugs and reduce the production of drug-resistant strains.

Iron status influences mitochondrial disease progression in Complex I-deficient mice.

Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to iron perturbations, thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice, while iron restriction delays the onset of these symptoms, reduces neuroinflammation, and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin and show changes in iron-responsive element-regulated proteins consistent with increased cellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.

Iron is a mineral that contributes to many vital body functions. But as people age, it accumulates in many organs, including the liver and the brain. Excess iron accumulation is linked to age-related diseases like Parkinson's disease. Too much iron may contribute to harmful chemical reactions in the body. Usually, the body has systems in place to mitigate this harm, but these mechanisms may fail as people age. Uncontrolled iron accumulation may damage essential proteins, DNA and fats in the brain. These changes may kill brain cells causing neurodegenerative diseases like Parkinson's disease. Mitochondria, the cell's energy-producing factories, use and collect iron inside cells. As people age, mitochondria fail, which is also linked with age-related diseases. It has been unclear if mitochondrial failure may also contribute to iron accumulation and associated diseases like Parkinson's. Kelly et al. show that mitochondrial dysfunction causes iron accumulation and contributes to neurodegeneration in mice. In the experiments, Kelly et al. used mice with a mutation in a key-iron processing protein in mitochondria. These mice develop neurodegenerative symptoms and die early in life. Feeding the mice a high-iron diet accelerated the animals' symptoms. But providing them with an iron-restricted diet slowed their symptoms and extended their lives. Low-iron diets also slowed iron accumulation in the animal's liver and reduced brain inflammation. The experiments suggest that mitochondrial dysfunction contributes to both iron overload and brain degeneration. The next step for scientists is understanding the processes leading to mitochondrial dysfunction and iron accumulation. Then, scientists can determine if they can develop treatments targeting these processes. This research might lead to new treatments for Parkinson's disease or other age-related conditions caused by iron overload.