Tumors evade immune cytotoxicity by altering the surface topology of NK cells.

The highly variable response rates to immunotherapies underscore our limited knowledge about how tumors can manipulate immune cells. Here the membrane topology of natural killer (NK) cells from patients with liver cancer showed that intratumoral NK cells have fewer membrane protrusions compared with liver NK cells outside tumors and with peripheral NK cells. Dysregulation of these protrusions prevented intratumoral NK cells from recognizing tumor cells, from forming lytic immunological synapses and from killing tumor cells. The membranes of intratumoral NK cells have altered sphingomyelin (SM) content and dysregulated serine metabolism in tumors contributed to the decrease in SM levels of intratumoral NK cells. Inhibition of SM biosynthesis in peripheral NK cells phenocopied the disrupted membrane topology and cytotoxicity of the intratumoral NK cells. Targeting sphingomyelinase confers powerful antitumor efficacy, both as a monotherapy and as a combination therapy with checkpoint blockade.

Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury.

Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.

Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation.

Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during zygotic genome activation (ZGA) at the 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle are essential for epigenetic remodeling and are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development.

Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors.

Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.

GmEID1 modulates light signaling through the Evening Complex to control flowering time and yield in soybean.

Soybean (Glycine max) morphogenesis and flowering time are accurately regulated by photoperiod, which determine the yield potential and limit soybean cultivars to a narrow latitudinal range. The E3 and E4 genes, which encode phytochrome A photoreceptors in soybean, promote the expression of the legume-specific flowering repressor E1 to delay floral transition under long-day (LD) conditions. However, the underlying molecular mechanism remains unclear. Here, we show that the diurnal expression pattern of GmEID1 is opposite to that of E1 and targeted mutations in the GmEID1 gene delay soybean flowering regardless of daylength. GmEID1 interacts with J, a key component of circadian Evening Complex (EC), to inhibit E1 transcription. Photoactivated E3/E4 interacts with GmEID1 to inhibit GmEID1-J interaction, promoting J degradation resulting in a negative correlation between daylength and the level of J protein. Notably, targeted mutations in GmEID1 improved soybean adaptability by enhancing yield per plant up to 55.3% compared to WT in field trials performed in a broad latitudinal span of more than 24°. Together, this study reveals a unique mechanism in which E3/E4-GmEID1-EC module controls flowering time and provides an effective strategy to improve soybean adaptability and production for molecular breeding.

Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring.

Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.

Reconstituted CD74+ NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.

GARP-mediated active TGF-ß1 induces bone marrow NK cell dysfunction in AML patients with early relapse post-allo-HSCT.

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor ß1 (TGF-ß1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-ß1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-ß1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-ß1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-ß1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-ß1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.

Topological protection of dual-polarization biphoton states in photonic crystals.

Polarization control is a major issue in topological quantum optics that limits reliable generation and transmission of quantum states. This study presents what we believe to be a novel topological photonic crystal design that provides topological protection for biphoton pairs for both TE and TM polarization. By well-designed cell configurations within the lattice, two topological boundaries emerge that can accommodate TM and TE modes at the same time. By adjusting the dispersion curves, we can further design nonlinear four-wave mixing processes within the topological photonic crystals and provide theoretical explanations for the entanglement of the dual-polarization biphoton states. Numerical results confirm the robust transport of entangled photon pairs, even when subjected to sharp bending. Moreover, combining the dual-polarization topological photonic crystal with a polarization beam splitter enables the preparation of polarization-encoded maximally entangled states. Our work exhibits significant potential for applications in robust optical quantum information processing and quantum secure communication.

Robotic-assisted total hip arthroplasty in patients with developmental dysplasia of the hip.

PURPOSES: Due to the morphological diversity of deformities, technical difficulties, improperly designed components, and so on, THA remains a challenging task in dysplastic hips, especially in highly dislocated hips. The purpose of this study was to comprehensively evaluate the clinical outcomes of robot-assisted THA in patients with DDH through a large cohort study, including the precision of acetabular cup positioning, indicators of inflammatory response, indicators of muscle damage, and complications. METHODS: We retrospectively analyzed patients with DDH who underwent THA in our prospectively constructed joint registry between August 2018 and August 2022. Finally, 147 manual THAs and 147 robotic-assisted THAs were included in the final analysis. Patient demographics, indicators of inflammation, indicators of muscle damage, operative time, Harris hip scores (HHS), and forgotten joint score (FJS) were recorded for analysis. The precision of the positioning of the acetabular component was assessed with plain radiographs. RESULTS: In the Crowe II/III groups, the reconstructed center of rotation (COR) in the robotic-assisted group was closer to the anatomical COR with less variation than the manual group (absolute horizontal distances of COR 3.5 ± 2.8 vs. 5.4 ± 4.9 mm, p < 0.05; absolute vertical distances of COR 6.4 ± 4.1 vs. 11.7 ± 8.2 mm, p = 0.001). For all Crowe subtypes, the robotic-assisted THA significantly increased the proportion of acetabular cups located in the safety zone within 5° (all p < 0.05). Interleukin-6 and creatine kinase levels were slightly lower and significantly different in the robotic-assisted group at three days postoperatively (all p < 0.05). CONCLUSIONS: Compared to the manual technique, the robot-assisted technique improved the precision and reproducibility of acetabular component positioning, particularly in DDH patients with Crowe types II/III. The robotic-assisted technique did not increase operative time, bleeding, complications, or revision rates, and had a slighter early inflammatory response and muscle damage.

Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that show a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. The JAK-signal transducer and activator of transcription (STAT) signaling was activated in Ctnnb1mut + sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). Additionally, mTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent antiproliferative effects in sgPten + KrasG12D tumor. We found that JAK-STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

A Nomogram That Characterizes a Patient's Odds of Developing Squeaking After Fourth-generation Ceramic-on-ceramic THA.

BACKGROUND: Although ceramic-on-ceramic (CoC) bearings result in the lowest wear rate of any bearing combination, postoperative squeaking remains worrisome. However, data concerning squeaking in long-term follow-up studies are still lacking, especially for fourth-generation CoC THA. QUESTIONS/PURPOSES: (1) After keeping the prosthesis in place for 10 years, what percentage of patients treated with fourth-generation CoC THA implants report squeaking, and are there points in time when squeaking occurs more frequently? (2) What are the characteristics, association with hip function, and factors associated with squeaking? (3) Can we create a nomogram that characterizes a patient's odds of experiencing squeaking based on the factors associated with it? METHODS: Between January 2009 and December 2011, 1050 patients received primary THAs at our institution, 97% (1017) of whom received fourth-generation CoC THAs because this was the preferred bearing during this period. Of the 1017 eligible patients, 5% (54) underwent THAs performed by low-volume surgeons, 3% (30) were implanted with cemented prostheses, 2% (22) died, 1% (10) were immobile, 1% (six) underwent revision surgery, and 17% (169) were lost to follow-up before 10 years, leaving 726 patients for analysis here at a mean of 11 ± 1 years. In the study cohort, 64% (464) were male and 36% (262) were female, with a mean age of 44 ± 13 years at primary THA. We extracted data about articular noise from follow-up records in our institutional database and used a newly developed questionnaire to ascertain the percentage of patients who reported squeaking at the latest follow-up interval. Although not validated, the questionnaire was modeled on previous studies on this topic. The longitudinal pattern for squeaking was explored to find timepoints when squeaking occurs more frequently. Based on the questionnaire data, we calculated the percentages of frequent, reproducible, and avoidable squeaking. Hip function was evaluated with the Harris Hip Score and WOMAC score and compared between the squeaking and nonsqueaking groups. Factors associated with squeaking, which were examined in a multivariate analysis, were used to develop a nomogram. RESULTS: At 10 years, 16% (116 of 726) of patients reported squeaking. Two squeaking peaks were determined, at 0 to 1 year and 8 to 10 years. Frequent, reproducible, and avoidable squeaking accounted for 42% (36 of 86), 20% (17 of 86), and 41% (35 of 86), respectively. The mean Harris Hip Score (93 ± 4 versus 94 ± 5; p = 0.81) and WOMAC score (16 ± 13 versus 15 ± 13; p = 0.23) did not differ between patients with squeaking and those without. After controlling for potential confounding variables such as etiology and head offset, we found that patients younger than 46 years (odds ratio 2.5 [95% confidence interval 1.5 to 5.0]; p < 0. 001), those who were male (OR 2.0 [95% CI 1.1 to 3.5]; p = 0.04), those having a total flexion and extension arc of less than 50° (OR 2.0 [95% CI 1.2 to 3.3]; p = 0.02), and those with the Corail hip implant (OR 4.1 [95% CI 2.1 to 7.7]; p < 0. 001) were more likely to report squeaking. We created a nomogram that can be used at the point of care that can help clinicians identify patients at a higher risk of experiencing squeaking; this nomogram had good performance (area under the receiver operating characteristic curve of 77%). CONCLUSION: As a potential late complication, squeaking after fourth-generation CoC THA is of concern and may be related to increased stripe wear. We recommend that surgeons use this nomogram to assess the odds of squeaking before selecting a bearing, especially in patients at high risk, to facilitate shared decision-making and improve patient satisfaction. Future external validation of the model is still needed to enhance its applicability.Level of Evidence Level III, therapeutic study.

Effective treatment of severe COVID-19 patients with tocilizumab.

After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People's Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.

Primary Total Hip Arthroplasty With Ceramic-On-Ceramic Articulations: Analysis of a Single-Center Series of 1,083 Hips at a Minimum of 10-Year Follow-Up.

BACKGROUND: There are limited long-term results of using ceramic-on-ceramic (CoC) bearings in total hip arthroplasty (THA) in a large number of patient cohorts. The purpose of this study was to evaluate the minimum 10-year clinical and radiological outcomes and survivorship in a single surgeon series of CoC-THA. METHODS: Among the 1,039 patients (1,391 hips) who underwent primary THA at our institution between 2008 and 2011, 49 patients (69 hips) experienced paralysis or death, and 194 patients (239 hips, 19%) were lost to follow-up. The remaining 796 patients (1,083 hips) were assessed at a mean of 11 years (range, 10 to 13 years) using the modified Harris hip score (mHHS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and a questionnaire on articular noises. Survival analysis was used to estimate the survivorship. Radiological evaluation was performed on 869 hips at the final follow-up. RESULTS: Survivorship at 11 years was 98.3% for revision or aseptic loosening, and 98.2% for reoperation. At the final follow-up, the mean mHHS and WOMAC scores were 93 (range, 12 to 100) and 14.4 (range, 3 to 66), respectively. There were 131 (12%) hips that experienced squeaking, but no patient required revision. No fracture of the ceramic was observed. Radiological evaluation at the final follow-up revealed that 3 (0.3%) hips exhibited loosening, 2 (0.2%) had femoral osteolysis, 81(9.3%) acquired radiolucencies, and 35 (4%) showed heterotopic ossification. CONCLUSION: This CoC bearing for THA had a high survivorship and excellent functional outcomes for at least 10 years.

Genome-Wide Identification and Comprehensive Analysis of the FtsH Gene Family in Soybean (Glycine max).

The filamentation temperature-sensitive H (FtsH) gene family is critical in regulating plant chloroplast development and photosynthesis. It plays a vital role in plant growth, development, and stress response. Although FtsH genes have been identified in a wide range of plants, there is no detailed study of the FtsH gene family in soybean (Glycine max). Here, we identified 34 GmFtsH genes, which could be categorized into eight groups, and GmFtsH genes in the same group had similar structures and conserved protein motifs. We also performed intraspecific and interspecific collinearity analysis and found that the GmFtsH family has large-scale gene duplication and is more closely related to Arabidopsis thaliana. Cis-acting elements analysis in the promoter region of the GmFtsH genes revealed that most genes contain developmental and stress response elements. Expression patterns based on transcriptome data and real-time reverse transcription quantitative PCR (qRT-PCR) showed that most of the GmFtsH genes were expressed at the highest levels in leaves. Then, GO enrichment analysis indicated that GmFtsH genes might function as a protein hydrolase. In addition, the GmFtsH13 protein was confirmed to be localized in chloroplasts by a transient expression experiment in tobacco. Taken together, the results of this study lay the foundation for the functional determination of GmFtsH genes and help researchers further understand the regulatory network in soybean leaf development.

Epigenetic Regulation by Suv4-20h1 in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease.

BACKGROUND: The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals. METHODS: To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of Suv4-20h1 knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. RESULTS: We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of Suv4-20h1 in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5'-upstream regulatory element of the superoxide dismutase 3 (Sod3) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in Suv4-20h1 mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization. CONCLUSIONS: Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases.

Natural killer cells promote intra-cellular-infected trophoblasts survival via APOD-LRP1 axis.

Natural killer (NK) cells are known for their potent ability to kill stressed cells, whereas host cells infected with intra-cellular bacteria may also be benefit from the selective killing function of NK cells and survive. The mechanism of how NK cells protect host cells infected with intra-cellular bacteria is still unclear. Here, we discovered that decidual NK (dNK) cells cannot only eliminate intra-cellular bacteria which infected trophoblasts, but can also synthesize more lipids and transport lipids to trophoblasts to avoid their apoptosis. Mechanically, NK cells synthesize more lipids accompanied by increasing expression of apolipoprotein APOD. Lipids in NK cells can be delivered to trophoblast cells through APOD, maintaining adequate lipid droplet content and lipid metabolism homeostasis in trophoblasts. Blocking the APOD receptor LRP1 abolished lipid transport from NK cells to trophoblasts, and the reduction of lipid droplets caused by bacterial infection in trophoblast cells could not be restored, culminating in cell apoptosis. Our study provides new evidence for the immune surveillance and protective effect of NK cells on embryos during early pregnancy.

Icaritin inhibits neuroinflammation in a rat cerebral ischemia model by regulating microglial polarization through the GPER-ERK-NF-κB signaling pathway.

BACKGROUND: Activated microglia play a key role in initiating the inflammatory cascade following ischemic stroke and exert proinflammatory or anti-inflammatory effects, depending on whether they are polarized toward the M1 or M2 phenotype. The present study investigated the regulatory effect of icaritin (ICT) on microglial polarization in rats after cerebral ischemia/reperfusion injury (CI/RI) and explored the possible anti-inflammatory mechanisms of ICT. METHODS: A rat model of transient middle cerebral artery occlusion (tMCAO) was established. Following treatment with ICT, a G protein-coupled estrogen receptor (GPER) inhibitor or an extracellular signal-regulated kinase (ERK) inhibitor, the Garcia scale and rotarod test were used to assess neurological and locomotor function. 2,3,5-Triphenyltetrazolium chloride (TTC) and Fluoro-Jade C (FJC) staining were used to evaluate the infarct volume and neuronal death. The levels of inflammatory factors in the ischemic penumbra were evaluated using enzyme-linked immunosorbent assays (ELISAs). In addition, western blotting, immunofluorescence staining and quantitative PCR (qPCR) were performed to measure the expression levels of markers of different microglial phenotypes and proteins related to the GPER-ERK-nuclear factor kappa B (NF-κB) signaling pathway. RESULTS: ICT treatment significantly decreased the cerebral infarct volume, brain water content and fluorescence intensity of FJC; improved the Garcia score; increased the latency to fall and rotation speed in the rotarod test; decreased the levels of interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), Iba1, CD40, CD68 and p-P65-NF-κB; and increased the levels of CD206 and p-ERK. U0126 (an inhibitor of ERK) and G15 (a selective antagonist of GPER) antagonized these effects. CONCLUSIONS: These findings indicate that ICT plays roles in inhibiting the inflammatory response and achieving neuroprotection by regulating GPER-ERK-NF-κB signaling and then inhibiting microglial activation and M1 polarization while promoting M2 polarization, which provides a new therapeutic for against cerebral ischemic stroke.

Uterine NK cell functions at maternal-fetal interface†.

During pregnancy, maternal decidual tissue interacts with fetal trophoblasts. They constitute the maternal-fetal interface responsible for supplying nutrition to the fetus. Uterine natural killer (uNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy and play critical roles throughout pregnancy. This review provides current knowledge about the functions of uNK cells. uNK cells have been shown to facilitate remodeling of the spiral artery, control the invasion of extravillous trophoblast (EVT) cells, contribute to the induction and maintenance of immune tolerance, protect against pathogen infection, and promote fetal development. Pregnancy-trained memory of uNK cells improves subsequent pregnancy outcomes. In addition, this review describes the distinct functions of three uNK cell subsets: CD27-CD11b-, CD27+, and CD27-CD11b+ uNK cells.

Comparison of Functional and Radiographic Outcomes Between Two Fixation Methods for Extended Trochanteric Osteotomy in Revision Total Hip Arthroplasty: A Retrospective Cohort Study.

BACKGROUND: To compare the functional and radiographic outcomes between two fixation methods for extended trochanteric osteotomy (ETO) in revision total hip arthroplasty (rTHA). METHODS: Included in this study were 64 patients who underwent ETO in rTHA using either claw-plate fixation (claw-plate group, n = 31) or cable-alone fixation (cable group, n = 33) in our hospital from 2008 to 2020. The functional and radiographic results and complications were compared between the groups during a mean follow-up period of 64 and 78 months. RESULTS: The Harris hip score and visual analogue scale at the last follow-up improved significantly in both groups, showing no significant statistical difference between the two fixation methods. In the cable group, the mean abductor lever arm, the proximal migration, and medial migration in the affected hip were significantly decreased compared to those in the contralateral normal hip (P < .05), whereas in the claw-plate group no significant statistical differences were observed between two sides. No or slight limping occurred in 25 patients (81%) in the claw-plate group and 16 patients (48%) in the cable group (P = .007). A multiple logistic regression demonstrated that claw-plate fixation could reduce the incidence of postoperative moderate-to-severe limping. CONCLUSION: Both claw-plate fixation and cable-alone fixation could improve the functional performance of rTHA with ETO, whereas claw-plate fixation could offer superior biomechanical results and gait improvement as compared with cable-alone fixation.