Multi-Objective Optimization of a Multi-Cavity, Significant Wall Thickness Difference Extrusion Profile Mold Design for New Energy Vehicles.

With the rapid development of the new energy vehicle market, the demand for extruded profiles for battery trays, mainly characterized by significant wall thickness differences in multiple chambers, is increasing, posing new challenges to production and quality control. This study examines the multi-objective optimization problem in the design process of aluminum profile dies with multi-cavity profiles and significant wall thickness differences. Using QFORM-extrusion professional aluminum extrusion finite element analysis software and the response surface analysis method, the standard deviation of the velocity (SDV), standard deviation of the pressure (SDP), and thick wall hydrostatic pressure (TWHP) on the profile section at the die exit are optimized. By analyzing the functional relationship between the key die structure parameters (the height of the baffle plates, the length of the bearing, and the height of the false mandrel) and the optimization objective, the optimal combination scheme of die structure parameters was obtained using the NSGA2 (non-dominated sorting genetic algorithm-2) multi-objective genetic optimization algorithm. The results show that, compared with the initial design scheme, the standard deviation of profile section velocity was reduced by 5.33%, the standard deviation of pressure was reduced by 11.16%, and the thick wall hydrostatic pressure was increased by 26.47%. The die designed and manufactured using this scheme successfully completed the hot extrusion production task, and the profile quality met the predetermined requirements, thus verifying the effectiveness of this study in optimizing the design of a multi-cavity aluminum profile die with significant differences in wall thickness for complex structures.

Robot-assisted laparoscopic retroperitoneal donor nephrectomy: a safe and efficient improvement.

PURPOSE: Reducing operative injuries is important in living donor nephrectomy. The robot-assisted transperitoneal approach has some advantages than traditional laparoscopic techniques. However, longer operation time and risks of abdominal complications indicate the need for improved techniques. The aim of this study is to present the robot-assisted laparoscopic retroperitoneal donor nephrectomy and evaluate its safety and feasibility. METHODS: This was a retrospective study. From June 2016 to December 2020, 218 living donors underwent robot-assisted laparoscopic retroperitoneal donor nephrectomy. Perioperative data such as operation time, warm ischemia time, length of stay and complications were collected and analyzed. To evaluate the feasibility of this surgical technique, the cumulative summation method was used to construct a learning curve. RESULTS: There were 60 male and 158 female donors aged 36-72 years, with an average age of 53.1 ± 6.8 years. Three patients (1.4%) were converted to open surgery. The mean operation time was 115.4 ± 41.9 min, the warm ischemia time was 206.6 ± 146.7 s, and the length of stay was 4.1 ± 1.4 days. Complications were reported in 22 patients (10.1%), three of whom (1.4%) had Clavien‒Dindo IIIa complications. No ileus occurred. No donors were readmitted. Four patients had delayed graft function. The cumulative summation curve showed that the number needed to reach proficiency was 33. The operation time and warm ischemia time after technical proficiency were 100.4 ± 21.6 min and 142.5 ± 50.7 s, respectively. CONCLUSION: Robot-assisted laparoscopic retroperitoneal donor nephrectomy is a safe and efficient technique that offers advantages of shorter operation time and no abdominal organ interference.

The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells.

Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.

Successful pregnancies in post-kidney transplant couples: four case reports.

Background: The fertility of female kidney transplant recipients is increasing with the progression of transplant management. This article aims to evaluate the clinical prognosis of mothers and newborns for post-kidney transplant couples. Methods: From January 2019 to April 2022, a total of four couples, all kidney transplant recipients, were successfully prepared for pregnancy after a rigorous preconception evaluation, including three cases of natural conception and one case of in vitro fertilization. Data regarding the mother and newborn, including general clinical condition and laboratory results, were recorded and assessed throughout the pregnancy and up until 12 months after delivery. Results: The mean conception age of the mothers was 34.8 years (30-38 years), and the mean interval between renal transplantation and pregnancy was 6.6 years (3.7-8.7 years). All deliveries were by cesarean section and took place without incident. There were three premature births (<37 weeks; average 35.1 weeks). In case 1 (in vitro fertilization), pre-eclampsia occurred during maternity, and this was the only case in which the fetal weight was less than 2,500 g (average 2,576.7 g). The mean Apgar score (1 min) was 7.8 (6-9) and reached 9 in all cases at 5 min. The mothers' eGFR rose during mid-gestation, decreased in late pregnancy, and was largely restored along with proteinuria 1 year postpartum. Postnatal evaluation at 6 months showed normal neurological development. In addition, NK cell and IFN-γ levels increased and Treg cell and IL-10 levels decreased along with the onset of pre-eclampsia. Conclusions: Pregnancies can succeed in couples who are both kidney transplant recipients. However, there might be higher risks of infertility, prematurity, and low birth weight.

Artificial Urinary Biomarkers for Early Diagnosis of Acute Renal Allograft Rejection.

Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near-infrared fluorescence signals to report cell-mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros-based urinalysis discriminates allograft rejection against other non-alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.

Outcomes of allograft from donor kidney microthrombi and secondary recipient thrombotic microangiopathy: should we consider loosening the belt? / ä¾›ä½“è‚¾å¾®è¡€æ “å’Œç»§å‘æ€§å—ä½“è¡€æ “æ€§å¾®è¡€ç®¡ç— å¯¹åŒç§å¼‚ä½“ç§»æ¤è‚¾çš„å½±å“ï¼šæˆ‘ä»¬åº”è¯¥æ”¾æ¾è­¦æƒ•å—ï¼Ÿ.

There is currently a huge worldwide demand for donor kidneys for organ transplantation. Consequently, numerous marginal donor kidneys, such as kidneys with microthrombi, are used to save patients' lives. While some studies have shown an association between the presence of microthrombi in donor kidneys and an increased risk for delayed graft function (DGF) (McCall et al., 2003; Gao et al., 2019), other studies have demonstrated that microthrombi negatively impact the rate of DGF (Batra et al., 2016; Hansen et al., 2018), but not graft survival rate (McCall et al., 2003; Batra et al., 2016; Gao et al., 2019). In contrast, Hansen et al. (2018) concluded that fibrin thrombi were not only associated with reduced graft function six months post-transplantation but also with increased graft loss within the first year of transplantation. On the other hand, Batra et al. (2016) found no significant differences in the DGF rate or one-year graft function between recipients in diffuse and focal microthrombi groups. To date, however, the overall influence of donor kidney microthrombi and the degree of influence on prognosis remain controversial, necessitating further research.

Wide-spectrum antibiotic prophylaxis guarantees optimal outcomes in drowned donor kidney transplantation.

BACKGROUND: Drowned victims possibly obtain various pathogens from drowning sites. Using drowned renal donors to expand the donor pool still lacks consensus due to the potential risk of disease transmission. RESEARCH DESIGN AND METHODS: This retrospective study enrolled 38 drowned donor renal recipients in a large clinical center from August 2012 to February 2021. A 1:2 matched cohort was generated with donor demographics, including age, gender, BMI, and ICU durations. Donor microbiological results, recipient perioperative infections, and early post-transplant and first-year clinical outcomes were analyzed. RESULTS: Compared to the control group, drowned donors had significantly increased positive fungal cultures (36.84% vs.13.15%, p = 0.039). Recipients in the drowned group had significantly higher rates of gram-negative bacteria (GNB) and multidrug-resistant GNB infections (23.68% vs.5.26%, 18.42% vs. 3.95%, both p < 0.05). Other colonization and infections were also numerically more frequent in the drowned group. Drowned donor recipients receiving inadequate antibiotic prophylaxis had more perioperative bloodstream infections, higher DGF incidences, and more first-year respiratory tract infections and recipient loss than those receiving adequate prophylaxis (all p < 0.05). Clinical outcomes were similar between the adequate group and the control group. CONCLUSIONS: Drowned donors could be suitable options under wide-spectrum and adequate antimicrobial prophylaxis.

Corrigendum: Immune tolerance induced by hematopoietic stem cell infusion after HLA identical sibling kidney transplantation.

[This corrects the article DOI: 10.3389/fimmu.2022.995243.].

Chrysanthemum MAF2 regulates flowering by repressing gibberellin biosynthesis in response to low temperature.

Chrysanthemum (Chrysanthemum morifolium) is well known as a photoperiod-sensitive flowering plant. However, it has also evolved into a temperature-sensitive ecotype. Low temperature can promote the floral transition of the temperature-sensitive ecotype, but little is known about the underlying molecular mechanisms. Here, we identified MADS AFFECTING FLOWERING 2 (CmMAF2), a putative MADS-box gene, which induces floral transition in response to low temperatures independent of day length conditions in this ecotype. CmMAF2 was shown to bind to the promoter of the GA biosynthesis gene CmGA20ox1 and to directly regulate the biosynthesis of bioactive GA1 and GA4 . The elevated bioactive GA levels activated LEAFY (CmLFY) expression, ultimately initiating floral transition. In addition, CmMAF2 expression in response to low temperatures was directly activated by CmC3H1, a CCCH-type zinc-finger protein upstream. In summary, our results reveal that the CmC3H1-CmMAF2 module regulates flowering time in response to low temperatures by regulating GA biosynthesis in the temperature-sensitive chrysanthemum ecotype.

Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx. To confirm the functional role of the identified gene with the MDH2 c.26C >T mutation, a homozygous MDH2 c.26C >T mutation in HMy2.CIR cell line was induced by CRISPR/Cas9 and co-cultured with podocytes, mesangial cells, or HK2 cells, respectively, to detect the potential pathogenicity of the c.26C >T variant in MDH2. A total of 32 nonsynonymous single nucleotide polymorphisms (SNPs) and 610 differentially expressed genes (DEGs) related to rFSGS were identified. DEGs are mainly enriched in the immune and metabolomic-related pathways. A variant in MDH2, c.26C >T, was found in all patients with rFSGS, which was also accompanied by lower levels of mRNA expression in PBMCs from relapsed patients compared with patients with remission after KTx. Functionally, co-cultures of HMy2.CIR cells overexpressing the mutant MDH2 significantly inhibited the expression of synaptopodin, podocin, and F-actin by podocytes compared with those co-cultured with WT HMy2.CIR cells or podocytes alone. We identified that MDH2 is a novel rFSGS susceptibility gene in patients with recurrence of FSGS after KTx. Mutation of the MDH2 c.26C >T variant may contribute to progressive podocyte injury in rFSGS patients.

Immune tolerance induced by hematopoietic stem cell infusion after HLA identical sibling kidney transplantation.

After the first attempt to induce operational tolerance, it has taken decades to implement it in clinical practice. Recipients with Human leukocyte antigen (HLA) identical sibling donors were enrolled. Hematopoietic stem cells (HSCs) infusion was done after HLA identical sibling kidney transplantation (KTx). Three cases included were followed up for over 8 years. The perioperative conditioning protocol included anti-CD20, rabbit anti-thymocyte globulin (ATG), total lymphoid irradiation (TLI), and cyclophosphamide. Infusion of CD3+ cells and CD34+ cells was conducted. The withdrawal of immunosuppression was determined by mixed lymphocyte reaction (MLR) and graft biopsy. Case 1 and Case 2 showed persistent chimerism, while chimerism was not detected in Case 3. All three recipients showed a low-level response to donor-specific stimulation. Case 1 and Case 3 met the withdrawal rules at 16 and 32 months after transplantation, respectively. Graft function was stable, and no rejection signs were observed in routine biopsies until 94 and 61 months after transplantation. Case 2 was diagnosed with graft-versus-host disease (GVHD) 9 months after transplantation and recovered after an enhanced immunosuppression therapy. Steroids were withdrawn after 1 year, and 0.5 mg tacrolimus twice a day is currently the only immunosuppression at 8 years and 8 months. In conclusion, our clinical experience indicated the efficacy of non-myeloablative conditioning protocol for tolerance induction in HLA identical patients. Complete chimerism might be a risk factor for GVHD.

Helper T Cell (CD4+) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity.

Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4+) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.

Brucellosis in kidney transplant donor: A case report.

Brucellosis is a rare systemic zoonotic disease in kidney transplantation that affects graft survival. Only 7 cases have been reported to date. Herein, we report one case of brucellosis in a kidney transplant donor, which is different from previously reported recipient cases.

Flower color mutation, pink to orange, through CmGATA4 - CCD4a-5 module regulates carotenoids degradation in chrysanthemum.

The carotenoids biosynthesis pathway in plants has been studied extensively, yet little is known about the regulatory mechanisms underlying this process, especially for ornamental horticulture plants. In this study, a natural variation of chrysanthemum with orange coloration was identified and compared with the wild type with pink coloration; the content and component of carotenoids were largely enriched in the mutant with orange coloration. CmCCD4a-5, the DNA sequence in both 'Pink yan' and the mutant, was identified and shown to function as a carotenoid degradation enzyme. Compared with 'Pink yan', the mutant shows lower expression level of CmCCD4a-5. Furthermore, CmGATA4 was found to have an opposite expression trend to CmCCD4a-5, and it could directly bind with the CmCCD4a-5 promoter. Taken together, this study demonstrates that CmGATA4 acts as a negative regulator of CmCCD4a-5 and, furthermore, low expression of CmCCD4a-5 resulted in carotenoid accumulation in the mutant.

In Vivo Kidney Allograft Endothelial Specific Scavengers for On-Site Inflammation Reduction under Antibody-Mediated Rejection.

Kidney transplantation is the most effective therapy for patients with end-stage renal disease. However, antibody-mediated rejection (ABMR) threatens long-term survival of renal grafts. Although ABMR can be controlled by donor-specific antibody clearance and B- or (and) plasma-cells inhibition, the treatment often causes severe side effects in patients. Therefore, there is need to explore site-specific scavengers. In this study, a nanovehicle carrying an anti-inflammatory drug is developed with complement component 4d targeting, a specific biomarker expressed on allograft endothelium under ABMR. Moreover, the nanovehicle is endowed with photothermal properties to control drug release. Analysis through systematic in vitro and in vivo toxicity, non-invasive targeted imaging, and in situ remote controlled drug release show the nanovehicle specifically targets allograft kidney endothelium, releases an anti-inflammatory drug, methylprednisolone, locally upon laser irradiation, and promotes recovery of injured endothelium, without affecting systemic inflammation or innate immune responses. This strategy has the potential for future clinical application in ABMR treatment.

Identification of PDCD1 as a potential biomarker in acute rejection after kidney transplantation via comprehensive bioinformatic analysis.

Background: Acute rejection is a determinant of prognosis following kidney transplantation. It is essential to search for novel noninvasive biomarkers for early diagnosis and prompt treatment. Methods: Gene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the intersected differentially expressed genes (DEGs) was calculated. We conducted the DEGs with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Distribution of immune cell infiltration was calculated by CIBERSORT. A hub gene marker was identified by intersecting the rejection-related genes from WGCNA and a selected KEGG pathway-T cell receptor signaling pathway (hsa04660), and building a protein-protein interaction network using the STRING database and Cytoscape software. We performed flow-cytometry analysis to validate the hub gene. Results: A total of 1450 integrated DEGs were obtained from five datasets (GSE1563, GSE174020, GSE98320, GSE36059, GSE25902). The GO, KEGG and immune infiltration analysis results showed that AR was mainly associated with T cell activation and various T-cell related pathways. Other immune cells, such as B cells, Macrophage and Dendritic cells were also associated with the progress. After utilizing the WGCNA and PPI network, PDCD1 was identified as the hub gene. The flow-cytometry analysis demonstrated that both in CD4+ and CD8+ T cells, PD1+CD57-, an exhausted T cell phenotype, were downregulated in the acute rejection whole blood samples. Conclusions: Our study illustrated that PDCD1 may be a candidate diagnostic biomarker for acute kidney transplant rejection via integrative bioinformatic analysis.

Donor-Derived Human Parvovirus B19 Infection in Kidney Transplantation.

Background: Donor-derived human parvovirus B19 (B19V) infections are rarely reported. Thus, its incidence in kidney transplantation is still unknown due to lack of surveillance studies. Similarly, whether the donor needs to be routinely screened for B19V and whether the kidneys from those with B19V DNAemia could be accepted also remain unknown. Methods: This retrospective study aims to evaluate the donor-derived B19V infections occurring in 823 living and 1,225 deceased donor kidney transplantations from January 2016 to December 2020. The serum viral load of living donors and their corresponding recipients was evaluated before and after transplantation. Meanwhile, for the deceased donor kidney transplantation, the serum viral load of recipients was only tested after transplantation; if recipients of a deceased donor subsequently developed B19V infection, the serum viral load of recipients and their corresponding donors before transplantation would then be further traced. Results: A total of 15 living donors were B19V DNAemia positive before the donation, of which B19V DNAemia occurred in three corresponding recipients. In deceased donor kidney transplantation, DNAemia occurred simultaneously in 18 recipients and their corresponding nine donors. A progressive decline in hemoglobin and reticulocyte count could be observed in one living donor recipient and other 11 deceased donor recipients, which were all well controlled by treatment eventually. Conclusion: The incidence of donor-derived B19V infection was 0.4% and 1.5% in living and deceased kidney transplantations, respectively. B19V was seemingly unnecessary to be routinely screened for the donor. Moreover, kidneys of the donors with B19V infection were acceptable.

Novel butterfly-shaped organic semiconductor and single-walled carbon nanotube composites for high performance thermoelectric generators.

Herein, a series of novel butterfly-shaped small-molecule organic semiconductors (OSCs) have been designed, synthesized and complexed with single-walled carbon nanotubes (SWCNTs) as p-type thermoelectric materials. The butterfly-shaped molecules exhibit curved molecular structures, which tune their frontier molecular orbitals and increase their interactions with SWCNTs. A systematic study shows that the composites based on butterfly-shaped OSCs exhibit significantly improved thermoelectric performances compared with that of the composite based on the analoguous planar OSC. The enhanced thermoelectric performances are attributable to the higher activation energy, improved doping level and charge transport process between the organic molecules and SWCNTs. The butterfly-shaped OSC and SWCNT composite opens up a new avenue for the design of thermoelectric materials and devices.

Wear-Resistant TiC Strengthening CoCrNi-Based High-Entropy Alloy Composite.

In order to improve the wear resistance of CoCrNi alloy, TiC was introduced into the alloy and wear-resistant CoCrNi/(TiC)x composites were designed. The effects of TiC contents on the microstructure, mechanical properties, and wear resistance of CoCrNi matrix were investigated, respectively. It was found that the TiC produced dissolution and precipitation process in CoCrNi alloy, and a large number of needled and blocky TiC particles were precipitated in the composites. The compressive yield strength of CoCrNi/(TiC)x composites increased with the increasing TiC content. Compared with the CoCrNi alloy, the yield strength of CoCrNi/(TiC)x composites increased from 108 to 1371 MPa, and the corresponding strengthening mechanism contributed to the second phase strengthening. The wear resistance of CoCrNi/(TiC)x composites was also greatly improved due to the strengthening of TiC. Compared with the CoCrNi alloy, the specific wear rate of CoCrNi/(TiC)1.0 alloy was reduced by about 77%. The wear resistance of CoCrNi/(TiC)x composites was enhanced with the increasing content of TiC addition.

Manipulating Carrier Concentration by Self-Assembled Monolayers in Thermoelectric Polymer Thin Films.

Conjugated polymers have attracted considerable attention for thermoelectric applications in recent years due to their plentiful resources, diverse structures, mechanical flexibility, and low thermal conductivity. Herein, we demonstrate a new strategy of modulating charge carrier concentration of chemical-doped polymer films by modifying the substrate with self-assembled monolayers (SAMs). The SAM with a trifluoromethyl terminal group is found to accumulate holes in the polymer thin films, while the SAM with an amino terminal group tends to donate electrons to the polymer films. Thermoelectric thin films of conjugated donor-acceptor copolymer exhibit high power factors of 55.6-61.0 µW m-1 K-2 on SAMs with polar terminal groups. These power factors are 49% higher than that on the SAM with the nonpolar terminal group and 3 times higher than that on pristine substrate. The high power factor is ascribed to the modulated charge carrier concentration and improved charge carrier mobility as induced by SAMs.